Trinda Irene Arung

UJIAN TENGAH SEMESTER FARMASI KLINIK
Nama : Trinda Irene Arung

NPM : 21340115
Kelas : C
 STUDY KASUS NO. 15

Pria berusia 68 th 70 kg 171 cm didiagnosa CKD. Mengeluh mual saat masuk
RS. Serum kreatinin 2.8 mg/dl, kadar gula darah acak 280 mg/dl. Riwayat
penyakit stroke dan DM tipe 2. Riwayat pengobatan sampai sekarang
aspirin 80 mg, clopidogrel 80 mg, metformin 2 x 500 mg.
 DATA PASIEN
 Nama pasien : Tn. NN
 Usia : 68 Th
 BB/TB : 70 kg/171 cm
 Riwayat alergi :-
 Diagnosa : CKD (chronic kindney disease)
 Keluhan : mual saat masuk RS
 Riwayat penyakit : stroke dan DM tipe II
 Post medical history : aspirin 80 mg, clopidogrel 80 mg, dan metformin
2x500 mg.
 Family history :-
 Sosial history :-
 CATATAN SOAP
 Subjektif
Mual saat masuk ke RS.
 Objektif
Hasil tes laboratorium
Parameter Nilai normal Hasil pemeriksaan

Kadar gula darah 150 mg/dl 280 mg/dl
Serum kreatinin 0,5-1,1 mg/dl 2,8 mg/dl
 Diagnosa dokter.
CKD (chronic kindney disease) atau gagal ginjal kronis,
 Riwayat penyakit stroke dan DM tipe II.
Terapi yang diberikan
Nama obat Dosis Frekuensi Rute

Aspirin 80 mg 1x1 sehari Oral
Clopidogrel 80 mg 1x1 sehari Oral
Metformin 2x500 mg 2x1 sehari Oral
 ASSESMENT
Problem medik Terapi DRP Keterangan

 Penggunaa
aspirin+clopido
grel dapat
meningkatkan
 Aspirin 1x1. C1.4: Kombinasi
resiko
Stroke  Clopidogrel obat tidak tepat.
pendarahan
1x1. C3. Pemilihan dosis.
yang lebih
besar.
 Pada obat
clopidogrel.
 Tidak aman
untuk pasien
Diabetes melitus type II  Metformin 2x1 P2. Keamanan obat
yang di
diagnosa CKD.
 PLAN
No Rekomendasi Alasan Monitoring

1 Pemberian aspirin dan clopidogrel  <150 ug/ml efek
menyebabkan resiko pendarahan lebih antiplatelet, antipiretik,
besar. analgesik.
Cukup diberikan saja aspirin 1x1 tanpa  150-300 ug/ml efek
kombinasi obat antiplatelet lainnya, antiinflamasi.
Non farmakologi : diberikan terapi  250-400ug/ml efek
relaxition guided imagery, foot message. antiinflamasi pada
terapi demam reumatik.
 >400 ug/ml dapat
meyebabkan
toksistatas.
2 Sitagliptin tunggal 2x1 untuk Kadar serum kreatinin.
penggunaan obat pada pasien CKD.
3 Vitamin D 1x1 Meningkatkan Kadar kalsium
dalam serum.
215
□ ORIGINAL ARTICLE □
Response to Clopidogrel and Its Association with Chronic

Kidney Disease in Noncardiogenic Ischemic Stroke Patients
Hajime Maruyama, Takuya Fukuoka, Ichiro Deguchi, Yasuko Ohe, Yuji Kato,
Yohsuke Horiuchi, Takeshi Hayashi, Yuito Nagamine, Hiroyasu Sano and Norio Tanahashi
Abstract
Objective Noncardiogenic ischemic stroke patients with chronic kidney disease (CKD) are known to have a
greater rate of ischemic stroke recurrence than those without. Although clopidogrel is often used to prevent
the recurrence of noncardiogenic ischemic stroke, the relationship between the response to clopidogrel and
CKD is unclear. In the present study, the relationship between the response to clopidogrel and the presence
of CKD was investigated in noncardiogenic ischemic stroke patients.
Methods A total of 129 noncardiogenic ischemic stroke patients receiving 75 mg/day of clopidogrel for ?1
week were evaluated. The VerifyNow P2Y12 Assay was used to measure the level of platelet aggregation in-
duced by 20 μM of adenosine diphosphate, and the degree of platelet aggregation and frequency of clopido-
grel resistance were compared between 34 patients with CKD and 95 patients without CKD. Clopidogrel re-
sistance was defined as a P2Y12 Reaction Units (PRU) value of >230 and/or % inhibition <20%.
Results The PRU value was 201.9±91.3 in the patients with CKD and 163.3±86.4 in the patients without
CKD (p=0.035). The frequency of a PRU value of >230 was 44.1% (15 patients) among the patients with
CKD and 17.9% (17 patients) among those without CKD (p=0.002). The percent inhibition was 29.9%±
28.1% among the patients with CKD and 41.1%±28.0% among the patients without CKD (p=0.030). The
frequency of % inhibition <20% was 47.1% (16 patients) among the patients with CKD and 26.3% (25 pa-
tients) among those without CKD (p=0.026).
Conclusion The present study showed that noncardiogenic ischemic stroke patients with CKD have a
greater frequency of clopidogrel resistance, thus suggesting that the response to clopidogrel is diminished in
these patients.
Key words: clopidogrel resistance, ischemic stroke, chronic kidney disease, VerifyNow P2Y12 Assay
(Intern Med 53: 215-219, 2014)

(DOI: 10.2169/internalmedicine.53.1316)
the patients had clopidogrel resistance (7-9). Several factors,

Introduction including genetic polymorphisms of the drug-metabolizing
enzyme CYP2C19, have been identified as causes of clo-
Chronic kidney disease (CKD) is an independent risk fac- pidogrel resistance (10, 11). However, the relationship be-
tor for stroke and is known to affect stroke outcomes (1-5). tween the antiplatelet effects of clopidogrel and the develop-
It has also been reported that noncardiogenic ischemic ment of CKD in noncardiogenic ischemic stroke patients has
stroke patients with CKD have a higher rate of ischemic not been elucidated. In this study, the VerifyNow P2Y12 As-
stroke recurrence (6). In Japan, the administration of aspirin, say (Accumetrics Inc., San Diego, CA, USA) was used to
clopidogrel and/or cilostazol is recommended to prevent the measure the degree of platelet aggregation in noncardiogenic
recurrence of noncardiogenic ischemic stroke. We previously ischemic stroke patients, and the relationship between the
measured the degree of platelet aggregation in noncardio- antiplatelet effects of clopidogrel and CKD was investigated.
genic ischemic stroke patients and reported that 8-29% of
Department of Neurology and Cerebrovascular Medicine, Saitama Medical University International Medical Center, Japan
Received for publication July 8, 2013; Accepted for publication August 22, 2013
Correspondence to Dr. Hajime Maruyama, hmaruyam@saitama-med.ac.jp
216
Intern Med 53: 215-219, 2014 DOI: 10.2169/internalmedicine.53.1316
Table 1. Baseline Clinical and Laboratory Characteristics were used in patients with AKI.
CKD group non-CKD group Table 1 shows the baseline clinical and laboratory charac-
Variables p value
teristics of the 34 patients with and the 95 patients without
CKD. Although the patients with CKD were older, there
were no significant differences in sex, body mass index
(BMI), smoking history, diabetes, hypertension or dyslipide-
mia between the patients with and those without CKD.
Blood test measurements of the levels of HbA1c, total cho-
lesterol, low-density lipoprotein cholesterol, high-density
lipoprotein cholesterol and triglycerides also showed no sig-
nificant differences between the two groups of patients. The
concomitant use of angiotensin II receptor blockers, proton
pump inhibitors or statins was not significantly different be-
tween the two groups. The frequencies of clinical stroke
types (atherothrombotic brain infarction, lacunar infarction
and transient ischemic attack) were also not different be-
tween the groups.
Blood samples (1.8 mL) were drawn from the patients us-
ing 21-G or greater blood collection needles into a vacu-
tainer containing 0.2 mL of 3.2% sodium citrate. The
VerifyNow P2Y12 Assay was used 10 minutes to four hours
after blood collection to measure the degree of platelet ag-
BMI: body mass index, HbA1c: hemoglobin A1c, TC: total cholesterol,
LDL-C: low-density lipoprotein cholesterol, HDL-C: high-density lipopro-
gregation induced by 20 μM of adenosine diphosphate
tein cholesterol, TG: triglycerides, sCr: serum creatinine, eGFR: estimated (ADP), and the patients were divided into two groups: those
glomerular filtration rate, ARB: angiotensin II receptor blocker, PPI: proton with CKD (34 patients) and those without (95 patients). The
pump inhibitor degree of platelet aggregation and frequency of clopidogrel
resistance were compared between the two groups of pa-
tients. In addition, to adjust for the effects of age, a multi-
variate analysis was performed with age, sCr, eGFR and
Materials and Methods BMI as factors, and the relationships of these factors to
clopidogrel resistance were assessed.
A total of 129 noncardiogenic ischemic stroke patients
Definition of clopidogrel
(98 men, 31 women, mean age: 66.7±9.6 years) ?2 weeks
resistance
since onset who had been taking 75 mg/day of clopidogrel
for ?1 week and had been treated at the stroke center of our Recently, the use of P2Y12 Reaction Units (PRU) as an
hospital between October 2009 and November 2012 were indicator of clopidogrel resistance has become widespread
evaluated. The clinical stroke types were atherothrombotic with the publication of The Gauging Responsiveness With a
infarction (84 patients), lacunar infarction (34 patients) and VerifyNow P2Y12 Assay: Impact on Thrombosis and Safety
transient ischemic attack (11 patients). None of the patients (GRAVITAS) trial (14). There are also several reports that
were concomitantly using antiplatelet agents aside from used the % inhibition as an indicator. In the present study,
clopidogrel. clopidogrel resistance was defined as PRU >230 (14-16)
CKD was defined as a glomerular filtration rate (GFR) of and/or % inhibition <20% (17-19), based on previous re-
<60 mL/min/1.73 m2 or kidney damage for ?3 months deter- ports.
mined based on the presence of urine, blood, imaging or
pathological abnormalities according to the Kidney Disease VerifyNow P2Y12 Assay
Outcome Quality Initiative (K/DOQI) (12). In Japan, the es- The VerifyNow P2Y12 Assay is an instrument that meas-
timated GFR (eGFR) determined based on the serum cre- ures P2Y12 receptor inhibition in platelets using whole
atinine (sCr) level is used to evaluate the renal function and blood samples. This assay measures the platelet function
is calculated using the following equation created by the based on the ability of activated platelets to bind to fibrino-
Japanese Society of Nephrology (13): eGFR (mL/min/1.73 gen. In the measurement cartridges, there are reaction cham-
m2)=194×sCr-1.094×age-0.287 (multiply by 0.739 for women). In bers with 20 μM of ADP +22 nM prostaglandin E1 and iso-
the present study, after excluding patients with acute kidney thrombin receptor activating peptide (iso-TRAP) as platelet
injury (AKI), defined as an eGFR of <60 mL/min/1.73 m2 at activating substances, each containing fibrinogen. The fi-
the time of the initial consultation, 34 patients were assigned brinogen molecules aggregate in whole blood proportionate
to the CKD group. In addition, the eGFR measurement val- to the number of glycoprotein (GP) IIb/IIIa receptors on ac-
ues obtained following the improvement of kidney damage tivated platelets. Changes in platelet activation are captured
by monitoring the changes in light transmittance caused by
217
p=0.035
400
350
300
250
230
200 201.9 ± 91.3
163.3 ± 86.4
150
100
50
0
CKD (eGFR<60) group non-CKD (eGFR•60) group
(n=34) (n=95)
Figure 1. P2Y12 Reaction Units (PRU) results. The PRU values were significantly greater in the
chronic kidney disease group. The frequency of a PRU value of >230 was also significantly greater in
this group.
aggregate formation. The extent of aggregation is expressed without CKD (p=0.035), with PRU values of 201.9±91.3
in terms of PRU and % inhibition. The PRU value indicates and 163.3±86.4, respectively. The frequency of a PRU value
the amount of aggregation induced by ADP specific to of >230 was also significantly greater in the patients with
platelet P2Y12 receptors and is calculated based on the CKD (15/34 patients, 44.1%) than in the patients without
speed and extent of platelet aggregation in a reaction cham- CKD (17/95 patients, 17.9%) (p=0.002).
ber containing ADP. The percent inhibition represents the The % inhibition results are shown in Fig. 2. The patients
percent change from the baseline aggregation ability and is with CKD had a % inhibition value of 29.9%±28.1%, while
calculated using the PRU and baseline (BASE) results. The those without CKD had a % inhibition value of 41.1%±
BASE is an independent measurement based on the speed 28.0%, indicating significantly lower % inhibition values in
and extent of platelet aggregation induced by thrombin re- the patients with CKD (p=0.030). The frequency of % inhi-
ceptors, particularly the protease-activated receptor-1, 4 bition <20% was significantly greater in the patients with
(PAR-1, 4). Iso-TRAP and PAR-4 activating peptide (PAR-4 CKD (16/34 patients, 47.1%) than in those without CKD
AP) are incorporated into the BASE measurement reaction (25/95 patients, 26.3%) (p=0.026).
chambers to activate platelets. The percent inhibition is de- Table 2 shows the results of the multivariate analysis of
termined by the following equation: % inhibition=100× the factors associated with a PRU value of >230. The results
(BASE-PRU)/BASE. demonstrated that the sCr and eGFR were associated with a
PRU value of >230; however, age and BMI were not.
Statistical analysis Table 3 shows the results of the multivariate analysis of
The IBM SPSS Statistics 20 software package (IBM the factors associated with % inhibition <20%. The results
SPSS Inc., Chicago, IL, USA) was used for the statistical indicated that only the eGFR was associated with % inhibi-
analysis. The Mann-Whitney U test or Pearson’s Chi-square tion <20%.
test were used to compare the baseline clinical and labora-
tory characteristics. The Mann-Whitney U test was used to Discuss
compare the PRU and % inhibition values. Pearson’s Chi-
square test was used to compare the frequency of clopido-
ion
grel resistance. A multiple logistic regression analysis was
In the present study, there was a relationship between the
used for the multivariate analyses. For all tests, p<0.05 was
renal function and the efficacy of clopidogrel, as well as a
considered to be significant.
higher frequency of clopidogrel resistance with weak platelet
Ethical approval aggregation inhibitor action in noncardiogenic ischemic
stroke patients with CKD.
This study was approved by the Saitama Medical Univer- Very few reports have investigated the relationship be-
sity Ethics Committee. tween CKD and the platelet aggregation inhibitor action of
clopidogrel. The current study is the first to report such an
association in the brain. Previous reports have evaluated pa-
Results CKD had significantly higher PRU values than the patients
The PRU results are shown in Fig. 1. The patients with

218
tients with coronary artery disease or peripheral artery dis-
ease (20-22). For example, Park et al. (20) investigated pa-
tients who underwent coronary angiography, coronary
vascular intervention or peripheral vascular intervention
and
219
p=0.030
100
80
%inhibition (%)
60
40 41.1 ± 28.0
29.9 ± 28.1
20
0
CKD (eGFR<60) group non-CKD (eGFR•60) group
(n=34) (n=95)
Figure 2. % inhibition results. Significantly lower % inhibition values were observed in the chron-
ic kidney disease group. Additionally, the frequency of % inhibition <20% was significantly greater
in this group.
Table 2. Factors Associated with a P2Y12 Re- Table 3. Factors Associated with % Inhibition <20%
action Units Value of >230
Factors
%inhibition <20% %inhibition •20% p value
PRU >230 PRU ‖230 p value (n=41) (n=88)
Factors
(n=32) (n=97) Age (years) 67.8 ± 10.8 66.1 ± 8.9 0.976
Age (years) 69.4 ± 10.9 65.8 ± 9.0 0.951 BMI (kg/m2) 24.5 ± 3.8 23.6 ± 3.0 0.236
BMI (kg/m2) 23.8 ± 3.7 23.7 ± 3.2 0.585 sCr (mg/dL) 0.91 ± 0.35 0.89 ± 0.49 0.081
sCr (mg/dL) 0.96 ± 0.37 0.88 ± 0.47 0.047 eGFR (mL/min/m2) 64.6 ± 18.1 72.5 ± 21.7 0.029
eGFR (mL/min/m2) 61.0 ± 17.6 72.9 ± 21.0 0.006 BMI: body mass index, sCr: serum creatinine, eGFR: estimated glomer-
BMI: body mass index, sCr: serum creatinine, eGFR: esti- ular filtration rate
mated glomerular filtration rate
ing to a diminished platelet effect. Furthermore, in patients

measured platelet aggregation using the VerifyNow P2Y12 with CKD, the platelet turnover rate is enhanced due to an
Assay in 23 normal renal function patients receiving 75 mg/ increased level of thrombopoietin (27) and the presence of
day of clopidogrel, 18 CKD patients receiving 75 mg/day of platelet function disorders, such as the degeneration of gly-
clopidogrel and 18 CKD patients receiving 150 mg/day of coprotein IIb/IIIa, abnormal release of ADP and serotonin
clopidogrel. They reported that the patients with CKD ex- from  granules, changes in prostaglandin metabolism and
hibited a reduced platelet aggregation inhibitor action in- structural abnormalities of the platelet cytoskeleton (20),
duced by clopidogrel and that the antiplatelet effects were which are thought to decrease the response to clopidogrel.
not ameliorated, even with a double dose of clopidogrel. There are several limitations to this study. First, it was not
Although the reasons why the antiplatelet effects of clo- possible to perform comparisons at each stage of CKD due
pidogrel are decreased in CKD patients remain unclear, sev- to the small number of patients enrolled in the study. Sec-
eral mechanisms can be postulated from the perspective of ond, the definition of clopidogrel resistance using the
drug metabolism and the platelet function. Since clopidogrel VerifyNow P2Y12 Assay has not yet been established in
is a prodrug, it becomes active and exerts its efficacy after Japanese patients. The frequency of clopidogrel resistance
being metabolized by the liver. However, patients with CKD differs greatly depending on the test method and cutoff
have a decreased expression of drug-metabolizing enzymes, value. Therefore, the definition of clopidogrel resistance has
such as CYP2C19, that are involved in clopidogrel metabo- yet to be standardized. Third, the formula for eGFR used in
lism (23-25). Muller et al. (22) reported that the frequency this study does not include body weight, unlike the
of clopidogrel resistance increases as the renal function de- Cockcroft-Gault equation. Lastly, the CYP2C19 genetic
creases. In contrast, Small et al. (26) investigated the effects polymorphism involved in clopidogrel resistance was not ex-
of prasugrel, a third-generation thienopyridine, in patients amined in this study. Racial differences in the frequency of
with a normal renal function, moderate renal insufficiency CYP2C19 gene mutations have been documented. For ex-
and end-stage renal disease and found that the inhibition of ample, Asians have been reported to have higher frequencies
platelet aggregation was similar in all patients. In addition, of the loss-of-function mutations CYP2 C19* 2 and
patients with CKD have impaired drug absorption and trans- CYP2C19*3 than Western populations, with many poor me-
port (24). For these reasons, patients with CKD are consid- tabolizers (*2/*2, *2/*3, *3/*3) (28). Therefore, investigating
ered to have a decreased response to clopidogrel, thus lead- genetic polymorphisms is necessary in the future.
220
In conclusion, the present study showed that noncardio- mated GFR from serum creatinine in Japan. Am J Kidney Dis 53:
genic ischemic stroke patients with CKD have a greater fre- 982-992, 2009.
14. Price MJ, Angiolillo DJ, Teirstein PS, et al. Platelet reactivity and
quency of clopidogrel resistance, thus suggesting that the re-
cardiovascular outcomes after percutaneous coronary intervention:
sponse to clopidogrel is reduced in these patients. a time-dependent analysis of the Gauging Responsiveness with a
VerifyNow P2Y12 assay: Impact on Thrombosis and Safety
The authors state that they have no Conflict of Interest (COI). (GRAVITAS) trial. Circulation 124: 1132-1137, 2011.
15. Brar SS, ten Berg J, Marcucci R, et al. Impact of platelet reactiv-
ity on clinical outcomes after percutaneous coronary intervention.
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221
Ⓒ 2014 The Japanese Society of Internal Medicine

http://www.naika.or.jp/imonline/index.html
HHS Public
Intern Med Access
53: 215-219, 2014 DOI: 10.2169/internalmedicine.53.1316
Author manuscript
JAMA. Author manuscript; available in PMC 2015 May 11.
Author Manuscript
Published in final edited form as:

JAMA. 2014 December 24; 312(24): 2668–2675. doi:10.1001/jama.2014.15298.
Metformin in Patients With Type 2 Diabetes and

Kidney Disease:
A Systematic Review
Silvio E. Inzucchi, MD, Kasia J. Lipska, MD, MHS, Helen Mayo, MLS, Clifford J. Bailey, PhD,
Author Manuscript
and Darren K. McGuire, MD, MHSc

Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut (Inzucchi,
Lipska); Health Sciences Digital Library and Learning Center, University of Texas Southwestern
Medical Center, Dallas (Mayo); School of Life & Health Sciences, Aston University, Birmingham,
United Kingdom (Bailey); Division of Cardiology, University of Texas Southwestern Medical
Center, Dallas (McGuire)
Abstract
IMPORTANCE—Metformin is widely viewed as the best initial pharmacological option to lower
glucose concentrations in patients with type 2 diabetes mellitus. However, the drug is
contraindicated in many individuals with impaired kidney function because of concerns of lactic
acidosis.
Author Manuscript
OBJECTIVE—To assess the risk of lactic acidosis associated with metformin use in individuals
with impaired kidney function.
EVIDENCE ACQUISITION—In July 2014, we searched the MEDLINE and Cochrane databases
for English-language articles pertaining to metformin, kidney disease, and lactic acidosis in
humans between 1950 and June 2014. We excluded reviews, letters, editorials, case reports, small
case series, and manuscripts that did not directly pertain to the topic area or that met other
exclusion criteria. Of an original 818 articles, 65 were included in this review, including
pharmacokinetic/metabolic studies, large case series, retrospective studies, meta-analyses, and a
clinical trial.
RESULTS—Although metformin is renally cleared, drug levels generally remain within the
therapeutic range and lactate concentrations are not substantially increased when used in patients
Author Manuscript
with mild to moderate chronic kidney disease (estimated glomerular filtration rates, 30-60 mL/min
per 1.73 m2). The overall incidence of lactic acidosis in metformin users varies across studies from
Copyright 2014 American Medical Association. All rights reserved

Corresponding Author: Silvio Inzucchi, MD, Section of Endocrinology, Yale School of Medicine, Fitkin 106, 333 Cedar St, New
Haven, CT 06520-8020 (silvio.inzucchi@yale.edu)..
Author Contributions: Drs Inzucchi and McGuire had full access to all of the data in the study and take responsibility for the
integrity of the data and the accuracy of the data analysis.
Study concept and design: Inzucchi, Bailey, McGuire.
Acquisition, analysis, or interpretation of data: Inzucchi, Lipska, Mayo, Bailey.
Drafting of the manuscript: Inzucchi, Mayo, Bailey, McGuire.
Critical revision of the manuscript for important intellectual content: Inzucchi, Lipska, Mayo, McGuire.
Administrative, technical, or material support: Inzucchi.
Supplemental content at jama.com
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of
Interest.
Inzucchi et al. Page 2
approximately 3 per 100 000 person-years to 10 per 100 000 person-years and is generally
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indistinguishable from the background rate in the overall population with diabetes. Data
suggesting an increased risk of lactic acidosis in metformin-treated patients with chronic kidney
disease are limited, and no randomized controlled trials have been conducted to test the safety of
metformin in patients with significantly impaired kidney function. Population-based studies
demonstrate that metformin may be prescribed counter to prevailing guidelines suggesting a renal
risk in up to 1 in 4 patients with type 2 diabetes mellitus—use which, in most reports, has not been
associated with increased rates of lactic acidosis. Observational studies suggest a potential benefit
from metformin on macrovascular outcomes, even in patients with prevalent renal
contraindications for its use.
CONCLUSIONS AND RELEVANCE—Available evidence supports cautious expansion of

metformin use in patients with mild to moderate chronic kidney disease, as defined by estimated
glomerular filtration rate, with appropriate dosage reductions and careful follow-up of kidney
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function.
Metformin has been prescribed in the United States for the management of type 2 diabetes
for 20 years. It is widely endorsed as initial therapy by professional organizations because of
its low cost, safety profile, and potential cardiovascular benefits.1 Another biguanide,
phenformin, was withdrawn in 1977 owing to risk of lactic acidosis. Because metformin is
cleared by the kidneys, it may accumulate when renal function decreases, with the potential
for exposure-dependent toxicity that could precipitate lactate accumulation. At its US
approval of metformin in 1994, the Food and Drug Administration (FDA) stipulated
stringent prescribing criteria based on kidney function that remain in place today (Box).2
Given the aging population as well as the most recent estimate of adults with diagnosed type
2 diabetes in the United States (21 million3) and the rate of this degree of impaired kidney
function in these individuals (estimated at 12%4), it is possible that prescribing criteria may
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preclude metformin use in many patients with renal clearance rates sufficient for adequate
drug elimination.
The original prescribing label was intended to provide a safety margin to minimize the risk
of metformin-associated lactic acidosis (MALA). The label warnings were based on a
modest amount of pharmacokinetic data about reduced metformin clearance in the setting of
kidney impairment, but the clinical relevance of these observations remains uncertain. The
incidence of lactic acidosis is estimated at approximately 1 per 23 000 to 30 000 person-
years among metformin users compared with approximately 1 per 18 000 to 21 000 person-
years among patients with type 2 diabetes using other agents.5,6 These data and the safety
profile after several decades of clinical experience have led to less restrictive policy
revisions outside the United States. Whether the FDA guidelines should be expanded to
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allow greater access to metformin in the United States is under consideration.
Literature Search
We conducted a search of the MEDLINE and Cochrane databases (Database of Systematic
Reviews, Central Register of Controlled Trials, and DARE [Database of Abstracts of
Reviews of Effects]) for articles on metformin in patients with chronic kidney disease
(CKD) using the search terms metformin, kidney, renal, CKD, lactic acidosis, and

glomerular filtration rate. We retrieved English-language human studies published between

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January 1950 and June 2014. Eight hundred twelve manuscripts were supplemented by an
additional 6 found on review of bibliographies of included studies and other sources.
Reviews, letters, editorials, case reports, series involving fewer than 10 patients, and animal
or in vitro studies were excluded, leaving 414 manuscripts. These were hand-searched; those
not pertaining to the topic (338), pharmacokinetic studies in patients without diabetes (1),
observational studies with cohorts not defined by kidney function (5), and older meta-
analyses later updated (5) were excluded. Thus, the final number of manuscripts was 65
(pharmacokinetic/metabolic investigations [10]; case series [20]; cross-sectional,
observational, and pharmacosurveillance studies [31]; metaanalyses [3]; and a clinical trial
[1]). (PRISMA diagram in eFigure in the Supplement.)
Box
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Current US Food and Drug Administration Prescribing Guidelines for

Metformin as Related to Kidney Function
• Metformin is contraindicated in ―renal disease or renal dysfunction (eg, as
suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL
[females]) or abnormal creatinine clearance (CrCl).‖
• Metformin ―should not be initiated in patients ≥80 years of age unless

measurement of creatinine clearance demonstrates that renal function is not
reduced.‖
Source: Metformin final printed labeling.2

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Results
Major Findings
Metformin, CKD, and Lactate Metabolism—Biguanides such as metformin inhibit the
mitochondrial respiratory chain, impairing the main site of energy generation through
aerobic metabolism. This results in a shift toward anaerobic metabolism, of which lactate is
a by-product, and less energy for gluconeogenesis. Reduced hepatic glucose production is a
major mechanism of the antihyperglycemic effect of metformin, although it has been
recently proposed that some glucose lowering may be mediated through the enteroendocrine
axis.7 Metformin is eliminated unchanged in the urine, and the drug may accumulate in
patients with kidney failure.8,9 Although mild to moderate CKD reduces metformin
clearance, drug levels typically remain within a safe range. Sambol et al 9 found that, in
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single-dose studies, mild CKD (creatinine clearance, 60-90 mL/min) was associated with
23% to 33% reductions in medication clearance and moderate CKD (30-60 mL/min) with
74% to 78% reductions. Metformin levels, however, were generally maintained in the
therapeutic range (0.47-2.5 mg/L [≈ 4-20 µmol/L]). Frid et al10 measured metformin levels
in 137 patients with diabetes mellitus receiving long-term therapy. Median trough levels
(upper therapeutic range, 20 µmol/L) were 4.50 µmol/L (range, 0.10-20.70) for estimated
glomerular filtration rates (eGFRs) greater than 60 mL/min per 1.73 m2, 7.71 µmol/L (range,

0.12-15.15) for eGFRs of 30 to 60 mL/min per 1.73 m2, and 8.88 µmol/L(range, 5.99-18.60)
for eGFRs less than 30 mL/min per 1.73 m2.
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Circulating lactate levels among metformin-treated patients are typically normal, even
among patients with kidney dysfunction. Liu et al11 measured lactate levels (normal, 5-15
mg/dL [0.6-1.7 mmol/L]) in 1024 patients with type 2 diabetes and normal kidney function.
Mean lactate was higher in patients taking metformin compared with those taking other
agents (1.32 [SD, 0.52] vs 1.14 [0.45] mmol/L, P < .01), and elevated concentrations (>2.0
mmol/L) were nearly 3 times more common in metformin-treated patients (9.2% vs 3.8%, P
< .001). However, none met diagnostic criteria for lactic acidosis. Lin et al12 found mean
lactate concentrations to be similar between 66 patients with type 2 diabetes older than 80
years and taking metformin (mean age, 83.6 years; mean creatinine clearance, 48.9 [SD,
12.9] mL/min), compared with 79 younger individuals (mean age, 59.9 years; mean
creatinine clearance, 80.3 [SD, 30.1] mL/min, P < .01): 1.47 [SD, 0.58] vs 1.50 [SD, 0.53]
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mmol/L. Lim et al13 studied a group of 97 patients taking metformin and found no
association between plasma lactate levels and kidney status (1.7 [SD, 0.3] mmol/L in groups
with eGFRs less than 60 mL/min per 1.73 m2, 1.8 [SD, 0.3] mmol/L in groups with eGFRs
of 60 through 90/mL/min per 1.73 m2, and 1.8 [SD, 0.4] mmol/L in groups with eGFRs
greater than 90 mL/min per 1.73 m2). Similar findings were reported by Duong et al14 and
Connolly and Kesson15 in studies that included patients with more advanced kidney
dysfunction. Among 493 patients with type 2 diabetes, Mongraw-Chaffin et al16 found
slightly higher (but still normal) lactate levels in those using metformin vs those using other
agents (1.00 [95% CI, 0.94-1.06] vs 0.93 [range, 0.88-0.97] mmol/L; P < .05). Similar
findings were reported by Davis et al17 in 272 patients (1.86 [SD, 1.34-2.59] for metformin
vs 1.58 [1.09-2.30] mmol/L for no metformin; P < .001.) Abbasi et al18 reported mildly
elevated lactate levels (mean, 2.17 [SD, 0.57] mmol/L) in 57% of 110 patients taking
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metformin with normal kidney function, but there was no control group.
The pharmacokinetics of metformin differ substantially from those of phenformin, an

original biguanide whose removal from the market nearly 4 decades ago was based on a
significantly increased risk of lactic acidosis. Metformin is entirely renally cleared (half-life,
6.5 hours)19; phenformin is both hepatically metabolized and more slowly renally excreted
(half-life, 7-15 hours). Compared with metformin, phenformin is also lipophilic, with a
higher affinity for mitochondrial membranes and more powerful inhibitory effect on the
mitochondrial respiratory chain. Phenformin increases muscle lactate release and inhibits
lactate oxidation, effects not shared by metformin.20 Three early investigations found a
relationship between phenformin and lactate levels not demonstrable with metformin.21-23
These data may explain reduced incidence of lactic acidosis in Swedish patients with
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diabetes during 1977-1991, comparing rates when phenformin was available (1.5 cases/10
000 patient-years) vs when metformin was the exclusive biguanide prescribed (0.24 cases/10
000 patient-years).24,25
In summary, although metformin clearance is decreased in the setting of CKD, drug levels
remain within therapeutic range when eGFR is greater than 30 mL/min per 1.73 m2 and do
not significantly affect circulating lactate levels. These conclusions are based on small

studies; larger data sets could reveal a closer alignment between metformin, kidney function,
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and predisposition to hyperlactatemia.
The Relationship Between Metformin and Lactic Acidosis—Lactic acidosis is an

anion-gap metabolic acidosis defined by plasma lactate level greater than 5 mmol/L and pH
less than 7.35. When severe, it is associated with multisystem organ dysfunction—
particularly neurologic (stupor, coma, seizures) and cardiovascular (hypotension, ventricular
fibrillation)—and carries a high mortality risk. Small series involving patients hospitalized
with lactic acidosis have explored associations with metformin exposure.19,26-44 In each, the
patients had a supervening illness that precipitated the metabolic decompensation, usually
infection, acute kidney or liver failure, or cardiovascular collapse. Although a possible role
for metformin could not be excluded, it was viewed predominately as a bystander—ie, not
causally implicated—by most authors. When metformin levels were measured, they were
normal or elevated but did not consistently correlate with the degree of acidosis. 28,34,45,46
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Lactate concentrations were not different than in patients who did not take metformin but
were contemporaneously admitted with lactic acidosis.38 In addition, drug concentrations
carried neither diagnostic nor prognostic significance. In one series, higher metformin levels
were associated with reduced mortality.35 In some studies30,31,34 the majority of patients
with metformin-associated lactic acidosis had antecedent normal kidney function—
suggesting that prescribing limitations based on renal parameters would not necessarily
prevent lactic acidosis, even if the drug were responsible.
Several larger observational studies have explored the relationship between metformin and
lactic acidosis.6,45,47-49 Stang et al47conducted an historical cohort analysis of the
Saskatchewan Health database, including information on metformin therapy during a 15-
year period. In that study, 11 797 patients received at least 1 prescription, for a total
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exposure of 22 296 years. Two patients were hospitalized for lactic acidosis (approximately
9/100 000 person-years); in both, other factors were identified to be primarily responsible.
For context, Brown et al50 studied 3 Kaiser Permanente databases prior to availability of
metformin in the United States. Among 41 000 patients with type 2 diabetes, 4 cases of
lactic acidosis were confirmed, resulting in a risk estimate of approximately 10 per 100 000
person-years. Bodmer et al6 conducted a nested case-control study using a general practice
database in the United Kingdom and identified 6 cases of lactic acidosis among 50 048
patients with type 2 diabetes. The estimated incidence was approximately 3.3 per 100 000
person-years among metformin users and approximately 4.8 per 100 000 person-years
among sulfonylurea users. One Dutch study found a higher rate of lactic acidosis in
metformin-treated patients (47 per 100 000 person-years), the majority ascribed to
underlying illnesses.51 The investigators did not estimate corresponding rates with other
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antihyperglycemic drugs, however.
Kajbaf and Lalau49 examined the quality of pharmacovigilance reporting of cases of

metformin-associated lactic acidosis in Europe. Of 869 cases during a 15-year period, only
41.3% met appropriate diagnostic criteria and in only 14% were metformin levels measured.
It was therefore impossible to assess whether metformin was causatively involved in 90% of
cases. In a more detailed study, Stades et al45 convened 6 critical care experts to review 47
case reports of suspected metformin-associated lactic acidosis published between

1959-1999. There was generally very low interobserver agreement as to causation ( K =

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0.041), challenging the notion of a simple, causal relationship between metformin and lactic
acidosis.
In conclusion, no consistent link between metformin and lactic acidosis has been found.
However, observational studies may underestimate the risk of MALA because of
confounding by indication. Patients prescribed metformin despite kidney dysfunction in
these studies may be healthier, and this may explain the low risk for lactic acidosis observed
in this group. On the other hand, ascertainment bias may overestimate the risk of MALA in
observational studies. Clinicians may be more likely to measure lactate levels in patients
taking metformin. Similarly, in pharmacosurveillance studies, the perception of risk for
MALA could lead to increased adverse event reporting. Accordingly, it is difficult to make
firm conclusions from these studies about metformin and lactic acidosis in patients with
kidney disease.
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Clinical Trials and Large Retrospective Studies—Salpeter et al5 compiled trials and
observational studies evaluating metformin therapy compared with placebo or other
antihyperglycemic drugs. The authors pooled data from 347 studies of type 2 diabetes and
discovered no cases of lactic acidosis during 70 490 patient-years in the metformin group or
during 55 451 patient-years in the nonmetformin group. The upper 95% confidence limit for
the true incidence of lactic acidosis per 100 000 patient-years was 4.3 cases with and 5.4
cases without metformin. Given the prevailing contraindications, many participants with
kidney dysfunction may have been excluded. It would therefore be inappropriate to use
absence of MALA cases therein as proof of drug safety in CKD—yet of the 334 prospective
trials examined, 43% did not exclude kidney disease at baseline.
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More recent observational studies suggest clinical benefits of metformin in patients with
impaired kidney function. Roussel et al52 analyzed data from 19 691 patients with type 2
diabetes with established atherosclerotic disease. Propensity scores for metformin
prescription were used to statistically account for differences in baseline characteristics.
Mortality rates were 6.3% (95% CI, 5.2%-7.4%) with and 9.8% (95% CI, 8.4%-11.2%)
without metformin therapy. The adjusted hazard ratio (HR) was 0.76 (95% CI, 0.65-0.89) in
metformin users. In prespecified subgroup analyses, apparent benefit persisted in those with
creatinine clearance of 30 to 60 mL/min per 1.73 m2 (adjusted HR, 0.64 [95% CI,
0.48-0.86]). The authors concluded that metformin therapy might reduce mortality in
patients with renal contraindications.
From the Swedish National Diabetes Register, Ekström et al53 studied 51 675 patients with
type 2 diabetes across a spectrum of kidney function, with mean follow-up of 3.9 years.
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Using patients receiving metformin monotherapy as the referent group and propensity
scoring, the hazard ratios for fatal or nonfatal cardiovascular disease events and all-cause
mortality were numerically (and in some circumstances statistically) higher in those treated
with other agents (sulfonylureas: HR, 1.02 [95% CI, 0.93-1.12] and 1.13 [95% CI,
1.01-1.27]); insulin: HR, 1.18 [95% CI, 1.07 to 1.29] and 1.34 [95% CI, 1.19 to 1.50]).
Among patients with eGFRs of 45 to 60 mL/min per 1.73 m2, those using metformin
monotherapy had a lower risk of acidosis, serious infection, or both (HR, 0.85 [95% CI,

0.74-0.97]) and all-cause mortality (HR, 0.87 [95% CI, 0.77-0.99]) compared with those
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using other single agents.
Other observational data appear to confirm those findings, although the lack of propensity
score adjustments make them more susceptible to confounding by indication. 54,55 Solini et
al54 analyzed data from 15 733 individuals with type 2 diabetes in an observational cohort
study. Cardiovascular disease prevalence was lower in patients taking metformin (20.2%) vs
other agents (32.4%), an observation consistent across all eGFR categories (including <60
mL/min per 1.73 m2) and age quartiles.
Two recent studies using a UK general practice database have added further controversy,
however. Eppenga et al56 analyzed data from 223 968 patients using metformin and 34 571
using other oral agents between 2004-2012. The primary outcome was lactic acidosis
defined by clinical code, lactate level greater than 5 mmol/L, or both. The overall incidence
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rate was 7.4 vs 2.2 per 100 000 person-years among metformin users vs nonusers. The
adjusted HR for patients using metformin was 4.06 (95% CI, 0.97-16.81). The investigators
reported an HR of 6.37 (95% CI, 1.48-27.5) in patients using metformin with eGFR less
than 60 mL/min per 1.73 m2, whereas the HR was not significantly increased (2.87 [95% CI,
0.67-12.3]) in those with eGFR greater than 60 mL/min per 1.73 m2. Using the eGFR cut-
point of 45 mL/min per 1.73 m2, the corresponding HRs were 6.74 (1.34-33.8) vs 3.16
(0.75-13.3). The risk among persons with impaired kidney function was increased further in
those taking higher daily doses (≥2 g/d) (HR, 13.0 [95% CI, 2.36-72.0]). The authors
concluded that the risk of lactic acidosis or elevated lactate level was significantly higher in
metformin-treated patients with mild to moderate CKD as compared with those using other
therapies, a risk compounded at higher doses.
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This study has several limitations. The number of events was small, and kidney function was
not documented in more than 25% of individuals. Lactic acidosis diagnoses were captured
through standardized terminology codes and not substantiated by chart review. Prior work
with this database reported that approximately 50% of diagnoses could not be confirmed on
manual medical record review.6 Last, the inclusion of increased lactate levels as part of the
composite end point (26% in this analysis) would tend to increase the estimate of risk among
metformin users, because clinicians may be more likely to measure lactate in patients taking
the drug. Conversely, patients using metformin tended to be younger with overall better
kidney function and may have been selected for therapy because their risk for lactic acidosis
appeared low.
Richy et al57 also used this database to determine whether, among metformin-treated
patients, those with abnormal kidney function experienced any increased risk for lactic
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acidosis. A total 35 events were identified during 2007-2012 among 77 601 metformin
users, for an overall incidence of 10.37 (95% CI, 7.22–14.42) per 100 000 patient-years.
Corresponding rates were 7.6 (95% CI, 0.9-27.5) per 100 000 patient-years among patients
with normal kidney function (eGFR >90 mL/min per 1.73 m2), 4.6 (95% CI, 2.00-9.15) per
100 000 patient-years among those with mildly impaired function (eGFR 60-90 mL/min per
1.73 m2), 17 (95% CI, 10.89-25.79) per 100 000 patient-years among those with moderately
impaired function (eGFR 30-60 mL/min per 1.73 m2), and 39 (95% CI, 4.72-140.89) per

100 000 patient-years among those with severely impaired function (eGFR <30 mL/min per
1.73 m2). The incidence rate ratios, compared with the normal kidney function group, were
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0.61 (0.12-5.26) for those with mildly impaired function, 2.27 (0.56-20.00) for those with
moderately impaired function, and 5.26 (0.37-71.43) for those with severely impaired
function. The authors concluded that lactic acidosis is rare with metformin and that
differences in the incidence rates between patients with normal and reduced kidney function
were not significant. However, numerical trends for increasing lactic acidosis events begin
with eGFRs less than 60 mL/min per 1.73 m2. With such small numbers of events,
conclusive statements cannot be made.
In summary, the frequency of lactic acidosis in the setting of metformin therapy is very low
and numerically similar to what appears to be the background rate in the population with
type 2 diabetes. Data from 2 recent observational studies suggest possible trends toward a
higher risk of either lactic acidosis or elevated lactate levels in patients taking metformin
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and with eGFRs less than 45 to 60 mL/min per 1.73 m2. For context, other studies have
suggested a significant clinical benefit for macrovascular outcomes from metformin, 58-61
with a pooled odds ratio from a single systematic review of 0.74 (95% CI, 0.62-0.89) for
cardiovascular mortality compared with other oral agents or placebo.59
Adherence to Current Prescribing Guidelines—Eppenga et al56 and Richy et al57

have observed that current prescribing guidelines for kidney dysfunction are not consistently
followed in real-world practice, and others have made similar observations (Table 1).31,62-75
In some studies, metformin was used despite recommendations concerning renal risk in up
to 1 of 4 patients. So, current regulatory cautions to avoid metformin in patients with mild to
moderate CKD apparently are not being followed. Yet lactic acidosis developed rarely and,
when it occurred, was considered primarily related to underlying disease.
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Other Treatment Options

During the past 15 years, many other glucose-lowering agents have become available, each
with unique safety profiles.1 Adverse effects are a particular concern in chronic diseases, in
which the treatment course is open ended and quality of life, drug cost, and safety are
critical components of patient-centered care. If metformin is discontinued or avoided
because of the development of mild to moderate CKD (a frequent scenario in diabetes,
particularly in elderly patients), other therapies may be required. Whether the alternatives
available are any safer in this setting is uncertain.76 There are concerns related to
hypoglycemia with sulfonylureas and insulin among patients with CKD. Kidney dysfunction
is associated with increased risk for peripheral edema and heart failure with the
thiazolidinediones.77 Sodium-glucose cotransporter 2 inhibitors are less effective as
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glucosuric agents if kidney function is impaired.78
Discussion
Summary of Key Findings
Because of concerns regarding MALA in the setting of CKD, guidelines in the United States
prohibit the use of metformin for at least 2.5 million individuals.4 The incidence of lactic

acidosis in the setting of metformin therapy is, however, low, and the drug is not necessarily
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responsible when lactic acidosis occurs in patients taking this medication. Although drug
levels are higher in those with kidney dysfunction, levels are still maintained largely within
the therapeutic range9,10 and lactate levels are not substantially increased when metformin is
used in those with reduced GFR.11-14 The risk of lactic acidosis is essentially nil in the
context of clinical trials, including those that did not specify kidney disease as an exclusion
criterion.5 Data from observational clinical practice data sets are conflicting, with most
appearing to confirm the drug’s overall safety profile, finding lactic acidosis rates not
different from those in the general population of patients with diabetes treated with other
agents.6,47 Current guidelines regarding use of metformin in patients with CKD are
commonly disregarded, but when the drug is prescribed despite renal contraindications, it is
associated with no greater occurrence of adverse events and may potentially have clinical
benefits in this population.52-54,79 Some recent data suggest that the risk of lactic acidosis or
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elevated lactate levels may be increased in metformin users with more advanced kidney
dysfunction compared with users of other drugs, although the absolute risk remains
extremely low. A conservative synthesis of these data is that, as long as kidney function is
stable and the patient is observed closely, metformin is un-likely to measurably increase the
risk of lactic acidosis in those with mild to moderate CKD (ie, eGFR 30-60 mL/min per 1.73
m2).
Current Clinical Practice Guidelines

The US FDA prescribing guidelines for metformin regarding kidney function are noted
above. In some other parts of the world, use of the drug extends to those with mild to
moderate CKD. In the United Kingdom, guidelines allow for use with eGFRs less than 60
mL/min per 1.73 m2,80 with the recommendation that dosing be reviewed if serum
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creatinine levels increase to more than 1.5 mg/dL or eGFR decreases to less than 45 mL/min
per 1.73 m2 and that the drug be stopped with creatinine levels more than 1.7 mg/dL or
eGFRs less than 30 mL/min per 1.73 m2. The European Medicines Agency stipulates that
metformin is contraindicated with creatinine clearance less than 60 mL/min.81 The Canadian
Diabetes Association allows for metformin use with creatinine clearance less than 60
mL/min but with a maximum dose of 1700 mg/d for patients with creatinine clearance of 60
to 90 mL/min and of 850 mg/d for patients with creatinine clearance of 30 to 60 mL/min.82
The 2012 American Diabetes Association–European Association for the Study of Diabetes
position statement on antihyperglycemic therapy in type 2 diabetes favors the eGFR-based
National Institute for Health and Care Excellence guidelines.1 The Kidney Disease
Outcomes Quality Initiative clinical practice guidelines recommend that metformin safety be
assessed in patients with stage 4 and stage 5 CKD.83
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There have been increasing calls to update the US metformin-prescribing guidelines to allow
for use of this agent in patients with mild to moderate CKD,84-87 with 2 citizens’ petitions
being considered by the FDA.88,89
Controversial/Unresolved Issues, Areas for Future Research

There have been no randomized clinical trials to test the specific hypothesis that metformin
is safe in patients with mild to moderate CKD. Randomized trials would help to better

inform evidence-based guidelines. However, given the rarity of lactic acidosis in the setting
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of metformin therapy, a study would need to examine hundreds of thousands of patients for
many years to demonstrate non-inferiority compared with other agents, which is clearly
impractical. National patient registries might be a reasonable alternative. However, for
regulatory bodies at this time, the best available evidence is limited to meta-analyses,
retrospective studies, and smaller mechanistic investigations reported herein.
Recommendations
Our review supports consideration of a change to metformin’s prescribing guidelines, with
use allowed in patients with mild to moderate CKD. Table 2 proposes a possible strategy,
but it has not been evaluated or validated in a clinical trial. It should be noted that, while
generally increasing access to metformin for many, this strategy may actually make
treatment in some older individuals more complex, with certain subgroups (mainly nonblack
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women with eGFRs of 30-44 mL/min per 1.73 m2) requiring dosage reductions not currently
specified in the US label (eg, a white woman aged 61 years with a serum creatinine level of
1.3 mg/dL but an eGFR of 44 mL/min per 1.73 m2). Any new expansion of metformin use
in patients with mild to moderate CKD will need to be accompanied by appropriate dosage
reductions and careful follow-up assessments of kidney function.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
Dr Inzucchi reported serving as a consultant for Merck, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, and
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Novo Nordisk; serving as a speaker for Merck; and receiving nonfinancial support from Takeda. Dr Lipska reported
receiving a grant from the National Institutes of Health and receiving a Yale Center for Clinical Investigation
Scholar Award and a Pepper Center Research Career Development Award. Dr Bailey reported serving as a
consultant for, and receiving honoraria and travel expenses from, AstraZeneca/Bristol-Myers Squibb, sanofi, Merck
Sharp & Dohme, Takeda, Boehringer Ingelheim/Lilly, and Novo. Dr McGuire reported receiving personal fees
from Boehringer Ingelheim, Janssen Research and Development LLC, sanofi-aventis Groupe, Genentech, Merck
Sharp & Dohme, Medscape Cardiology, Pri-Med Institute, The Brigham and Women’s Hospital, Inc, Duke Clinical
Research Institute, The Cleveland Clinic Coordinating Center for Clinical Research, The University of Oxford,
Daiichi Sankyo, Lilly USA, Novo Nordisk, F. Hoffmann La Roche, Axio Research, INC Research LLC,
GlaxoSmithKline, Takeda Pharmaceuticals North America, Bristol-Myers Squibb, AstraZeneca, Orexigen,
Lexicon, Eisai, and Regeneron and receiving nonfinancial support from Gilead Sciences.
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Table 1
Retrospective Studies Examining the Frequency of Metformin Use in Patients With Active Renal
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Contraindications
Renal Contraindication
a
Source No. Setting Frequency, No. (%) Definition Frequency of Lactic Acidosis
Kosmalski et 335 Hospital 56 (16.7) eGFR <60 No cases
al,62 2012
234 Outpatient 36 (15.4) eGFR <60 No cases

Vasisht et al,63
2010
Scotton 283 Hospital 17 (6.0) SCr >1.5 (men) Not reported

et al,31 2009 SCr >1.4 (women)
Kamber et 425 Outpatient 78 (8.4) eGFR <60 b

al,64 2008 No
cases
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92 Outpatient 4 (4.4) Not reported

Runge et al,65 SCr ≥ 1.5 (men)
2008 SCr ≥ 1.3 (women)
Sweileh et 124 Outpatient 34 (27.4) Renal impairment Not reported

al,66 2007
11 297 Outpatient 880 (25.5) eGFR <60 Unknown

Warren et al,67
2007
Kennedy 4838 Outpatient 219 (4.5) eGFR <60 Not reported

et al,68 2005 290 (13.4) [men] SCr ≥1.5 (men)
362 (17.7) SCr ≥1.4 (women)
[women]
Millican 83 Hospital 12 (14.5) eGFR <50 or Not reported

et al,69 2004 SCr >1.7
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22 Outpatient 8 (36.4) Not reported

Horlen et al,70 SCr ≥1.5 (men)
2002 SCr ≥1.4 (women)
Calabrese 263 Hospital 32 (12.2)

et al, 71 2002 SCr ≥1.5 (men) 3 cases (metformin could not
SCr ≥1.4 (women) be ruled out as the cause)
Emslie-Smithet 1347 Outpatient 63 (4.7) SCr ≥1.7

al,72 2001 1 case, unrelated (extensive
myocardial infarction, renal
function previously normal)
Holstein 308 Hospital 59 (19.2) eGFR <60 No cases

et al,73 1999
9875 Outpatient 128 (1.3) SCr ≥1.5

Selby et al,74 1 case, likely unrelated (renal
1999 function normal)
89 Outpatient 2 (2.3) SCr ≥1.4 Not reported

Sulkin et al,75
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1997
Abbreviations: eGFR, estimated glomerular filtration rate; SCr, serum creatinine.

SI conversion factor: To convert serum creatinine values to µmol/L, multiply by 88.4.
a
Estimated glomerular filtration rate values reported in mL/min per 1.73 m2; serum creatinine values reported in mg/dL.

b
During study follow-up (1993 to 2001); authors reported 3 patients with metformin-associated lactic acidosis during extended follow-up via data
linkage through 2006, each of whom had at least 1 major comorbidity associated with lactic acidosis (estimated incidence similar to that of patients
not treated with metformin [P = .4]).
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Table 2
Possible Approach to Metformin Prescribing in the Setting of CKDa

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Maximal Total Daily Dose,

CKD Stage eGFR, mL/min per 1.73 m2 mg Other Recommendations
1 ≥90 2550
2 60 -<90 2550
3A 45 -<60 2000
Avoid if kidney function is or expected to become unstable
Consider more cautious follow-up of kidney function
3B 30 -<45 1000
Do not initiate therapy at this stage but drug may be continued
4 15 -<30 Do not use
5 <15 Do not use

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Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate.
a
This strategy has not been evaluated or validated in a clinical trial; there are no data to support its efficacy, safety, or potential to improve clinicaloutcomes.
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Metformin in Patients With Type 2 Diabetes and Kidney Disease:
A Systematic Review
Silvio E. Inzucchi, MD, Kasia J. Lipska, MD, MHS, Helen Mayo, MLS, Clifford J. Bailey, PhD,
and Darren K. McGuire, MD, MHSc
Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut (Inzucchi,
Lipska); Health Sciences Digital Library and Learning Center, University of Texas Southwestern
Medical Center, Dallas (Mayo); School of Life & Health Sciences, Aston University, Birmingham,
United Kingdom (Bailey); Division of Cardiology, University of Texas Southwestern Medical
Center, Dallas (McGuire)
Abstract
IMPORTANCE—Metformin is widely viewed as the best initial pharmacological option to lower
glucose concentrations in patients with type 2 diabetes mellitus. However, the drug is
contraindicated in many individuals with impaired kidney function because of concerns of lactic
acidosis.
OBJECTIVE—To assess the risk of lactic acidosis associated with metformin use in individuals
with impaired kidney function.
EVIDENCE ACQUISITION—In July 2014, we searched the MEDLINE and Cochrane databases
for English-language articles pertaining to metformin, kidney disease, and lactic acidosis in
humans between 1950 and June 2014. We excluded reviews, letters, editorials, case reports, small
case series, and manuscripts that did not directly pertain to the topic area or that met other
exclusion criteria. Of an original 818 articles, 65 were included in this review, including
pharmacokinetic/metabolic studies, large case series, retrospective studies, meta-analyses, and a
clinical trial.
RESULTS—Although metformin is renally cleared, drug levels generally remain within the
therapeutic range and lactate concentrations are not substantially increased when used in patients
with mild to moderate chronic kidney disease (estimated glomerular filtration rates, 30-60 mL/min
per 1.73 m2). The overall incidence of lactic acidosis in metformin users varies across studies from
Copyright 2014 American Medical Association. All rights reserved
Corresponding Author: Silvio Inzucchi, MD, Section of Endocrinology, Yale School of Medicine, Fitkin 106, 333 Cedar St, New Haven, CT
06520-8020 (silvio.inzucchi@yale.edu)..
Author Contributions: Drs Inzucchi and McGuire had full access to all of the data in the study and take responsibility for the
integrity of the data and the accuracy of the data analysis.
Study concept and design: Inzucchi, Bailey, McGuire.
Acquisition, analysis, or interpretation of data: Inzucchi, Lipska, Mayo, Bailey.
Drafting of the manuscript: Inzucchi, Mayo, Bailey, McGuire.
Critical revision of the manuscript for important intellectual content: Inzucchi, Lipska, Mayo, McGuire.
Administrative, technical, or material support: Inzucchi.

Supplemental content at jama.com
Conflict of Interest Disclosures: All authors

JAMA. Authorhave completedavailable
manuscript; and submitted the2015
in PMC ICMJE Form
May 11.for Disclosure of Potential Conflicts of
Interest.
Inzucchi et al.
Intern Med 53: 215-219, 2014 DOI: 10.2169/internalmedicine.53.1316 Page 2
approximately 3 per 100 000 person-years to 10 per 100 000 person-years and is generally
Author Manuscript
indistinguishable from the background rate in the overall population with diabetes. Data
suggesting an increased risk of lactic acidosis in metformin-treated patients with chronic kidney
disease are limited, and no randomized controlled trials have been conducted to test the safety of
metformin in patients with significantly impaired kidney function. Population-based studies
demonstrate that metformin may be prescribed counter to prevailing guidelines suggesting a renal
risk in up to 1 in 4 patients with type 2 diabetes mellitus—use which, in most reports, has not been
associated with increased rates of lactic acidosis. Observational studies suggest a potential benefit
from metformin on macrovascular outcomes, even in patients with prevalent renal
contraindications for its use.
CONCLUSIONS AND RELEVANCE—Available evidence supports cautious expansion of
metformin use in patients with mild to moderate chronic kidney disease, as defined by estimated
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glomerular filtration rate, with appropriate dosage reductions and careful follow-up of kidney
function.
Metformin has been prescribed in the United States for the management of type 2 diabetes
for 20 years. It is widely endorsed as initial therapy by professional organizations because of
its low cost, safety profile, and potential cardiovascular benefits. 1 Another biguanide,
phenformin, was withdrawn in 1977 owing to risk of lactic acidosis. Because metformin is
cleared by the kidneys, it may accumulate when renal function decreases, with the potential
for exposure-dependent toxicity that could precipitate lactate accumulation. At its US
approval of metformin in 1994, the Food and Drug Administration (FDA) stipulated
stringent prescribing criteria based on kidney function that remain in place today (Box).2
Given the aging population as well as the most recent estimate of adults with diagnosed type
2 diabetes in the United States (21 million3) and the rate of this degree of impaired kidney
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function in these individuals (estimated at 12%4), it is possible that prescribing criteria may
preclude metformin use in many patients with renal clearance rates sufficient for adequate
drug elimination.
The original prescribing label was intended to provide a safety margin to minimize the risk
of metformin-associated lactic acidosis (MALA). The label warnings were based on a
modest amount of pharmacokinetic data about reduced metformin clearance in the setting of
kidney impairment, but the clinical relevance of these observations remains uncertain. The
incidence of lactic acidosis is estimated at approximately 1 per 23 000 to 30 000 person-
years among metformin users compared with approximately 1 per 18 000 to 21 000 person-
years among patients with type 2 diabetes using other agents. 5,6 These data and the safety
profile after several decades of clinical experience have led to less restrictive policy
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revisions outside the United States. Whether the FDA guidelines should be expanded to
allow greater access to metformin in the United States is under consideration.
Literature Search
We conducted a search of the MEDLINE and Cochrane databases (Database of Systematic
Reviews, Central Register of Controlled Trials, and DARE [Database of Abstracts of
Reviews of Effects]) for articles on metformin in patients with chronic kidney disease
(CKD) using the search terms metformin, kidney, renal, CKD, lactic acidosis, and

Inzucchi et al.
glomerular filtration rate. We retrieved English-language human studies published between

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January 1950 and June 2014. Eight hundred twelve manuscripts were supplemented by an
additional 6 found on review of bibliographies of included studies and other sources.
Reviews, letters, editorials, case reports, series involving fewer than 10 patients, and animal
or in vitro studies were excluded, leaving 414 manuscripts. These were hand-searched; those
not pertaining to the topic (338), pharmacokinetic studies in patients without diabetes (1),
observational studies with cohorts not defined by kidney function (5), and older meta-
analyses later updated (5) were excluded. Thus, the final number of manuscripts was 65
(pharmacokinetic/metabolic investigations [10]; case series [20]; cross-sectional,
observational, and pharmacosurveillance studies [31]; metaanalyses [3]; and a clinical trial
[1]). (PRISMA diagram in eFigure in the Supplement.)
Box
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Current US Food and Drug Administration Prescribing Guidelines for

Metformin as Related to Kidney Function
• Metformin is contraindicated in ―renal disease or renal dysfunction (eg, as

suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL
[females]) or abnormal creatinine clearance (CrCl).‖
• Metformin ―should not be initiated in patients ≥80 years of age unless

measurement of creatinine clearance demonstrates that renal function is not
reduced.‖
Source: Metformin final printed labeling.2

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Results
Major Findings
Metformin, CKD, and Lactate Metabolism—Biguanides such as metformin inhibit the
mitochondrial respiratory chain, impairing the main site of energy generation through
aerobic metabolism. This results in a shift toward anaerobic metabolism, of which lactate is
a by-product, and less energy for gluconeogenesis. Reduced hepatic glucose production is a
major mechanism of the antihyperglycemic effect of metformin, although it has been
recently proposed that some glucose lowering may be mediated through the enteroendocrine
axis.7 Metformin is eliminated unchanged in the urine, and the drug may accumulate in
patients with kidney failure.8,9 Although mild to moderate CKD reduces metformin
clearance, drug levels typically remain within a safe range. Sambol et al9 found that, in
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single-dose studies, mild CKD (creatinine clearance, 60-90 mL/min) was associated with
23% to 33% reductions in medication clearance and moderate CKD (30-60 mL/min) with
74% to 78% reductions. Metformin levels, however, were generally maintained in the
therapeutic range (0.47-2.5 mg/L [≈ 4-20 µmol/L]). Frid et al10 measured metformin levels
in 137 patients with diabetes mellitus receiving long-term therapy. Median trough levels
(upper therapeutic range, 20 µmol/L) were 4.50 µmol/L (range, 0.10-20.70) for estimated
glomerular filtration rates (eGFRs) greater than 60 mL/min per 1.73 m2, 7.71 µmol/L (range,

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0.12-15.15) for eGFRs of 30 to 60 mL/min per 1.73 m2, and 8.88 µmol/L(range, 5.99-18.60)
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for eGFRs less than 30 mL/min per 1.73 m2.
Circulating lactate levels among metformin-treated patients are typically normal, even
among patients with kidney dysfunction. Liu et al11 measured lactate levels (normal, 5-15
mg/dL [0.6-1.7 mmol/L]) in 1024 patients with type 2 diabetes and normal kidney function.
Mean lactate was higher in patients taking metformin compared with those taking other
agents (1.32 [SD, 0.52] vs 1.14 [0.45] mmol/L, P < .01), and elevated concentrations (>2.0
mmol/L) were nearly 3 times more common in metformin-treated patients (9.2% vs 3.8%, P
< .001). However, none met diagnostic criteria for lactic acidosis. Lin et al 12 found mean
lactate concentrations to be similar between 66 patients with type 2 diabetes older than 80
years and taking metformin (mean age, 83.6 years; mean creatinine clearance, 48.9 [SD,
12.9] mL/min), compared with 79 younger individuals (mean age, 59.9 years; mean
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creatinine clearance, 80.3 [SD, 30.1] mL/min, P < .01): 1.47 [SD, 0.58] vs 1.50 [SD, 0.53]
mmol/L. Lim et al13 studied a group of 97 patients taking metformin and found no
association between plasma lactate levels and kidney status (1.7 [SD, 0.3] mmol/L in groups
with eGFRs less than 60 mL/min per 1.73 m2, 1.8 [SD, 0.3] mmol/L in groups with eGFRs
of 60 through 90/mL/min per 1.73 m2, and 1.8 [SD, 0.4] mmol/L in groups with eGFRs
greater than 90 mL/min per 1.73 m2). Similar findings were reported by Duong et al14 and
Connolly and Kesson15 in studies that included patients with more advanced kidney
dysfunction. Among 493 patients with type 2 diabetes, Mongraw-Chaffin et al16 found
slightly higher (but still normal) lactate levels in those using metformin vs those using other
agents (1.00 [95% CI, 0.94-1.06] vs 0.93 [range, 0.88-0.97] mmol/L; P < .05). Similar
findings were reported by Davis et al17 in 272 patients (1.86 [SD, 1.34-2.59] for metformin
vs 1.58 [1.09-2.30] mmol/L for no metformin; P < .001.) Abbasi et al18 reported mildly
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elevated lactate levels (mean, 2.17 [SD, 0.57] mmol/L) in 57% of 110 patients taking
metformin with normal kidney function, but there was no control group.
The pharmacokinetics of metformin differ substantially from those of phenformin, an

original biguanide whose removal from the market nearly 4 decades ago was based on a
significantly increased risk of lactic acidosis. Metformin is entirely renally cleared (half-life,
6.5 hours)19; phenformin is both hepatically metabolized and more slowly renally excreted
(half-life, 7-15 hours). Compared with metformin, phenformin is also lipophilic, with a
higher affinity for mitochondrial membranes and more powerful inhibitory effect on the
mitochondrial respiratory chain. Phenformin increases muscle lactate release and inhibits
lactate oxidation, effects not shared by metformin.20 Three early investigations found a
relationship between phenformin and lactate levels not demonstrable with metformin.21-23
These data may explain reduced incidence of lactic acidosis in Swedish patients with
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diabetes during 1977-1991, comparing rates when phenformin was available (1.5 cases/10
000 patient-years) vs when metformin was the exclusive biguanide prescribed (0.24 cases/10
000 patient-years).24,25
In summary, although metformin clearance is decreased in the setting of CKD, drug levels
remain within therapeutic range when eGFR is greater than 30 mL/min per 1.73 m2 and do
not significantly affect circulating lactate levels. These conclusions are based on small

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studies; larger data sets could reveal a closer alignment between metformin, kidney function,
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and predisposition to hyperlactatemia.
The Relationship Between Metformin and Lactic Acidosis—Lactic acidosis is an

anion-gap metabolic acidosis defined by plasma lactate level greater than 5 mmol/L and pH
less than 7.35. When severe, it is associated with multisystem organ dysfunction—
particularly neurologic (stupor, coma, seizures) and cardiovascular (hypotension, ventricular
fibrillation)—and carries a high mortality risk. Small series involving patients hospitalized
with lactic acidosis have explored associations with metformin exposure.19,26-44 In each, the
patients had a supervening illness that precipitated the metabolic decompensation, usually
infection, acute kidney or liver failure, or cardiovascular collapse. Although a possible role
for metformin could not be excluded, it was viewed predominately as a bystander—ie, not
causally implicated—by most authors. When metformin levels were measured, they were
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normal or elevated but did not consistently correlate with the degree of acidosis. 28,34,45,46
Lactate concentrations were not different than in patients who did not take metformin but
were contemporaneously admitted with lactic acidosis.38 In addition, drug concentrations
carried neither diagnostic nor prognostic significance. In one series, higher metformin levels
were associated with reduced mortality.35 In some studies30,31,34 the majority of patients
with metformin-associated lactic acidosis had antecedent normal kidney function—
suggesting that prescribing limitations based on renal parameters would not necessarily
prevent lactic acidosis, even if the drug were responsible.
Several larger observational studies have explored the relationship between metformin and
lactic acidosis.6,45,47-49 Stang et al47conducted an historical cohort analysis of the
Saskatchewan Health database, including information on metformin therapy during a 15-
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year period. In that study, 11 797 patients received at least 1 prescription, for a total
exposure of 22 296 years. Two patients were hospitalized for lactic acidosis (approximately
9/100 000 person-years); in both, other factors were identified to be primarily responsible.
For context, Brown et al50 studied 3 Kaiser Permanente databases prior to availability of
metformin in the United States. Among 41 000 patients with type 2 diabetes, 4 cases of
lactic acidosis were confirmed, resulting in a risk estimate of approximately 10 per 100 000
person-years. Bodmer et al6 conducted a nested case-control study using a general practice
database in the United Kingdom and identified 6 cases of lactic acidosis among 50 048
patients with type 2 diabetes. The estimated incidence was approximately 3.3 per 100 000
person-years among metformin users and approximately 4.8 per 100 000 person-years
among sulfonylurea users. One Dutch study found a higher rate of lactic acidosis in
metformin-treated patients (47 per 100 000 person-years), the majority ascribed to
underlying illnesses.51 The investigators did not estimate corresponding rates with other
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antihyperglycemic drugs, however.
Kajbaf and Lalau49 examined the quality of pharmacovigilance reporting of cases of

metformin-associated lactic acidosis in Europe. Of 869 cases during a 15-year period, only
41.3% met appropriate diagnostic criteria and in only 14% were metformin levels measured.
It was therefore impossible to assess whether metformin was causatively involved in 90% of
cases. In a more detailed study, Stades et al45 convened 6 critical care experts to review 47
case reports of suspected metformin-associated lactic acidosis published between

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1959-1999. There was generally very low interobserver agreement as to causation ( K =

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0.041), challenging the notion of a simple, causal relationship between metformin and lactic
acidosis.
In conclusion, no consistent link between metformin and lactic acidosis has been found.
However, observational studies may underestimate the risk of MALA because of
confounding by indication. Patients prescribed metformin despite kidney dysfunction in
these studies may be healthier, and this may explain the low risk for lactic acidosis observed
in this group. On the other hand, ascertainment bias may overestimate the risk of MALA in
observational studies. Clinicians may be more likely to measure lactate levels in patients
taking metformin. Similarly, in pharmacosurveillance studies, the perception of risk for
MALA could lead to increased adverse event reporting. Accordingly, it is difficult to make
firm conclusions from these studies about metformin and lactic acidosis in patients with
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kidney disease.
Clinical Trials and Large Retrospective Studies—Salpeter et al5 compiled trials and
observational studies evaluating metformin therapy compared with placebo or other
antihyperglycemic drugs. The authors pooled data from 347 studies of type 2 diabetes and
discovered no cases of lactic acidosis during 70 490 patient-years in the metformin group or
during 55 451 patient-years in the nonmetformin group. The upper 95% confidence limit for
the true incidence of lactic acidosis per 100 000 patient-years was 4.3 cases with and 5.4
cases without metformin. Given the prevailing contraindications, many participants with
kidney dysfunction may have been excluded. It would therefore be inappropriate to use
absence of MALA cases therein as proof of drug safety in CKD—yet of the 334 prospective
trials examined, 43% did not exclude kidney disease at baseline.
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More recent observational studies suggest clinical benefits of metformin in patients with
impaired kidney function. Roussel et al52 analyzed data from 19 691 patients with type 2
diabetes with established atherosclerotic disease. Propensity scores for metformin
prescription were used to statistically account for differences in baseline characteristics.
Mortality rates were 6.3% (95% CI, 5.2%-7.4%) with and 9.8% (95% CI, 8.4%-11.2%)
without metformin therapy. The adjusted hazard ratio (HR) was 0.76 (95% CI, 0.65-0.89) in
metformin users. In prespecified subgroup analyses, apparent benefit persisted in those with
creatinine clearance of 30 to 60 mL/min per 1.73 m2 (adjusted HR, 0.64 [95% CI,
0.48-0.86]). The authors concluded that metformin therapy might reduce mortality in
patients with renal contraindications.
From the Swedish National Diabetes Register, Ekström et al53 studied 51 675 patients with
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type 2 diabetes across a spectrum of kidney function, with mean follow-up of 3.9 years.
Using patients receiving metformin monotherapy as the referent group and propensity
scoring, the hazard ratios for fatal or nonfatal cardiovascular disease events and all-cause
mortality were numerically (and in some circumstances statistically) higher in those treated
with other agents (sulfonylureas: HR, 1.02 [95% CI, 0.93-1.12] and 1.13 [95% CI,
1.01-1.27]); insulin: HR, 1.18 [95% CI, 1.07 to 1.29] and 1.34 [95% CI, 1.19 to 1.50]).
Among patients with eGFRs of 45 to 60 mL/min per 1.73 m2, those using metformin
monotherapy had a lower risk of acidosis, serious infection, or both (HR, 0.85 [95% CI,

Inzucchi et al.
0.74-0.97]) and all-cause mortality (HR, 0.87 [95% CI, 0.77-0.99]) compared with those
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using other single agents.
Other observational data appear to confirm those findings, although the lack of propensity
score adjustments make them more susceptible to confounding by indication. 54,55 Solini et
al54 analyzed data from 15 733 individuals with type 2 diabetes in an observational cohort
study. Cardiovascular disease prevalence was lower in patients taking metformin (20.2%) vs
other agents (32.4%), an observation consistent across all eGFR categories (including <60
mL/min per 1.73 m2) and age quartiles.
Two recent studies using a UK general practice database have added further controversy,
however. Eppenga et al56 analyzed data from 223 968 patients using metformin and 34 571
using other oral agents between 2004-2012. The primary outcome was lactic acidosis
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defined by clinical code, lactate level greater than 5 mmol/L, or both. The overall incidence
rate was 7.4 vs 2.2 per 100 000 person-years among metformin users vs nonusers. The
adjusted HR for patients using metformin was 4.06 (95% CI, 0.97-16.81). The investigators
reported an HR of 6.37 (95% CI, 1.48-27.5) in patients using metformin with eGFR less
than 60 mL/min per 1.73 m2, whereas the HR was not significantly increased (2.87 [95% CI,
0.67-12.3]) in those with eGFR greater than 60 mL/min per 1.73 m2. Using the eGFR cut-
point of 45 mL/min per 1.73 m2, the corresponding HRs were 6.74 (1.34-33.8) vs 3.16
(0.75-13.3). The risk among persons with impaired kidney function was increased further in
those taking higher daily doses (≥2 g/d) (HR, 13.0 [95% CI, 2.36-72.0]). The authors
concluded that the risk of lactic acidosis or elevated lactate level was significantly higher in
metformin-treated patients with mild to moderate CKD as compared with those using other
therapies, a risk compounded at higher doses.
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This study has several limitations. The number of events was small, and kidney function was
not documented in more than 25% of individuals. Lactic acidosis diagnoses were captured
through standardized terminology codes and not substantiated by chart review. Prior work
with this database reported that approximately 50% of diagnoses could not be confirmed on
manual medical record review.6 Last, the inclusion of increased lactate levels as part of the
composite end point (26% in this analysis) would tend to increase the estimate of risk among
metformin users, because clinicians may be more likely to measure lactate in patients taking
the drug. Conversely, patients using metformin tended to be younger with overall better
kidney function and may have been selected for therapy because their risk for lactic acidosis
appeared low.
Richy et al57 also used this database to determine whether, among metformin-treated
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patients, those with abnormal kidney function experienced any increased risk for lactic
acidosis. A total 35 events were identified during 2007-2012 among 77 601 metformin
users, for an overall incidence of 10.37 (95% CI, 7.22–14.42) per 100 000 patient-years.
Corresponding rates were 7.6 (95% CI, 0.9-27.5) per 100 000 patient-years among patients
with normal kidney function (eGFR >90 mL/min per 1.73 m2), 4.6 (95% CI, 2.00-9.15) per
100 000 patient-years among those with mildly impaired function (eGFR 60-90 mL/min per
1.73 m2), 17 (95% CI, 10.89-25.79) per 100 000 patient-years among those with moderately
impaired function (eGFR 30-60 mL/min per 1.73 m2), and 39 (95% CI, 4.72-140.89) per

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100 000 patient-years among those with severely impaired function (eGFR <30 mL/min per
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1.73 m2). The incidence rate ratios, compared with the normal kidney function group, were
0.61 (0.12-5.26) for those with mildly impaired function, 2.27 (0.56-20.00) for those with
moderately impaired function, and 5.26 (0.37-71.43) for those with severely impaired
function. The authors concluded that lactic acidosis is rare with metformin and that
differences in the incidence rates between patients with normal and reduced kidney function
were not significant. However, numerical trends for increasing lactic acidosis events begin
with eGFRs less than 60 mL/min per 1.73 m2. With such small numbers of events,
conclusive statements cannot be made.
In summary, the frequency of lactic acidosis in the setting of metformin therapy is very low
and numerically similar to what appears to be the background rate in the population with
type 2 diabetes. Data from 2 recent observational studies suggest possible trends toward a
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higher risk of either lactic acidosis or elevated lactate levels in patients taking metformin
and with eGFRs less than 45 to 60 mL/min per 1.73 m2. For context, other studies have
suggested a significant clinical benefit for macrovascular outcomes from metformin,58-61
with a pooled odds ratio from a single systematic review of 0.74 (95% CI, 0.62-0.89) for
cardiovascular mortality compared with other oral agents or placebo.59
Adherence to Current Prescribing Guidelines—Eppenga et al56 and Richy et al57

have observed that current prescribing guidelines for kidney dysfunction are not consistently
followed in real-world practice, and others have made similar observations (Table 1).31,62-75
In some studies, metformin was used despite recommendations concerning renal risk in up
to 1 of 4 patients. So, current regulatory cautions to avoid metformin in patients with mild to
moderate CKD apparently are not being followed. Yet lactic acidosis developed rarely and,
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when it occurred, was considered primarily related to underlying disease.
Other Treatment Options

During the past 15 years, many other glucose-lowering agents have become available, each
with unique safety profiles.1 Adverse effects are a particular concern in chronic diseases, in
which the treatment course is open ended and quality of life, drug cost, and safety are
critical components of patient-centered care. If metformin is discontinued or avoided
because of the development of mild to moderate CKD (a frequent scenario in diabetes,
particularly in elderly patients), other therapies may be required. Whether the alternatives
available are any safer in this setting is uncertain.76 There are concerns related to
hypoglycemia with sulfonylureas and insulin among patients with CKD. Kidney dysfunction
is associated with increased risk for peripheral edema and heart failure with the
thiazolidinediones.77 Sodium-glucose cotransporter 2 inhibitors are less effective as
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glucosuric agents if kidney function is impaired.78
Discussion
Summary of Key Findings
Because of concerns regarding MALA in the setting of CKD, guidelines in the United States
prohibit the use of metformin for at least 2.5 million individuals.4 The incidence of lactic

Inzucchi et al.
acidosis in the setting of metformin therapy is, however, low, and the drug is not necessarily
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responsible when lactic acidosis occurs in patients taking this medication. Although drug
levels are higher in those with kidney dysfunction, levels are still maintained largely within
the therapeutic range9,10 and lactate levels are not substantially increased when metformin is
used in those with reduced GFR.11-14 The risk of lactic acidosis is essentially nil in the
context of clinical trials, including those that did not specify kidney disease as an exclusion
criterion.5 Data from observational clinical practice data sets are conflicting, with most
appearing to confirm the drug’s overall safety profile, finding lactic acidosis rates not
different from those in the general population of patients with diabetes treated with other
agents.6,47 Current guidelines regarding use of metformin in patients with CKD are
commonly disregarded, but when the drug is prescribed despite renal contraindications, it is
associated with no greater occurrence of adverse events and may potentially have clinical
benefits in this population.52-54,79 Some recent data suggest that the risk of lactic acidosis or
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elevated lactate levels may be increased in metformin users with more advanced kidney
dysfunction compared with users of other drugs, although the absolute risk remains
extremely low. A conservative synthesis of these data is that, as long as kidney function is
stable and the patient is observed closely, metformin is un-likely to measurably increase the
risk of lactic acidosis in those with mild to moderate CKD (ie, eGFR 30-60 mL/min per 1.73
m2).
Current Clinical Practice Guidelines

The US FDA prescribing guidelines for metformin regarding kidney function are noted
above. In some other parts of the world, use of the drug extends to those with mild to
moderate CKD. In the United Kingdom, guidelines allow for use with eGFRs less than 60
mL/min per 1.73 m2,80 with the recommendation that dosing be reviewed if serum
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creatinine levels increase to more than 1.5 mg/dL or eGFR decreases to less than 45 mL/min
per 1.73 m2 and that the drug be stopped with creatinine levels more than 1.7 mg/dL or
eGFRs less than 30 mL/min per 1.73 m2. The European Medicines Agency stipulates that
metformin is contraindicated with creatinine clearance less than 60 mL/min. 81 The Canadian
Diabetes Association allows for metformin use with creatinine clearance less than 60
mL/min but with a maximum dose of 1700 mg/d for patients with creatinine clearance of 60
to 90 mL/min and of 850 mg/d for patients with creatinine clearance of 30 to 60 mL/min.82
The 2012 American Diabetes Association–European Association for the Study of Diabetes
position statement on antihyperglycemic therapy in type 2 diabetes favors the eGFR-based
National Institute for Health and Care Excellence guidelines.1 The Kidney Disease
Outcomes Quality Initiative clinical practice guidelines recommend that metformin safety be
assessed in patients with stage 4 and stage 5 CKD.83
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There have been increasing calls to update the US metformin-prescribing guidelines to allow
for use of this agent in patients with mild to moderate CKD, 84-87 with 2 citizens’ petitions
being considered by the FDA.88,89
Controversial/Unresolved Issues, Areas for Future Research

There have been no randomized clinical trials to test the specific hypothesis that metformin
is safe in patients with mild to moderate CKD. Randomized trials would help to better

Inzucchi et al.
inform evidence-based guidelines. However, given the rarity of lactic acidosis in the setting
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of metformin therapy, a study would need to examine hundreds of thousands of patients for
many years to demonstrate non-inferiority compared with other agents, which is clearly
impractical. National patient registries might be a reasonable alternative. However, for
regulatory bodies at this time, the best available evidence is limited to meta-analyses,
retrospective studies, and smaller mechanistic investigations reported herein.
Recommendations
Our review supports consideration of a change to metformin’s prescribing guidelines, with
use allowed in patients with mild to moderate CKD. Table 2 proposes a possible strategy,
but it has not been evaluated or validated in a clinical trial. It should be noted that, while
generally increasing access to metformin for many, this strategy may actually make
treatment in some older individuals more complex, with certain subgroups (mainly nonblack
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women with eGFRs of 30-44 mL/min per 1.73 m2) requiring dosage reductions not currently
specified in the US label (eg, a white woman aged 61 years with a serum creatinine level of
1.3 mg/dL but an eGFR of 44 mL/min per 1.73 m2). Any new expansion of metformin use
in patients with mild to moderate CKD will need to be accompanied by appropriate dosage
reductions and careful follow-up assessments of kidney function.
Acknowledgments
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Dr Inzucchi reported serving as a consultant for Merck, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, and
Novo Nordisk; serving as a speaker for Merck; and receiving nonfinancial support from Takeda. Dr Lipska reported
receiving a grant from the National Institutes of Health and receiving a Yale Center for Clinical Investigation
Scholar Award and a Pepper Center Research Career Development Award. Dr Bailey reported serving as a
consultant for, and receiving honoraria and travel expenses from, AstraZeneca/Bristol-Myers Squibb, sanofi,
MerckSharp & Dohme, Takeda, Boehringer Ingelheim/Lilly, and Novo. Dr McGuire reported receiving personal
fees from Boehringer Ingelheim, Janssen Research and Development LLC, sanofi-aventis Groupe, Genentech,
Merck Sharp & Dohme, Medscape Cardiology, Pri-Med Institute, The Brigham and Women’s Hospital, Inc, Duke
ClinicalResearch Institute, The Cleveland Clinic Coordinating Center for Clinical Research, The University of Oxford,
Daiichi Sankyo, Lilly USA, Novo Nordisk, F. Hoffmann La Roche, Axio Research, INC Research LLC, GlaxoSmithKline,
Takeda Pharmaceuticals North America, Bristol-Myers Squibb, AstraZeneca, Orexigen, Lexicon, Eisai, and
Regeneron and receiving nonfinancial support from Gilead Sciences.
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Table 1
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Retrospective Studies Examining the Frequency of Metformin Use in Patients With Active Renal
Contraindications
Renal Contraindication
a
Definitio
Source No. Setting Frequency, No. (%) n Frequency of Lactic Acidosis
Kosmalski 335 Hospital 56 (16.7) eGFR <60 No cases
et al,62 2012
Vasisht et al,63 234 Outpatient 36 (15.4) eGFR <60 No cases

2010
Scotton 283 Hospital 17 (6.0) SCr >1.5 (men) Not reported

et al,31 2009 SCr >1.4 (women)
b
Kamber et 425 Outpatient 78 (8.4) eGFR <60 No
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al,64 2008 cases
Runge et al,65 92 Outpatient 4 (4.4) SCr ≥ 1.5 (men) Not reported

2008 SCr ≥ 1.3 (women)
Sweileh et 124 Outpatient 34 (27.4) Renal impairment Not reported

al,66 2007
Warren et al,67 11 297 Outpatient 880 (25.5) eGFR <60 Unknown

2007
Kennedy 4838 Outpatient 219 (4.5) eGFR <60 Not reported

et al,68 2005 290 (13.4) [men] SCr ≥1.5 (men)
362 (17.7) SCr ≥1.4 (women)
[women]
Millican 83 Hospital 12 (14.5) eGFR <50 or Not reported

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et al,69 2004 SCr >1.7
Horlen et al,70 22 Outpatient 8 (36.4) SCr ≥1.5 (men) Not reported

2002 SCr ≥1.4 (women)
Calabrese 263 Hospital 32 (12.2) SCr ≥1.5 (men) 3 cases (metformin could not
et al, 71 2002 SCr ≥1.4 (women) be ruled out as the cause)
Emslie-Smith 1347 Outpatient 63 (4.7) SCr ≥1.7 1 case, unrelated (extensive

et al,72 2001 myocardial infarction, renal
function previously normal)
Holstein 308 Hospital 59 (19.2) eGFR <60 No cases

et al,73 1999
Selby et al,74 9875 Outpatient 128 (1.3) SCr ≥1.5 1 case, likely unrelated (renal
1999 function normal)
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Sulkin et al,75 89 Outpatient 2 (2.3) SCr ≥1.4 Not reported

1997
Abbreviations: eGFR, estimated glomerular filtration rate; SCr, serum creatinine.
SI conversion factor: To convert serum creatinine values to µmol/L, multiply by 88.4.
a
Estimated glomerular filtration rate values reported in mL/min per 1.73 m2; serum creatinine values reported in mg/dL.

b
During study follow-up (1993 to 2001); authors reported 3 patients with metformin-associated lactic acidosis during extended follow-up via
data linkage through 2006, each of whom had at least 1 major comorbidity associated with lactic acidosis (estimated incidence similar to that of
patientsnot treated with metformin [P = .4]).
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Table 2
Possible Approach to Metformin Prescribing in the Setting of CKDa

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Maximal Total Daily Dose,

CKD Stage eGFR, mL/min per 1.73 m2 mg Other Recommendations
1 ≥90 2550
2 60 -<90 2550
3A 45 -<60 2000 Avoid if kidney function is or expected to become unstable

3B 30 -<45 1000 Do not initiate therapy at this stage but drug may be continued
4 15 -<30 Do not use

5 <15 Do not use
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Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate.
a
This strategy has not been evaluated or validated in a clinical trial; there are no data to support its efficacy, safety, or potential to improve clinicaloutcomes.
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HHS Public Access
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N Engl J Med. 2018 July 19; 379(3): 215–225. doi:10.1056/NEJMoa1800410.
Clopidogrel and Aspirin in Acute Ischemic Stroke and High-RiskTIA

S. Claiborne Johnston, M.D., Ph.D., J. Donald Easton, M.D., Mary Farrant, M.B.A., William
Barsan, M.D., Robin A. Conwit, M.D., Jordan J. Elm, Ph.D., Anthony S. Kim, M.D., Anne S.
Lindblad, Ph.D., Yuko Y. Palesch, Ph.D., and Clinical Research Collaboration, Neurological
Emergencies Treatment Trials Network, and the POINT Investigators*
Dean’s Office, Dell Medical School, University of Texas at Austin, Austin (S.C.J.); the Department
of Neurology, University of California, San Francisco, San Francisco (J.D.E., M.F., A.S.K.); the
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Department of Emergency Medicine, University of Michigan, Ann Arbor (W.B.); the Division of
Clinical Research, National Institute of Neurological Disorders and Stroke, Bethesda (R.A.C.),
and Emmes, Rockville (A.S.L.) – both in Maryland; and the Data Coordination Unit, Department
of Public Health Sciences, Medical University of South Carolina, Charleston (J.J.E., Y.Y.P.).
Abstract
BACKGROUND—Combination antiplatelet therapy with clopidogrel and aspirin may reduce the
rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient
ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has
shown a reduction in the risk of recurrent stroke. We tested this combination in an international
population.
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METHODS—In a randomized trial, we assigned patients with minor ischemic stroke or high-risk
TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per
day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone.
The dose of aspirin in each group was selected by the site investigator. The primary efficacy
outcome in a time-to-event analysis was the risk of a composite of major ischemic events, which
was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at
90 days.
RESULTS—A total of 4881 patients were enrolled at 269 international sites. The trial was halted
after 84% of the anticipated number of patients had been enrolled because the data and safety
monitoring board had determined that the combination of clopidogrel and aspirin was associated
with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin
alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving
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clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard
ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P = 0.02), with most events occurring
during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%)
*A complete list of the POINT Investigators is provided in the Supplementary Appendix, available at NEJM.org.
Address reprint requests to Dr. Johnston at Dell Medical School, University of Texas at Austin, 1501 Red River St., Austin, TX 78701, or
at clay.johnston@utexas.edu.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Johnston et al. Page 2
receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard
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ratio, 2.32; 95% CI, 1.10 to 4.87; P = 0.02).
CONCLUSIONS—In patients with minor ischemic stroke or high-risk TIA, those who received a
combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk
of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National
Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number,
NCT00991029.)
The risk of ischemic stroke ranges from 3 to 15% in the 90 days after a minor ischemic
stroke or a transient ischemic attack (TIA).1–5 In several trials, aspirin has been shown to
reduce the risk of recurrent stroke by approximately 20%. 6–10 Clopidogrel blocks platelet
aggregation through the P2Y12-receptor pathway, a mechanism that is synergistic with
aspirin in platelet-aggregation assays. The combination of the two drugs has been more
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effective than aspirin alone in reducing the risk of ischemic events in patients with acute
coronary syndromes.11
We conducted the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke
(POINT) trial to evaluate clopidogrel plus aspirin, as compared with aspirin alone, in an
international population of patients who had a minor ischemic stroke or TIA. The
Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events
(CHANCE) trial, which was initiated after the POINT trial and was completed before the
termination of the POINT trial, showed a 32% lower risk of stroke recurrence among
Chinese patients who were treated within 24 hours after a minor ischemic stroke or TIA with
a combination of clopidogrel and aspirin than among those who were treated with aspirin
alone, with no increase in the risk of hemorrhagic complications. 12 The restricted ethnic
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population and patterns of care in that trial limited the generalizability of the results, and the
combination of clopidogrel and aspirin has not been recommended routinely in guidelines
for the treatment of stroke.6,10
METHODS
TRIAL DESIGNS AND OVERSIGHT
We enrolled patients in this randomized, double-blind, placebo-controlled trial from May 28,
2010, to December 19, 2017, at 269 sites in 10 countries in North America, Europe,
Australia, and New Zealand, with the majority of the patients (82.8%) enrolled in the United
States. The trial was approved by the ethics committee at each participating site. The trial
protocol is available with the full text of this article at NEJM.org, as is the Supplementary
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Appendix, which provides lists of trial committees, sites, and investigators. Details regarding
the trial rationale, design, and methods have been described previously.13
An executive committee was responsible for the design, interpretation, and supervision of
the trial, including the development of the protocol and protocol amendments. The trial was
sponsored by the National Institute of Neurological Disorders and Stroke (NINDS). Sanofi
provided the clopidogrel and matching placebo for 75% of the patients enrolled in the trial
and provided comments on an earlier version of the manuscript. There was no other industry
involvement in the trial and no confidentiality agreement between the authors and Sanofi.
N Engl J Med. Author manuscript; available in PMC 2019 January 19.

The authors vouch for the accuracy and completeness of the data and reporting of adverse
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events and for the adherence of the trial to the protocol.
An independent data and safety monitoring board provided recommendations to NINDS and
guidance to the executive committee, along with monthly assessments of safety and study
conduct and oversight of the interim analyses. The members of an independent clinical-event
committee who were unaware of group assignments adjudicated primary and secondary
efficacy outcomes and major and minor bleeding events.
TRIAL POPULATION
Patients who were at least 18 years of age were enrolled if they could undergo
randomization within 12 hours after having an acute ischemic stroke with a score of 3 or less
on the National Institutes of Health Stroke Scale (NIHSS) (scores range from 0 to 42, with
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higher scores indicating greater stroke severity) or a high-risk TIA with a score of 4 or more
on the ABCD2 scale14 (which estimates the risk of recurrent stroke after a TIA on the basis
of age, blood pressure, clinical features, duration of symptoms, and presence of diabetes;
scores ranges from 0 to 7, with higher scores indicating a greater risk of stroke). They were
also required to undergo computed tomography or magnetic resonance imaging to rule out
intracranial bleeding or other conditions that could explain the neurologic symptoms or
detect any contraindications to a trial treatment. Patients with TIA and minor, nondisabling
ischemic stroke are generally not considered to be candidates for thrombolysis or
endovascular therapy.10 Additional details regarding the inclusion and exclusion criteria are
provided in the protocol.13
Patients were ineligible if the symptoms of the initial TIA were limited to isolated
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numbness, isolated visual changes, or isolated dizziness or vertigo or if they had received
any thrombolytic therapy within 1 week before the event. Patients were also ineligible if
they were candidates for thrombolysis, endovascular therapy, or endarterectomy; had
planned use of antiplatelet therapy or anticoagulation therapy (including those with
presumed atrial fibrillation or cardiovascular disease, in whom anticoagulation would be
indicated); had a contraindication to aspirin or clopidogrel; or had anticipated use of a
nonsteroidal antiinflammatory drug for more than 7 days during the trial period. Written
informed consent was required before the performance of any trial procedure.
TRIAL TREAMENTS
Patients were randomly assigned in a 1:1 ratio to receive either clopidogrel plus aspirin or
placebo plus aspirin, with stratification according to trial site, with the use of an interactive
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Web-based system. Patients in the group receiving clopidogrel plus aspirin were given a
600-mg loading dose of clopidogrel, followed by 75 mg per day from day 2 to day 90, and a
dose of open-label aspirin that ranged from 50 mg to 325 mg per day. Patients in the aspirin-
only group received placebo that matched the appearance and taste of the clopidogrel tablets
and the same range of aspirin doses. In the two groups, the dose of aspirin was selected by
the treating physician. A dose of 162 mg daily for 5 days followed by 81 mg daily was
recommended, consistent with guidelines.6,10 The first dose of trial medication was to be

given as soon after randomization as possible. Patients were to be followed for 90 days (with
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a window of ±14 days) after randomization.
OUTCOME
S
The primary outcome was the risk of a composite of ischemic stroke, myocardial infarction,
or death from ischemic vascular causes (major ischemic events) on the basis of standard
definitions.13 The primary safety outcome was the risk of major hemorrhage, which was
defined as symptomatic intracranial hemorrhage, intraocular bleeding causing vision loss,
transfusion of 2 or more units of red cells or an equivalent amount of whole blood,
hospitalization or prolongation of an existing hospitalization, or death due to hemorrhage.
15,16
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Key secondary efficacy end points were each component of the primary efficacy outcome, a
composite of the primary efficacy outcome and major hemorrhage, and the total number of
ischemic and hemorrhagic strokes. Secondary safety outcomes included hemorrhagic stroke,
symptomatic intracerebral hemorrhage, other symptomatic intracranial hemorrhage, major
hemorrhage other than intracranial hemorrhage, minor hemorrhage that included
asymptomatic intracranial hemorrhage, and death from any cause. 13 Additional prespecified
secondary and tertiary outcomes are provided in the statistical analysis plan in the
Supplementary Appendix.
STASTISTICAL ANALYSIS
We determined that a sample of 4150 patients would provide the trial with a power of 90%
to detect a hazard ratio of 0.75 with a two-sided alpha level of 0.05 on the basis of an event
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rate of 15% in the aspirin-only group. The sample was inflated to account for two interim
analyses of the primary efficacy outcome with the use of an O’Brien–Fleming spending
function. The spending-function approach allowed for additional efficacy interim analyses to
be conducted at the request of the data and safety monitoring board while maintaining the
type I error rate. On the basis of the observed event rate in the aspirin-only group at the first
interim analysis, the sample was increased to 5840 patients to provide the trial with a power
of 80% with other variables remaining unchanged in the calculation.
We performed the analyses according to the intention-to-treat principle, using adjudicated

outcomes and data from all the patients who had undergone randomization. Data for patients
who did not have a 90-day assessment were censored on the 7-day assessment date, on the
date of an event, or on the date of death, whichever came later. We performed a secondary,
as-treated analysis of the primary outcome that included patients who had received at least
Author Manuscript
one dose of a trial regimen, with data censored 1 day after permanent discontinuation of trial
medication.
We used the log-rank test to compare the time from randomization to the first occurrence of
any given end point and a Cox proportionalhazards model to estimate the hazard ratio and
95% confidence intervals. There was no adjustment for baseline covariates or for the aspirin
dose in the primary efficacy or safety analyses. Interactions between treatment assignment
and prespecified subgroups were evaluated in the Cox model. A P value for interaction of
less than 0.05 was considered to indicate statistical significance. We used a Cox model
stratified according to time point to perform a secondary analysis of the primary efficacy and
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primary safety outcomes comparing the treatment effect during four time periods: days 0 to
7 versus days 8 to 90 and days 0 to 30 versus days 31 to 90. Secondary efficacy outcome
analyses were not adjusted for multiple comparisons and are considered to be exploratory. A
post hoc Bonferroni calculation was made for reference purposes to derive an adjusted
threshold for P values to account for multiple comparisons of secondary outcomes.
RESULTS
Trial Discontinuation
In August 2017, the prespecified boundary for a safety signal of major hemorrhage was
exceeded. Because of the small number of patients with hemorrhage, it was decided to
follow these events until a planned meeting of the data and safety monitoring board in
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December 2017. At that meeting, the board recommended halting enrollment to the trial
because of confirmation of a significant excess in the number of patients with major
hemorrhage in the combined antiplatelet group, and a planned analysis determined that a
treatment effect had crossed the significance boundary for efficacy. A summary of the
board’s decision to halt the trial early is provided in the Supplementary Appendix.
PATIENTS
At the time that the trial was halted, 4881 patients had been enrolled, which represented
83.6% of the anticipated number of patients. Of these patients, 4782 (98.0%) had been
followed for at least 7 days, and 4557 (93.4%) had completed the 90-day trial visit or had
died (Fig. 1). Discontinuation of a trial medication occurred in 29.6% of the patients in the
group receiving clopidogrel plus aspirin and in 27.5% of those receiving aspirin alone; rates
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of withdrawal from the trial or loss to follow-up were 6.4% in the group receiving
clopidogrel plus aspirin and 6.8% in the aspirin group. There were no significant differences
in the baseline characteristics between the two groups (Table 1, and Table S5 in the
Supplementary Appendix).
Primary and Secondary Efficacy Outcomes

The composite primary efficacy outcome occurred in 121 patients (5.0%) receiving
clopidogrel plus aspirin and in 160 patients (6.5%) receiving aspirin alone (hazard ratio,
0.75; 95% confidence interval [CI], 0.59 to 0.95; P = 0.02) (Table 2 and Fig. 2A). The
secondary outcome of ischemic stroke occurred in 112 patients (4.6%) receiving clopidogrel
plus aspirin and in 155 patients (6.3%) receiving aspirin alone (hazard ratio, 0.72; 95% CI,
0.56 to 0.92; P = 0.01). Except for stroke, there were no significant differences between
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treatment groups in the other components of the composite primary efficacy outcome (Table
2). The risk of total ischemic or hemorrhagic stroke was lower with clopidogrel plus aspirin
than with aspirin alone (hazard ratio, 0.74; 95% CI, 0.58 to 0.94; P = 0.01). A post hoc
Bonferroni-corrected P value that incorporates five main secondary outcome comparisons is
shown in Table 2 for reference.
There were no significant treatment-by-subgroup interactions in prespecified subgroups, but

the number of patients with available data for analysis limited the power to determine

interactions (Fig. 3). There was no difference in treatment effect according to the
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predominant daily aspirin dose received during the trial period.
The proportional-hazard assumption of the treatment effect over a period of 90 days did not
hold for the primary efficacy outcome. In a secondary analysis of the treatment effect
according to time period, the benefit of clopidogrel plus aspirin was greater in the first 7
days and in the first 30 days than at 90 days (P = 0.04 for days 0 to 7 and P = 0.02 for days 0
to 30), whereas the risk of hemorrhage with clopidogrel plus aspirin versus aspirin alone was
greater during the period from 8 to 90 days than during the first 7 days (P = 0.04 for days 8
to 90 and P = 0.34 for days 0 to 7) (Table S4 in the Supplementary Appendix).
The outcome of ischemic stroke, myocardial infarction, death from ischemic vascular
causes, or major hemorrhage occurred in 141 patients (5.8%) receiving clopidogrel plus
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aspirin and in 167 patients (6.8%) receiving aspirin alone (hazard ratio, 0.84; 95% CI, 0.67
to 1.05; P = 0.13). Additional secondary and tertiary analyses are shown in Table S6 in the
PRIMARY AND SECONDARY SAFETY OUTCOMES

The primary safety outcome of major hemorrhage occurred in 23 of 2432 patients (0.9%)
receiving clopidogrel plus aspirin and in 10 of 2449 patients (0.4%) receiving aspirin alone
(hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P = 0.02) (Table 2 and Fig. 2B). In analyses of
secondary safety outcomes, there were no significant differences between groups in the rates
of hemorrhagic stroke, symptomatic intracerebral hemorrhage, or other symptomatic
intracranial hemorrhage considered separately (Table 2). Death from hemorrhagic vascular
causes occurred in 3 patients receiving clopidogrel plus aspirin and in 2 patients receiving
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aspirin alone (0.1% in each group). Nonfatal, nonintracranial hemorrhage accounted for
most of the major hemorrhages (16 in patients receiving clopidogrel plus aspirin and 7 in
those receiving aspirin alone). Minor hemorrhage occurred in 40 patients (1.6%) receiving
clopidogrel plus aspirin and in 13 (0.5%) receiving aspirin alone (hazard ratio, 3.12; 95% CI,
1.67 to 5.83; P = 0.002).
Serious adverse events other than components of the primary efficacy outcome were similar
in the two groups, except that more patients receiving clopidogrel plus aspirin had events
included in the Medical Dictionary for Regulatory Activities, version 15, coding designation
―general disorders and administration-site conditions‖ (e.g., fever, fatigue, and edema) than
those receiving aspirin alone (19 vs. 5, P = 0.004) (Tables S1 and S2 in the Supplementary
Appendix). Reasons for early discontinuation of a trial drug are provided in Table S3 in the
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AS-TREATED ANALYSES
In the as-treated analysis, major ischemic events occurred in 102 of 2398 patients (4.3%)
treated with clopidogrel plus aspirin and in 141 of 2421 patients (5.8%) treated with aspirin
alone (hazard ratio, 0.73; 95% CI, 0.56 to 0.94; P = 0.01). Major hemorrhage occurred in 21
patients (0.9%) treated with clopidogrel plus aspirin and in 6 patients (0.2%) treated with
aspirin alone (hazard ratio, 3.57; 95% CI, 1.44 to 8.85; P = 0.003). Data regarding outcomes

and adverse events in the as-treated population are provided in Tables S2 and S6 in the
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DISSCUSSION
In this international, multicenter, randomized trial, we found that patients with minor
ischemic stroke or high-risk TIA who received a combination of clopidogrel and aspirin had
a lower risk of major ischemic events but a higher risk of major and minor hemorrhage than
did those receiving aspirin alone. Ischemic stroke accounted for most of the composite
events of the primary efficacy outcome, and the effect of dual antiplatelet treatment was
attributable to a reduction in the rate of these strokes. It is not possible to make direct
comparisons between clinical and safety outcomes because disability due to each of the
outcomes cannot be ascertained, but we estimate that for every 1000 patients who are treated
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with clopidogrel plus aspirin during a period of 90 days, such treatment would prevent
approximately 15 ischemic events and would cause 5 major hemorrhages.
The results of our trial broaden the results of the CHANCE trial involving Chinese patients
to more diverse populations and care settings.12 In the CHANCE trial, there was a rate of
moderate-to-severe bleeding of 0.3% in both the combined-antiplatelet group and the aspirin
group. The results in the two trials apply to patients with stroke who were not appropriate
candidates for anticoagulation, which thereby excluded those with stroke caused by
presumed cardioembolism and those who were not candidates for treatment by intravenous
thrombolysis or endovascular thrombectomy because their strokes were too mild to justify
the use of these two treatments. The CHANCE trial tested a different combination of
clopidogrel and aspirin than was used in our trial (two medications combined for the first 21
days, followed by clopidogrel alone with an initial loading dose of 300 mg, as compared
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with 600 mg of clopidogrel, followed by 75 mg per day, for the duration of our trial). 12 The
smaller loading dose or limited duration of combined clopidogrel plus aspirin may have
reduced the risk of hemorrhage in the CHANCE trial, a hypothesis that is consistent with
our finding that the benefit of clopidogrel plus aspirin was concentrated in the first month of
the trial, whereas the risk of hemorrhage remained relatively constant throughout the trial. In
addition, polymorphisms in the gene encoding CYP2C19 that are associated with
incomplete metabolism of clopidogrel into its active form are common among persons of
Asian ancestry.17
The international SOCRATES (Acute Stroke or Transient Ischemic Attack Treated with
Aspirin or Ticagrelor and Patient Outcomes) trial compared ticagrelor, a P2Y 12 inhibitor,
with aspirin in an international population and found no between-group difference in the risk
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of major vascular events.18 The combination of ticagrelor and aspirin is being tested in the
THALES (Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and ASA
[acetylsalicylic acid] for Prevention of Stroke and Death) trial (ClinicalTrials .gov number,
NCT03354429). Blockade of platelet activity beyond what is achieved by clopidogrel and
aspirin may lead to excess hemorrhage. In the TARDIS (Triple Antiplatelets for Reducing
Dependency after Ischemic Stroke) trial, investigators compared a combination of
clopidogrel, aspirin, and dipyridamole with either clopidogrel alone or aspirin plus
dipyridamole administered within 48 hours after the onset of ischemic stroke or TIA.19 They

found that patients who received the triple combination had no benefit with regard to the
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incidence and severity of recurrent stroke but had a higher rate of hemorrhage than those
who received fewer medications.
Our trial has limitations. Patients with moderate-to-severe stroke, those with cardioembolic
stroke, and those who are candidates for thrombolysis or thrombectomy were not
represented in the trial, so results cannot be generalized to these groups. Entry criteria also
resulted in a limited number of patients with symptomatic carotid atherosclerosis, a group
that may benefit from platelet inhibition.20 A trial drug was discontinued permanently in
29% of the patients before trial follow-up was complete. However, rates of discontinuation
were similar in the two treatment groups, and reasons for discontinuation were similar.
Furthermore, most outcome events occurred early, before the majority of the
discontinuations had occurred, and results in an as-treated analysis were similar to those in
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the intentionto-treat analysis. The overall event rates in our trial were lower than expected,
1–4 particularly among the patients in the TIA group who had low ABCD 2 scores, which
suggests that some patients may not have had a TIA and would have been unlikely to benefit
from treatment. The aspirin dose varied in the two treatment groups, which reflected the
clinical practices of local investigators; however, in a potentially underpowered analysis, no
difference in treatment effect was shown across aspirin doses.
In conclusion, in patients from diverse countries with minor ischemic stroke or high-risk
TIA, those who received a combination of clopidogrel and aspirin had a lower risk of a
composite of ischemic stroke, myocardial infarction, or death from ischemic vascular causes
but had a higher risk of major hemorrhage than patients who received aspirin alone during
the 90-day trial period.
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Acknowledgments
Supported by grants (U01 NS062835, U01 NS056975, and U01 NS059041) from the National Institute of
Neurological Disorders and Stroke. Sanofi provided clopidogrel and placebo for 75% of the patients in the trial.
Dr. Johnston reports receiving grant support from AstraZeneca; Dr. Easton, receiving grant support from
AstraZeneca and consulting fees from Boehringer Ingelheim; Ms. Farrant, receiving grant support from
AstraZeneca; and Dr. Kim, receiving grant support from SanBio and fees for serving as a member of a data and
safety monitoring board from Neuravi. No other potential conflict of interest relevant to this article was
Author Manuscript
reported.
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diagnosis of transient ischemic attack. JAMA 2000;2 84: 2901–6.
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ischaemic attack or minor stroke: implications for public education and organisation of services.
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3. Giles MF, Rothwell PM. Risk of stroke early after transient ischaemic attack: a systematic review
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4. Wu CM, McLaughlin K, Lorenzetti DL, Hill MD, Manns BJ, Ghali WA. Early risk of stroke after
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5. Amarenco P, Lavallee PC, Labreuche J, et al. One-year risk of stroke and major cardiovascular
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6. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with
stroke and transient ischemic attack: a guideline for healthcare professionals from the American
Heart Association/American Stroke Association. Stroke 2014; 45:2 160–236.
7. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of
antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
BMJ 2002; 324: 71–86. [PubMed: 11786451]
8. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-controlled
trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet 1997; 349: 1641–9.
[PubMed: 9186381]
9. International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised
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trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic
stroke. Lancet 1997; 349:1 569–81.
10. Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the early management of
patients with acute ischemic stroke: a guideline for healthcare professionals from the American
Heart Association/American Stroke Association. Stroke 2018; 49(3):e46–e110. [PubMed:
29367334]
11. Bowry AD, Brookhart MA, Choudhry NK. Meta-analysis of the efficacy and safety of clopidogrel
plus aspirin as compared to antiplatelet monotherapy for the prevention of vascular events. Am J
Cardiol 2008; 101: 960–6. [PubMed: 18359315]
12. Wang Y, Wang Y, Zhao X, et al. Clopi-dogrel with aspirin in acute minor stroke or transient
ischemic attack. N Engl J Med 2013; 369:1 1–9. [PubMed: 23782160]
13. Johnston SC, Easton JD, Farrant M, et al. Platelet-Oriented Inhibition in New TIA and Minor
Ischemic Stroke (POINT) trial: rationale and design. Int J Stroke 2013;8 : 479–83. [PubMed:
23879752]
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14. Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and refinement of scores to
predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369:2 83–92.
15. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and
Standardization Committee of the International Society on Thrombosis and Haemostasis.
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nonsurgical patients. J Thromb Haemost 2005; 3: 692–4. [PubMed: 15842354]
16. Diener HC, Sacco RL, Yusuf S, et al. Effects of aspirin plus extended-release dipyridamole versus
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with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes
(PRoFESS) trial: a double-blind, active and placebo-controlled study. Lancet Neurol 2008; 7:8 75–
84.
17. Wang Y, Zhao X, Lin J, et al. Associa-tion between CYP2C19 loss-of-function allele status and
efficacy of clopidogrel for risk reduction among patients with minor stroke or transient ischemic
attack. JAMA 2016; 316:7 0–8.
18. Johnston SC, Amarenco P, Albers GW, et al. Ticagrelor versus aspirin in acute stroke or transient
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ischemic attack. N Engl J Med 2016; 375: 35–43. [PubMed: 27160892]

19. Bath PM, Woodhouse LJ, Appleton JP, et al. Antiplatelet therapy with aspirin, clopidogrel, and
dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral
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20. Amarenco P, Albers GW, Denison H, et al. Efficacy and safety of ticagrelor versus aspirin in acute
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Figure 1. Enrollment and Outcomes (Intention-to-Treat Analysis).
Patients who discontinued a trial drug were included in the intention-to-treat analysis, as
were patients who withdrew consent or were lost to follow-up. In the as-treated analysis,
data for patients who received a trial drug were censored at the time of discontinuation.
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Figure 2. Primary Efficacy and Safety Outcomes.
Shown are the percentages of patients with the primary efficacy outcome (a composite of
ischemic stroke, myocardial infarction, or death from ischemic vascular causes) (Panel A)
and the primary safety outcome of major hemorrhage (Panel B). Inset graphs show the same
data on an expanded y axis.

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Figure 3. Primary Efficacy Outcome, According to Predefined Subgroup.
Race was determined by the investigator. Among patients with ischemic stroke, the
qualifying score for participation in the trial was 3 or less on the National Institutes of
Health Stroke Scale (NIHSS), which ranges from 0 to 42, with higher scores indicating
greater stroke severity. The NIHSS score was missing at baseline for 23 patients, and 6
patients had an NIHSS score above 3 and were excluded from the subgroup analysis of
NIHSS score (score of 0 or 1 vs. score of 2 or 3). Among patients with transient ischemic
attack (TIA), the qualifying score was 4 or more on the ABCD2 scale, which is used to

estimate the risk of recurrent stroke on the basis of age, blood pressure, clinical features,
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duration of symptoms, and presence of diabetes, with scores ranging from 0 to 7, with
higher scores indicating a greater risk of stroke. CT denotes computed tomography, and MRI
magnetic resonance imaging.
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Table 1.
Characteristics of the Patients at Baseline.*
Johnston et
Characteristic Clopidogrel plus Aspirin (N = 2432) Aspirin (N = 2449)
Median age (IQR) — yr 65.0 (55.0–74.0) 65.0 (56.0–74.0)
Female sex — no. (%) 1097 (45.1) 1098 (44.8)
Race — no./total no. (%)†
White 1774/2360 (75.2) 1781/2378 (74.9)

Black 473/2360 (20.0) 493/2378 (20.7)

Asian 77/2360 (3.3) 67/2378 (2.8)
Other 36/2360 (1.5) 37/2378 (1.6)
Hispanic ethnic group — no./total no. (%)† 144/2320 (6.2) 146/2328 (6.3)
Region — no. (%)

United States 2014 (82.8) 2029 (82.9)
Other countries 418 (17.2) 420 (17.1)
Medical history — no./total no. (%)
Ischemic heart disease 257/2426 (10.6) 240/2443 (9.8)
Hypertension 1693/2423 (69.9) 1680/2437 (68.9)
Diabetes mellitus 678/2425 (28.0) 662/2447 (27.1)
Medication use at presentation — no. (%)
Aspirin 1417 (58.3) 1397 (57.0)
Clopidogrel 48 (2.0) 42 (1.7)
Time from presentation to randomization
Mean time (±SD) — hr 7.4±3.0 7.3±2.9
Interval — no./total no. (%)
<6 hr 755/2431 (31.1) 789/2449 (32.2)
≥6 hr 1676/2431 (68.9) 1660/2449 (67.8)
Qualifying event — no. (%)
TIA 1056 (43.4) 1052 (43.0)
Ischemic stroke 1376 (56.6) 1397 (57.0)
Median qualifying neurologic score (IQR)
Page 14
ABCD2 for TIA‡ 5.0 (4.0–6.0) 5.0 (4.0–5.0)
Characteristic Clopidogrel plus Aspirin (N = 2432) Aspirin (N = 2449)
2.0 (1.0–2.0) 2.0 (1.0–2.0)
Johnston et
§
*
There were no significant differences in baseline characteristics between the two groups. IQR denotes interquartile range, and TIA transient ischemic attack.
†
Race or ethnic group was determined by the investigator. Hispanic ethnic group was assessed only in patients in the United States; the denominator excludes 233 patients for whom Hispanic status was
unknown.
‡
Among patients with TIA, the qualifying score was 4 or more on the ABCD 2scale, which ranges from 0 to 7, with higher scores indicating a greater risk of stroke. The scale is used to estimate the risk of
recurrent stroke after a TIA on the basis of age, blood pressure, clinical features, duration of symptoms, and presence of diabetes. Scores were available for 2104 of the 2108 patients with TIA (1055
patientsin the clopidogrel group and 1049 in the aspirin group).
§
A mong patients with ischemic stroke, the qualifying score was 3 or less on the National Institutes of Health Stroke Scale (NIHSS), which ranges from 0 to 42, with higher scores indicating a greater stroke
severity. Scores were available for 2750 of the 2773 patients with ischemic stroke (1365 patients in the clopidogrel group and 1385 in the aspirin group).
Page 15
Table 2.
Efficacy and Safety Outcomes.

Diabetes Ther (2015) 6:627–634
Outcome Clopidogrel plus Aspirin (N = Aspirin (N = 24

2432)
number (percent)
Primary efficacy outcome
Composite of ischemic stroke, myocardial infarction, or death from ischemic vascular causes 121 (5.0) 160 (6.5)
Secondary efficacy outcomes
Ischemic stroke 112 (4.6) 155 (6.3)
Myocardial infarction 10 (0.4) 7 (0.3)

Death from ischemic vascular causes 6 (0.2) 4 (0.2)
Ischemic or hemorrhagic stroke 116 (4.8) 156 (6.4)
Composite of ischemic stroke, myocardial infarction, death from ischemic vascular causes, or major 141 (5.8) 167 (6.8)
hemorrhage
Primary safety outcome
Major hemorrhage 23 (0.9) 10 (0.4)
Other safety outcomes
Hemorrhagic stroke 5 (0.2) 3 (0.1)
Symptomatic intracerebral hemorrhage 2 (0.1) 2 (0.1)

Other symptomatic intracranial hemorrhage 2 (0.1) 0
Major hemorrhage other than intracranial hemorrhage 17 (0.7) 7 (0.3)
Minor hemorrhage 40 (1.6) 13 (0.5)
Death from any cause 18 (0.7) 12 (0.5)
*
Post hoc correction for multiple testing of five secondary end points by the Bonferroni method resulted in a P value of 0.01 to indicate a significant difference
between groups.
DOI 10.1007/s13300-015-0133-z
BRIEF REPORT
Characterization of Sitagliptin Use in Patients with Type

2 Diabetes and Chronic Kidney Diseaseby Cross-
Sectional Analysis of a Medical InsuranceClaims
Database
Kimberly G. Brodovicz . Yong Chen . Zhiwen Liu .
Mary E. Ritchey . Jane Liao . Samuel S. Engel
To view enhanced content go to www.diabetestherapy-open.com

Received: January 29, 2015 / Published online: October 5, 2015
© The Author(s) 2015. This article is published with open access at Springerlink.com
ABSTRACT Boehringer Ingelheim Pharmaceuticals, Inc.,Ridgefield, CT,

USA
Introduction: Chronic kidney disease (CKD) is
common in patients with type 2 diabetes Present Address:
(T2DM) and makes them particularly M. E. Ritchey
susceptible to safety/tolerability issues related
to many classes of oral antihyperglycemic Procter & Gamble, Cincinnati, OH, USA
agents (OAHA). Dipeptidyl peptidase-4
inhibitors (DPP-4is) like sitagliptin are
generally well tolerated in patients with T2DM
and renal disease and therefore may be
preferentially used in patients with CKD. To
assess the extent of this preference, the
characteristics of sitagliptin users with
T2DM
Electronic supplementary material The online

version of this article (doi:10.1007/s13300-015-0133-z)
contains supplementary material, which is available to
authorized users.
K. G. Brodovicz · Y. Chen · Z. Liu · M. E. Ritchey ·
J. Liao · S. S. Engel (&)
Merck, Kenilworth, NJ, USA
e-mail: samuel_engel@merck.com
Present Address:
K. G. Brodovicz
and CKD were compared with those of
other (non-DPP-4i) OAHA users with
T2DM and CKD. Methods: Patients with
T2DM and CKD with claims between 2006
and 2012 were identified from a United
States insurance claims database. Patients
starting sitagliptin or another OAHA as
mono, dual, or triple therapy were
compared. Demographic and clinical
characteristics within 5 years before starting
or escalating to new therapies were
assessed.
Results: Compared to patients with CKD
starting other OAHAs, patients with CKD
starting sitagliptin as mono or dual therapy
were older, had more physician visits, were
more likely to have a history of heart failure
and to use loop diuretics. In triple therapy
patients, the differences between groups
were not as pronounced, but the overall
prevalences of comorbidities was higher.
Conclusion: Similar to prior observations in
a general T2DM population, patients with
T2DM and CKD prescribed sitagliptin tend
to be older and have more comorbidities
than those prescribed other classes of
OAHA. If not recognized and analyzed
appropriately, this channeling could lead
to biased treatment
effect estimates in comparative analyses that (channeling bias) could lead to inaccurate
include users of sitagliptin. treatment effect estimates in comparative
Funding: Merck & Co., Inc., Kenilworth, NJ, analyses that include sitagliptin [8]. The
USA. objective of this study was to describe the
baseline characteristics of patients with T2DM
Keywords: Channeling bias; Chronic kidney and CKD initiating treatment with sitagliptin or
disease; Observational study; non-DPP-4i OAHAs to ascertain whether
Oralantihyperglycemic agents; channeling exists in this patient population.
Treatment outcomes;
Type 2 diabetes METHODS
INTRODUCTION The Truven Health MarketScan ® Databases

(MarketScan, Truven Health Analytics, Ann
Chronic kidney disease (CKD) is a common Arbor, MI, USA) contain medical claims
condition in patients with type 2 diabetes records for more than 150 million unique
(T2DM). An estimated 20–35% of patients patients dating from 1996. The records are
with T2DM have moderate to severe renal derived from outpatient and inpatient insurance
impairment [1, 2]. However, many claims for employees of over 100 employers
antihyperglycemic medications are participating in more than 12 health plans, and
contraindicated or need to be used with caution their beneficiaries in the United States. Records
in patients with CKD, complicating T2DM consist of commercial claims and healthcare
treatment choices and management [3]. Patients encounters, including information on
with T2DM and CKD are particularly demographics, health plan membership,
susceptible to safety and tolerability issues International Classification of Diseases, Ninth
related to many classes of oral Revision, Clinical Modification (ICD-9-CM)
antihyperglycemic agents (OAHA). Dipeptidyl codes, and Current Procedure Terminology
peptidase-4 inhibitors (DPP-4i) such as (CPT) codes. The records of retirees with
sitagliptin are well tolerated in a broad range supplemental insurance are included in the
of T2DM patient types, including those with database thus providing data on the elderly
renal disease, and may therefore be with continuity of care across those \65 and
preferentially used in patients with CKD. Prior C65 years of age.
studies have demonstrated the preferential useof Patients C25 years of age with T2DM and
sitagliptin in several populations [4–7]. In CKD, with claims in the United States (US)
general, patients initiating treatment with between January 2006 and June 2012, were
sitagliptin were older and had more identified in MarketScan. Of these patients,
complications of diabetes and comorbidities those initiating sitagliptin or a non-DPP-4i
than patients initiating other OAHA were categorized by complexity of
antihyperglycemic therapies [4–7]. If not antihyperglycemic treatment.
recognized and appropriately considered in the Patients were identified as having T2DM if
analysis, this preferential selection of patients MarketScan records for the patient indicated at
with specific demographic and disease least one inpatient or outpatient diagnosis of
characteristics for treatment with sitagliptin
Diabetes Ther (2015) 6:627–634 629
diabetes and at least one prescription for OAHA complications, cancers, and cardiovascular
medication. (CV), metabolic, gastrointestinal, hepatic,
Patients with CKD were identified by infectious, psychiatric, pulmonary, and
ICD-9-CM diagnostic codes (585, 585.3, neurological events. Types of health care
585.4, resource utilization recorded in the database
585.5, 585.6, 585.9, 403, 403.0, 403.00, 403.01, included physician and emergency department
403.1, 403.10, 403.11, 403.9, 403.90, 403.91, visits, hospitalizations, days hospitalized, and
250.4, 404, 404.0, 404.00, 404.01, 404.02, number of medications received.
404.03, 404.1, 404.10, 404.11, 404.12, 404.13, Differences between sitagliptin and non-DPP-
404.9, 404.90, 404.91, 404.92, 404.93, 582, 4i OAHA treatment groups were compared using
582.0, 582.1, 582.2, 582.4, 582.8, 582.81, absolute standardized differences (ASD) [9]. ASD
582.89, 582.9). is the difference of two means or proportions
Antihyperglycemic treatment was defined as: divided by the pooled estimate of the standard
(1) initiating monotherapy (C1 new outpatient deviation. Unlike thetraditional p value, ASD is a
prescription record on or after the T2DM measure of difference that is not influenced by
diagnosis); (2) escalating to dual combination large sample sizes and has been demonstrated
therapy (C1 new prescription for a 2nd class to be a better measure of covariate balance [10,
C90 days after the 1st class, with prescription 12]. An ASD of at least 10% was used to indicate
for 1st class overlapping the index date of 2nd a meaningful difference between treatment
class); (3) escalating to triple combination groups [12].
therapy (C1 new prescription for a 3rd class This article does not contain any new studies
C90 days after the 2nd class, with prescriptions with human or animal subjects performed by
for 1st and 2nd classes overlapping the index any of the authors.
date of 3rd class).
Patients were required to have at least 1 year RESULTS
of continuous enrollment in the database prior
to initiation/escalation of antihyperglycemic A total of 35,922 patients with T2DM and CKD
treatment. Patients were excluded from the were identified as meeting the inclusion criteria.
analysis if they had a diagnosis of type 1 Over 45% of patients (46.7%; n = 16,742)
diabetes, ketoacidosis, malnutrition-associated initiated sitagliptin (n = 1234) or a non-DPP-4i
diabetes, drug-induced diabetes or gestational OAHA monotherapy (n = 15,508), 40.5%
diabetes without a subsequent T2DM diagnosis (n = 14,540) initiated an escalation to dual
code. Patients with ICD-9-CM codes explicit combination therapy (sitagliptin, n = 2683;
for mild renal disease (stage 1 and 2) and OAHA, n = 11,857), and 12.9% (n =
patients on insulin or other injectable therapy 4640)
were alsoexcluded from the analysis. initiated an escalation to triple combination
Demographics, and clinical conditions and therapy (sitagliptin, n = 1385;
health care resource utilization recorded up to5 OAHA, n = 3255). Roughly, 15% of patients
years before therapy initiation were assessed as with T2DM and CKD (14.8%; n = 5302)
baseline characteristics. Over 70 clinical initiated treatment with sitagliptin. In
conditions and comorbidities may have been comparison, in the patients excluded from this
recorded in the database, including diabetes analysis due to a
Diabetes Ther (2015) 6:627–634 630
lack of recorded CKD, the percentage of patients DISCUSSION

initiating sitagliptin was 7.4%.
The greatest differences between treatment In this study of patients with T2DM from an
groups were observed in patients initiating employee-based insurance database, sitagliptin
monotherapy or an escalation to dual was initiated in a higher percentage of patients
combination therapy. Compared to patients with T2DM and CKD (14.8%) compared to
initiating monotherapy with non-DPP-4i patients with T2DM but no record of CKD
OAHAs, patients initiating monotherapy with (7.4%). Unlike many other OAHAs, sitagliptin
sitagliptin were older (mean [standard deviation is approved for patients with any stage of renal
(SD)]: sitagliptin 68.8 [12.5] years, non-DPP- disease [11]. In light of this and its favorable
4i renal safety profile [12–15], the higher use of
66.6 [12.8] years; ASD 17%), were more likely sitagliptin in patients with CKD observed in the
to have a history of heart failure (Fig. 1a; current analysis is not surprising.
sitagliptin 23.0%, non-DPP-4i 18.6%; ASD In general, patients with T2DM and CKD
11%) or arrhythmia (Fig. 1a; sitagliptin 37.7%, whoinitiated treatment with sitagliptin tended to
non-DPP-4i 31.7%; ASD 13%), were more be older and were more likely to have a pre-
likely to use loop diuretics (Fig. 1a; sitagliptin treatment history of heart failure, arrhythmia, or
44.2%, non-DPP-4i 38.0%; ASD 13%) or beta- use of loop diuretics or beta-blockers than
blockers (Fig. 1a; sitagliptin 66.3%, non-DPP- patients initiating otherclasses of OAHA. In this
4i 61.3%; ASD 11%), and had more context, it is worth noting the results of a large,
physician visits (Fig. 1b; mean [SD]: sitagliptin recently completed clinical trial examining
73.2 [57.6] physician visits, non-DPP-4i 66.3 the effects of adding sitagliptin to usual care
[55.4] physician visits; ASD 12%). The in patients with T2DM and CV disease [16]. In
differences between treatment groups (non- the overall study population, no difference in
DPP-4i OAHA users versus sitagliptin users) CV event rates compared with placebo was
observed in patients initiating an escalation to observed (hazard ratio [HR] for the primary
dual therapy were similar to those observed in composite CV outcome was 0.98; 95%
patients initiating monotherapy, with the confidence interval
exception that the between-group agedifference (CI): 0.88, 1.09; p\0.001 for
was not as great (mean [SD]: sitagliptin noninferiority) [16]. Additionally, in patient
71.1 [11.1] years, non-DPP-4i subgroups evaluated by renal function, no
70.0 [11.0] years; ASD 10%) and the differences difference in CV risk was noted for patients
for history of arrhythmia and use of beta-blockers with CKD [estimated glomerular filtration
were not meaningful (Fig. 1c, d). rate (eGFR)
In patients initiating an escalation to triple \60 mL/min/1.73 m2; HR = 0.92; 95% CI:
0.78,
combination therapy, the differences between
1.10) or those without CKD (eGFR C60
treatment groups (non-DPP-4i OAHA users
versus sitagliptin users) were not as pronounced mL/min/ 1.73 m2; HR = 1.00; 95% CI: 0.89,
as those seen in patients initiating monotherapy 1.13) [16].
or escalation to dual therapy, including the The most pronounced differences in baseline
between-group age difference (mean [SD]: characteristics between the treatment groups
sitagliptin 68.9 [10.9] years, non-DPP-4i were observed between patients initiating
68.4 [10.5] years; ASD 5%; Fig. 1e, f). monotherapy. As treatment complexity
increased, the differences in baseline
characteristics between treatment groups
Diabetes Ther (2015) 6:627–634 631
Fig. 1 Baseline characteristics of patients with type 2 groups. For any between-group difference of ASD of at least
diabetes and chronic renal disease up to 5 years before 10%, the ASD value is in bold type. ASD absolute
initiating treatment with sitagliptin or non-DPP-4i oral standardized difference, CHF congestive heart failure,
antihyperglycemic agent as monotherapy or as part of dual DPP-4i dipeptidyl peptidase-4 inhibitor, Hosp hospital,
or triple therapy. a, c, e Clinical conditions and comor- HTN hypertension, Meds medications, MI myocardial
bidities. b, d, f Health care resource utilization. ASD of infarction, Phys physician, TIA transient ischemic attack
C10% indicates a meaningful difference between treatment
Diabetes Ther (2015) 6:627–634 632
persisted but were attenuated, presumably due to for this publication were funded by Merck &
diminishing treatment options with increasing Co., Inc. All named authors meet the
treatment complexity. These observations of International Committee of Medical Journal
channeling in patients receiving treatment with Editors (ICMJE) criteria for authorship for this
sitagliptin are similar to those previously manuscript, take responsibility for the integrity
reported in a general T2DM population [4–7]. of the work as a whole, and have given final
While the MarketScan database includes approval to the version to be published. The
insurance claims data on a large, diverse authors acknowledge Edward A. O’Neill, Ph.D.,
population from the US, these results may not be Alan Meehan, Ph.D., and Kristen Lewis, all of
generalizable to the overall US population or to ex- Merck Sharp & Dohme Corp., a subsidiary of
US populations. In addition, the primary uses of Merck & Co., Inc., Kenilworth, NJ, for editorial
these data are for administrative purposes, not and submission assistance. Some of the data
research. Consequently, the database has missing reported in this manuscript were previously
or limited data on a number of important presented as a poster at the 2014 American
disease characteristics and comorbidities. Diabetes Association Conference in San
Importantly for this study, patients with end-stage Francisco, CA, USA (Brodovicz K, Chen Y,
renal disease are likely underrepresented since Liu Z, Ritchey ME, Liao J, Engel SS.
these patients are Medicare eligible. Chronic renal Characterization of sitagliptin use in patients
disease was defined solely through ICD-9-CM with type 2 diabetesand chronic renal disease by
codes as laboratory data are not available in our cross-sectional analysis of a medical insurance
dataset. claims database).
CONCLUSIONS Disclosures. K. G. Brodovicz was an

employee of Merck Sharp & Dohme Corp., a
This study further documents the presence of
subsidiary of Merck & Co., Inc., Kenilworth,
channeling in patients initiating treatment with
NJ, at the time this analysis was carried out
sitagliptin. In this study, patients with CKD
and may own stock and/or hold stock options in
initiating treatment with sitagliptin were
the company. Y. Chen is an employee of
generally older and were more likely to have a
Merck Sharp & Dohme Corp., a subsidiary of
pre-treatment history of heart failure, arrhythmia,
Merck & Co., Inc., Kenilworth, NJ and may
or use of loop diuretics or beta-blockers than
own stock and/or hold stock options in the
patients initiating other classes of oral therapies.
company.
If not recognized and analyzed appropriately, this
Z. Liu is an employee of Merck Sharp &
channeling could lead to biased treatment effect
Dohme Corp., a subsidiary of Merck & Co.,
estimates in comparative analyses, including
Inc., Kenilworth, NJ and may own stock
those involving users of sitagliptin.
and/or hold stock options in the company. M. E.
Ritchey was an employee of Merck Sharp &
ACKNOWLEDGMENTS Dohme Corp., a subsidiary of Merck & Co.,
Inc., Kenilworth, NJ, at the time this analysis
This analysis was funded by Merck & Co., Inc., was carried out and may own stock and/or hold
Kenilworth, NJ, USA. Article processing stock options in the company. J. Liao is an
charges employee of Merck Sharp & Dohme Corp., a
subsidiary of Merck & Co., Inc., Kenilworth,
NJ
Diabetes Ther (2015) 6:627–634 633
and may own stock and/or hold stock options claims database (abstract). Diabetes.
in the company. S. S. Engel is an employee of 2012;61(S1):A350.
Merck Sharp & Dohme Corp., a subsidiary of
Merck & Co., Inc., Kenilworth, NJ and may 5. Brodovicz KG, Kou TD, Alexander CM, O’Neill
EA, Senderak M, Engel SS, Girman CJ. Recent
own stock and/or hold stock options in the trends in the characteristics of patients prescribed
company. sitagliptinand other oral antihyperglycaemic agents
in a large US claims database. Int J Clin Pract.
2013;67:449–54.
Compliance with ethics guidelines. This
article does not contain any new studies with 6. Cai B, Katz L, Alexander CM, Williams-Herman
D, Girman CJ. Characteristics of patients
human or animal subjects performed by any of prescribed sitagliptin and other oral
antihyperglycaemic agents in a large US claims
the authors. database. Int J Clin Pract. 2010;64:1601–8.
7. Zhang Q, Rajagopalan S, Mavros P, Engel SS,

Open Access. This article is distributed Davies MJ, Yin D, Radican L. Baseline
characteristic differences between patients
under the terms of the Creative Commons prescribed sitagliptin vs. other oral
Attribution-NonCommercial 4.0 International antihyperglycemic agents: analysis of a US
electronic medical record database. Curr Med Res
License (http://creativecommons.org/licenses/ by- Opin. 2010;26:1697–703.
nc/4.0/), which permits any noncommercial
8. Brookhart MA, Sturmer T, Glynn RJ, Rassen J,
use, distribution, and reproduction in any Schneeweiss S. Confounding control in healthcare
medium, provided you give appropriate credit to database research: challenges and potential
approaches. Med Care. 2010;48:S114–20.
the original author(s) and the source, provide a
link to the Creative Commons license, and 9. Austin PC. Balance diagnostics for comparing the
distribution of baseline covariates between treatment
indicate if changes were made. groups in propensity-score matched samples. Stat
Med. 2009;28:3083–107.
10. Ali MS, Groenwold RH, Pestman WR, Belitser SV,

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2
Diabetes Ther (2015) 6:627–634 3
Cardiovascular risk of sitagliptin in ischemic stroke patients with

type 2 diabetes and chronickidney disease
A nationwide cohort study
Chung-Yu Liang, MDa,b, Dong-Yi Chen, MDc, Chun-Tai Mao, MDa,b, I-Chang Hsieh, MDc,
Ming-Jui Hung, MD, PhDa,b, Chao-Hung Wang, MD, PhDa,b, Ming-Shien Wen, MDc,
associated with increased or decreased risk of adverse CV events.
ACEI = angiotensin-converting enzyme inhibitor, ARB = angiotensin receptor blocker, BBB = blood brain barrier,
CKD = chronic kidney disease, CV = cardiovascular, DKA = diabetic ketoacidosis, DPP-4 = dipeptidyl peptidase-4, eGFR =
estimated glomerular filtration rate, GLP-1 = glucagon-like peptide 1, HHS = Hyperosmolar hyperglycemic state, ICD-9-CM =
Wen-Jin Cherng, MDc, Tien-Hsing Chen, MDa,b,∗
Medicine (2018) 97:52(e13844)

1. Introduction
Patients diagnosed with type 2 diabetes mellitus (T2DM) Received: 25 September 2018 / Received in final form: 31 October 2018 /
have ahigher risk of cardiovascular (CV) events with double Accepted: 5 December 2018
of the risk of ischemic stroke compared to those without http://dx.doi.org/10.1097/MD.0000000000013844
diabetes.[1] Acute
Editor: Elena Cecilia Rosca.
Chung-Yu Liang and Dong-Yi Chen: These authors contributed equally to this
study.
The authors report no relationships that could be construed as a conflict of

interest.
a
Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial
Hospital, Keelung, b Chang Gung University College of Medicine, Taoyuan,
c
Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial
Hospital, Linkou, Taiwan.
∗ Correspondence:Tien-Hsing Chen, No. 222, Maijin Road, Keelung City 204,

Taiwan (e-mail: skyheart0826@gmail.com).
Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.

This is an open access article distributed under the terms of the Creative
Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is
permissible to download, share, remix, transform, and buildup the work provided
it is properly cited. The work cannot be used commercially without permission
from the journal.
3
stDrioakbeetecsanThaelrso(2l0e1a5d) t6o:6a2b7n–6o3r4malities in glucose metabolism 4
thatcan result in poor clinical outcomes.[2] Patients with
acuteischemic stroke who have a history of DM are
associated with ahigher incidence of mortality than those who
have yet to developDM.[3] Nonetheless, strategies for blood
sugar control duringacute stroke vary. Hyperglycemia has
been found to be associatedwith poor outcomes in large
vessel infarction or corticalinfarction,[4,5] but moderate
hyperglycemia is also reported tobe associated with
favorable outcomes in patients with lacunarinfarction.[6]
Intensive glucose control in acute stroke has beensuggested
based on previous experience and implemented in the
intensive-care unit (ICU),[7] but was found to be associated
withsevere hypoglycemia and event-related poorer
outcomes.[8]Therefore, controversies still exist about the
benefits of anti-hyperglycemic treatment for patients after
acute ischemic stroke.Sitagliptin is the first approved
dipeptidyl peptidase-4 (DPP-4) inhibitor with
antihyperglycemic effects provided by enhancingthe
availability of incretin hormones.[9] Results of the Trial
Evaluating Cardiovascular Outcomes with Sitagliptin
(TECOS)Study suggested that sitagliptin did not increase the
risk of majoradverse CV events among patients with type
2 diabetes andestablished CV disease.[10] However, that study
excluded patientswith estimated glomerular filtration rate
(eGFR) less than 30 ml/min/1.73 m2 of body-surface area who
may have experiencedmore CV events after acute ischemic
stroke. Our previous
4
Liang et al. Medicine (2018) 97:52 Medicine
study,[11] which comprised patients with chronic kidney

prior to analysis to protect their privacy and ensure patient
disease (CKD) who were precluded from participating in
anonymity, therefore informed consent was waived. The
TECOS, has also demonstrated that sitagliptin was
study protocol was reviewed and approved by the Ethics
associated with a neutral CV effect in T2DM with recent
Institutional Review Board of Chang Gung Memorial
ischemic stroke, but those with end stage renal disease
Hospital, and this work was supported by grants from the
(ESRD) receiving renal replacement therapy were excluded.
Chang Gung Memorial Hospital, Taiwan (CGRPG2F0011,
Therefore, only limited published data are available for
CLRPG2C0024, and CLRPG2G0081).
evaluating the safety and efficacy of sitagliptin among acute
ischemic stroke patients with T2DM and CKD (with or
without renal replacement therapy). The CV risk associated 2.2. Study group and cohort definition
with sitagliptin in the CKD patient group remains unclear in A total of 5479 T2DM patients with CKD were identified
the real-world clinical setting. As a result, we conducted this who were admitted for acute ischemic stroke between March
population-based cohort study using data from the NHIRD 1, 2009 and December 31, 2011. Ischemic stroke and CKD
of Taiwan to investigate the CV outcomes of sitagliptin in were identified using the International Classification of
patients with ischemic stroke and CKD. Diseases (the 9th Revision) Clinical Modification [ICD-9-
CM] codes 433 to
435 and 585 registered by the clinician respectively. The
2. Methods accuracy of diagnosis for T2DM, acute ischemic stroke,
2.1. Data source and CKD have been validated in previous NHIRD
studies.[12–16] A flowchart of the inclusion of the study
Data for this national cohort study were retrieved from the cohort is shown in
NHIRD, which consists of standard computerized claims Figure 1. The patients were divided into two study groups,
data submitted by medical institutions that seek sitagliptin users (n = 311) and non-sitagliptin users (n =
reimbursement through the NHI program. The NHI program 4,206). Patients who received a prescription of sitagliptin for
offers compre-hensive medical care for more than 23 million 90 consecutive days following index discharge were defined
residents, representing more than 99% of the population of as the sitagliptin group, whereas patients who did not receive
Taiwan. Previous studies have described the NHIRD in sitagliptin were considered the comparison cohort. The index
detail and hospitalization was defined as the index date when the
the accuracy of its diagnostic data has been validated.[12–16] patient was admitted for ischemic stroke. The follow-up
The information and records of the patients were de- period was defined as from the index date to the date of
identified
event occurrence,
5
Figure 1. Inclusion and exclusion of the study patients.
6
Liang et al. Medicine (2018) 97:52 www.md-journal.com
death or until the end of the study period (December 31, of the logit of the propensity score. The matching procedure
2011),whichever occurred first. was performed using the procedure of ‘psmatch’ in SAS
version 9.4
2.3. Exclusion criteria (SAS Institute, Cary, NC).
The clinical characteristics between the two study groups
Patients were excluded if they met any of the following (sitagliptin and comparison groups) were compared by chi-
criteria: square test for categorical variables and independent sample t
1. age <40 years; test for continuous variables. Risk of time-to-event
2. newly diagnosed T2DM, which was defined as T2DM outcomes
diagnosed during index hospitalization, which was done
to ensure consistency in disease severity and duration
among diabetic patients;
3. use of sitagliptin but less than 90 days, which was done to avoid
carry-over effect;
4. received DPP-4 inhibitors other than sitagliptin before or after
index hospitalization;
5. expired during index hospitalization or developed any composite
major adverse cardiac and cerebrovascular event (MACCE)
(defined as ischemic stroke, hemorrhagic stroke, myocardial
infarction (MI) or CV death) within 30 days of discharge;
6. were followed for less than 30 days after the index
hospitalization.
2.4. Study outcomes and covariate measurements

The baseline comorbidities were defined as least 2 outpatient
claims or 1 hospitalization of ICD-9 diagnosis codes one
year prior to the index date. A majority of these
comorbidities based on ICD-9-CM codes have been
validated previously.[15] Medications were defined as at least
2 outpatient prescriptions or 1 refilled prescription at
pharmacies within 3 months after the index date. The primary
outcome was defined as MACCEs. The study outcomes were
required to be the same as the discharge diagnosis to avoid
misclassification. CV death was defined according to the
criteria of the Standardized Definitions for End Point Events
in CV Trials published by the Food and Drug
Administration (FDA).[17] Deaths were identified by the
patients’ withdrawal from NHI.[18] Other CV outcomes of
interest were
any stroke, death of any cause and admission due to heart
failure. Diagnosis of heart failure was validated in a previous
NHIRD study.[16] Indications for safety outcomes included
acute pancreatitis, chronic pancreatitis, hypoglycemia,
diabetic ketoacidosis (DKA) or hyperosmolar
hyperglycemic state (HHS).
2.5. Statistical analysis

To mitigate the treatment selection-bias, propensity score
matching (PSM) was conducted in which 1 patient in the
sitagliptin cohort was matched with 4 counterparts in the
comparison cohort. The propensity score was the predicted
probability of being treated with sitagliptin given the
patient’s
covariates. Those covariates included patient’s
characteristics,
baseline comorbidities, non-study medications, and the index
date. The "greedy nearest neighbor” matching method was
adopted and the caliper was set as 0.2 times standard deviation
7
comparison
between the study groups was compared using the Cox groups (Table 3). Figure 2 illustrates the cumulative event rate
proportional hazard model in which the study group was the of
only explanatory variable and the matching pairs were recurrent ischemic stroke and MACCE in both study groups
stratified. Unadjusted cumulative event rate of primary during the follow-up period. It was observed that the group
outcomes (recurrent ischemic stroke and MACCE) was difference in the curves was trivial and the log-rank tests
calculated and plotted. Subgroup analysis was performed to revealed non-significant difference between the groups (P =
determine whether the hazard ratio of primary outcomes for .434 for recurrent ischemic stroke and P = .769 for
the sitagliptin and non- sitagliptin groups were similar in the MACCE).
pre-specified subgroups (age group, gender, atrial fibrillation, Regarding other secondary outcomes, no statistically
ESRD, and previous stroke). significant differences were found in the risks of heart failure
Statistical significance was set at 2-tailed P <.05 and no admission (HR 1.12; 95% CI 0.59–2.14), or death from
adjustment of multiple testing (multiplicity) was made in any cause (HR
this
0.78; 95% CI 0.55–1.10) between the 2 study groups. In terms
study. All data analysis was conducted using IBM SPSS of
softwareversion 22 (IBM SPSS Inc, Chicago, IL). safety outcomes, no significant differences were found
between
3. Results
3.1. Patients’ characteristics
The data of a total of 275 sitagliptin-treated patients and
1100 non-sitagliptin treated patients admitted from March 1,
2009 through December 31, 2011, were eligible for data
analysis. Themean age for the overall cohort was 69.2 years
(standard deviation [SD] = 10.8 years). Approximately 40% of
patients had previous strokes. The mean follow-up period was
1.07 years (SD= 0.73 years) and the maximal follow-up time
was 2.83 years. After PSM, the two study groups were well
balanced in all baseline characteristics, comorbidities,
medications for T2DM and CV disease after discharge
(Table 1).
Among all patients, 28.4% of the sitagliptin group and
26.6% of the non-sitagliptin group were ESRD patients
receiving dialysis. Patients with atrial fibrillation accounted
for 10.2% of patients in the sitagliptin group and 9.5% in the
comparison group (P =.749). The CHADS2 score was 5.0
for the sitagliptin group and 5.0 for the comparison group,
and CHA2DS2-VASc score was 6.8 for the sitagliptin group
and 6.6 for the comparison group (P = 0.797 and 0.674).
Prevalence of atrial fibrillation, CHA2DS2-VASc, and
CHADS2 scores were also comparable between the two
study groups.
3.2. CV outcomes
The primary outcome of MACCE occurred in 45 patients in
the sitagliptin group (16.4%) and in 165 patients in the non-
sitagliptin group (15.0%) (Hazard ratio [HR] 1.05; 95%
confidence interval [CI] 0.75–1.45) at the last follow up. No
significant differences in the MACCEs were detected between
the2 study groups at 3-month follow-up (HR 0.59; 95% CI
0.29–
1.20), 1-year follow up (HR 0.92; 95% CI 0.63–1.35) and at
the
end of the study (Table 2). No significant differences were
found
in the individual composite endpoint of ischemic stroke (HR
0.82; 95% CI 0.51–1.32), hemorrhagic stroke (HR 1.50; 95%
CI 0.58–3.82), MI (HR 1.14; 95% CI 0.49–2.65), or CV
death (HR
1.06 ; 95% CI 0.61–1.85) between the sitagliptin and
8
Table 1 Table 3
Baseline demographic and clinical characteristics of study
patients after propensity score matching. Secondary outcomes at the end of follow up.
Number of events (%) Sitagliptin vs Comparison
Sitagliptin Comparison HR
Sitagliptin Comparison
Outcome (n = 275) (n = 1100)
Characteristics (n = 275) (n = 1100) P
(95% CI) P
Age (years) 69.3 ± 10.8 69.1 ± 10.9 0.822
Other CV outcomes
Age≧75 years 94 (34.2) 365 (33.2) 0.753
Gender 0.744 Any stroke 27 (9.8) 121 (11.0) 0.85 (0.56–1.29) 0.438
Ischemic stroke 21 (7.6) 97 (8.8) 0.423
0.82 (0.51–1.32)
Hemorrhage stroke 6 (2.2) 16 (1.5) 0.401
1.50 (0.58–3.82)
MI 7 (2.5) 24 (2.2) 0.757
1.14 (0.49–2.65)
Non-fatal ischemic 20 (7.3) 91 (8.3) 0.472
Previous stroke 0.84 (0.52–1.36)
Any
∗ 114 (41.5) 483 (43.9) 0.463 stroke
Hemorrhage 12 (4.4) 50 (4.5) 0.897 Non-fatal MI 6 (2.2) 20 (1.8) 0.735

1.17 (0.47–2.91)
53 (19.3) 221 (20.1) 0.761 CV death 16 (5.8) 59 (5.4) 1.06 (0.61–1.85) 0.824
Unspecified
Comorbidity
Death from any cause 38 (13.8) 191 (17.4) 0.78 (0.55–1.10) 0.157
ESRD 78 (28.4) 293 (26.6) 0.564 Heart failure 12 (4.4) 42 (3.8) 0.721
1.12 (0.59–2.14)
Neuropathy 86 (31.3) 358 (32.5) 0.686
Retinopathy 38 (13.8) 156 (14.2) 0.877

Coronary artery disease 82 (29.8) 335 (30.5) 0.837
Any pancreatitis 0 (0.0) 3 (0.3) NA NA
pulmonary disease Chronic pancreatitis 0 (0.0) 1 (0.1) NA NA
Atrial fibrillation 28 (10.2) 105 (9.5) 0.749 Hypoglycemia 8 (2.9) 43 (3.9) 0.72 (0.34–1.53) 0.394
CHADS2 score† 5.0 ± 0.9 5.0 ± 0.9 0.797 DKA or HHS 1 (0.4) 19 (1.7) 0.20 (0.03–1.53) 0.122
CHA2DS2-VASc‡ 6.8 ± 1.4 6.6 ± 1.4 0.674
Peripheral arterial disease 53 (19.3) 213 (19.4) 0.973 CI =confidence interval, CV = cardiovascular, DKA= diabetic ketoacidosis, HHS = hyperosmolar
hyperglycemic state, HR = hazard ratio, MI= myocardial infarction, NA = not applicable.
Hypertension 258 (93.8) 1,031 (93.7) 0.956
Heart failure 71 (25.8) 272 (24.7) 0.708

the 2 groups in the risks of hypoglycemia (2.9% and 3.9%;
Dyslipidemia 143 (52.0) 566 (51.5) 0.871 P = .394), DKA or HHS (0.4% and 1.7%; P = .122) (Table 3).
Malignancy 22 (8.0) 85 (7.7) 0.880
In
the subgroup analysis, no significant interactions (all P values
Cirrhosis 7 (2.5) 29 (2.6) 0.933 >0.1) were found between the study groups by the pre-specified
Previous PCI 13 (4.7) 51 (4.6) 0.949
Previous carotid stenting 2 (0.7) 7 (0.6) 0.867
T2DM medication
Insulin 87 (31.6) 360 (32.7) 0.730

subgroups on recurrent ischemic stroke or MACCE (Fig. 3). It
Metformin 44 (16.0) 188 (17.1) 0.666
CV TdZisD
ease medication 19 (6.9) 89 (8.1) 0.515
aintrdiiaclatfiebdritlhlaatiothne, oEbSsR
erD
veadnndeu
ptrreavlio
efufsecsttroof kseit.agliptin was not
Aspirin 173 (62.9) 683 (62.1) 0.802
Clopidogrel 138 (50.2) 542 (49.3) 0.787
Warfarin 13 (4.7) 46 (4.2) 0.690
4. Discussion
Beta-blockers 103 (37.5) 400 (36.4)
D iuretics 85 (30.9) 344 (31.3)
0. 97307 sitagliptin with a specific focus on T2DM patients with recent
Statins
103 (37.5) 408 (37.1) 0.911 ischemic stroke and CKD. Study results revealed that treatment
Fibrate with DPP-4 inhibitor sitagliptin resulted in similar rates of major
9
27 (9.8) 113 (10.3) 0.824
Values are mean ± SD or n (%). cardiac and cerebrovascular events of ischemic stroke,
hemorrhagic stroke, MI or CV death when compared with
ACEI =angiotensin-converting enzyme inhibitor, ARB =angiotensin receptor blocker, COPD = chronic non- sitagliptin users in the cohort of T2DM patients with
obstructive pulmonary disease, ESRD = end stage renal disease, PCI =percutaneous coronary
intervention, T2DM = Type 2 diabetes mellitus, TZD =thiazolidinedione. CKD and recent ischemic stroke. Secondary outcome analysis
demonstrated no significant differences between the
∗ A discrepancy may exist between the sum of a subgroup and the total as a result of a single patient sitagliptin and comparison groups with regard to
having had two or more strokes.
pancreatitis, hypoglycemia episodes, complications of
hyperglycemia or all-cause mortality. Furthermore, the
† The CHADS2 score is a measure of the risk of stroke in which congestive heart failure, hypertension, present study has shown that sitagliptin does not increase
heart failure-related hospitalization events in patients with
an age of 75 years or older, and diabetes mellitus are each assigned 1 point and previous stroke or
transient ischemic attack is assigned 2 points; the score is calculated by summing all the points for a
recent ischemic stroke and CKD who have higher CV risk
given patient. and are susceptible to fluid overload.
‡ The CHA2DS2-VASc [congestive heart failure, hypertension, age ≥75 (doubled), diabetes, stroke
(doubled), vascular disease, age 65 to 74, and sex category (female)].
Table 2
∗
Primary MACCE outcomes in various follow-up periods.
Number of event (%) Sitagliptin vs Comparison

Outcome Sitagliptin (n = 275) Comparison (n = 1,100) HR (95% CI) P
3 month follow up 9 (3.3) 59 (5.4) 0.59 (0.29–1.20) 0.144
1 year follow up 33 (12.0) 137 (12.5) 0.666
0.92 (0.63–1.35)
At the end of follow up 45 (16.4) 165 (15.0) 0.791
1.05 (0.75–1.45)
CI = confidence interval, CV = cardiovascular HR = hazard ratio, MACCE = major adverse cardiac and cerebrovascular events, MI = myocardial infarction.
∗ Any one of ischemic stroke, hemorrhage stroke, myocardial infarction or CV death.
1
Figure 2. Unadjusted cumulative event rate of recurrent ischemic stroke (A) and MACCE (B) during the follow up. MACCE = major adverse cardiac and
cerebrovascular events.
stroke. Furthermore, CKD patients were excluded in the

In the present study, the study population in which CV TECOS trial. In contrast, all patients in the present study
risk of sitagliptin was evaluated is different from that in the were CKD subjects
previous TECOS trial.[10] The TECOS trial enrolled patients
with established CV diseases among which only 24.5% had
prior cerebrovascular disease; however, all subjects included
in the present study had experienced recent acute ischemic
1
among whom approximately one third had received renal

replacement therapy. Sitagliptin has been licensed for use in
CKD patients with or without dialysis. Patients with T2DM
and CKD for whom sitagliptin was prescribed tend to be
older and have more complications of DM and more
comorbidities.[19] Thus, this high-risk group of patients is
especially susceptible to safety and tolerability issues.
Nonetheless, most of the current evidence reported in CV
outcomes studies of DPP4-inhibitor was obtained
1
Figure 3. Pre-specified subgroup analysis of recurrent ischemic stroke (A) and MACCE (B). MACCE =major adverse cardiac and cerebrovascular events.
from major populations of non-CKD subjects (eGFR over 60 risk than patients in other studies. With a mean follow-up period
ml/ min/1.73 m2).[10,20,21] The present study examined only of 1.07 years, 14% of subjects in the present study developed a
CKD subjects who had a recent episode of ischemic stroke primary
hospitalization, placing the study cohort at a much higher
1
composite CV event. However, the study results

demonstrated that use of sitagliptin is not associated
with increased risk of CV events among these patients
at high CV risk.
To date, there are only a limited number of studies on
the effects of sitagliptin on acute ischemic stroke
patients. An animal study has shown that sitagliptin
attenuates transient cerebral
1
ischemia or reperfusion injury in diabetic rats.[22] Linagliptin, natriuretic peptide. Finally, our present study has a mean of
another form of DPP-4 inhibitor, was also found to be able 1.07 years and a maximum of 2.83 years of follow-up
to counteract stroke in diabetic mouse brain.[23] DPP-4 because of our available data of the NHIRD. A study with
inhibitors do not have direct actions on the central nervous longer duration of follow-up in the future could give more
system because they cannot cross the blood brain barrier robust information to confirm our finding.
(BBB). Nonetheless, acute stroke-mediated BBB damage
has been reported to increase permeability and it remains
controversial whether this effect may exhibit the benefit of
5. Conclusions
neuroprotection from sitagliptin. A previous study by our Among T2DM patients with CKD after recent ischemic
cardiology group in a majority of non-CKD patients stroke, sitagliptin use was not associated with an increased
addressed a neutral neuroprotective benefit of sitagliptin in risk of MI, CV death, ischemic stroke or hemorrhage stroke.
acute ischemic stroke patients with type 2 DM.[11] Results of Even in patients
the present study demonstrated that sitagliptin is not associated
with increased cerebrovascular risk, but it did not provide a
neuroprotective benefit in acute ischemic stroke patients,
regardless of whether patients were in the non-CKD or
CKD population.
Interestingly, subgroup analysis in patients with ESRD
and recent ischemic stroke suggested no significant
differences in cardiac and cerebrovascular outcomes between
sitagliptin users and a comparison group not receiving
sitagliptin. However, in contrast, one previous study reported
that DPP-4 inhibitors may improve ischemic stroke in
patients with T2DM and ESRD.[24] The discrepancy between
our results and those of that previousstudy may be related to
differences in study populations and medications. In the
previous study,[24] only about 40% of patients had a history
of cerebrovascular disease, which is in contrast to the cohort
in the present study in which all patients had recent ischemic
stroke. Additionally, patients in the previous study took not
only sitagliptin, but also other DPP-4 inhibitors, including
vidaglipitin, sxagliptin, and linagliptin. The effect of reduced
ischemic stroke in the previous study was derived primarily
by the effect of saxagliptin rather than vildagliptin,
sitagliptin or linagliptin. Therefore, in the subgroup analysis
of the previous study, sitagliptin was not associated with
fewer ischemic stroke events, which is also consistent with
results of the present study.
4.1. Study limitations
Although the present study provides important information

about sitagliptin use in fragile patients with recent ischemic
stroke and CKD, several limitations must be noted. First, the
severity of hypertension and diabetes are the major risk factors
for recurrent
stroke but the data about patients’ blood pressure or blood
glucose were not included in data from NHIRD. However,
the
use of anti-hypertensive and oral antidiabetic drugs was
matched between the sitagliptin and comparison groups.
Second, for the patients with CKD without dialysis, the stage
of CKD could not be identified because patients’ body weight
and blood creatinine levels were not provided by NHIRD.
Third, the NHIRD lacked
laboratory information, including lipid profiles (eg, low-
density lipoprotein, high-density lipoprotein, etc.),
inflammatory factors such as high sensitivity C-reactive
protein (hsCRP), and levels of N terminal pro B-type
1
[12] Lin CC, Lai MS, Syu CY, et al. Accuracy of diabetes diagnosis in
with ESRD, the use of sitagliptin did not increase composite health insurance claims data in Taiwan. J Formos Med Assoc
cardiac-cerebrovascular events. Furthermore, use of 2005;104:157– 63.
[13] Hsieh CY, Chen CH, Li CY, et al. Validating the diagnosis of acute
sitaglipitin was not associated with increased risk of heart ischemic stroke in a National Health Insurance claims database. J
failure hospitalization even in patients with CKD who are Formos Med Assoc 2015;114:254–9.
more susceptible to fluid status. Therefore, sitaglipin use is [14] Cheng CL, Kao YH, Lin SJ, et al. Validation of the National Health
Insurance Research Database with ischemic stroke cases in Taiwan.
safe in T2DM patients with recent ischemic stroke and
Pharmacoepidemiol Drug Saf 2011;20:236–42.
CKD.
[15] Wu CS, Lai MS, Gau SS, et al. Concordance between patient self-reports
and claims data on clinical diagnoses, medication use, and health system
Acknowledgments utilization in Taiwan. PLoS One 2014;9:e112257.
We thank Hsing-Fen Lin for statistical assistance. [16] Cheng CL, Chien HC, Lee CH, et al. Validity of in-hospital mortality
data among patients with acute myocardial infarction or stroke in National
Health Insurance Research Database in Taiwan. Int J Cardiol 2015;201:96–
101.
Author contributions
Conceptualization: Chung-Yu Liang, Dong-Yi Chen, and
Tien- Hsing Chen.
Methodology: Chung-Yu Liang, Dong-Yi Chen, Chun-Tai
Mao,and Tien-Hsing Chen.
Supervision: I-Chang Hsieh, Ming-Jui Hung, Chao-Hung
Wang, Ming-Shien Wen, Wen-Jin Cherng, and Tien-
Hsing Chen.
Writing – original draft: Chung-Yu Liang and Dong-Yi
Chen.
Writing – review & editing: Chun-Tai Mao.
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[1] Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood
glucose concentration, and risk of vascular disease: a collaborative meta-
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[2] Capes SE, Hunt D, Malmberg K, et al. Stress hyperglycemia and
prognosis of stroke in nondiabetic and diabetic patients: a systematic
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[3] Jia Q, Zhao X, Wang C, et al. Diabetes and poor outcomes within 6
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[4] Bruno A, Biller J, Adams HPJr, et al. Acute blood glucose level and
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[5] Kruyt ND, Nys GM, van der Worp HB, et al. Hyperglycemia and
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[6] Uyttenboogaart M, Koch MW, Stewart RE, et al. Moderate hyper-

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[7] van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy
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[9] Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1
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[10] Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on
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[11] Chen DY, Wang SH, Mao CT, et al. Sitagliptin After ischemic stroke in
type 2 diabetic patients: a nationwide cohort study. Medicine (Baltimore)
2015;94:e1128.
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[18] Wu CY, Chen YJ, Ho HJ, et al. Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma
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[19] Brodovicz KG, Chen Y, Liu Z, et al. Characterization of sitagliptin use in
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2015;6:627–34.
[20] Gallwitz B, Rosenstock J, Rauch T, et al. 2-year efficacy and safety of

linagliptin compared with glimepiride in patients with type 2 diabetes
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[21] Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular
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[22] El-Sahar AE, Safar MM, Zaki HF, et al. Sitagliptin attenuates transient
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[23] Darsalia V, Ortsater H, Olverling A, et al. The DPP-4 inhibitor linagliptin

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[24] Chan SY, Ou SM, Chen YT, et al. Effects of DPP-4 inhibitors on
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HHS Public Access
Author manuscript
Author Manuscript

Indian J Pediatr. 2012 August ; 79(8): 1062–1068. doi:10.1007/s12098-012-0765-1.
Vitamin D in Chronic Kidney Disease

Yahn-Yir Chau and
Taipei Cathay General Hospital, Taipei, Taiwan
Juhi Kumar
Weill Cornell Medical College, New York, NY, USA
Author Manuscript
505 East 70th Street, Helmsley Towers 3, New York, NY 10021, USA
Juhi Kumar: juk2013@med.cornell.edu
Abstract
Vitamin D deficiency is widespread in both the pediatric and adult chronic kidney disease (CKD)
population. CKD is characterized by dysregulation of vitamin D and mineral metabolism.
Secondary hyperparathyroidism and its management puts patients with CKD at increased
cardiovascular risk. Emergence of experimental and some clinical data suggesting beneficial
effects of vitamin D on proteinuria, blood pressure, inflammation and cardiovascular outcomes has
pushed it to the center stage of CKD research. Pediatric data on vitamin D dysregulation and its
consequences are still in its infancy. Ongoing prospective studies such as Chronic Kidney disease
Author Manuscript
in Children (CKiD) and the Cardiovascular Comorbidity in Children with CKD (4 C) should help
to delineate the evolution of disturbances in mineral metabolism and its adverse effects on growth,
CKD progression and cardiovascular outcomes.
Keywords
Hyperparathyroidism; Cardiovascular; Proteinuria; Hypertension; Inflammation
Introduction
In the past decade vitamin D has become the subject of intense scientific inquiry and has
found a new place under the sun. Secondary to the discovery of 1-α hydroxylase enzyme and
Author Manuscript
vitamin D receptor (VDR) in non-renal tissues there have been numerous preclinical studies
centered on the non-classical actions of vitamin D. These novel actions of vitamin D are of
great importance to nephrologists and have generated tremendous interest in clinical
research aimed at discerning its role in chronic kidney disease.
Vitamin D Physiology
Vitamin D is either synthesized endogenously in the skin after sunlight exposure or ingested
in the diet. 7-dehydrocholesterol is converted to previtamin D3 by solar UVB radiation
Correspondence to: Juhi Kumar, juk2013@med.cornell.edu.
2
Conflict of Interest None.
2
Chau and Kumar Page 2
which is converted to vitamin D3. Vitamin D2 (from food sources such as dairy products,
Author Manuscript
fortified breads and cereals, oily fish and supplements) and D3 are transported to the liver,
where they are hydroxylated in the 25 position to yield 25-hydroxyvitamin D [25(OH)D],
which is the main storage form of vitamin D. It has a half-life of 2–3 wk and is measured to
assess vitamin D status. 25 (OH)D is further hydroxylated by the enzyme 1-α-hydroxylase
in the kidney proximal tubule, to yield 1, 25-dihyroxyvitamin D [1,25(OH)2D], which is the
active form of vitamin D, and is responsible for its biologic actions [1]. The half-life of
1,25(OH)2D is 8–10 h and its levels are affected by changes in calcium, phosphorus,
parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF 23) levels. For these
reasons 1,25(OH)2D levels are not a good reflection of vitamin D status. Both 25(OH)D and
1,25 (OH)2D are converted to biologically inactive metabolites by 25 hydroxyvitamin D-24-
hydroxylase. This enzyme is activated by 1,25(OH)2D and FGF-23 and helps regulate levels
of 25 (OH)D and 1,25(OH)2D.
Author Manuscript
Vitamin D Actions
Calcemic Actions
The well-known action of vitamin D is to maintain serum calcium and phosphorus levels.
1,25(OH)2D enhances intestinal calcium absorption in the small intestine by increasing the
expression of calcium transport proteins, epithelial calcium channel TRPV6 and Calbindin 9
K [2]. Without vitamin D, only 10–15 % of dietary calcium and about 60 % of phosphorus
are absorbed. In the presence of 1,25 (OH) 2D, the efficiency of intestinal calcium and
phosphorus absorption increases to 30–40 % and 80 %, respectively [3].
1,25(OH)2D is a potent negative regulator of PTH production. It binds with the vitamin D
Author Manuscript
receptor (VDR) complex on parathyroid cells and down regulates PTH gene expression,
increases expression of VDRs and increases transcription of the calcium sensing receptors
(CaSR) [4]. A recent study has shown that the parathyroid glands may function as a vitamin
D autocrine system as they express 1-α hydroxylase and also 25-hydroxylase, allowing the
gland to produce their own 1,25(OH)2D to regulate PTH production [5]. This may explain
why PTH levels correlate inversely with 25(OH)D levels in mild to moderate CKD with no
changes in 1,25(OH)2D levels [6]. A prolonged deficiency of vitamin D metabolites leads to
a need for higher serum calcium levels and vitamin D doses as there is a markedly reduced
VDR and CaSR expression by the parathyroid cells [4].
In bones, 1,25(OH)2D induces pre-osteoclasts to become mature osteoclasts. Mature

osteoclasts remove calcium and phosphorus from the bone to maintain their respective levels
in the blood. Osteoblasts express both 25-hydroxylase as well as 1-α hydroxylase enzyme
Author Manuscript
systems and can function as independent 1,25(OH)2D-producing cells [7]. The above
calcium and phosphorus mobilizing action is at odds with the known mineralization
promoting action of vitamin D. By enhancing the absorption of Ca2+ and PO43− from the
intestine and the renal tubules, vitamin D raises the concentrations of both Ca 2+ and PO43−
in the blood and extracellular fluid. This increase in the calcium and phosphorus product
results in net bone mineralization. Several studies have shown an association between
25(OH)D levels and rickets and bone mineral density [8].
Indian J Pediatr. Author manuscript; available in PMC 2016 June 01.

Non-calcemic actions
Author Manuscript
It is estimated that~3 % of the human genome is regulated by 1,25(OH) 2D [9]. The genomic
actions of vitamin D are mediated by the VDR which acts as a heterodimer with the retinoid
X receptor (RXR). This heterodimer interacts with specific DNA sequences called vitamin D
response elements (VDRE) within promoter region of target genes causing the activation or
repression of gene transcription. This regulates two major cellular functions, proliferation
and differentiation [10]. Many tissues such as the pancreatic islets, prostate; the colon; the
breast; macrophages; malignant and immune cells and vascular smooth muscle cells, possess
1-α-hydroxylase and are capable of locally producing 1,25 (OH) 2D [11]. This has suggested
a role for 1,25(OH)2D in preventing cancers, modulating innate and adaptive immunity,
affecting endocrine systems such as the renin-angiotensin-aldosterone axis and insulin
release [3, 12]. Epidemiological evidence also associates vitamin D deficiency with cancer,
autoimmune diseases, hypertension, and diabetes [3, 13].
Author Manuscript
Extra renal 1-α-hydroxylase activity is dependent on availability of substrate 25(OH)D and

is not influenced by the hormones that control renal 1,25(OH)2D production [14].
Vitamin D Deficiency in Pediatric CKD

There is no consensus as to what defines Vitamin D deficiency. The recent Institute of
Medicine (IOM) guidelines recommend that levels>20 ng/ml are sufficient [15]. In normal
adults PTH levels are elevated if 25(OH)D levels are less than 30–40 ng/ml and intestinal
calcium transport is suboptimal below 25(OH)D levels of 32 ng/ml [16, 17]. So levels below
30 ng/ml may constitute vitamin D insufficiency and many experts believe that the current
IOM recommended levels and doses are inadequate [18].
Author Manuscript
The Kidney Disease Outcome Quality Initiative (KDOQI) guidelines define 25 (OH) D
deficiency as levels below 15 ng/ml, with levels between 16 to 30 ng/ml being considered as
vitamin D insufficiency [19]. Multiple studies in adults with CKD have shown a high
prevalence of 25 (OH) D deficiency, but there are very few, small pediatric prevalence
studies [20–24]. Menon et al conducted a retrospective analyses of 57 pediatric CKD
patients and found 77 % to have levels≤30 ng/ml. PTH was higher in those with deficiency
and responded to ergocalciferol treatment [23]. Ali et al evaluated prevalence of 25 (OH)D
deficiency in children with CKD in two different decades with different management
guidelines. They showed a 20–75 % prevalence of deficiency (≤15 ng/ml) in their patients
from 1987–1996, with increasing deficiency as the decade progressed. In 2005–2006, after
the KDOQI guidelines for 25 (OH)D supplementation became available, the prevalence of
levels ≤15 ng/ml was still high at 33 % and 72 % of the 88 patients had levels less than 32
Author Manuscript
ng/ml. PTH levels had an inverse relationship to 25 (OH)D levels in their study [20].
Recently, Kalkwarf et al found 25(OH)D levels<20 ng/ml in half of the 182 patients (ages 5
to 21) with chronic kidney disease (stages 2 to 5). The risk of deficiency was significantly
greater in advanced CKD. Focal segmental glomerulosclerosis, low albumin and high PTH
levels were significantly associated with lower 25(OH)D levels [25].
The etiology of 25 (OH)D deficiency in CKD is multifactorial [26]. Poor nutrition and
decreased consumption of vitamin D and calcium-rich foods are major reasons, as is the

inability to participate in outside physical activity, thereby limiting sun exposure. Response
Author Manuscript
to sunlight is also impaired in patients with CKD, as they are unable to produce vitamin D3
in the skin even though the concentrations of provitamin D 3 in the epidermis are similar to
age-matched controls [27]. Proteinuric renal diseases predispose to hypovitaminosis D due
to urinary loss of vitamin D binding protein and vitamin D metabolites [28, 29]. A low
calcium diet can also lead to low 25 (OH)D levels as the secondarily elevated PTH levels
will cause a rapid degradation of 25 (OH)D to inactive metabolites. Secondary
hyperparathyroidism worsens 25 (OH)D deficiency by promoting the activity of 24, 25-
dihydroxylase enzyme and increasing degradation of 25 (OH)D [30].
1,25(OH)2D deficiency occurs as the kidney loses its ability to convert 25 (OH)D to
1,25(OH)2D. This is due to multiple reasons [3, 11]:
• Raised serum phosphate and FGF-23 down regulate renal 1-α hydroxylase [31]
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• Suppression of 1-α hydroxylase due to uremia and acidosis
• Reduced availability of substrate 25 (OH)D and dependency of 1-α hydroxylase on

substrate in CKD patients [6, 32]
• Reduced renal Megalin expression:- Megalin endocytosis of the 25(OH)D-VDBP
complex is essential for delivery of 25 (OH)D from the glomerular ultrafiltrate to
the 1-α hydroxylase enzyme in the proximal tubule [33]
In addition, the biological activity of the available 1,25 (OH) 2D is lower in CKD patients
due to less binding of VDR to the response element in the DNA within the uremic milieu
[34].
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Treatment of Vitamin D Deficiency

Earlier guidelines from KDOQI had recommended measuring 25(OH)D levels in stages 3–4
CKD only when the PTH levels were above the target range for stage of CKD. The most
recent KDOQI and the KDIGO guidelines recommend measuring 25(OH)D levels once a
year in children with CKD stages 2 to 5 [35, 36]. Supplementation is initiated if the levels
are<30 ng/ml as per the Table 1 below [20].
KDOQI guidelines do not make a distinction between using ergocalciferol (D2) vs.
cholecalciferol (D3) as there is insufficient data to prove the superiority of one over the
other. Studies in healthy adults have shown conflicting results. Holick et al in a randomized,
placebo-controlled, double-blinded study of 68 healthy adults demonstrated no difference in
25 (OH)D levels when supplemented with 1000 IU vitamin D3 or 1000 IU vitamin D2, or
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500 IU vitamin D2 plus 500 IU vitamin D3 daily [37]. Heaney et al, in a single blind
randomized controlled trial in 33 healthy, Caucasian adults compared weekly 50,000 IU D2
vs. D3 and found higher peak 25 (OH)D levels and higher calciferol content in fat tissue in
the cholecalciferol group [38]. There are no studies comparing ergocalciferol and
cholecalciferol in children with CKD.
Doses required to maintain normal 25 (OH) D levels once repletion is achieved are not
known. The 2008 KDOQI clinic practice guidelines for nutrition in children with CKD give

a wide range of 200–1000 units daily as maintenance doses and recommend annual
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monitoring of levels [20]. The adequacy of these doses needs to be studied. Certain groups
of children, especially those with proteinuric diseases and those living in northern latitudes,
may need more frequent assessment of levels. Adolescents are notorious for non-compliance
with medications and may need a more diligent follow up of levels.
There are very few small studies of vitamin D supplementation in pediatric CKD and all
have used different dosing regimens of either ergocalciferol or cholecalciferol. Most of them
have shown improvement in 25(OH)D levels and decrease in PTH levels post
supplementation [21–23].
Recently Shroff et al tested the hypothesis that nutritional vitamin D (ergocalciferol)

supplementation in children with CKD stages 2–4 delays the onset of secondary
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hyperparathyroidism in a randomized, double-blinded, placebo-controlled study in children

with CKD 2–4. Forty-seven children were 25(OH)D-deficient and randomly assigned to
receive ergocalciferol or placebo. Nine of 20 children on placebo and 3 of 20 children on
ergocalciferol developed hyperparathyroidism (odds ratio, 4.64; 95 % confidence interval,
1.02–21.00). The time to development of hyperparathyroidism was significantly longer with
ergocalciferol treatment compared with placebo (hazard ratio, 0.30; 95 % confidence
interval, 0.09–0.93, P00.05). They concluded that ergocalciferol is an effective treatment that
delays the development of secondary hyperparathyroidism in children with CKD 2–3 [39].
Calcitriol and alfacalcidol are widely used in children to suppress PTH levels. They have
demonstrated efficacy when given in daily or intermittent doses [40, 41]. Newer vitamin D
receptor activators (VDRA) have been developed to maximize affinity for parathyroid tissue,
while minimizing the adverse effects of increased calcium and phosphorus absorption.
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Doxercalciferol (1α-hydroxyvitamin D2) and paricalcitol (19-nor-1,25-dihydroxyvitamin

D2) are the two new VDRA’s available in the United States. Doxercalciferol was found to be
as effective as calcitriol in controlling PTH levels and suppressing bone formation rate in a
randomized trial of 60 children on peritoneal dialysis. There was no difference in
phosphorus levels between the two groups [42]. Paricalcitol decreased iPTH levels in
children receiving hemodialysis with no significant changes in serum calcium, phosphorus,
or Ca × P product in a double blind, placebo-controlled trial in pediatric patients on
hemodialysis [43]. In a retrospective analysis comparing IV calcitriol and Paricalcitol, both
were equally effective in lowering PTH. However, more episodes of elevated calcium ×
phosphorus product were seen in the calcitriol group [44].
Adverse Effects of Vitamin D

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Active vitamin D can cause hypercalcemia and hyperphosphatemia. In dialysis patients

1,25(OH)2D levels correlated with carotid artery intima media thickness (cIMT), carotid
artery stiffness and carotid artery calcifications (CAC). cIMT and CAC scores were
significantly higher at both low and high 1,25(OH)2D levels [45]. This suggests a narrow
therapeutic window for the use of these compounds.

Vitamin D and Growth

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Growth failure in CKD is multifactorial. Renal osteodystrophy alters growth plate

physiology. PTH levels required for normal growth are not well defined. Adynamic bone
diseases as well as elevated PTH levels result in growth suppression.
Langman et al in a prospective study of 9 children with moderate CKD demonstrated a

significant correlation between pre therapy and 1 y values of growth velocity and 25(OH)D
concentrations. There was improvement in linear growth velocity from below 2 SD in the
pre therapy year to normal range (+/− 2 SD) [46]. Chesney et al also showed increased
growth after supplementation with 1,25 (OH) 2D for 26 mo in 6 preadolescent children with
renal osteodystrophy [47]. Chan et al demonstrated improved growth velocity in pre pubertal
children with severe CKD (GFR <20 ml/min) after 1,25-dihydroxyvitamin D treatment [48].
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These were small non-randomized studies. The role of vitamin D in growth failure needs to
be evaluated in large clinical trials.
Vitamin D and it Potential Renoprotective Actions

Vitamin D analogues can affect renal outcomes by affecting proteinuria, blood pressure and
inflammation. Most of the clinical data for these outcomes is in adults.
Multiple animal models have suggested a role for active vitamin D in cardiac structure and
function, albuminuria, and kidney fibrosis. The hemodynamic and proinflammatory actions
of the activated renin angiotensin aldosterone system (RAAS) have been shown to play an
important role in the progression of CKD, 1,25(OH) 2D being negative regulator of this
system [12]. The vitamin D receptor knockout mice develop elevated BPs and left
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ventricular hypertrophy [18], which occurs due to a rise in renin consequent to loss of
normal suppression of the renin-angiotensin system by vitamin D [19]. In rats with
spontaneous hypertension, treatment with vitamin D analogs ameliorates left ventricular
hypertrophy and improves left ventricular diastolic measures [20]. Mizobuchi et al showed
that combined therapy with enalapril and paricalcitol significantly decreased proteinuria,
glomerulosclerotic index, and tubulointerstitial volume in uremic rats [49].
Vitamin D and Proteinuria

There are now a few randomized control trials in adults that have evaluated the effect of
active vitamin D therapy on albuminuria [50, 51]. Agarwal et al in a double-blind,
randomized, placebo-controlled trial evaluated the safety and efficacy of oral Paricalcitol.
CKD Stage 3–4 patients with secondary hyperparathyroidism were randomized to oral
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Paricalcitol or placebo and followed for 24 wk. Patients on Paricalcitol (regardless of age,
sex, race, diabetes mellitus, hypertension, or use of ACEI/ARB) were more likely (OR=3.2,
95 % CI 1.5–6.9) to have reduction of proteinuria [52].
The VITAL study, a large, randomized placebo controlled trial of Paricalcitol (1 and 2 µg) in
281 subjects with type 2 diabetes and proteinuria showed significant reduction in urine
albumin creatinine ratios with a dose dependent reduction in proteinuria when compared to
placebo [53].

Vitamin D and Blood Pressure

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Observational studies have shown an association between lower 25(OH)D levels and
incident hypertension in the non-CKD population [54]. The VITAL study described above
also showed that BP was significantly lower in the participants randomized to the 2 µg dose
by a mean of approximately 8 mmHg [53]. There is only one pediatric study that compared
the effect of a 2 µg/m2 dose of IV 1,25-dihydrocholecalciferol in 7 children on hemodialysis
and 7 healthy controls. Children on dialysis showed normalization of BP and insulin
sensitivity [55].
Vitamin D and Progression of Chronic Kidney Disease

Epidemiological studies have shown low 25(OH)D and 1,25 (OH) 2D levels to be
independent predictors of disease progression and death in patients with CKD and End Stage
Renal Disease (ESRD) [56, 57].
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Melamed et al evaluated the contribution of low 25(OH) D levels to the incidence of ESRD
using data from the Third National Health and Nutrition Examination Survey-linked
Medicare claims files. 25(OH)D levels<15 ng/ml were associated with increased risk for
ESRD after multivariable adjustment [58]. Ravani et al followed 168 adult Caucasian
patients with CKD for 6 y. Forty eight started dialysis and 68 died after average follow up of
4 y. 25(OH)D predicted both time to death and end-stage renal disease on crude as well as
after multivariable adjustment [59].
Use of activated vitamin D has been associated with slower progression of chronic kidney
disease and improved survival in adult CKD and ESRD patients [ 60–62]. There are no
pediatric studies that have evaluated the association of CKD progression with vitamin D
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levels or activated vitamin D use.
Vitamin D and Cardiovascular Effects in CKD

Experimental studies suggest that active vitamin D analogues at low doses protect against
aortic calcification, prevent cardiac/vascular remodeling, reverse LVH, ameliorate
myocardial renin over expression and lower blood pressure [63, 64].
However, recently reported results of the PRIMO trial, a randomized double blinded study of
CKD 3–4 subjects, investigating effects of oral paricalcitol compared to placebo on LVMI,
failed to show any reduction in left ventricular mass after 48 wk of treatment.
Patange et al explored the relationship between parameters of calcium–phosphorus

metabolism including 25(OH)D and arterial wall stiffness in 43 pediatric patients with CKD/
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ESRD, who had no history of underlying congenital or structural cardiac disease. Multiple
regression analysis showed that 25(OH)D was the only significant independent predictor of
increased central arterial stiffness in the subgroup of children receiving hemodialysis [65].
Vitamin D and Inflammation

Uremia is a state of chronic inflammation and preclinical data suggests active vitamin D
decreases inflammatory biomarkers [66, 67].

Alborzi et al evaluated change in hsCRP in a randomized controlled trial of 24 patients,

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allocated to placebo,1 and 2 µg of Paricalcitol. The CRP levels showed a 50 % increase in

the placebo group and a decrease of 20 and 30 % in the 1 and 2 µg groups respectively [51].
Kalkwarf et al evaluated 182 patients (ages 5 to 21) with CKD stages 2 to 5 and found 33 %
of them had 25(OH)D levels <20 ng/ml. The lower 25(OH)D levels were associated with
higher levels of inflammatory markers (C-reactive protein and IL-6), despite adjusting for
the severity of kidney disease [25].
Vitamin D Supplementation in CKD: Nutritional vs Active Form?

The big unanswered question is whether to supplement with active or nutritional vitamin D.
25(OH)D concentrations are 1000 times higher than 1,25(OH) 2D and may overcome VDR
resistance seen in uremia. Local extrarenal calcitriol production is substrate dependent and
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requires sufficient levels of 25(OH)D for paracrine actions. However at GFR<50 ml/min,
active vitamin D compounds are also needed. 1,25(OH) 2D facilitates cellular uptake of 25
(OH)D in uremic states by enhancing megalin expression. It seems that combined use of
nutritional and activated vitamin D may be synergistic for both the classic and non-classical
actions. However, combined use of these agents needs to be studied for dosage and potential
toxicity.
Conclusions
Vitamin D deficiency is highly prevalent in CKD. Correction of 25(OH)D deficiency may
prevent early secondary hyperparathyroidism. Dosage guidelines for 25(OH)D deficiency
management in children are opinion based. Normal 25(OH)D levels in late CKD are
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desirable to provide adequate substrate for the paracrine, non calcemic actions of
1,25(OH)2D. Active vitamin D compounds for treatment of secondary hyperparathyroidism
have to be used judiciously to prevent cardiovascular complications.
Prospective studies such as CKiD and 4 C should help to evaluate the role of vitamin D
insufficiency/deficiency in growth failure, progression of chronic kidney disease and
cardiovascular outcomes. Randomized clinical trials are needed to define the dosage and
monitoring guidelines for treating vitamin D deficiency, optimum PTH levels for growth and
to compare the effectiveness of different vitamin D receptor agonists.
Acknowledgments
Role of Funding Source Dr. Kumar is supported by a K 23 grant, DK084339 from the National Institute of
Author Manuscript
Diabetes and Digestive and Kidney Diseases, National Institutes of Health.
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Table 1
Recommended supplementation for vitamin D deficiency/insufficiency in patients with CKD
Serum 25 Definition Dose of ergocalciferol/cholecalciferol Duration

(OH)D
(ng/ml)
<5 Severe 25(OH)D deficiency −8,000 IU/d orally or enterally for 4 wk or (50,000 IU/wk for 4 wk); followed by 3 mo
4,000 IU/d or (50,000 IU twice per mo for 2 mo)
5–15 Mild 25(OH)D deficiency 4,000 IU/d orally or enterally for 12 wk or (50,000 IU every other wk, for 12 wk) 3 mo
16–30 25 (OH)D insufficiency 2,000 IU daily or (50,000 IU every 4 wk) 3 mo
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UJIAN TENGAH SEMESTER FARMASI KLINIK

Nama : Trinda Irene Arung

 STUDY KASUS NO. 15

Parameter Nilai normal Hasil pemeriksaan

Nama obat Dosis Frekuensi Rute

Problem medik Terapi DRP Keterangan

No Rekomendasi Alasan Monitoring

Response to Clopidogrel and Its Association with Chronic

(Intern Med 53: 215-219, 2014)

the patients had clopidogrel resistance (7-9). Several factors,

The PRU results are shown in Fig. 1. The patients with

ing to a diminished platelet effect. Furthermore, in patients

Ⓒ 2014 The Japanese Society of Internal Medicine

Published in final edited form as:

Metformin in Patients With Type 2 Diabetes and

and Darren K. McGuire, MD, MHSc

Copyright 2014 American Medical Association. All rights reserved

CONCLUSIONS AND RELEVANCE—Available evidence supports cautious expansion of

allow greater access to metformin in the United States is under consideration.

JAMA. Author manuscript; available in PMC 2015 May 11.

glomerular filtration rate. We retrieved English-language human studies published between

Current US Food and Drug Administration Prescribing Guidelines for

• Metformin ―should not be initiated in patients ≥80 years of age unless

Source: Metformin final printed labeling.2

JAMA. Author manuscript; available in PMC 2015 May 11.

The pharmacokinetics of metformin differ substantially from those of phenformin, an

JAMA. Author manuscript; available in PMC 2015 May 11.

and predisposition to hyperlactatemia.

The Relationship Between Metformin and Lactic Acidosis—Lactic acidosis is an

antihyperglycemic drugs, however.

Kajbaf and Lalau49 examined the quality of pharmacovigilance reporting of cases of

JAMA. Author manuscript; available in PMC 2015 May 11.

1959-1999. There was generally very low interobserver agreement as to causation ( K =

JAMA. Author manuscript; available in PMC 2015 May 11.

using other single agents.

JAMA. Author manuscript; available in PMC 2015 May 11.

Adherence to Current Prescribing Guidelines—Eppenga et al56 and Richy et al57

Other Treatment Options

glucosuric agents if kidney function is impaired.78

JAMA. Author manuscript; available in PMC 2015 May 11.

Current Clinical Practice Guidelines

Controversial/Unresolved Issues, Areas for Future Research

JAMA. Author manuscript; available in PMC 2015 May 11.

JAMA. Author manuscript; available in PMC 2015 May 11.

33(6):1291–1293. [PubMed: 20215446]

JAMA. Author manuscript; available in PMC 2015 May 11.

191–195. [PubMed: 21261578]

32. Seidowsky A, Nseir S, Houdret N, Fourrier F. Metformin-associated lactic acidosis: a prognostic

Med Pharmacol Sci. 2013; 17(suppl 1):45–49. [PubMed: 23436666]

JAMA. Author manuscript; available in PMC 2015 May 11.

JAMA. Author manuscript; available in PMC 2015 May 11.

Metab Res. 2008; 40(7):491–497. [PubMed: 18401838]

Type 2 Diabetes. CDA website. http://guidelines.diabetes.ca/Browse/Chapter13. Accessed August

JAMA. Author manuscript; available in PMC 2015 May 11.

JAMA. Author manuscript; available in PMC 2015 May 11.

234 Outpatient 36 (15.4) eGFR <60 No cases

Scotton 283 Hospital 17 (6.0) SCr >1.5 (men) Not reported

Kamber et 425 Outpatient 78 (8.4) eGFR <60 b

92 Outpatient 4 (4.4) Not reported

Sweileh et 124 Outpatient 34 (27.4) Renal impairment Not reported

11 297 Outpatient 880 (25.5) eGFR <60 Unknown

Kennedy 4838 Outpatient 219 (4.5) eGFR <60 Not reported

Millican 83 Hospital 12 (14.5) eGFR <50 or Not reported