Management of type 2 diabetes in

patients with renal deterioration

Diabetes: A Healthcare “Tsunami”

IDF Diabetes Atlas, 2015

 Diabetes Melitus
“Penyakit menahun yang ditandai dengan kadar glukosa darah yang
melebihi nilai normal (hiperglikemia).Terjadi gangguan metabolisme
karbohidrat akibat produksi insulin kurang atau krn resistensi insulin”
GULA DARAH
S
S S

400
S S
S S S

GLUKOSA S S S

S S S
S

Aliran Darah
S S
S S S
S

300
S S S
S S
S S
S
S
S
S
S S S
S S S
S S S

S S S
S S S

200
S S
S S
S S S
S S
S S
S S S S
S S
S S
S S
S S
S S S
S

S
S
S
100
S S S S S S S
S S S
S S
S S S
S S S S S S
S
S S
S S
S
S

S S
S S S
S
S S
S S
S

SEL
S

Sel
S

S S

S
S
Lemak SEL
SEL
Sel
S

Se l Otot
H a ti
3
 Glukosa
METABOLISME
Karbohidrat merupakan sumber
KARBOHIDRAT
energi utama selain lemak
Polisakarida

Karbohidrat ada dalam bentuk Karbohidrat

polisakarida
Disakarida
Glukosa : Produk akhir Maltosa, Laktosa, Sukrosa
metabolisme karbohidrat, bentuk
monosakarida yang diserap oleh
Monosakarida
tubuh
Glukosa, Galaktosa, Fruktosa

4
 Metabolisme Karbohidrat
SAL. CERNA SEL (Otot, Hati, Otak, dsb)

Glikogen Lemak/
Karbohidrat
Protein
Glukosa
Enzim Glukosa Piruvat
(darah)

Glukosa E Siklus
Krebs
N
Insulin
E
R Fosforilasi
Oksidatif
G
I 5
Organ penting yang berperan dalam
Pankreas
metabolisme karbohidrat, lemak & protein

6
 Insulin
Hormon yang
dikeluarkan oleh sel β
pankreas yang
berperan dalam
Fungsi
metabolisme
menormalkan kadar glukosa
karbohidrat
dalam tubuh melalui proses :
• Glikogenesis (hati dan otot)
• Up take glukosa oleh jaringan
perifer dan oksidasi glukosa
• ↓↓Glikogenolisis (Pemecahan
Glikogen → Glukosa) &
glukoneogenesis
• ↓↓lipolisis dan ketogenesis
Glukagon
Hormon yang dikeluarkan oleh
sel α pankreas yang berperan
pada metabolisme karbohidrat
Fungsi
meningkatkan kadar glukosa
dalam tubuh bila tubuh
kekurangan glukosa melalui
proses :
• Glikogenolisis : glikogen →
glukosa dlm hati
• Glukoneogenesis :
pembentukan glukosa dari
senyawa organik lain
• Up take glukosa oleh jaringan
perifer diturunkan
Type 2 diabetes significantly increases risk of complications1,2

1. International Diabetes Federation. Time to Act. 2001. http://www.idf.org/webdata/docs/Diabetes%20and%20CVD.pdf. Accessed February 28, 2012.
2. Seaquist ER. Diabetes. 2010;59:4-5.
Type 2 diabetes—CVD is a leading cause of death

Emerging Risk Factors Collaboration. N Engl J Med. 2011;364(9):829-841.

Type 2 diabetes—approximately one-half of
patients are uncontrolled

Wong ND, et al. Persistent undertreatment of cardiovascular risk factors among subjects with type 2 diabetes in the United States 2005-2006. Presented at:
American Diabetes Association 70th Scientific Sessions; June 25-29, 2010; Orlando, FL.
Type 2 diabetes—many therapies are associated with weight
gain over time1,2

1. Inzucchi SE, et al. ADA/EASD Position Statement. Diabetes Care. 2012;35:1-16. Epub 20 April 2012. 2. Mitri J, Hamdy O. Expert Opin Drug Saf. 2009;8(5):573-584.
Type 2 diabetes—controlling multiple parameters is essential

Incremental reductions sustained

over time in HbA1c and other
parameters can benefit the
physical health of patients with
type 2 diabetes1-5

1. Stratton IM, et al. BMJ. 2000;321:405-412. 2. Pi-Sunyer FX. Postgrad Med. 2009;121(5):94-107. 3. Williamson DF, et al. Diabetes Care. 2000;23(10):1499-1504. 4.
Patel A. Lancet. 2007;370(9590):829-840. 5. Pyǒrälä K, et al. Diabetes Care. 1997;20(4):614-620.
Type 2 diabetes—guidelines recommend managing multiple
parameters1-5

Although the EASD and ADA Guidelines each set forth specific HbA1C target goals, an ADA/EASD Joint Position
Statement on management of hyperglycemia (2012) recommends that treatment targets be individualized. 6
ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes; ESC=Task Force on Diabetes and Cardiovascular Diseases of the
European Society of Cardiology; AACE=American Association of Clinical Endocrinologists; CDA=Canadian Diabetes Association; WHO=World Health Organization.

1. Guidelines for the prevention, management and care of diabetes mellitus. Cairo, Egypt, World Health Organization, 2006. 2. The Task Force on Diabetes and
Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J. 2007;28:88-
136.
3. American Diabetes Association. Diabetes Care. 2012;35(suppl 1):S4-S10. 4. Handelsman Y, et al. American Association of Clinical Endocrinologists Medical
Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17(suppl 2):1-53. 5. Canadian Diabetes
Association Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2008;32(suppl 1):S1-S201. 6. Inzucchi SE, et al. ADA/EASD Position Statement. Diabetes
Care. 2012;35:1-16.
The need for a pathway that acts
independently of insulin in
type 2 diabetes
Multiple Defects Contribute
to the Pathophysiology of T2DM1
Glucose β Insulin
production secretion

Glucagon Glucose
secretion α uptake
Chronic
Hyperglycemia

Incretin
Lipolysis
effect

Glucose Neurotransmi
reabsorption tter function

 To help improve glycemic control, treatments with complementary

mechanisms of action should be considered to be used in combination2
T2DM=type 2 diabetes mellitus.
1. DeFronzo RA. Diabetes. 2009;58:773-795.
2. Garber AJ et al. Endocr Pract. 2013;19:536-557.
Type 2 diabetes—characterized by insulin resistance and β-
cell dysfunction1-4

1. Ramlo-Halsted BA, et al. Prim Care. 1999;26(4):771-789. 2. Piya MK, et al. Br J Clin Pharmacol. 2010;70(5):631-634. 3. DeFronzo RA. Med Clin N Am.
2004;88(4):787-835. 4. Stratton IM, et al. BMJ. 2000;321:405-412.
Continuous Glucose Reabsorption Perpetuates the Cycle of
Glucotoxicity in Patients With Type 2 Diabtes1–3
Reabsorption
↓ Peripheral glucose uptake of filtered glucose back
into the bloodstream
via SGLT2

Type 2
Diabetes:
Chronic
Hyperglyce
mia

Prolonged hyperglycemia, exacerbated by continued glucose reabsorption,

contributes to a vicious cycle of glucotoxicity in the progression of type 2
diabetes
SGLT=sodium-glucose cotransporter.
1. DeFronzo RA. Diabetes. 2009;58:773-795.
2. Gerich JE. Diabet Med. 2010;27:136-142.
3. Poitout V et al. Endocr Rev. 2008;29:351-366.
Definitions of kidney disease

Chronic kidney disease (CKD): abnormalities of kidney

structure or function, present for >3 months, with
implications for health1
Diabetic kidney disease (DKD): refers to kidney disease that is
specific to diabetes; based primarily on the presence of
elevated albumin in the urine2
Diabetic nephropathy (DN): damage to the kidney caused by
diabetes;
kidney biopsy may help for definitive diagnosis2,3
The terms DKD and DN are often used interchangeably; both ultimately lead to
CKD1–3

1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int Suppl 2013;3:1;
2. National Kidney Foundation. KDOQI™ Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis
2007;49:S1-S180;
3. Haneda M et al. J Diabetes Invest 2015;6:242

GPM-TJTJD-0015-ID
1
Estimated glomerular filtration rate is the
most commonly used index of renal function

• eGFR is generally reduced after widespread structural damage to the kidney

• It is categorised as follows:

Normal Mildly Mildly-to- Moderately- Severely Kidney

decreased moderately to-severely decreased failure
decreased decreased
≥90 60–89 45–59 30–44 15–29 <15

eGFR (ml/min/1.73 m2)

eGFR, estimated glomerular filtration rate

Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int Suppl 2013;3:1

1
Albuminuria is a key marker of kidney damage
• Albuminuria indicates increased glomerular permeability
• Albuminuria can be categorised according to urine albumin-to-creatinine ratio
or to 24 h urine albumin excretion, as follows:

Normal to mildly increased Microalbuminuria/ Macroalbuminuria/

moderately increased* severely increased*

UACR (mg/g) <30 30–300 >300

24 h UAE (mg/24 h) <30 30–300 >300

*Note that KDIGO 2012 guidelines recommend avoiding the terms microalbuminuria and macroalbuminuria. UACR, urine albumin-to-creatinine
ratio; UAE, urine albumin excretion Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int Suppl 2013;3:1

2
 eGFR and albuminuria are key indicators
of renal function
eGFR is generally reduced in case Albuminuria indicates increased
of damage to the kidney glomerular permeability

Normal Normal to mildly increased

UACR (mg/g) or 24 h UAE (mg/24 h)

≥90 <30
Mildly decreased
eGFR (mg/ml/1.73 m2)

60–89
Mildly to moderately decreased Microalbuminuria/
45–59 moderately increased*
Moderately to severely decreased 30–300
30–44
Severely decreased
15–29
Macroalbuminuria/
Kidney failure severely increased*
<15 >300

*KDIGO 2012 guidelines recommend avoiding the

GPM-TJTJD-0015-ID
 eGFR and albuminuria categories
indicate CKD prognosis
Low CKD risk Albuminuria stages, description and range (mg/g)
(if no other markers of kidney disease, no CKD)
Moderately increased risk A1 A2 A3

High risk Normal to mildly Moderately Severely

increased increased increased
Very high risk
<30 30–300 >300
G1 Normal or high ≥90
description and range

G2 Mild decrease 60–89

GFR categories,

(ml/min/1.73 m2)

Mild–moderate
G3a 45–59
decrease
Moderate–severe
G3b 30–44
decrease
G4 Severe decrease 15–29
G5 Kidney failure <15

CKD, chronic kidney disease; GFR, glomerular

filtration rate
 Measuring renal function
• GFR is not easy to measure directly in clinical practice1
• Instead, it is estimated from equations using serum creatinine level, age, race,
sex and body size:

• MDRD formula: estimates glomerular filtration rate (eGFR)2

• CKD-EPI equation: developed to provide a more precise eGFR than the MDRD
formula in the higher range of GFR2,3
• Cockcroft–Gault formula: estimates creatinine clearance (eCrCl)4

• GFR is considered the best overall index of renal function5

• UACR evaluation may be more relevant in specific clinical contexts; both should be used in
clinical assessment6

CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-
creatinine ratio; MDRD, Modification of Diet in Renal Disease
1. Levey AS et al. Ann Intern Med 2009;150:604; 2. Levey AS et al. Ann Intern Med 1999;130:461; 3. Levey AS et al. Ann Intern Med
2006;145:247;
4. Cockcroft DW & Gault MH. Nephron 11976;16:3; 5. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int
Suppl 2013;3:1; 6. Polkinghorne KR et al. Clin Biochem Rev 2014;35:67 2
Topics
• Kidney disease and measurement
• Renal complication as result of diabetes
• Diabetes kidney disease
• Use of Linagliptin in T2D with renal impairment

GPM-TJTJD-0015-ID
 Approximately 40% of T2DM patients have
renal complications
• Typical progression of CKD†1

CKD CKD eGFR % of T2DM

2 stage (mL/min) pts
CKD CKD
3 Missing data – ~9.5%
1

CKD No CKD ≥90* ~50.8%

4–5 1 ≥90** ~9%
2 60–89 ~11%
No
CKD 3 30–59 ~18%
4–5 <29 ~2%
* No signs of kidney damage
** Albuminuria – kidney damage

†Based on data from 1462 patients aged ≥20 years with T2DM who participated in the Fourth National Health
and Nutrition Examination Survey . (NHANES IV) in the years 1999 through 2004
1. Koro CE, et al. Clin Ther 2009;31:2608–17.
Patients with diabetes are at high risk of
kidney disease
• Diabetes remains the most common
reason for progression to end-stage
renal disease in many parts of the
world1−2
• DKD is a strong predictor of mortality
in patients with diabetes3,4
• DKD occurs as a consequence of 10–40%
multiple pathogenic pathways in the
diabetic kidney1
• Hyperglycaemia plays a major, but
not exclusive, role Up to 40% of those
with T2D will eventually
suffer from kidney
failure2,5
DKD, diabetic kidney disease; T2D, type 2 diabetes
1. Toth-Manikowski S & Atta MG. J Diabetes Res 2015;2015:697010; 2. Stewart JH et al. Nephrology 2007;12:520;
3. Reidy K et al. J Clin Invest 2014;124:2333; 4. USRDS. Am J Kidney Dis 2003;42:1;
5. National Kidney Foundation. 2015. www.kidney.org/atoz/content/diabetes (accessed 22 Feb 2016)
GPM-TJTJD-0015-ID
2
 Typical pattern of kidney damage in T2D
patients

Glomerulus from a patient with Glomerulus from a patient with typical

near-normal renal structure diabetic nephropathology
Mild
interstitial
fibrosis

Advanced
arteriolar
hyalinosis

Minimal mesangial expansion Diffuse mesangial expansion

T2D, type 2 diabetes

Fioretto P et al. Diabetologia 1996;39:1569
Photographs courtesy of Dr Fioretto GPM-TJTJD-0015-ID
2
 Mortality risk doubles* in co-morbid
T2DM and CKD
Mortality among Medicare patients, 2-
year
40 follow-up (N=1.1 million)1
32.3
30
Patients (%)

29.5

20
15.7
10 10.3

0
No T2DM, T2DM, CKD, T2DM,
no CKD no CKD no T2DM CKD
* Relative to diabetes alone.
1. Collins AJ, et al. Kidney Int 2003;64(suppl 87):S24–S31.
Mortality is more frequent in T2D patients with
kidney disease than in those without

Increased
mortality

70
Standardised 10-year cumulative

47.0%
incidence of mortality (95% CI)

60
50
40 23.9%
17.8% Excess
30 mortality
20 4.1%
10 7.7%

0
No kidney Albuminuria Impaired GFR Albuminuria & No diabetes, no
disease impaired GFR kidney disease

Percentages indicate absolute excess mortality above the reference group (individuals with no diabetes
or kidney disease)
*No diabetes and no kidney disease; GFR, glomerular filtration rate; T2D, type 2 diabetes
Afkarian M et al. J Am Soc Nephrol 2013;24:302 2
Diabetic kidney disease

Kidney disease is a common complication of diabetes

– Up to 40% of patients with T2D will eventually suffer from kidney failure

Albuminuria (marker of kidney damage) and reduced eGFR are key

criteria in the diagnosis of DKD

Impaired renal function is associated with increased CV and

mortality risk

Intensive multifactorial treatment is effective in reducing CV and renal

outcomes, but many patients still experience disease progression

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3
A multifactorial intervention strategy is
recommended in DKD

Glucose
HbA1c target individualised, but
generally ~7%1
BP Target of <130/80 mmHg2

ACEi/ARB Use ACEi or ARBs when albumin excretion ≥30

mg/g1
Lipids Lipid-lowering recommended to reduce risk of
atherosclerotic events; statins not recommended in
patients on haemodialysis1
ACEi, angiotensin-converting-enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; DKD,
diabetic kidney disease;
HbA1c, glycated haemoglobin
1. National Kidney Foundation. Am J Kidney Dis 2012;60:850;
2. NICE. Clinical guideline: Type 2 diabetes (CG87), May 2009 GPM-TJTJD-0015-ID
3