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ADA 2014: Update

Dr. D. A. Khandke MD
AVP- Medical Services
Broad Topics of Interest
Vitamin D:
Diabetic Kidney Disease:
Diabetic Neuropathy
Diabetic Retinopathy
Diabetic Dyslipidemia
Gestational DM
SU usage
Metformin Use and Vit B12 def
Meet the Experts
New Molecules Discussed
What was HOT at ADA 2014
New Anti-Obesity Molecules licensed by FDA


Association of Vitamin D Deficiency with Insulin
Resistance in Newly Detected Diabetics and with
Cardiovascular Risk Factors in All Diabetics in
South India- Indian Data

- 76% (35 out of 46) of patients who had high FPG,
hypertension had low (i.e. <20 ng/ml) Vitamin D level.
- Correlation coefficient between insulin resistance and
Vitamin D levels is -0.32 in the 23 newly detected
diabetics.
Vitamin D & Diabetes
Association of Vitamin D Deficiency with Insulin Resistance
in Newly Detected Diabetics and with Cardiovascular Risk
Factors in All Diabetics in South India- Indian Data

- Correlation values between Vitamin D level and FPG,
hypertension are -0.44, and -0.40.

Conclusion
- Vitamin D has a role in better management of patients
with diabetes mellitus and metabolic syndrome.
- It can indirectly help in reducing cardiovascular
morbidity and mortality

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Vitamin D & Diabetes
Vitamin D & Diabetes
Correlation between 25(OH) Vitamin D Levels and Diabetic
Nephropathy Progression among Japanese Type 2 Diabetes
Patients

- Lower 25(OH) vitamin D levels were independently
associated with a higher risk of death and diabetic
nephropathy progression


Link between Atherogenic Dyslipidemia (AD),
Macroangiopathy and Vitamin D Deficiency (VDD) in
T2DM Patients
- Vitamin D-deficient patients had a significantly much higher
prevalence of macroangiopathies and AD prevalence
Vitamin D
Without VDD VDD
%Relative
Increase in
prevalence
Atherogenic
Dyslipidemia
32% 46% 44%
Macroangiopath
y
44% 57% 30%
Vitamin D Inhibits Human Platelet Aggregation (PA):
Implications for Hypercoagulable State in Diabetes

- Vit. D
3
and 1,25 D
3
significantly decrease human PA which
suggest that platelets may possess enzymatic machinery
to activate D3 to 1,25 D3.



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Vitamin D
Implication: Due to its unique mitochondrial location, VDR
(Vitamin D Receptors) in platelets may be a potential target
for new pharmacological agents for treatment and/or
prevention of CV events
Vitamin D Levels, Body Composition, and Metabolic
Factors in Asian Indians: Results from the MASALA
Study
- Lower vitamin D levels are associated with worse
metabolic and cardiovascular (CV) risk
- Asian Indians have more vitamin D deficiency, adiposity,
and type 2 diabetes compared to Whites
- Vitamin D deficiency was associated with higher blood
pressure and fasting glucose overall, and with higher
adiposity measures in women alone
- Lower 25-OH vitamin D level was associated with higher
fasting glucose levels among Asian Indian women.
Vitamin D: MASALA study
Diabetic Kidney Disease:
Management
BP levels:
JNC 8 <140/90
ADA <140/90
KDIGO <140/90
ESH/ESC <140/85

ARB data positive with RENAAL & IDNT
Keep ACE/ARB till refractory hyperkalemia (also with
diuretic use)
Dont combine ARB and ACE
Diabetic Kidney Disease: Some
Interesting Studies
Comparison of Statins on Kidney Function in
Patients with Type 2 Diabetes
- In an analysis using the IPTW method, patients treated
with pravastatin also had a significantly slower eGFR
decline (0.8 0.3 mL/min/1.73 m 2/year) than those
treated with rosuvastatin (1.8 0.3 mL/min/1.73 m2/year,
P= 0.012), atorvastatin (1.9 0.3 mL/min/1.73 m 2/ year,
P= 0.004) and pitavastatin (2.3 0.7 mL/min/1.73
m2/year, P= 0.040)

- Pravastatin may be superior to rosuvastatin, atorvastatin,
and pitavastatin in preserving kidney function in type 2
diabetic patients

Podocyte B7-1 Inhibition as a Therapeutic
Strategy for Diabetic Nephropathy

- Glomerular podocytes, damaged during diabetic
nephropathy (DN), may express B7-1 (or CD80).
- B7-1 upregulation leads to podocyte alteration and specific
B7.1-targeting therapy (CTLA4-Ig/Abatacept) may be
protective from high glucose(HG)-induced damage

- Compound candidate B7-1 as a new therapeutic target
for DN.

Diabetic Kidney Disease: Some
Interesting Studies
Diabetic Neuropathy
Drugs in Diabetic Neuropathy: Lidocaine, Duloxetine,
Pregabalin, Tapentadol
Guidelines: Amitryptyline, Duloxetine, gabapentine,
pregabalin, venlaflaxine, topical clonidine, topical capsaicin
patch(first line)
Tapentedol (rescue medicine)
Opioids (3
rd
line)


L-methylfolate Calcium (as Metafolin

) 3mg
Pyridoxal 5-phosphate 35mg
Methylcobalamin 2mg
Mentax Trial:
Results:
Sensory Score/NTSS-6 score improved
Primary end point not reached
24 weeks not enough for disease modification at least 3
yrs required

Diabetic Neuropathy
Diabetic Retinopathy
Only FDA approved: Ranibizumab
Anti-VEGF standard
Proliferative Diabetic Retinopathy- Laser but could
be Anti-VEGF

Diabetic Dyslipidemia
Fenofibrate Protects Against Adverse Effects of the
In Vitro Diabetes Metabolic Environment on
Telomeres and Trf Gene Regulation
- Can have implications to decreased
complications of DM

Metabolic Syndrome
Correlates of IGT and Diabetes in South
Asians: Results from the MASALA Study
- Most factors of the metabolic syndrome remained
independently associated with IGT and DM even after
accounting for insulin resistance and cell function.
- Central adiposity and insulin resistance appear to be
stronger correlates of IGT and DM than lower cell
function.
- Further investigation is needed to better understand why
lower socioeconomic status contributes to significantly
greater IGT risk.

Gestational Diabetes
Use of Glyburide (5mg BID) + Metformin (500 mg BID)
Pro:
- No long term ill effects on infants (Rowan et al, Diabetes Care
2011)
- Metformin freely passes placenta, Glyburide does not)
Con:
- Pregnancy is insulin resistant state, GDM has poor insulin
secretion
- ACOG guidelines recommend only insulin
- Glyburide failure rate higher and metformin is
pharmacologically active in infants

MAJORITY OF AUDIENCE WAS AGAINST THERAPY

Metformin-Pregnancy
Predictors of Metformin Failure in Gestational
Diabetes Mellitus (GDM)
- GDM is common and affects up to 18% of pregnancy. After
dietary failure, insulin is the only universal acceptable option
to control glycaemia but metformin is being increasingly
used
- Metformin was given in 66%(151/228) and 58.9%(89/151) of
the metformin-treated needed insulin. Both groups had
similar post-treatment HbA1c (5.45 vs 5.5, p=0.49)
- Metformin failure was predicted with 67% sensitivity and
63% specificity if GTT fasting >4.8mmol/l, and 87%
sensitivity and 64% specificity if GTT fasting >4.8mmol/l, or if
4.8 & GA at dietary failure 27 +5 weeks.
Predictors of Metformin Failure in Gestational
Diabetes Mellitus (GDM)

- There were no differences in birth weight, APGAR at 1 and
5 minutes and caesarean section rates.
- Premature delivery (<37weeks) were higher in the failure
group (OR: 11.3; 95%CI 1.43,89.15).
- Starting metformin early, at diagnosis, based on the fasting
glucose may provide a better treatment strategy and
success with metformin.

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Metformin-Pregnancy
Sulphonylurea Use
Popularity of Sulfonylureas (SU) in Real-World Practice:
Perspectives from Diabetes FORWARD (DF)
- DF, a large practice-based research network focused on T2DM
patients and their providers across the US, to explore real-world
OAD utilization patterns
- A large proportion (52.4%) were receiving SU alone or in a
combination;
- they were generally older, had longer T2DM duration, and higher A1C
at registration
- Data from DF suggest that in clinical practice, SU are commonly
used in T2DM patients.
- Established habits, insurance directives, and lower cost may
drive SU use
Comparative Effectiveness of Several Second-Line Dual
Oral Antidiabetic Combinations in Reducing
Cardiovascular Events in Type 2 DiabetesA Nationwide
Study

Study Design: A retrospective cohort study using the
Taiwan National Health Insurance claims database

Primary end point: as conducted to compare the risks of
myocardial infarction and stroke among patients receiving
several 2nd-line dual oral anti-diabetic regimens during
2009-2011
Sulphonylurea Use
Result: As compared with pioglitazone plus metformin, the
adjusted HR (95% CI) of myocardial infarction






Conclusion: These findings gave clinical support to the use
of these 2nd-line drugs, without concern about potential
cardiovascular disease risk

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Sulphonylurea Use
Combination Adjusted HR (95% CI)
Sulfonylurea plus metformin 1.32
Glinide plus metformin 0.52
Alpha-glucosidase inhibitor plus
metformin
0.72
DPP4-inhibitor plus metformin. 1.49
Vitamin B12 and Metformin
Vitamin B12 Status and Its Relation with Depression,
Cognition, and Neuropathy in Patients with Type 2
Diabetes Mellitus Using Metformin
- Metformin use is associated with vitamin B12 deficiency
which can cause neurologic, psychiatric and cognitive
symptoms
- Only B12 deficiency was significantly associated with
depression
- Primary care physicians should take a vitamin B12
deficiency into account in depressive patients with T2DM
using metformin

Metformin & Lifestyle
Lifestyle, Metformin, Can Delay Diabetes, 15-Year DPP
Data Show
New data from the ongoing US Diabetes Prevention
Program (DPP) show that intensive lifestyle change or oral
metformin can reduce or delay the development of type 2
diabetes in overweight adults for up to 15 years in some
cases.

Although 50% of the subjects did become diabetic over the
years, "the results show that diabetes is not inevitable in
people at high risk; we established that it can be prevented
or delayed," said Marinella G. Temposa, PhD, of George
Washington University, Washington, DC.
Meet The Experts Session
Diabetic Kidney Disease:
- BP< 140/90, Lipid control, DM control
- Factors which lead to progression: NSAIDs, salt restriction,
- ARBs (type 2 DM), ACE (type 1 DM)
- Night time BP reduction with ramipril
- Add Aldosterone receptor blocker
- Monitor eGFR and early reference for CKD 4
- Chlorthalidone can be used if eGFR < 30
- Metformin ok till eGFR < 30
New Molecules Discussed
DPP- 4 inhibitor: Alogliptin
GLP-1 agonist: Liraglutide, Exenatide Erelease
Insulin Degludec
SGLT-2 inhibitors: Dapagliflozin, Emprogliflozin
WHAT WAS HOT AT ADA
ADA guideline on Type 1 DM
A new ADA position statement on type 1 diabetes
recommends
- a glycemic control target of HbA
1c
less than 7.5% across all pediatric
age groups
- now in line with that of the International Society for Pediatric and
Adolescent Diabetes, the Pediatric Endocrine Society, and the
International Diabetes Federation.

The single set of guidelines will "cross the entire lifespan for
our patients with type 1 diabetes so we can be assured as
we pass our patients to our adult providers we will all be
singing the same song," said Lori M.B. Laffel, MD, of the
Joslin Diabetes Center, Boston, Massachusetts
ACC/AHA Lipid Guidelines
ACC/AHA Lipid Guidelines: A Step up in
Diabetes Care, or Not?
- Debate continues on the new lipid guidelines developed by ACC
and the AHA
- Clinicians don't need LDL-cholesterol "goals" when treating
diabetic patients at high risk for cardiovascular disease
- Strong evidence to support specific targets doesn't exist and
clinicians should be using "common sense" and the new risk
calculator, argues Robert H. Eckel, MD, of the University of
Colorado, Denver.
- But debate adversary Henry Ginsberg, MD, from Columbia
University, New York, disagrees, saying the new lipid guidelines
do not provide appropriate direction for treating diabetic patients,
because they try to make things too simple
Artificial Pancreas
"Bionic Pancreas" Works for 5 Days in Outpatient
Settings
Development of a closed-loop bihormonal "artificial
pancreas" has hit a new milestone, improving blood
glucose levels in adults and teenagers with type 1
diabetes for 5 days straight in real-world settings,
reported Steven J. Russell, MD, PhD, of Massachusetts
General Hospital and Harvard Medical School, Boston.
- The findings, from 2 separate studies of 20 adults and
32 adolescents, published in the New England Journal
of Medicine.
Bionic pancreas:
- Wearable and automated and incorporates glucagon in
addition to insulin.
- Don't required any restrictions on [subjects'] diet, activities,
or their routine

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Artificial Pancreas
Islet-Cell Transplants
Islet-Cell Transplants Successful in Type 1
Diabetes
- It eliminated the need for insulin in more than half of a
group of type 1 diabetes patients experiencing frequent
severe hypoglycemia in a federally funded phase 3 study
- He didn't report the primary outcome the proportion of
subjects with HbA
1c
less than 7% at day 365 and free of
severe hypoglycemic events from day 28 to day 365
inclusive following the first islet transplant because the
manuscript has been submitted for publication.
- However, he did report other efficacy and safety
parameters that suggest a high degree of success
BMI
Usual BMI Cut Point May Miss Diabetes in Thin
Asian Americans
- BMI 25 kg/m
2
or greater to screen for diabetes may fail to
identify 1 in 5 Asian Americans who are diabetic, a study
finds.
- BMI cut point of 24 or greater may be more appropriate to
detect diabetes in this population, which includes Japanese
and Filipino Americans
- The research grew out of observations in the Veterans
Affairs system that many of the patients with diabetes on
renal dialysis were thin Asians
Diabetic Foot
Diabetic Foot: A Cinderella Story Needs a Team
Approach
Managing foot complications of diabetes requires a
multidisciplinary team approach.

"One of the difficulties in diabetic foot care in the US
is the lack of a cohesive treatment plan," said
session chair Paul Kim, DPM, from Georgetown
University School of Medicine, Washington, DC.
CVS Risk
LDL-C May Not Be Best Predictor of CVD Risk in Type 1
Diabetes
The total HDL-cholesterol ratio was a more reliable risk
marker than LDL-C for predicting a cardiovascular disease
(CVD) event over 7 years in a study of patients with type 1
diabetes
This is the first large study looking at CVD risk in patients with
type 1 diabetes
The study subjects also had a relatively low risk for a CVD
event, since their LDL-cholesterol levels were all around 100
mg/dL.
Thus, more research is needed, Dr. Seaquist cautioned
Depression and DM
Depression Predicts Type 1 Diabetes Death, but Hope
Prevails
Depression predicted worse survival in a 20-year
observational study of patients with type 1 diabetes,
Another trial showed that behavioral therapies that treat
"diabetes distress" were effective in reducing symptoms of
depression in adults with type 2 diabetes.
"The combination of depression and diabetes is truly a toxic
combination," said William Polonsky, PhD, from the
Behavioral Diabetes Institute, University of California, San
Diego, who led a press briefing to discuss the 2 trials
New Anti-Obesity Molecules
licensed by FDA
Page 43
Qsymia
TM
(Phentermine 7 5/15mg plus
topiramate 46/92 mg)

Effects of low-dose, controlled-release, phentermine plus
topiramate combination on weight and associated
comorbidities in overweight and obese adults (CONQUER): a
randomised, placebo-controlled, phase 3 trial
Study Design: 56-week phase 3 trial randomized, multicentre
trial
Study patients: overweight or obese adults (aged 18-70 years)
body-mass index of 27-45 kg/m(2) and two or more comorbidities
(hypertension, dyslipidaemia, diabetes or prediabetes, or
abdominal obesity)
Study Drug: once-daily phentermine 75 mg plus topiramate 460
mg, or once-daily phentermine 150 mg plus topiramate 920 mg
in a 2:1:2 ratio
Primary endpoints: percentage change in bodyweight and the
proportion of patients achieving at least 5% weight loss

Qsymia
TM
- (CONQUER Trial)
Results:
Placeb
o

Phentermine 75 mg
plus topiramate 460
mg

Phentermine 150
mg plus topiramate
920 mg
Change in
bodyweight
(56 weeks)
14 kg 81 kg 102 kg
Weight Loss >5% Weight loss > 10%
Placebo 204 (21%) 72 (7%)
Phentermine 75 mg
plus topiramate 460
mg
303 (62%; odds ratio
63, 95% CI 49 to 80;
p<00001)
182 (37%; 76, 56 to
102; p<00001)
Phentermine 150 mg
plus topiramate 920
mg
687 (70%; 90, 73 to
111; p<00001)
467 (48%; 117, 89 to
154; p<00001)
S/E: Dry Mouth , Parasthesia, Constipation, Dizziness,
Lancet. 2011 Apr 16;377(9774):1341-52
Qsymia
TM
- (CONQUER Trial)
Qsymia
TM
- (EQUIP Trial)
Controlled-Release Phentermine/Topiramate in Severely
Obese Adults: A Randomized Controlled Trial (EQUIP)

- Men and women with class II and III obesity (BMI 35
kg/m2) were randomized to placebo, PHEN/TPM CR
3.75/23 mg, or PHEN/TPM CR 15/92 mg, added to a
reduced-energy diet
- Primary end points were percent WL and proportions of
patients achieving 5% WL

0.00%
2.00%
4.00%
6.00%
8.00%
10.00%
12.00%
Placebo Phentermine 3.75
mg plus
topiramate 23 mg
Phentermine 15
mg plus
topiramate 92 mg
1.60%
5.10%
10.90%
Weight loss at 56 weeks from baseline body
weight
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Qsymia
TM
- (EQUIP Trial)
0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
70.00%
Placebo Phentermine 3.75
mg plus
topiramate 23 mg
Phentermine 15
mg plus
topiramate 92 mg
17.30%
44.90%
66.70%
Loss of 5% Body weight
Page 49
Qsymia
TM
- (EQUIP Trial)
Qsymia
TM
- (EQUIP Trial)
Qsymia
TM
- (EQUIP Trial)
Qsymia
TM
- (EQUIP Trial)
Adverse Effects: paresthesia, dry mouth,
constipation, dysgeusia, and insomnia.
Dropout rate from the study was 47.1% for placebo
patients, 39.0% for 3.75/23 patients, and 33.6% of
15/92 patients
Qsymia
TM
- (EQUIP Trial)
BELVIQ (lorcaserin
hydrochloride)
BELVIQ is a serotonin 2C receptor agonist
Indicated as an adjunct to a reduced-calorie diet
and increased physical activity for chronic weight
management in adults with an initial body mass
index (BMI) of:
- 30 kg/m2 or greater (obese) or
- 27 kg/m2 or greater (overweight) in the presence of at least
one weight-related comorbid condition, (e.g., hypertension,
dyslipidemia, type 2 diabetes)

MOA:
- Lorcaserin is believed to decrease food
consumption and promote satiety by selectively
activating 5-HT2C receptors on anorexigenic
pro-opiomelanocortin neurons located in the
hypothalamus
- The exact mechanism of action is not known
BELVIQ (lorcaserin
hydrochloride)
Longitudinal Weight Change (kg) in Completer Population: Studies
1 and 2
BELVIQ (lorcaserin
hydrochloride)
Body Weight Changes during Study 1 in the Completers
Population
BELVIQ (lorcaserin
hydrochloride)
Most common adverse reactions (greater than 5%)
in non-diabetic patients are headache, dizziness,
fatigue, nausea, dry mouth, and constipation, and in
diabetic patients are hypoglycemia, headache, back
pain, cough, and fatigue

Thirty-four percent (34%) of patients in Belviq and
38% in placebo dropped out before the 52-week
endpoint
BELVIQ (lorcaserin
hydrochloride)
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