ada update 2014

ADA 2014: Update

Dr. D. A. Khandke MDAVP- 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 2014New 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



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%

Macroangiopathy

44% 57% 30%

Vitamin D Inhibits Human Platelet Aggregation (PA): Implications for Hypercoagulable State in Diabetes

- Vit. D3 and 1,25 D3 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 <140/90ADA <140/90KDIGO <140/90ESH/ESC <140/85

ARB data positive with RENAAL & IDNT Keep ACE/ARB till refractory hyperkalemia (also with diuretic use)

Don’t 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 (3rd 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 β cell function.

- Central adiposity and insulin resistance appear to be stronger correlates of IGT and DM than lower β cell function.

- Further investigation is needed to better understand why lower socioeconomic status contributes to significantly greater IGT risk.

Gestational DiabetesUse 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-PregnancyPredictors 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 Diabetes–A 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 & LifestyleLifestyle, Metformin, Can Delay Diabetes, 15-Year DPP Data ShowNew 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 HbA1c 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 HbA1c 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

BMIUsual BMI Cut Point May Miss Diabetes in Thin Asian Americans- BMI 25 kg/m2 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 FootDiabetic 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 RiskLDL-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

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QsymiaTM (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 7·5 mg plus topiramate 46·0 mg, or once-daily phentermine 15·0 mg plus topiramate 92·0 mg in a 2:1:2 ratio

Primary endpoints: percentage change in bodyweight and the proportion of patients achieving at least 5% weight loss

QsymiaTM- (CONQUER Trial)

Results:

Placebo

Phentermine 7·5 mg plus topiramate 46·0 mg


Change in bodyweight (56 weeks)

1·4 kg 8·1 kg 10·2 kg

Weight Loss >5% Weight loss > 10%

Placebo 204 (21%) 72 (7%)


303 (62%; odds ratio 6·3, 95% CI 4·9 to 8·0; p<0·0001)

182 (37%; 7·6, 5·6 to 10·2; p<0·0001)


687 (70%; 9·0, 7·3 to 11·1; p<0·0001)

467 (48%; 11·7, 8·9 to 15·4; p<0·0001)

S/E: Dry Mouth , Parasthesia, Constipation, Dizziness,

Lancet. 2011 Apr 16;377(9774):1341-52

QsymiaTM- (CONQUER Trial)

http://www.ncbi.nlm.nih.gov/pubmed/21481449

QsymiaTM- (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%4.00%8.00%

12.00%1.60%

5.10%

10.90%

Weight loss at 56 weeks from baseline body weight

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0.00%

30.00%

60.00%17.30%

44.90%66.70%

Loss of 5% Body weight

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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


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


Longitudinal Weight Change (kg) in Completer Population: Studies 1 and 2


Body Weight Changes during Study 1 in the Completers Population


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


Thank You

ada update 2014

Documents

detected diabetics

obesity molecules

diabetic kidney disease

metal silver ada

vit b12 defmeet

insulin resistance

cardiovascular risk

south india indian data