The Year in Diabetes2013-2014

Guillermo Umpierrez, MD, CDEEmory University

Atlanta, GA

Outline• Clinical Care

– Individualization of Goals– Medications– Hypoglycemia

• Technology– Low glucose suspend– Outpatient artificial pancreas studies– Bi-hormonal artificial pancreas

• Epidemiology– Look AHEAD

Diabetes Care 35: 1364-1379, 2012

T2DM Anti-hyperglycemic Therapy: General Recommendations Diabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596

SU TZD DPP-4 GLP-1 Insul

Met

SU +TZD

+DPP4

+GLP1

+Insulin

+

Insulin(multiple daily doses)

Insulin

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print](Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)

7%

Diabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596

Patient characteristics that influence judgement for treatment of hyperglycemia.

Diabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596

Figure 1 Diabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596

Garber et al. Endocrine Practice, in press 2013

Turner LW Diabetes Care epub 22 NOV 2013

SGLT-2 Inhibitor – kidney is target organRenal glucose reabsorption

Glucose

Proximal tubule

S1 segment

SGLT2~90%

glucose reabsorption

SGLT-1~10%

glucose reabsorption

S3 segment

Collectingducts

SGLT-2 Inhibitor – Mechanism of Action

Glucose

SGLT-2Inhibitor

s

Glucosuria Loss of calories

Stenlöf et al, Diabetes Obes Metab. 2012 Dec 26. [Epub ahead of print]

Canagliflozin monotherapy vs Placebo in Patients with T2D

Stenlöf et al, Diabetes Obes Metab. 2012 Dec 26. [Epub ahead of print]

Canagliflozin monotherapy vs Placebo in Patients with T2D

Weight Change

Meta-analysis for HbA1c change from baseline, 10 mg dapagliflozin versus placebo

Clar et al, BMJ 2 (5): 1-7, 2012

Perspectives on SGLT2 Inhibition

• Concerns– Polyuria– Electrolyte disturbances– Bacterial urinary tract

infections– Fungal genital infections– Malignancies

• Advantages– Improved glycemic

control– Weight loss (75g urine

glucose = 300kcal/day)– Low risk of hypoglycemia– Blood pressure

lowering?

GLP1–Based Therapies and Risk of Hospitalization for Acute Pancreatitis in Type 2 Diabetes Mellitus

Singh et al. JAMA Intern Med. 2013;173(7):534-539

Design: Population-based case-control study.

Setting: A large administrative database in the U.S.

Results: Adjusted risk (including metformin therapy), current use of GLP-1–based therapies within 30 days (OR 2.24 [95% CI, 1.36-3.68]) and past use >30 days and < 2 years (2.01 [1.37-3.18]) relative to the odds in nonusers.

Pancreatitis and Exenatide

• 30 cases of exenatide associated pancreatitis via FDA AERS.

• Onset of symptoms from 3-400 days after drug initiation.

• Resolution of symptoms concurrent with stopping exenatide in 22/30

• Recurrent symptoms in 3 patients restarted on drug• 27/30 patients had another risk factor for

pancreatitis- obesity, hyperlipidemia, ETOH

Ahmad, S New Eng J Med 358: 1970-1971, 2008

Database Studies

M Elashoff, Gastroenterology, 2010S Singh, JAMA Internal Med, 2013

D Dore, Curr Med Res Op, 2009R Garg, Diabetes Care, 2010D Dore, DOM, 2011

Pancreatic glucagon expressing neuroendocrine tumor and microadenoma.

Butler et al, Diabetes, 2013

~40% increased pancreatic mass in DM treated with incretin therapy with both increased exocrine cell proliferation (p<0.0001) and dysplasia (increased pancreatic intraepithelia neoplasia, p<0.01).

α cell hyperplasia and glucagon expressing microadenomas (3/8) and a neuroendocrine tumor.

Preclinical studiesStudies demonstrating histopathology

Studies demonstrating no histopathology

JS Nachnani, Diabetologia, 2010AV Matveyenko, Diabetes, 2009B Gier, Diabetes 2012

J Koeleher, Diabetes, 2009K Tatarkiewicz, AJP, 2010N Nyborg, Diabetes 2012K Tatarkiewicz, DOM, 2013K Aston-Mourney, AJP, 2013

Non-Matching Cohorts in Autopsy Study from Butler (Diabetes 62:2595-2604, 2013)

Harja E et al Diab Tech Ther 15: July 2013 epub DOI: 10.1089/dia.2013.0177

Staining Specificity of GLP-1R Antibodies

Pyke C et al: Endocrinology 154:4-8; 2013

Monoclonal ab3F52

Polyclonal abAB39072

Polyclonal abLS-A1205

Polyclonal abAP23801

Non-transfectedBHK cells

GLP-1RtransfectedBHK cells

Endocrine Society Statement - 6/18/2013

• Patients should be made aware of this potential side effect of incretins and the symptoms of pancreatitis.

• Providers should balance risk and benefit of particular treatment paradigms, especially in patients with other risk factors for pancreatitis.

• Patients should not stop medications on their own without consulting their health care provider.

• Manufacturers should make the data on rates of pancreatitis and pancreatic cancer available to an independent scientists for analysis.

Incretin Agents

FDA Postmarket Drug Safety Information for Patients and ...www.fda.gov/Drugs/DrugSafety/Postmarketdrugsafe

Cardiovascular Outcome Studies with DPP-4i and GLP-1RA

Kahn SE, Diabetes 62: 2178-2180, 2013

Cardiovascular Outcome Studies with DPP-4i and GLP-1RA

Kahn SE, Diabetes 62: 2178-2180, 2013

increased rate of hospitalization for heart failure

Outline• Clinical Care

– Individualization of Goals– Medications

–Hypoglycemia• Technology

– Low glucose suspend– Outpatient artificial pancreas studies– Bi-hormonal artificial pancreas

• Epidemiology– Look AHEAD

J Clin Endo Metab April 15, 2013 doi: 10.2337/dc12-2480

New Categories of Hypoglycemia

1) Severe hypoglycemia:– requiring assistance of another person.

2) Documented symptomatic hypoglycemia:– typical symptoms of hypoglycemia are accompanied by glucose

concentration ≤70 mg/dL

3) Asymptomatic hypoglycemia: – No symptoms but with glucose concentration ≤ 70 mg/dL

4) Probable symptomatic hypoglycemia:– Symptoms of hypoglycemia are not accompanied by glucose measure

5) Pseudo-hypoglycemia: – symptoms of hypoglycemia with a measured glucose >70 mg/dL

Diabetes Care 36:3535–3542, 2013

Diabetes Care 36:3535–3542, 2013

JCEM epub ahead of print Jan 10, 2014

Outline• Clinical Care

– Individualization of Goals– Medications– Ischemic preconditioning– Hypoglycemia

• Technology

–Low glucose suspend– Outpatient artificial pancreas studies– Bi-hormonal artificial pancreas

• Epidemiology– Look AHEAD

• Two New Hormones– Irisin– Betatrophin

Veo* Insulin Pump

Linked Meter

MiniLink Sof-Sensor®

CareLink USB®™

Low Alerts: Hypoglycemia,Predictive, Suspend

N Engl J Med 369:224-32, 2013

N Engl J Med 368:824-33, 2013

Outline• Clinical Care

– Individualization of Goals– Medications– Ischemic preconditioning– Hypoglycemia

• Technology– Low glucose suspend– Outpatient artificial pancreas studies

–Bi-hormonal artificial pancreas• Epidemiology

– Look AHEAD

CMAJ 2013, 185: 297-205

Diabetes Care 35:2148–2155, 2012

Outline• Clinical Care

– Individualization of Goals– Medications– Ischemic preconditioning– Hypoglycemia

• Technology– Low glucose suspend– Outpatient artificial pancreas studies– Bi-hormonal artificial pancreas

• Epidemiology

–Look AHEAD

N Engl J Med Published June 24, 2013. DOI: 10.1056/NEJMoa1212914

Design

• 16 U.S. study centers - 5145 overweight or obese DM type 2 randomized to:– an intensive lifestyle intervention that promoted

weight loss through decreased caloric intake and increased physical activity (intervention group)

Or – diabetes support and education (control group)

• The primary outcome was a composite of death from CV causes, nonfatal MI, nonfatal stroke, or hospitalization for angina during a maximum follow-up of 13.5 years.

Outline• Clinical Care

– Individualization of Goals– Medications– Ischemic preconditioning– Hypoglycemia

• Technology– Low glucose suspend– Outpatient artificial pancreas studies– Bi-hormonal artificial pancreas

• Epidemiology– Look AHEAD

THANK YOU