Diabetes Update 2012

Brian Lake, D.O. Endocrinology, Diabetes, and Metabolism Gessler Clinic, P.A. 601 First Street N Winter Haven, FL 33881 Office: 863-294-0670 863 Email: brian.lake@gesslerclinic.com May 2, 2012

Financial disclosures
Speakers bureau for:
Byetta / Bydureon (Amylin) Lantus and Apidra (Sanofi Aventis) Humalog in Medtronic Revel Pump (Lilly) Tradjenta (Boeringer Boeringer Ingelheim / Lilly) Synthroid (Abbott)

Objectives
Discuss the epidemiology of type 2 diabetes Discuss the pathogenesis of diabetes as a progressive disease Review ACCORD, VADT, ADVANCE trials and glycemic goals Examine the AACE algorithm for diabetes treatment Review newer diabetes medications to help patients achieve goals

What is the scope of the problem?

Facts on Diabetes
Of 311 million Americans, 26 million Americans have diabetes An estimated 79 million American adults have pre diabetes A condition that increases their risk of type 2 diabetes, heart disease and stroke Diabetes more likely to affect older Americans Almost 27% of people age 65 years and older had diabetes in 2010 Diabetes affects 8.3% of all Americans and 11.3% of adults age 20 and older Some 27% of people with diabetes 7 million Americans do not know they have the disease

http://www.cdc.gov/Features/DiabetesFactSheet/ Accessed 3/1/2012. http://www.cdc.gov/Features/DiabetesFactSheet/.

Estimated percentage of people aged 20 years or older with diagnosed and undiagnosed diabetes, by age group, United States, 2005 2008
26.9%

13.7%

3.7%

20-44

45-64 Age Group

65

Source: 20052008 National Health and Nutrition Examination Survey.

Estimated number of new cases of diagnosed diabetes among people aged 20 years or older, by age group, United States, 2010
1,052,000

465,000 390,000

20-44

45-64 Age Group

65

Source: 20072009 2009 National Health Interview Survey estimates projected to the year 2010.

Diabetes Epidemiology 1956-2009 1956

Age-adjusted adjusted percentage of adults aged 20 years with diagnosed diabetes, 2007

MMWR 58:1259-1263, 2009

Age-adjusted adjusted percentage of adults aged 20 years who are obese, 2007

MMWR 58:1259-1263, 2009

Estimated lifetime risk of developing diabetes for individuals born in the United States in 2000
60 50 Percent 40 30 20 10 0 Men Women
Total Non-Hispanic Black Non-Hispanic White Non Hispanic

Narayan et al, JAMA, 2003

The Big Picture with Type 2 DM

177 million worldwide 4th leading cause of death by disease India 33 million people with diabetes China 23 million people with diabetes Population of diabetes will double to triple by 2025 One out of every three Americans born today will develop diabetes
Time magazine December 2003; CDC

So what have we learned over the last few decades to help attack to problem?

Diabetes is a progressive disease

Two basic underlying mechanisms lead to type 2 diabetes:
Insulin resistance Impaired insulin secretion from beta cells within the pancreas

Diabetes is a progressive disease

Up to 70-80% 80% of beta cell function is lost at the time of diagnosis of type 2 diabetes1 Generally, alterations in glucose handling have been present for 5+ years prior to the laboratory diagnosis of type 2 diabetes Newer therapies are being targeted at mechanisms of preserving and improving beta cell function and altering insulin resistance
1. DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting Lecture]. Diabetes. 2009: 58: 773-795.

-Cell Cell mass in Type 2 diabetes

3.5 3.0 2.5
volume (%)

-50%

2.0 1.5 1.0 0.5 0.0 ND IFG

-63% 63%

b-Cell Cell

T2DM

ND

T2DM

Obese
ND=non-diabetic; IFG=impaired fasting glucose; T2DM=Type 2 diabetes mellitus Butler et al. Diabetes. 2003

Lean

The New Paradigm

DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting Lecture]. Diabetes. 2009: 58: 773-795.

Knowing the scope of the problem, how are we doing controlling patients?

Percentage of Patients With Diabetes Having A1C <7%

100 80 60

US Adults With Diagnosed Diabetes in 1988-94 1988 NHANES III 73 45 26

Percent at goal

38
40 20 0 Diet alone Oral agents Therapy used Insulin

Whole population

Harris MI, et al. Diabetes Care. 1999;22:403-408.

IRIS-Study Study (representative cohort of 4575 type 2 diabetic patients in Germany): Proportion of patients achieving specific HbA1c targets
100 90 80 70 60 50 40 30 20 10 0

% of Patienten

18
<6.5%

32
<7.0%

48
<7.5%

61
<8.0%

HbA1c target
Rihl, Biermann, Standl: Diabetes & Stoffw. (2002)11:150-158 (2002)11:150

Percentage of adults with diagnosed diabetes receiving treatment with insulin or oral medication, United States, 20072009

16%

12% 14%

58%

Insulin only

Insulin and oral medication

Oral medication only

No medication

Source: 20072009 2009 National Health Interview Survey.

What about the newer studies showing minimal cardiovascular benefit with intensive glycemic control?
i.e. ACCORD, ADVANCE, VADT

Relative Risk of Progression of Diabetic Complications - DCCT

15 13 11
Retinop Neph Neurop

RELATIVE RISK

9 7 5 3 1 6 7 8 9 10 11 12

Mean A1C
DCCT Research Group, N Engl J Med 1993, 329:977-986.

Lifetime Benefits of Intensive Therapy (DCCT)

Gain of 15.3 years of complication free living compared to conventional therapy Gain of 5.1 years of life compared to conventional therapy

DCCT Study Group, JAMA 1996, 276:1409-1415.

DCCT
10% reduction in HbA1c 43% reduced risk of retinopathy progression 18% increased risk of severe hypoglycemia with coma and/or seizure

DCCT Research Group, N Engl J Med 1993, 329:977-986.

Lowering A1C Reduces Risk of Complications

United Kingdom Prospe spective Diabetes Study (UKPDS)
Reduction in risk (%)*
0 -10 -20 -30 -40 -50
*Percent risk reduction per 0.9% decrease in HbA1C; UKPDS. Lancet. 1998;352:837-853.

Any diabetesrelated endpoint

-12
p=0.029

-16
p=0.052

-21

Microvascular endpoint MI
-34 34
p=0.000054

-25
p=0.0099

p=0.015

Retinopathy Albuminuria at 12 years

Current recommendations address lack of evidence of reduction in macrovascular disease with strict glycemic control

ADA position statement 2010 Standards of Care guideline

ADA Standards of Care. Diabetes Care 2010;33

6.4% vs. 7.5%

6.3% vs. 7.0%

6.9% vs. 8.5%

More advanced disease, in general, with average time from diagnosis of DM2 of 811 years.
Sklyer JS, et al. Intentive glycemic control and the prevention of cardiovascular events. A position statement of the ADA/ACC/AHA. ADA/ACC Diabetes Care 2009;32:187-92.

ACCORD study - 2008

ACCORD study - 2008

Halted after 3.5 years 54 additional deaths in intensive group (257 vs. 203) Increased hypoglycemia, including severe requiring assistance Increased weight gain in intensive group We remain unsure of reasons for increased death rate (possibly magnitude or speed of A1c reduction, hypoglycemia, adverse rxns, etc)
ACCORD Study Group. Effects of Intensive Glucose Lowering in Type 2 Diabetes. NEJM 2008; NEJM 2008 Jun 12; 358(24): 2545-59.

ADVANCE study - 2008

Summary most patients on gliclazide MR (SU) and metformin Intensive glucose control resulted in: 10% reduction in combined, major micromicro or macrovascular events 14% reduction in microvascular events 21% reduction in nephropathy No significant effects on macrovascular events No significant effects on all-cause all or cardiovascular mortality Consistent treatment effects in patient subgroups
ADVANCE Collaborative Group. Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes. NEJM 2008; 358(24):2560-2572. 358(24):2560

VADT -2008
No statistically significant effect on cardiovascular events or death No statistically significant effects on microvascular events Increased risk of hypoglycemia in intensive group (link found with CV events) Rosiglitazone used in 85% of intensive and 72% of standard group and no association found with CV events or death
Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. NEJM. 2008 Dec 17.

Three large trials of glycemic control published in 2008 failed to find CVD benefit

Sklyer JS, et al. Intentive glycemic control and the prevention of cardiovascular events. A position statement of the ADA/ACC/AHA. Diabetes Care 2009;32:187-92.

2012 ADA guideline appropriately discusses microvascular benefits of A1C < 7% while acknowledging lack of proven macrovascular benefits at the A1C values that were studied.

ADA Standards of Care. Diabetes Care January 2012;35: Supplement 1

2. Lipid recommendations in type 2 diabetes

ADA Standards of Care; Diabetes Care, January 2011

April 29, 2010 NEJM Conclusion: : The combination of fenofibrate and simvatatin did not reduce the rate of fatal cardiovascular events, non-fatal fatal MI or non-fatal non stroke, as compared with simvastatin alone.

ACCORD BP: Results

Conclusions: : In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mmHg, as compared with less than 140 mmHg, did not reduce the rate of fatal and nonfatal major CVD events.

Conclusions:
New clinical trial data has solidified current treatment goals: A1C ~ 7% SBP ~ 130 mmHg LDLc < 100mg with statin (ACCORD lipid achieved 80 mg/dL) mg/ Use of ASA in higher risk patients with diabetes

Same data suggests that more aggressive targets not warranted for CVD reduction: A1C < 7% SBP < 130 (ACCORD achieved 119 mmHg SBP) Addition of fibrate or niacin to statin to target TG if LDLc already at goal ASA should not be used if CVD risk is low

Now that we know the newer recommendations, and how we are doing globally, what is available to help us get our patients to goal?

Standards of Medical Care in Diabetes

Standards of Medical Care in Diabetes 2012 Diabetes Care January 2012 35:S11-S63; 35:S11 doi:10.2337/dc12 doi:10.2337/dc12-s011 Published yearly by the ADA in Diabetes Care as a robust list of recommendations and changes in standard of care for patients with diabetes

AACE/ACE Diabetes Algorithm for Glycemic Control

A1c based algorithm addressing newer therapies allowing for flexibility in medications utilized. Evidence based.

AACE/ACE Diabetes Algorithm for Glycemic Control

Permission granted for electronic use of algorithm from the American Association of Clinical Endocrinologists. Algorithm available at: https://www.aace.com/sites/degault/files/glycem iccontrolalgorithmppt.pdf Accessed 4/17/12

What do we now have to bring patients to glycemic goals, avoid hypoglycemia, and help reduce risk of MICROvascular complications?

Therapeutic Options for Type 2 DM

1995
Sulfonylureas INSULIN NPH Regular Ultralente

2012
Sulfonylureas INSULIN NPH Regular Insulin analogues Peak-less basal insulins Metformin TZDs Alpha glucosidase inhibitors
Meglitinides Incretin mimetics Amylin analogues DPP IV inhibitors Bile Acid binding sequestrants Bromocriptine

DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting Lecture]. Diabetes. 2009: 58: 773-795.

Newer therapies
There is no one perfect medication to attack all eight currently accepted defects in glycemic handling Targeting glycemic goals more aggressively earlier in the disease process has durable reductions in risk Most newer therapies are aimed at reducing hypoglycemia and restoring endogenous insulin secretion

Current Oral Therapies Do Not Address the Multiple Defects in Type 2 Diabetes
Glucose influx from GI1 tract Impaired insulin action Inadequate glucagon suppression (-cell cell dysfunction) Acute -cell dysfunction Chronic -cell decline

-Glucosidase inhibitors

TZDs2 Metformin

unmet need

Sulfonylureas

unmet need

Glinides

Plasma glucose and disease progression

Gastrointestinal Thiazolidinedione Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003;3(suppl 1):S24S40 1):S24
2 1

48

Incretin effect on insulin secretion

Control subjects (n=8)
80

People with Type 2 diabetes (n=14)

80

Insulin (mU/l)

40

Incretin effect

Insulin (mU/l)

60

60

40

20

20

0 0 60 120 180

0 0 60 120 180

Time (min) Oral glucose load Intravenous glucose infusion

Time (min)

Nauck et al. Diabetologia. 1986

GLP-1: 1: effects in humans

After food ingestion Stimulates glucosedependent insulin secretion Suppresses glucagon secretion Slows gastric emptying GLP-1 is secreted from L-cells of the jejunum and ileum Leads to a reduction of food intake Improves insulin sensitivity

That in turn

Long-term effects in animal models: Increase of -cell mass and improved -cell function

Drucker. Curr Pharm Des. 2001 Drucker. Mol Endocrinol. 2003

GLP-1 preserves human islet morphology GLPand function in cultured islets in vitro
Control + GLP-1

Day 1

Day 3

Day 5

Farilla et al. Endocrinology. 2003

GLP-1 1 receptor agonists

Exenatide, Liraglutide Injectable medications that allow supraphysiologic levels of exogenous GLP-1 GLP to exert their effects Available as BID, QD, and Qweek injections Generally targets post-prandial prandial glucose levels but exerts effects on fasting glucose as well Hypoglycemia is rare without concurrent use of sulfonylureas or insulin Can perpetuate a weight benefit Average of approximately a 1.5% HbA1c reduction

GLP-1 1 receptor agonists (negatives)

Cost Potential for nausea Cases of pancreatitis reported (including hemorrhagic and necrotizing) C-cell cell hyperplasia seen in animal models with black box warnings for medullary thyroid cancer (with extended release preparations). Unsure of relevance in humans

GLP-1 1 pathway
Endogenous GLP-1 1 is primarily degraded by the dipeptidyl peptidase-4 4 (DPP-4) (DPP enzyme within a matter of minutes 4 enzyme inhibition keeps endogenous DPP-4 GLP-1 1 concentrations stable for longer periods of time in circulation allowing it to exert its effects

Inhibition of DPP-4 4 Increases Active GLP-1 GLP

Meal Intestinal GLP-1 release Active GLP-1

DPP-4 DPP DPP-4 inhibitor

GLP-1 inactive

Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.

DPP-4 4 inhibitors
Sitagliptin, Saxagliptin, Linagliptin Decrease the rapid degradation of endogenous GLP-1 GLP to allow it to exert its effects longer Generally targets post-prandial prandial glucose values with a minimal effect on fasting glucose Generally a very tolerable drug class with minimal potential side effects Hypoglycemia rare without concurrent use of sulfonylureas or insulin Weight neutral

DPP-4 4 Inhibitor (negatives)

Cost Cases of pancreatitis reported (including hemorrhagic and necrotizing) Small HbA1c lowering power ~0.5%

DPP-4 4 therapy ideal patient

Patients with renal dysfunction or intolerant of metformin as first line therapy In combination with metformin, particularly early into the diagnosis of diabetes Patients with multiple co morbidities wishing to avoid hypoglycemia Patients with post-prandial prandial hyperglycemia (potentially as a substitute of a sulfolylurea)

Other Topics in the News

Pioglitazone and Bladder Cancer

6/15/11 The FDA issued a statement to the public to inform them of a possible association of increased risk of bladder cancer in patients who took pioglitazone for >1 year (based on 5-yr 5 interim data) Increased risk based on dose and duration 27.5 excess cases of bladder cancer per 100,000 person-years years follow-up, follow compared to never use of pioglitazone
1. Lewis JD, Ferrara A, PengHedderson M, Bilker WB, QuesenberryJr, et al. Diabetes Care. 2011;34:916-22. 2. SDI, Vector One: Total Patient Tracker (TPT). January 2010-October October 2010. Data extracted 12-15-10. 12

Pioglitazone and Bladder Cancer

Also, epidemiologic study in France showing similar association of bladder cancer with pioglitazone with increasing dose and duration FDA guidance is to not use pioglitazone in patients with active bladder cancer and to use with caution in patients with a history of bladder cancer
1. US Food and Drug Administration. http://www.fda.gov/Drugs/DrugSafety/ucm259150.htm

Summary
Diabetes is an epidemic problem that is showing no signs of slowing AACE and ADA algorithms can help guide us toward achieving control and preventing complications in our diabetic patients A goal HbA1c of < 7% remains a realistic goal to reduce diabetic microvascular complications

Summary
With ACCORD, VADT, and ADVANCE trials showing minimal cardiovascular benefit of intensive glycemic control on patients with advanced disease, we should be cautious in this subset of patients Goals and therapies should continue to be discussed with patients as we continue to evolve in our knowledge of the care and control of diabetes

Questions???