Oral Therapy for Type 2 Diabetes

Oral Therapy for Type 2 Diabetes
Investigations • Innovation • Clinical Application New Frontiers and Advances in Oral Therapy for Type 2 Diabetes Focus on DPP-4 Inhibition and Incretin-Based Therapy (IBT) Program Chairman Charles Faiman, MD, FRCPC,MACE Past Chairman Consultant Staff Department of Endocrinology, Diabetes and Metabolism Cleveland Clinic Foundation

Welcome and Program Overview
CME-certified symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from Bristol-Myers Squibb and AstraZeneca Partnership Faculty disclosures: Listed in program syllabus

Program Faculty Program Chairman Alexander Turchin, MD, MS
Charles Faiman, MD, FRCPC,MACE Past Chairman Consultant Staff Department of Endocrinology, Diabetes and Metabolism Cleveland Clinic Foundation Samir Malkani, MD Director, Adult Diabetes Clinic, University Campus UMass Memorial Medical Center Clinical Associate Professor of Medicine University of Massachusetts Medical School UMASS Memorial Medical Center Worcester, MA Alexander Turchin, MD, MS Assistant Professor Harvard Medical School Brigham and Women's Hospital Boston, MA Derek LeRoith, MD, PhD, FACP Chief, Division of Endocrinology, Diabetes and Bone Disease Director, Metabolism Institute, Mount Sinai School of Medicine New York, NY

Type 2 Diabetes 2010: New Frontiers
New Frontiers and Advances in Oral Therapy for Type 2 Diabetes Type 2 Diabetes 2010: New Frontiers Program Chairman Charles Faiman, MD, FRCPC,MACE Past Chairman Consultant Staff Department of Endocrinology, Diabetes and Metabolism Cleveland Clinic Foundation

Number of People with Diabetes (20-79 years)
2010 and 2030 Country/Territory 2010 Millions India 50.8 China 43.2 United States 26.8 Russian Federation 9.6 Brazil 7.6 Germany 7.5 Pakistan 7.1 Japan Indonesia 7.0 Mexico 6.8 Country/Territory 2030 Millions India 87.0 China 62.6 United States 36.0 Pakistan 13.8 Brazil 12.7 Indonesia 12.0 Mexico 11.9 Bangladesh 10.4 Russian Federation 10.3 Egypt 8.6 IDF Diabetes Atlas, 4th ed. International Diabetes Federation, 2009

At a Glance: World At a Glance 2010 2030
Total world population (billions) 7.0 8.4 Adult population (20-79 yrs, billions) 4.3 5.6 Diabetes (20-79 Years) Global prevalence (%) 6.6 7.8 Comparative prevalence (%) 6.4 7.7 Number of people with diabetes (millions) 285 438 IGT (20-79 years) 7.9 Number of people with IGT (millions) 344 472

Number of People with Diabetes by Age Group, 2010 and 2030
Millions

Number of People with Impaired Glucose Tolerance by Age Group, 2010 and 2030
Millions

North America and Caribbean Region
At a Glance 2010 2030 Total population (millions) 477 555 Adult population (20-79 yrs, millions) 320 390 Diabetes (20-79 Years) Regional prevalence (%) 11.7 13.6 Comparative prevalence (%) 10.2 12.1 Number of people with diabetes (millions) 37.4 53.2 IGT (20-79 years) 11.4 12.6 10.4 11.6 Number of people with IGT (millions) 36.6 49.1

North America and Caribbean Region
At a Glance 2010 2030 Type 1 diabetes (0-14 years) Number of children with type 1 diabetes (thousands) 96.7 Number of newly-diagnosed cases per year (thousands) 14.7 Diabetes mortality (20-79 years) Number of deaths, male (thousands) 141.0 Number of deaths, female (thousands) 172.2 Health expenditure for diabetes (USD) Total health expenditure, R=2 (billions) 214.2 288.7

Highest Prevalence Diabetes
Pacific Island - 43% Arab Gulf States (U.A.E.) - 19% U.S.A. / Canada - Natives - Blacks / Hispanics

United States $198 billion World $376 billion
Costs for DM Care: 2010 United States $198 billion World $376 billion

Definition of Diabetes
Indicator American (mg/dL) SI (mmo/L) Glucose – Fasting Normal 3.6 – 5.5 DM > 126 > 7.0 Random (with symptoms) > 200 > 11.1 GTT (2 hr.) HbA1c > 6.5%

Definition of Impaired Glucose Tolerance
Indicator mg/dL mmo/L Fasting glucose 100 – 125 >5.6 – 6.9 Glucose tolerance test 140 – 199 7.8 – 11.0 HbA1c 5.7% – 6.4%

Types Of Diabetes Type 1 (Juvenile-Onset) Type 2 (Adult-Onset)
Other types including: - Gestational diabetes - MODY (maturity onset diabetes of the young) - LADA (latent auto-immune diabetes of adults) - Others

Auto-immune destruction of insulin-producing β-cells in the pancreas
Cause of Type 1 DM Auto-immune destruction of insulin-producing β-cells in the pancreas

Cause of Type 2 DM Insulin resistance (genetics)
- aggravated by obesity - aggravated by lack of exercise “Exhaustion” of insulin-producing β-cells

Major Metabolic Defects in Type 2 Diabetes
Peripheral insulin resistance in muscle and fat Decreased pancreatic insulin secretion Increased hepatic glucose output The endocrine characteristics of type 2 diabetes include peripheral insulin resistance in muscle and fat tissue, decreased pancreatic insulin secretion, and increased hepatic glucose output. Haffner SM, et al. Diabetes Care, 1999

Development and Progression
of Type 2 Diabetes* 3/27/2017 9:33 PM NGT ® Insulin ® IGT/ IFG ® Type 2 Diabetes Resistance Postprandial glucose Glucose Fasting glucose -10 -5 5 10 15 20 25 30 Development and Progression of Type 2 Diabetes Speaker notes This conceptual diagram shows a recently proposed paradigm on the development and progression of pathophysiology in type 2 diabetes. The horizontal axis in the figure shows the years from diagnosis of diabetes. Insulin resistance rises during disease development and continues to rise during impaired glucose tolerance (IGT). Over time, insulin resistance remains stable during the progression of type 2 diabetes.1,2 The insulin secretion rate increases, to compensate for the decrease in insulin effectiveness due to insulin resistance. This increase is often misperceived as an increase in beta-cell function. Thus, beta-cell function can decrease even as insulin secretion increases. Over time, beta-cell compensatory function deteriorates and insulin secretion decreases. Beta-cell function progressively fails. Initially, fasting glucose is maintained in near-normal ranges. The pancreatic beta cells compensate by increasing insulin levels, leading to hyperinsulinemia. This compensation keeps glucose levels normalized for a time, but as beta cells begin to fail, IGT develops with mild postprandial hyperglycemia. As the disease progresses, the beta cells continue to fail, resulting in higher postprandial glucose levels. With further loss of insulin secretory capacity, fasting glucose and hepatic glucose production increase. Once beta cells cannot secrete sufficient insulin to maintain normal glycemia at the fasting or postprandial stage, type 2 diabetes (hyperglycemia) becomes evident. Insulin resistance and beta-cell dysfunction are established well before type 2 diabetes is diagnosed.1,3 Relative Activity Purpose: To address the common misconception that an increase in insulin secretion (hyperinsulinemia) connotes an improvement in beta-cell function. Takeaway: Both insulin resistance and beta-cell dysfunction start early–and well before diabetes is diagnosed–leading to rises in fasting and postprandial glucose levels. Insulin resistance —hepatic and peripheral Insulin level Beta-cell function –10 –5 5 10 15 20 25 30 Years from Diabetes Diagnosis *Conceptual representation. NGT=normal glucose tolerance; IGT=impaired glucose tolerance; IFG=impaired fasting glucose. Adapted from Ferrannini E. Presentation at 65th ADA in Washington, DC, 2006.; and Ramlo-Halsted et al. Prim Care. 1999;26:771–789. References 1. Ferrannini E. Symposium: When does hyperglycemia become diabetes? Impaired β-cell function. Presentation at 65th ADA in Washington, DC, Available at Accessed October 2006. 2. Ramlo-Halsted BA, Edelman SV. The natural history of type 2 diabetes. Implications for clinical practice. Prim Care. 1999;26:771–789. 3. Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia. 2003;46:3–19.

Functional Defects in ß-Cells in the Development of Diabetes
Progressive decrease in b-cell insulin secretion in response to nutrients First manifested as a decrease in early or acute insulin secretion (decreased first phase insulin secretion) Loss of normal minute-by-minute pulsatile insulin secretion and daily ultradian rhythm of secretion Decreases in insulin processing with increased proinsulin:insulin ratio Functional Defects in b-Cells in the Development of Diabetes Several functional defects in b-cells insulin secretion occur prior to the onset of diabetes. First, there is a decrease in early or acute insulin secretion following meals or a glucose challenge. There is a disruption in the normal pulsatile insulin secretion and the ultradian variation in serum insulin levels. Insulin is secreted in a pulsatile manner over short time periods. There is also a variation in the amount of insulin secreted during the day, due to factors related to diet, changes in counter regulatory hormones, and other factors. The increased demand for insulin could cause a decrease in the time insulin is available to processing machinery, resulting in decreased C-peptide cleavage and an increase in the proinsulin/insulin ratio.

Type 2 Diabetes: Pathogenesis in a Nutshell (cont.)
Type 2 diabetes has been considered a PROGRESSIVE disease -cell dysfunction first leads to impaired glucose tolerance, which in some individuals progresses to type 2 diabetes -cell dysfunction starts long before blood glucose rises and worsens after diabetes develops Hyperglycemia may cause additional defects in insulin secretion and insulin action (glucotoxicity) C (core) represents a core slide in this curriculum. Type 2 Diabetes: Pathogenesis in a Nutshell (cont.) Early in the natural history of type 2 diabetes, insulin resistance becomes established, but glucose tolerance remains normal because of an ability of the b-cells to compensate for insulin needs. As a result of several poorly understood mechanisms, b-cells lose their ability to compensate, leading to impaired glucose tolerance. Many (but not all) individuals continue to lose insulin secretory capacity, or have increases in insulin resistance and “fall further off the curve,” resulting in type 2 diabetes. Thus, type 2 diabetes is a progressive disease occurring in a gradual succession of stages of increasing glucose intolerance and insulin resistance. The hyperglycemia associated with type 2 diabetes can lead to additional effects on insulin secretion and insulin action by way of glucotoxicity. Glucotoxicity refers to the decreased sensitization of b-cells to the presence of glucose and the deleterious effects of accumulated fatty acids and their metabolic products on b-cells. Although some free fatty acids are needed for normal insulin secretion, prolonged increases result in b-cell dysfunction with decreased insulin secretion and impaired conversion of proinsulin to insulin. Buchanan TA. Clin Ther. 2003;25(suppl B):B32-B46. DeFronzo RA. Med Clin North Am. 2004;88: Kahn SE. J Clin Endocrinol Metab. 2001;86: Buchanan TA. Clin Ther. 2003;25(suppl B):B32-B46. DeFronzo RA. Med Clin North Am. 2004;88: Kahn SE. J Clin Endocrinol Metab. 2001;86:

UKPDS: Progressive Deterioration in Glycemic Control Over Time
A1C 9 100 8 80 Median A1C (%) 60 b-cell function (%) 7 Conventional 40 Intensive 20 6 C (core) represents a core slide in this curriculum. UKPDS: Progressive Deterioration in Glycemic Control Over Time This slide demonstrates the progressive nature of hyperglycemia despite treatment in patients with established type 2 diabetes. It also demonstrates the loss of b-cell function as glucose levels rise. In the United Kingdom Prospective Diabetes Study (UKPDS), 3,867 subjects with symptomatic type 2 diabetes were randomized at entry to one of two treatment arms—conventional treatment with dietary therapy alone or intensive treatment with sulfonylurea or insulin. The glycemic goal of conventional treatment was fasting plasma glucose (FPG) <15 mmol/L (<270 mg/dL). Patients attended UKPDS clinics every 3 months; patients who eventually failed conventional diet treatment (FPG >15 mmol/L, >270 mg/dL) were subsequently randomized to one of the intensive treatment arms. The aim of the intensive treatment groups was FPG <6 mmol/L (<180 mg/dL). Although levels of A1C initially dropped in patients in the intensive treatment arm, eventually A1C deteriorated over time in all treatment groups, albeit the levels were significantly lower in the intensive treatment group compared with the conventional group. The figure on the right shows the change in b-cell function assessed by homeostasis model assessment (HOMA) measurements over time. The dashed line extrapolated from the plotted data suggests that deterioration in b-cell function may have begun from 10 to 12 years prior to the diagnosis of diabetes. Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352: 3 6 9 12 15 -12 -10 -8 -6 -4 -2 2 4 6 Time from randomization (y) Years from diagnosis Holman RR. Diabetes Res Clin Pract ;40(suppl):S21-S25. UKPDS Group. Lancet. 1998;352:

Mechanisms Responsible for Changes in Insulin Levels
Normal b-cell adaptation to insulin resistance Increased secretion from each cell Increased b-cell mass Impaired b-cell adaptation in type 2 diabetes result of Decreased secretion from each cell Reduced b-cell mass C (core) represents a core slide in this curriculum. Mechanisms Responsible for Changes in b-Cell Function Normal b-cell adaptation to insulin resistance can occur through increased secretion from each b-cell and/or an increase in the b-cell mass. Type 2 diabetes results from an inadequate insulin secretion from each b-cell or an inadequate b-cell mass for the levels of prevailing insulin sensitivity. This relates back to the concept of adaptation to acute or chronic changes in insulin sensitivity. An individual can have a reduced insulin secretion or reduced b-cell mass but can have normal glucose levels. These individuals have sufficient insulin sensitivity such that their insulin secretion is adequate.

Potential Causes for Declining Insulin Secretion
Glucotoxicity Lipotoxicity b-cell Apoptosis Insulin Secretion Prentki M et al. Diabetes. 2002;51(suppl 3):s405-s413.

Abnormalities of α-Cell Function in Type 2 Diabetes
Elevated glucagon levels Loss of insulin-induced suppression Loss of glucose-induced suppression Increased stimulatory effect of arginine Dunning BE et al. Diabetologia. 2005;48:

Summary Islets can adapt to insulin resistance
Failure of adaptation results in impaired glucose tolerance and eventually, type 2 diabetes Failure appears to be due to reduced insulin secretion per islet and a reduction in the number of islets Increased glucagon contributes to hyperglycemia in type 2 diabetes

Global Cardiometabolic Risk*
We have understood for decades the roles of ‘classical’ risk factors – elevated LDL-cholesterol, hypertension, elevated blood glucose and smoking – in the pathogenesis of cardiovascular disease. More recent research is continuing to define the contribution of emerging risk factors to the risk of developing type 2 diabetes and cardiovascular disease, particularly in the setting of insulin resistance. Abdominal obesity is associated with multiple cardiometabolic risk factors such as atherogenic elevated blood glucose (hypertriglyceridaemia and low HDL-cholesterol), elevated blood glucose and inflammation, which are major drivers of cardiovascular disease and type 2 diabetes. In addition, atherosclerosis is increasingly regarded as an inflammatory condition. * working definition Gelfand EV et al, 2006; Vasudevan AR et al, 2005 Gelfand EV et al. Rimonabant: a cannabinoid receptor type 1 blocker for management of multiple cardiometabolic risk factors. J Am Coll Cardiol 2006:47(10):1919–26. Vasudevan AR, Ballantyne C et al, Cardiometabolic risk assessment: an approach to the prevention of cardiovascular disease and diabetes mellitus. Clin Cornerstone 2005; 7(2-3):7–16.

Differentiating Type 1 Vs. Type 2 DM
Presentation with ketoacidosis Age at onset Testing for C-peptide levels Testing for antibodies - GAD-65 - IA2 - Insulin - Islet-cell Trial of oral agents

Other Kinds of Diabetes
LADA (latent autoimmune disease of adults) MODY (maturity-onset diabetes of the young) Gestational diabetes Stress-induced Post-transplant

Complications of Diabetes
Small Blood Vessel - eye (retina) – blindness - kidney failure – dialysis Large Blood Vessel - heart attacks - strokes - peripheral vascular : amputations Neuropathy Erectile dysfunction (both vascular and nerve damage)

Avoiding Complications - I
Diet / exercise ‘Girth’ control Sugar control Lipid (cholesterol) control Blood pressure control

Avoiding Complications - II
Self-monitoring glucose Visits to PCP – endocrinologist: goals Eye exams Podiatry exams Periodic blood / urine lab testing

Standards of Care American Diabetes Association
AACE goals HbA1c 6.5% FPG 110 mg/dL PP 140 mg/dL Glycemia: HbA1c <7.0%, FPG mg/dL, PP <180 mg/dL Blood Pressure: <130/80 mm Hg Lipids: LDL <100 mg/dL; TG <150 mg/dL Yearly Dilated eye exam; urinary protein; foot exam; flu shot Other Aspirin usage; pneumococcal vaccine NCEP LDL ≤70 mg/dL FPG – fasting plasma glucose PP - Postprandial ADA. Diabetes Care. 2009;32(suppl 1);S13-S61. 34

Oral Drugs for Rx DM2 Metformin (glucophage)
Sulfonylureas (glyburide, glipizide, glimepiride) Thiazolidinediones (actos, avandia) DPP-IV inhibitors (januvia, onglyza) Glucosidase inhibitors (acarbose, miglitol) Others: colesevelam ; bromocriptine

Injectables For RX DM2 Pramlintide (Symlin)
Exenatide (Byetta) / liraglutide (Victoza) Insulins Native Regular (short-acting) - Isophane (NPH : intermediate) - Mixtures Analogues Glargine / Detemir (long-acting) - Humalog, Novolog, Apidra (rapid) - Mixtures

Conclusions No specific drugs or regimens seem to have a necessarily adverse effect on cardiovascular event rates despite expressed concerns about certain drugs A1C goal should be individualized <6.5% if healthy, and short duration diabetes and long life expectancy <7% average patient <7.5-8% medically complex, clinical cardiovascular disease, failed to achieve lower target with lifestyle, metformin and adequate doses of insulin The future: continuing surveillance of newer classes of drugs for adverse – or beneficial – cardiovascular effects

Future Rx DM2 Longer acting GLP-1 analogues More DPP-IV inhibitors
More TZD’s Newer drug classes : e.g., SGLT2-inhibitors NOTE : FDA requires longer duration studies in DM2 to better understand risk / benefit before approval

Prevention of DM TYPE 1 - Immune modulation TYPE 2 - Diet/exercise
- Drugs: Metformin TZD’s Glucosidase inhibitors Others?

Today’s Program Evolving science & medicine of incretin- based therapy
Options, strategies and combinations Practice – focused overview T2DM Rx in 2010 – where are we?

Stamp Out Diabetes!

Investigations • Innovation • Clinical Application
The Current Armamentarium of Oral Agents for Type 2 Diabetes Mellitus—Sequencing Oral Therapy When and Where Do We Start? When Do We Add? How Do The Guidelines Guide Us? Samir Malkani, MD Director, Adult Diabetes Clinic, University Campus UMass Memorial Medical Center Clinical Associate Professor of Medicine University of Massachusetts Medical School UMASS Memorial Medical Center Worcester, MA

Number and Percentage of U. S
Number and Percentage of U.S. Population with Diagnosed Diabetes, Methodology Number and percent of the U.S. population with diagnosed diabetes were obtained from the National Health Interview Survey (NHIS, available at of the National Center for Health Statistics (NCHS), Centers for Disease Control and Prevention (CDC) for years. Conducted continuously since 1957, the NHIS is a health survey of the civilian, noninstitutionalized population of the United States. The survey provides information on the health of the United States population, including information on the prevalence and incidence of disease, the extent of disability, and the utilization of health care services. The multistage probability design of the survey has been described elsewhere (1,2). Estimates for years were obtained from published data (3) and estimates from 1980 forward were derived directly from the NHIS survey data. References 1. Massey JT, Moore TF, Parsons VL, Tadros W. Design and estimation for the National Health Interview Survey, Hyattsville, MD: National Center for Health Statistics. Vital and Health Statistics 1989;2(110). 2. Botman SL, Moore TF, Moriarity CL, Parsons VL. Design and estimation for the National Health Interview Survey, 1995–2004. National Center for Health Statistics. Vital and Health Statistics 2000;2(130). 3. Harris MI: Prevalence of noninsulin-dependent diabetes and impaired glucose tolerance. Chapter VI in Diabetes in America, Harris MI, Hamman RF, eds. NIH publ. no , 1985. CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at

U.S. Population with Diagnosed Diabetes, 1995-2008

2001

Too fat Too thin

Natural History of Type 2 Diabetes
Insulin resistance 100 200 300 –10 –5 5 10 15 20 25 30 Relative -cell function (%) At risk for diabetes Insulin output Beta-cell failure Years of diabetes 50 100 200 300 Glucose (mg/dL) Post-meal glucose Fasting glucose Diabetes

The Importance of ß-Cell Failure in the Development and Progression of Type 2 Diabetes
Steven E Kahn FIG. 7. Model for the relationship between b cell dysfunction and deterioration of glucose tolerance. As b cell function declines, glucose tolerance deteriorates so that the criteria for impaired fasting glucose and/or impaired glucose tolerance are reached. Subsequently, with a further loss of b cell function, diabetes develops based on either or both the fasting and 2-h glucose levels The Journal of Clinical Endocrinology & Metabolism, September 2001, 86(9):4047–4058

HbA1c Trend with Time - UKPDS

Targets for Glycemia Control
Recommendations for glycemia control from the American Diabetes Association and the American Association of Clinical Endocrinologists. *The glycated hemoglobin (HbA1c) goal for patients in general is less than 7.0%, while the HbA1c goal for selected patients is as close to normal (<6.0%) as possible without significant hypoglycemia. Sources: American Diabetes Association. Diabetes Care. 2010;33(suppl 1):S11-S61; ACE/AACE Diabetes Road Map Task Force. Endocr Pract. 2007;13:

Dietary Therapy Best implemented by a registered dietitian experienced in behavioral modification Individualized diet based on weight, lipids, lifestyle Total carbohydrates 45-65% of daily energy intake Avoid sugars, increase complex carbohydrates, 50 gram of fiber daily Fat <30% calories (<7% saturated) Dietary therapy alone can reduce A1C by % or more Diabetes Care, (Supp 1) S11-S48

Physical Activity Perform at least 150 minutes of moderate-intensity* aerobic physical activity per week In the absence of contraindications, perform resistance training three times a week DIAD study JAMA 2009 did not show any benefit of screening asymptomatic individuals with normal EKG * 50-70% of max heart rate Diabetes Care, (Supp 1) S11-S48

Patient Education in Diabetes Mellitus: 10 Content Areas
Promoting Care prior to and during Pregnancy Diabetes Disease Process Integrating Psychosocial Adjustment To Daily Living Nutritional Management Goal setting for Health & Daily Living Diabetes Self- Management Education Physical Activity Preventing, Detecting & Treating Chronic Complications Preventing, Detecting & Treating Acute Complications Utilizing Medication Monitoring Blood Glucose Funnell et. al. Diabetes Care 2010:33 (Suppl1) S89-96

Type 2 Diabetes Medication Choices Experience and Potency
Route Year Efficacy as monotherapy: %  in HgbA1c Insulin s.c. 1921 2.5 Sulfonylureas Oral 1946 1.5 Glinides 1997 Metformin 1995 -glucosidase inhibitors TZDs 1999 GLP analogue 2005 0.6 DPP-IV Inhibitors 2006 Amylin analogue Colesevelam 2008 0.5 Bromocriptine mesylate 2009

Mechanisms of Action of Pharmacologic Agents for Diabetes
Improving Outcomes in Patients With Type 2 Diabetes Mellitus: Practical Solutions for Clinical Challenges James R. Gavin, III, MD, PhD; Mark W. Stolar, MD; Jeffrey S. Freeman, DO; Craig W. Spellman, DO, PhD JAOA • Vol 110 • No 5suppl6 • May 2010 • 2-14

Oral Medications for Type 2 Diabetes
Drug Initial Dose Maximum Dose Usual Dose Biguanide Metformin 500 mg bid 2550 mg/d mg bid Metformin XR 500 mg/d 2000 mg/d mg/d Sulfonylurea Glimepiride 1-2 mg/d 8 mg/d 4 mg/d Glipizide 2.5-5 mg/d 40 mg/d 10-20 mg/d Glipizide SR 20 mg/d 5-20 mg/d Glyburide 5-10 mg/d Glyburide Micronized mg/d 12 mg/d 3-12 mg/d Thiazolidinedione Pioglitazone 15-30 mg/d 45 mg/d 15-45 mg/d Rosiglitazone 4-8 mg/d a-Glucosidase inhibitor Acarbose 25 mg tid 100 mg tid mg tid Miglitol Metiglinide Repaglinide 0.5 mg before meals 4 mg before meals 0.5-4 mg before meals Nateglinide mg tid before meals 120 mg tid before meals DPP4 Inhibitor Sitagliptin 100 mg/d Saxagliptin 2.5 mg/d 5 mg/d Bile Acid Sequestrants Colesevelam 375 mg/day Adapted from: Annals of Internal Medicine, March 2010 “In the Clinic”

Type 2 Diabetes Medication Choices and Potency
Higher baseline A1C levels predict greater drop in A1C Shorter duration of diabetes predicts greater drop in A1C with any oral agent All oral agents require presence of some endogenous b cell function, as they work by either increasing insulin sensitivity or augmenting b cell insulin release Practical Tips! Sherifali et.al. Diabetes Care. 2010; 33:

Percentage of Individuals with A1C>7% NHANES surveys
Hoerger TJ et. al. Diabetes Care. 2008; 31:81-86

Metformin - Drug Profile
Advantages No hypoglycemia Weight loss Cardiovascular benefit Reduces LDL-C (approx 10 mg/dL), reduces TG Disadvantages Diarrhea is common Contraindicated in renal impairment, liver failure, advanced cardiac failure Risk of lactic acidosis not increased in meta-analyses and systematic reviews Concomitant use with other drugs Can be used as monotherapy and with all classes including insulin

Sulfonylureas - Drug Profile
Advantages Potent glucose lowering effect Favorable adverse effect profile Disadvantages Hypoglycemia, more with Glyburide Glyburide contraindicated in renal impairment ?Glyburide impairs ischemic preconditioning in heart (UKPDS did not reveal increased cardiac risk) Concomitant use with other drugs Can be used as monotherapy and with all classes including insulin

Repaglinide and Nateglinide: Drug Profiles
Advantages Less hypoglycemia than sulfonylureas Favorable adverse effect profile Disadvantages Less potent than sulfonylureas; target mainly post-prandial glucose Nateglinide less potent than Repaglinide Concomitant use with other drugs Can be used with all classes including insulin

Concomitant use with other drugs
TZDs - Drug Profile Advantages No hypoglycemia May be useful in nonalcoholic fatty liver disease Disadvantages Increased fracture risk Weight gain Edema and exacerbation of CHF Rosiglitazone increases LDL-C (10mg/dL), TG (15-50mg/dL) and possible increase in MI Concomitant use with other drugs Can be used with other classes including insulin. Increased fluid retention and weight gain with insulin

Alpha Glucosidase Inhibitor (AGI) - Drug Profile
Advantages No hypoglycemia Weight neutral Disadvantages Targets only postprandial glucose GI side effects Concomitant use with other drugs Can be used as monotherapy and with all classes including insulin

DPP4 Inhibitors – Drug Profile
Advantages Weight neutral Favorable adverse effect profile No hypoglycemia Disadvantages Limited track record Nasopharyngitis, upper respiratory infections Rare pancreatitis Concomitant use with other drugs Can be used as monotherapy and with SU, TZD, metformin (some have been studied with insulin)

Colesevelam - Drug Profile
Advantages No hypoglycemia Reduces LDL-C (approx 10 mg/dL), Disadvantages Constipation is common Increase in triglycerides Malabsorption of fat soluble vitamins Concomitant use with other drugs Can be used as combination therapy with metormin

ADA/EASD Guidelines

ADA/EASD: Considerations for the Guidelines
Use of information from clinical trials that address the efficacy and safety of different modalities of treatment Paucity of high quality evidence was an impediment Clinical judgment of the panel participants Extrapolation of UKPDS data that glucose lowering of drugs (metformin, sulfonylureas, insulin) predicted decrease in complications. Nonglycemic effects of medication, such as effect on CV risk, lipids, hypertension or insulin resistance Safety, side effects, ease of use and expense

ADA Algorithm for Management of Diabetes Diabetes Care
Tier 1: Well-validated core therapies At diagnosis: Lifestyle + Metformin Lifestyle+Metformin + Basal Insulin Lifestyle+Metformin + Intensive insulin Lifestyle+Metformin + Sulfonylurea Step 1 Step 2 Step 3 Tier 2: less well-validated therapies Lifestyle+Metformin + Pioglitazone Sulfonylurea Lifestyle+Metformin + Pioglitazone (No hypoglycemia, edema, CHF, bone loss) *Useful when hypoglycemia is to be avoided Lifestyle+Metformin + GLP1 (No hypoglycemia, wt loss, Nausea/vomiting) Lifestyle+Metformin + Basal Insulin Amylin agonists, Glinides DPP-4 inhibitors may be appropriate in selected patients

Review Annals of Internal Medicine Systematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes Mellitus Shari Bolen, MD, MPH; Leonard Feldman, MD; Jason Vassy, MD, MPH; Lisa Wilson, BS, ScM; Hsin-Chieh Yeh, PhD; Spyridon Marinopoulos, MD, MBA; Crystal Wiley, MD, MPH; Elizabeth Selvin, PhD; Renee Wilson, MS; Eric B. Bass, MD, MPH; and Frederick L. Brancati, MD, MHS Background: As newer oral diabetes agents continue to emerge on the market, comparative evidence is urgently required to guide appropriate therapy. Purpose: To summarize the English-language literature on the benefits and harms of oral agents (second-generation sulfonylureas, biguanides, thiazolidinediones, meglitinides, and -glucosidase inhibitors) in the treatment of adults with type 2 diabetes mellitus. Conclusions: Compared with newer, more expensive agents (thiazolidinediones, aglucosidase inhibitors, and meglitinides), older agents (second-generation sulfonylureas and metformin) have similar or superior effects on glycemic control, lipids, and other intermediate end points. Large, long-term comparative studies are needed to determine the comparative effects of oral diabetes agents on hard clinical end points. Ann Intern Med. 2007;147:

Type 2 Diabetes: Assessing the Relative Risks and
Benefits of Glucose-lowering Medications Richard M. Bergenstal, MD, Clifford J. Bailey, PhD David M. Kendall, MD International Diabetes Center, Minneapolis, Minn; Diabetes Research, Life and Health Sciences, Aston University, Birmingham, UK. The American Journal of Medicine (2010) 123, 374. Figure 4 Events per 1000 patient-years for representative endpoints. Black bars indicate excess risk of events in diabetes patients relative to nondiabetic subjects;19,75,85,86 gray bars indicate excess risk of events in patients treated with specific glucose- lowering medications relative to diabetic patients on other agents;2,25,41,54,60,61,74 and white bars indicate the decreased risk of events in patients undergoing intensive glucose control policies. Foley RN et al. J Am Soc Nephrol. 2005;16(2): ; b = 19Haffner SM et al. N Engl J Med.1998;339(4) ; c = 75Noel RA et al. Diabetes Care. 2009;32(5): ;d = 86Trautner C et al. Diabetes Care. 1997;20(7): ; e = 60,61HamptonT. JAMA. 2007;297(15):1645 and Meier C et al. Arch Intern Med. 2008;168(8): ; f = 41Lago RM et al. Lancet. 2007;370(9593): ; g = 25Patel A et al. N Engl J Med. 2008;358(24): ; h = 2Nissen SE, Wolski K. N Engl J Med. 2007;356(24) ; i = 54Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2006; j = 74Dore DD et al.

Type 2 Diabetes: Assessing the Relative Risks and Benefits of Glucose-lowering Medications
Richard M. Bergenstal, MD, Clifford J. Bailey, PhD David M. Kendall, MD International Diabetes Center, Minneapolis, Minn; Diabetes Research, Life and Health Sciences, Aston University, Birmingham, UK. Glucose-lowering medications have a favorable risk-benefit profile The most common adverse event is hypoglycemia, particularly among patients receiving sulfonylureas or insulin. Metformin-associated lactic acidosis, exenatide-associated pancreatitis, and sitagliptin-associated hypersensitivity reactions appear to be rare. Increased risks of congestive heart failure and bone fractures in thiazolidinedione-treated patients, and reports of increased cardiovascular events in rosiglitazone-treated patients remain an issue.

Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy
Steven E. Kahn, M.B., Ch.B., Steven M. Haffner, M.D., Mark A. Heise, Ph.D., William H. Herman, M.D., M.P.H., Rury R. Holman, F.R.C.P., Nigel P. Jones, M.A., Barbara G. Kravitz, M.S., John M. Lachin, Sc.D., M. Colleen O’Neill, B.Sc., Bernard Zinman, M.D., F.R.C.P.C., and Giancarlo Viberti, M.D., F.R.C.P., for the ADOPT Study Group * 40 Hazard ratio (95% CI) Rosiglitazone vs. metformin, 0.68 (0.55–0.85); P<0.001 Rosiglitazone vs. glyburide, 0.37 (0.30–0.45); P<0.001 Glyburide 30 20 Cumulative Incidence of Monotherapy Failure Metformin Rosiglitazone 10 Years Rosiglitazone 1393 1207 1078 957 844 324 Metformin 1397 1205 1076 950 818 311 Glyburide 1337 1114 958 781 617 218 Figure 2. Kaplan–Meier Estimates of the Cumulative Incidence of Monotherapy Failure at 5 Years. Treatment was considered to have failed if a patient had a confirmed or adjudicated level of fasting plasma glucose of more than 180 mg per deciliter. Risk reduction is listed for comparisons of pairwise groups from a baseline covariateadjusted Cox proportionalhazards model. Gray’s estimates of cumulative incidence adjusted for all deaths were smaller than Kaplan–Meier estimates of treatment failure: 10% in the rosiglitazone group, 15% in the metformin group, and 25% in the glyburide group. I bars indicate 95% CIs. N Engl J Med 2006;355:242743

AACE/ACE: Considerations for the Guidelines
Minimizing risk and severity of hypoglycemia Minimizing weight gain Inclusion of all major classes of FDA-approved glycemic medications Selection of therapy stratified by hemoglobin A1C (A1C) and based on documented A1C lowering potential Consideration of both fasting and postprandial glucose levels as end points Consideration of total cost of therapy to individual and society - includes cost of medication, glucose monitoring, hypoglycemic events, drug adverse events, and treatment of complications

LIFESTYLE MODIFICATION
A1C % A1C % A1C >9% Monotherapy Dual Therapy Drug naïve, No symptoms MET DPP4 GLP1 TZD AGI MET + GLP1 or DPP4 or TZD SU or Glinides Triple Therapy MET + GLP1 or DPP4 +SU TZD +TZD Dual Therapy MET + GLP-1 or DPP4 TZD Glinide or SU Colesevelam AGI Triple Therapy MET + GLP1 or DPP4 +TZD +SU TZD Symptoms or under treatment Triple Therapy MET + GLP1 or DPP4 + TZD Glinides or SU Adapted from AACE December 2009 update with permission Insulin + other agents

AACE/ACE Diabetes Algorithm
ADA/ EASD Criteria Evidence based Recognize that beta cell failure is progressive, and eventually insulin will be required, so recommends this transition early Greater emphasis on direct medication costs and efficacy Emphasis on one or two drug regimens, minimizes use of multiple drugs AACE/ ACE Criteria Attempts to provide a place and recommendation for all FDA approved drugs Greater emphasis on hypoglycemia avoidance Recognizes that people may want choices, so allows a wide variety of choices and combinations for individual situations

National Trends in Use of Different Therapeutic Drug Classes to Treat Diabetes, 1994-2007
Alexander, G. C. et al. Arch Intern Med 2008;168:

Leading Diabetes Medications
by Treatment Class Alexander, G. C. et al. Arch Intern Med 2008;168:

Complex Physiology Complex Management
Lifestyle Insulin SFU, glitinides, exenatide Metformin, TZDs, AGIs, DPP4 AGI: alpha glucosidase inhibitor SFU: sulfonylurea 50 100 200 300 Glucose (mg/dL) Post-meal glucose Fasting glucose Insulin resistance 100 200 300 –10 –5 5 10 15 20 25 30 Relative -cell function (%) At risk for diabetes Beta-cell failure Insulin output Years of diabetes

Factors to Consider when Choosing Pharmacological Agent(s) for Diabetes
Current A1C Duration of diabetes Body weight (BMI, abdominal obesity) Age of patient Co-morbidities Cost of medication Convenience

Considerations when Choosing a Drug Within a Class
Adverse effects are not “class-specific” Phenformin vs. Metformin Troglitazone vs. Rosiglitazone vs. Pioglitazone Drugs within a class may not be equally effective

LIFESTYLE MODIFICATION
Monotherapy MET DPP4 GLP1 TZD AGI MET + GLP-1 or DPP4 TZD Glinide or SU Colesevelam AGI Dual Therapy MET + GLP1 or DPP4 +SU TZD +TZD symptomatic or severe hyperglycemia Triple Therapy Insulin + other agents

The Role of Incretin Mimetics in Treating Type 2 Diabetes
Investigations • Innovation • Clinical Application The Role of Incretin Mimetics in Treating Type 2 Diabetes Program Chairman Charles Faiman, MD, FRCPC,MACE Past Chairman Consultant Staff Department of Endocrinology, Diabetes and Metabolism Cleveland Clinic Foundation

Case Presentation 50-year-old patient with type 2 diabetes on glyburide 5 mg/d and metformin 1000 bid presents with a random blood sugar of 240 mg/dL and HbA1c 8.0% Weight 250 lb Ht 5’9” BMI 36.9

What would be the best therapeutic option to treat this patient’s diabetes?
1. Add pioglitazone 30 mg/d 2. Add insulin glargine 10 units qhs 3. Start nateglinide 120 mg tid 4. Start sitagliptin 100 mg/d 5. Start exenatide 5 mcg bid

David M. Nathan, MD The New England Journal of Medicine
Perspectives February 1, 2007 “A host of medications that are already available are effective as monotherapy or in combination with metformin or one of the TZDs (the approved uses of sitagliptin). The fact that these medications achieve better glycemic control than sitagliptin suggests the need for caution in approving a new medication that has received limited testing.”

A Consensus Statement From the American Diabetes Association and the European Association for the Study of Diabetes Nathan DM et al. Diabetes Care. 2006;29:

Management of Hyperglycemia in T2DM
Diagnosis Lifestyle intervention + Metformin A1C≥7% No Yes* Add basal insulin* - most effective Add sulfonylurea - least effective Add glitazone - no hypoglycemia No A1C≥7% Yes* No A1C≥7% Yes* No A1C≥7% Yes* Intensify insulin* Add glitazone* Add basal insulin* Add sulfonylurea* No A1C≥7% Yes* No A1C≥7% Yes* Add basal or intensify insulin* Intensive insulin + metformin ± glitazone Adapted from Nathan DM et al. Diabetes Care. 2006;29:

Algorithm Overview The algorithm takes into account the characteristics of the individual interventions, their synergies, and expense The goal is to achieve and maintain glycemic levels as close to the nondiabetic range as possible and to change interventions at as rapid a pace as titration of medications allows Pramlintide, exenatide, α-glucosidase inhibitors, and the glinides are not included in this algorithm, owing to their generally lower overall glucose-lowering effectiveness, limited clinical data, and/or relative expense. These may, however, be appropriate choices in selected patients

ADOPT: A Diabetes Outcome Progression Trial—Safety Profile
Incidence of Selected Adverse Events Selected Events RSG (N=1456) n (%) MET (N=1454) SU (N=1441) Gastrointestinal 335 (23.0) 557 (38.3)* 316 (21.9) Edema 205 (14.1) 104 (7.2)* 123 (8.5)* Hypoglycemia 142 (9.8) 168 (11.6) 557 (38.7)* MI, fatal 2 (0.1) 3 (0.2) MI, non-fatal 25 (1.7) 21 (1.4) 15 (1.0) CHF 22 (1.5) 19 (1.3) 9 (0.6)† Stroke 16 (1.1) 17 (1.2) Change in weight observed in study: RSG +0.7 kg/year; MET -0.3 kg/year; SU 0.2 kg/year * P≤0.01 vs RSG † P≤0.05 vs RSG Data from Kahn SE et al. N Engl J Med. 2006;355:

ADOPT—Implications Current oral agent therapy is associated with significant adverse events Weight gain, edema, lactic acidosis, GI side effects, and hypoglycemia are significant problems GLP-1 agonists cause significant weight loss DPP-4 inhibitors have no associated weight gain or complications

Relationship Between Weight Gain in Adulthood and Risk of T2DM
Men Women Relative Risk -10 -5 5 10 15 20 Weight Change (kg) Data from Willett WC et al. N Engl J Med. 1999;341:427.

Weight Gain and Glycemic Control
Weight gain seems to be inseparable from glycemic control with many antidiabetic treatments, including sulfonylureas, insulin, and thiazolidinediones, which have an estimated 2 kg weight gain for every 1% decrease in HbA1C Buse J et al. Clin Ther. 2007;29:

Clinical Role of GLP-1—Mimetics
Overweight patients with type 2 diabetes requiring initial treatment Overweight patients with type 2 diabetes on metformin, sulfonylurea, or combination Addition to thiazolidinediones to avoid weight gain

Reduced Incretin Effect in Patients With T2DM
Control subjects T2DM patients 80 60 40 20 80 60 40 20 Intravenous glucose Oral glucose Insulin (mU/L) Insulin (mU/L) * * * * * * * * * * Time (min) Time (min) *P≤0.05 Data from Nauck M et al. Diabetologia. 1986;29:46-52.

Summary of GLP-1— Effects in Humans
Central nervous system Promotes satiety and reduction of appetite Liver  Glucagon reduces hepatic glucose output β cell Enhances secretion of glucose-dependent insulin Stomach Regulates gastric emptying Potential increase in β-cell mass α cell  Glucagon secretion post-meal Flint A et al. J Clin Invest. 1998;101: Larsson H et al. Acta Physiol Scand. 1997;160: Nauck MA et al. Diabetologia. 1996;39: Drucker DJ. Diabetes. 1998;47:

Glucose-dependent Effects of GLP-1 Infusion on Insulin and Glucagon Levels in T2DM Patients
15.0 250 12.5 Placebo Glucose mmol/L * 200 10.0 mg/dL GLP-1 7.5 150 5.0 100 *P<0.05 Patients with T2DM (N=10) 2.5 50 250 When glucose levels approach normal values, insulin levels decrease. * 40 Insulin 200 pmol/L 30 150 mU/L 100 20 50 * 10 * 20 20 When glucose levels approach normal values, glucagon levels rebound. * Glucagon pmol/L 15 15 pmol/L 10 10 5 5 Infusion –30 60 120 180 240 Minutes Adapted from Nauck MA et al. Diabetologia. 1993;36:

Exenatide: HbA1C and Body Weight Reductions
Preliminary Analysis for Subjects Treated for 2 Years Two-year data for 82-wk cohort (N=146) Mean ± SE Δ A1C (%) Δ Body Weight (kg) Placebo- controlled Placebo- controlled Open-label Extensions Open-label Extensions 0.0 Baseline A1C: 8.2% Baseline weight: 100 kg -2 -0.5 -5.5±0.5 kg -1.2±0.1% -1.0 -4 -1.5 -6 0.0 0.5 1.0 1.5 2.0 0.0 0.5 1.0 1.5 2.0 Duration of Treatment (Years) Duration of Treatment (Years) Kendall D. ADA

Insulin glargine, mean dose at endpoint = 25.0 U/day
Effect of Exenatide vs Insulin Glargine in Pts with Suboptimally Controlled T2DM on HbA1C 0.0 6.5 7.0 7.5 8.0 8.5 A1C (%) Exenatide, 10 mg BID 8.2% Insulin glargine, mean dose at endpoint = 25.0 U/day DISCUSSION: HbA1c was measured at screening (Week -4), baseline (Week 0), Week 12, Week 26 (endpoint) and, if possible, at the time of discontinuation for those who dropped out of the study before completion of Week 26. Eight patients in each group discontinued without a post-baseline measurement of HbA1c. Thus, the intent-to-treat sample is made up of 275 exenatide and 260 insulin glargine patients. HbA1c was significantly reduced from baseline at Week 26 in both treatment arms (change from baseline to endpoint, exenatide: ± 0.059%, insulin glargine: ± 0.058%). The 95% CI for the difference between treatments (exenatide–insulin glargine) was % to 0.157%. This is within the non-inferiority criteria of the upper limit <0.4%. STUDY BACKGROUND: At endpoint, the average dose of insulin glargine was 25.0 IU/day (n = 244). 21.6% of insulin glargine patients, compared with 8.6% of exenatide patients, achieved a fasting glucose of <5.6 mmol/L (100 mg/dL). The daily insulin dose achieved in the present study is lower when compared to other published large-scale randomized clinical trials of insulin glargine (Riddle et al, Diabetes Care. 2003; Benedetti et al, Horm Metab Res 2003; Fritsche et al, Ann Intern Med 2003; Rosenstock et al, Diabetes Care 2001; Yki-Jarvinen et al, Diabetes Care 2000). However, in the present study, the baseline HbA1c was lower than each of those previous trials, possibly resulting in less insulin required to attain a certain glycemic improvement, and all patients entered this trial already taking two oral agents. The mean reduction in HbA1c in the present trial was within the range of reductions observed in previous insulin glargine trials with comparable study designs (ranging from -0.4 to -1.0% for weeks), except the Treat-to-Target trial (-1.65% at 24 weeks) (Riddle et al, Diabetes Care. 2003). In the Treat-to-Target trial, Riddle et al described a number of factors to explain the magnitude of the HbA1c decrease observed, including an ambitious titration target combined with a protocol for encouraging patient adherence. Although problematic to compare across trials, the Treat-to-Target trial also reported a higher incidence of symptomatic (13.9 events per year) and nocturnal hypoglycemia (4.0 events per year) and slightly greater weight gain (+3.0 kg) than observed in the present trial. Moreover, the mean HbA1c achieved at study endpoint in the Treat-to-Target trial (6.96%) was not greatly different from the mean value achieved in the current study (7.12%), and the proportion of patients achieving HbA1c 7% was 58% (Treat-to-Target) versus 48% (present study). Two recently published trials have demonstrated very favorable results adding insulin glargine to patients receiving metformin and/or combination oral therapy (Janka et al, Diabetes Care, 2005 and Raskin et al, Diabetes Care 2005). However the study designs of these trials included the addition of new sulfonylurea therapy (Janka) or the discontinuation of some oral therapies during a run-in period (Raskin), making a direct comparison of these trial results somewhat difficult to interpret. The insulin glargine titration schedule and approach to encouraging patient adherence in the present trial may have been more reflective of real-world usage; as a result, the data (~1% lowering) may better indicate the broader clinical experience with insulin glargine. Intent-to-treat sample was defined as any randomized patient who had at least one post-baseline measurement of the dependent variable. 7.1% Week 12 26 ITT population; Mean ± SE shown Adapted from Heine R et al. Ann Intern Med. 2005;143:

Change in Body Weight—Time Course
Exenatide +1.8 kg 2 Insulin glargine 1 Difference of 4.1 kg between groups DISCUSSION: Insulin glargine patients gained weight throughout the trial period, while exenatide was associated with progressive reductions in weight. Mean body weight was significantly different between the two treatments as early as 2 weeks, and this difference persisted throughout the study. Adjusted mean change in body weight at endpoint was -5.1 ± 0.4 lbs for exenatide, +4.0 ± 0.4 lbs for insulin glargine. Mean difference (exenatide - insulin glargine) was -9.0 lbs, 95% CI for the difference -10.1, -7.7 lbs. Baseline body weights were exenatide: 87.5 ± 16.9 kg and insulin glargine: 88.3 ± 17.9 kg. Enhancing insulin secretion in the absence of weight gain is an important aspect of the incretin mimetics, and may represent an important therapeutic advance in the treatment of type 2 diabetes. STUDY BACKGROUND: Intent-to-treat sample was defined as any randomized patient who had at least one post-baseline measurement of the dependent variable. Change in Body Weight (kg) * -1 * * * -2 * -2.3 kg * -3 2 4 8 12 18 26 Week ITT population; Mean ± SE shown; *P<0.0001, exenatide vs insulin glargine at same time point *P<0.0001 Adapted from Heine R et al. Ann Intern Med. 2005;143:

Effects of Exenatide and Placebo on Body Weight
Patients With T2DM Treated With a TZD with or Without Metformin Exenatide 1.0 Placebo 0.5 0.0 Change in Body Weight (kg) -0.5 * -1.0 † † † -1.5 -2.0 -2.5 4 8 8 12 16 Weeks *P <0.01: †P <0.001 Adapted from Zinman B et al. Ann Intern Med. 2007;146:

Liraglutide Is a Long-acting
Human GLP-1 Incretin Knudsen LB et al. J Med Chem. 2000;43: ; Degn KB et al. Diabetes. 2004;53: 108

Changes in HbA1c From Baseline for Liraglutide 1
Changes in HbA1c From Baseline for Liraglutide 1.8 mg vs Comparator and Placebo Data originally presented as Marre M et al. Diabetes. 2008;57(suppl 1):A4 (LEAD 1); Nauck MA et al. Diabetes. 2008;57(suppl 1):A15 (LEAD 2); Garber A et al. Lancet. 2009;373: (LEAD 3); Zinman B et al. Diabetologia. 2008;51(suppl 1): A898 (LEAD 4); Russell-Jones D et al. Diabetes. 2008;57(suppl 1):A159 (LEAD 5). 109

Body Weight Change: Liraglutide 1.8 mg vs Comparator and Placebo
Data originally presented as Marre M et al. Diabetes. 2008;57(suppl 1):A4 (LEAD 1); Nauck MA et al. Diabetes. 2008;57(suppl 1):A15 (LEAD 2); Garber A et al. Lancet. 2009;373: (LEAD 3); Zinman B et al. Diabetologia. 2008;51(suppl 1): A898 (LEAD 4); Russell-Jones D et al. Diabetes. 2008;57(suppl 1):A159 (LEAD 5). 110

Liraglutide Consistently Reduces Systolic Blood Pressure
Data originally presented as Marre M et al. Diabetes. 2008;57(suppl 1):A4 (LEAD 1); Nauck MA et al. Diabetes. 2008;57(suppl 1):A15 (LEAD 2); Garber A et al. Lancet. 2009;373: (LEAD 3); Zinman B et al. Diabetologia. 2008;51(suppl 1): A898 (LEAD 4); Russell-Jones D et al. Diabetes. 2008;57(suppl 1):A159 (LEAD 5). 111

Outline of LEAD 6 Study Design
Buse JB et al. Diabetes Care Mar 23. 112

LEAD 6 14-week Extension: Shifting Patients to Liraglutide Improves HbA1c Control

LEAD 6 14-week Extension: Shifting Patients to Liraglutide Improves FPG Control

Potential Roles of GLP-1 Mimetics
Once-weekly injection of exenatide-LAR in overweight patients with T2DM who require initial therapy or combination with other oral agents Potential treatment for overweight nondiabetic patients Potential treatment of overweight, insulin- treated patients with T2DM

Exenatide LAR 15-Week Study in T2DM: Results
Baseline HbA1C (mean ± SD) 8.5 ± 1.2% Baseline fasting BG 9.9 ± 2.3 mmol/L *Blood glucose Kim D. Diabetes Care. 2007;30:

Exenatide LAR 15-Week Study in T2DM: Results—Safety and Tolerability
Reaction Placebo Exenatide 0.8 mg/wk Exenatide 2 mg/wk Nausea (mild–moderate) * 15% 19% 27% Injection site bruising 0% 13% 7% Injection-site pruritus 6% % patients with exenatide antibodies 67% of all exenatide LAR-treated patients Weight change -0.04 kg -0.03 kg -3.8 kg *No vomiting noted No severe hypoglycemia or withdrawal due to adverse events observed Kim D. Diabetes Care. 2007;30:

Will the DPP-4 Inhibitors Replace GLP-1 Mimetics?
DPP-4 inhibitors have similar action to GLP-1 agonists but do not result in weight loss; therefore, for patients in whom weight loss is needed, GLP-1 agonists are indicated. Lack of weight loss with DPP-4 inhibition is thought to be due to lesser increase in GLP-1 levels (3x) compared with that of GLP-1 mimetic (10x) or due to lack of PYY* activation by DPP-4 *PPY = peptide YY (intestinal satiety hormone)

Sitagliptin: Mechanism of Action
Glucose- dependent  Insulin (GLP-1and GIP)  Glucose uptake by peripheral tissue Ingestion of food Pancreas Release of active incretins GLP-1 and GIP Beta cells Alpha cells GI tract  Blood glucose in fasting and postprandial states DPP-4 enzyme Glucose- dependent Mechanism of Action of Sitagliptin This illustration describes the mechanism of action of JANUVIA™ (sitagliptin phosphate). The incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon levels, along with higher insulin levels, lead to reduced hepatic glucose production and are associated with a decrease in blood glucose levels in the fasting and postprandial states. The effects of GLP-1 and GIP are glucose dependent. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly inactivates incretin hormones. Concentrations of the active intact hormones are increased by JANUVIA, thereby increasing and prolonging the action of these hormones.  Hepatic glucose production  Glucagon (GLP-1) Inactive GLP-1 Inactive GIP Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels  in response to a meal GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

Sitagliptin: Mechanism of Action (cont)
Glucose dependent  Insulin (GLP-1and GIP)  Glucose uptake by peripheral tissue Ingestion of food Pancreas Release of active incretins GLP-1 and GIP Beta cells Alpha cells GI tract  Blood glucose in fasting and postprandial states Sitagliptin (DPP-4 inhibitor) X DPP-4 enzyme Glucose- dependent Mechanism of Action of Sitagliptin This illustration describes the mechanism of action of JANUVIA™ (sitagliptin phosphate). The incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and levels are increased in response to a meal. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. With higher insulin levels, tissue glucose uptake is enhanced. In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon levels, along with higher insulin levels, lead to reduced hepatic glucose production and are associated with a decrease in blood glucose levels in the fasting and postprandial states. The effects of GLP-1 and GIP are glucose dependent. The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly inactivates incretin hormones. Concentrations of the active intact hormones are increased by JANUVIA, thereby increasing and prolonging the action of these hormones.  Hepatic glucose production  Glucagon (GLP-1) Inactive GLP-1 Inactive GIP Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels  in response to a meal Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the actions of these hormones GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

Role of DPP-4 Inhibitors
Approved as single agents or in combination with a glitazone, sulfonylurea, or metformin Sitagliptin approved to be used in combination with insulin

Saxagliptin: Difference from Placebo in
Adjusted Mean Change from Baseline in HbA1c Rosenstock J et al. Curr Med Res Opin. 2009;25: ; Hollander P et al. J Clin Endocrinol Metab. 2009;94: ; DeFronzo RA et al. Diabetes Care. 2009;32:

Inclusion Criteria: 7%–10%
Sitagliptin Provides Significant and Progressively Greater Reductions in A1C With Progressively Higher Baseline A1C Inclusion Criteria: 7%–10% 18-Week Study Baseline A1C (%) Mean (%) <8% 8<9% >9% <8% 8<9% >9% n=96 n=130 n=70 Reduction in A1c (%) Reduction in A1C (%) n=62 n=27 n=37 Reductions are placebo-subtracted Adapted from Raz I et al. and Aschner P et al. ADA 2006.

regimen of glimepiride
Placebo-controlled Sitagliptin Add-on to Glimepiride or Glimepiride/Metformin Study—Design and Patients R A N D O M I Z T 441 Randomized patients with T2DM age 18–78 yrs Placebo Placebo Sitagliptin 100 mg qd Sitagliptin 100 mg qd Stratum 1 Glim (≥4 mg/day) alone Stratum 2 Glim + MF (≥1500 mg/day) Screening Period Single-blind Placebo Double-blind Phase B Week 0 Week 24 Week 80 Continue/start regimen of glimepiride ± metformin Week-2 eligible if A1C 7.5%–10% Hermansen K et al. Diabetes Obes Metab. 2007;9:

Summary of Conclusions (24 weeks)
Sitagliptin significantly improved A1C when added to: Overall cohort: Sitagliptin reduced A1C by 0.7% (P<0.001) Stratum 1: Glimepiride = -0.6% Stratum 2: Glimepiride + Metformin = -0.9% Hypoglycemia rates were similar to those observed for other AHA when added to SFU Sitagliptin + glimepiride = 7.5% Sitagliptin + glimepiride + metformin = 16.4% Hermansen K et al. Diabetes Obes Metab. 2007;9:

Saxagliptin: Drug Interactions and Use in Specific Populations
Drug interactions: Because ketoconazole, a strong CYP3A4/5 inhibitor, increased saxagliptin exposure, the dose should be limited to 2.5 mg when coadministered with a strong CYP3A4/5 inhibitor (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) Patients with renal impairment: Saxagliptin dose is 2.5 mg/d for patients with moderate or severe renal impairment, or with ESRD requiring hemodialysis (CrCl ≤50 mL/min). Saxagliptin should be administered following hemodialysis. Saxagliptin has not been studied in patients undergoing peritoneal dialysis. Assessment of renal function is recommended prior to initiation of saxagliptin and periodically thereafter Pregnant and nursing women: There are no adequate and well-controlled studies in pregnant women. Saxagliptin, like other antidiabetic medications, should be used during pregnancy only if clearly needed. It is not known whether saxagliptin is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when saxagliptin is administered to a nursing woman. Pediatric patients: Safety and effectiveness of saxagliptin have not been established. Onglyza ® (saxagliptin) [package insert]. Princeton, NJ; Bristol-Myers Squibb; 2009.

Addition of Sitagliptin to Insulin— Effect on HbA1c at 24 Weeks
Sitagliptin change from baseline in A1C at Week (P<0.001) Placebo change from baseline

Why DPP-4 Inhibitors? Excellent in patients with mild hyperglycemia requiring insulin secretagogue No contraindication in heart failure and no risk of edema or lactic acidosis Can be used in renal insufficiency without risk of hypoglycemia or lactic acidosis No weight gain Immediate activity without causing hypoglycemia

Should DPP-4 Inhibitors Be First-line Agents?
If β-cell-sparing effect shown in rats proves to be true in humans, DPP-4 inhibitors could become the preferred first-line agents Appropriate for patients with mild elevation of glucose with contraindications to other agents that cause hypoglycemia Should be considered early in overweight patients Should be considered in patients with heart failure Strongly considered in patients with renal failure

Ratio (pmol/L/pmol/L)
Sitagliptin Improved Markers of β-Cell Function — 24-week Monotherapy Study 0.55 80 Proinsulin/insulin ratio HOMA-β 75 0.5 70 P<0.001* 65 0.45 60 P<0.001* Ratio (pmol/L/pmol/L) 55 0.4 50 45 0.35 40 35 0.3 30 Placebo Sitagliptin 100 mg Placebo Sitagliptin 100 mg ∆ from baseline vs pbo=13.2 (95% CI 3.9, 21.9) ∆ from baseline vs pbo=0.078 (95% CI , ) Hatched = Baseline Solid = Week 24 *P value for change from baseline compared to placebo Aschner P et al. ADA

GLP-1 Improves β-cell Mass in Fatty Zucker Diabetic Rats
β-cell Mass (mg) β-cell Proliferation (%) β-cell Apoptosis (%) 16 12 8 4 2.5 2.0 1.5 0.5 1.0 30 20 10 P<0.05 P<0.01 P<0.001 Beta-Cell Mass (mg) Proliferating Beta Cells (%) Apoptotic Beta Cells (%) Control GLP-1- treated Control GLP-1- treated Control GLP-1- treated Weeks Adapted from Farilla L et al. Endocrinology. 2002;143:

Conclusions—GLP-1 Mimetics
GLP-1 mimetics are important new therapeutic options that have important roles in current therapy and major potential future roles GLP-1 mimetics have excellent glucose-lowering efficacy and are associated with significant weight loss Combination with glitazones prevents glitazone-induced weight gain Long-acting GLP-1 mimetics will increase their acceptance β-cell preservation, if proven in humans, may make these mimetics early treatment options in the future Use in patients with glucose intolerance or simple obesity for weight reduction needs further evaluation

Conclusions—DPP-4 Inhibitors
DPP-4 inhibitors have a major role in diabetes management Ability to use in renal insufficiency, heart failure, and hepatic disease markedly increases therapeutic options for our patients Quick onset of action and lack of hypoglycemia may make these first-line agents in hospitalized patients Excellent agents for the growing population of patients requiring modest glucose lowering Efficacy is enhanced with increased baseline HbA1C New data support efficacy with sulfonylureas, which will greatly enhance the usefulness of DPP-4 inhibitors May be used as single agents or in combination with metformin, glitazones, sulfonylurea, or insulin

Future Management Directions in DM2
Longer – acting incretin mimetics Other DPP-IV inhibitors Other agents - e.g., SGLT-2 inhibitors Newer insulin formulations (oral / inhaled) Weight (“girth”) control - medical / surgical DM2 prevention - action in the pre-diabetes (impaired tolerance) phase

SGLT-2 Inhibitors – Useful Adjuncts?
Mechanism of action - sodium-glucose transporter inhibition – prevents glucose reabsorption in the proximal tubal resulting in glucose loss (analogous to the apparently benign condition of renal glycosuria) Not insulin dependent. Effective in DM2 and DM1. Studies to date - monotherapy and as add on to metformin, SU’s, TZD’s, DPP-IV inhibitors & insulin – most studies preliminary Route - oral, daily (contraindicated with severe CKD) Efficacy - HbA1c reduction ~ % : weight loss – 1-2 kg Side effects - small(?) increase in U.T.I.’s & genital moniliasis. No hypoglycemia with monotherapy. See Lancet 2010;375: &

Stamp Out Diabetes!

Sequencing Oral Therapy in Type 2 Diabetes: DPP-4 Inhibitors as Monotherapy or Combination Therapy with Metformin, Sulfonylureas, and TZDs—Constructing Outcome-Optimizing Oral Regimens Aligning Oral Therapy with Appropriate Patient Subgroups and Clinical Situations Alexander Turchin, MD, MS Assistant Professor, Harvard Medical School Brigham and Women's Hospital Boston, MA

Topics DPP-4 inhibitors as monotherapy or combination therapy with metformin, sulfonylureas, and TZDs - constructing outcome-optimizing oral regimens Aligning oral therapy with appropriate patient subgroups: how to choose and what to choose - a systematic, guideline-consistent approach based on clinical evidence

DPP-IV Inhibitors Sitagliptin (Januvia) Saxagliptin (Onglyza)
[Vildagliptin] [Alogliptin] Glucose-dependent stimulation of insulin secretion Reduction of gastric emptying Reduction of inappropriate glucagon secretion Beta-cell proliferation / regeneration Adapted from: Nauck MA et al. (2009). Diabetes Care 32(S2):S223

SIDE EFFECTS (putative)
Risks & Benefits EFFICACY ↓A1c 0.7% (up to 1.5% if starting A1c higher) COST $200 / month* DPP-IV inhibitors SIDE EFFECTS (common) - none SIDE EFFECTS (putative) Pancreatitis Pharyngitis CONTRAINDICATIONS h/o pancreatitis * Source – drugstore.com

Risks: Immunodeficiency
DPP-4 is found on the surface of lymphocytes It inhibits breakdown of multiple cytokines and hormones including many involved in immune cell regulation BUT Meta-analysis of 12 Phase IIb / III trials involving 3,415 patients on sitagliptin vs. 2,724 patients on placebo showed incidence of infections 34.5% vs. 32.9% (NS) Incidence of nasopharyngitis was 7.1% vs. 5.9% (NS) From: Williams-Herman, D et al. (2008). BMC End Dis 8(14)

Risks: Pancreatitis 88 cases of pancreatitis in patients on sitagliptin have been reported to the FDA by 09/2009 BUT Retrospective study of 786,656 patients including patients with h/o chronic pancreatitis and other pancreatitis risk factors 15,826 patients on sitagliptin Incidence of pancreatitis increased in patients with diabetes; no difference for sitagliptin From: Garg R et al. (2010). Diabetes Care online 08/03/10

The Rest - Daily Efficacy (A1c) Cost* (1 month) Side effects -1.5%
Thiazolidinediones (TZD) Metformin Sulfonylureas Efficacy (A1c) -1.5% -1.0% -1.5% $250 $4§ Cost* (1 month) $4§ Hypoglycemia Weight gain CHF Weight gain Bone loss Side effects GI All are approved as monotherapy or in combination with each other * Source – drugstore.com if not specified otherwise § Wal-Mart

α-glucosidase inhibitors
The Rest – with Meals α-glucosidase inhibitors Glinides Efficacy (A1c) -1.5% -0.7% $200 Cost* (1 month) $100 Hypoglycemia Weight gain GI Side effects All are approved as monotherapy or in combination with each other * Source – drugstore.com if not specified otherwise

ADA Consensus Algorithm
lifestyle + metformin + basal insulin lifestyle + metformin + intensive insulin At diagnosis: lifestyle + metformin lifestyle + metformin + sulfonylurea DPP-IV inhibitors not recommended due to lack of long-term safety record lifestyle + metformin + pioglitazone lifestyle + metformin + sulfonylurea + basal insulin Less well validated therapies lifestyle + metformin + GLP-1 agonist Adapted from: Nathan DM et al. (2009). Diabetes Care 32(1):193

ACE / AACE Algorithm

Patient Preference: Efficacy
sulfonylurea DPP4 inhibitor metformin TZD α -glucosidase inhibitors glinide

Patient Preference: Cost
TZD metformin sulfonylurea DPP4 inhibitor α-glucosidase inhibitor

Patient Preference: Weight
sulfonylurea metformin DPP4 inhibitor α -glucosidase inhibitor TZD

Hypoglycemia Avoidance
Patient Preference: Hypoglycemia Avoidance sulfonylurea DPP4 inhibitor metformin α -glucosidase inhibitor TZD glinide

Questions? Alexander Turchin, MD, MS aturchin@partners.org
Investigations • Innovation • Clinical Application Questions? Alexander Turchin, MD, MS

Cardiovascular, Metabolic, and Renal Considerations: Optimizing Efficacy and Safety of DPP-4 Inhibitor Therapy in High Risk Patients Evidence-Based Therapy for T2D in Patients with CV and/or Renal Risk Factors or Dysfunction Derek LeRoith, MD, PhD, FACP Chief, Division of Endocrinology, Diabetes and Bone Disease Director, Metabolism Institute, Mount Sinai School of Medicine New York, NY

No A1C threshold is apparent
Slide 4 The risk of CHD is significantly increased in patients with Type 2 diabetes. Cardiovascular disease causes 80% of all diabetic mortality, and in 75% of those cases, it is a result of coronary atherosclerosis. Cardiovascular disease causes greater than 75% of all hospitalizations for diabetic complications. Greater than 50% of patients with newly diagnosed Type 2 diabetes have pre-existing cardiovascular disease. This means that the risk factors for macrovascular disease are already at work before the diagnosis of diabetes. These points provide a rationale for early and aggressive management of cardiovascular risk in patients with diabetes. No A1C threshold is apparent Finnish study by Kuusisto et al;UKPDS epidemiologic analysis; EPIC-Norfolk Study Impaired glucose tolerance (IGT) and postprandial hyperglycemia are CV risk factors Funagata Diabetes Study,;Honolulu Heart Program; DECODE Study; Rancho Bernardo Study

Mortality in Multiple Risk Factor Intervention Trial (MRFIT)
Diabetes (n = 5163) No Diabetes (n = 342,815) Relative Risk* CVD 85.13 22.88 3.0 CHD 65.91 17.03 3.2 Stroke 6.72 1.75 2.8 Other CVD 12.99 4.08 2.3 Other 160.13 53.20 2.5 *Age-adjusted rate per 10,000 person-years. Relative risk adjusted for age, race, income, systolic BP, and smoking. Savage PJ. Ann Intern Med. 1996;124: 154

“Ticking clock” hypothesis: Glucose abnormalities increase CV risk
“Ticking Clock” Hypothesis: Glucose Abnormalities Increase CV Risk, Even Before Dx DM Nurses’ Health Study, N = 117,629 women, aged 30–55 years; follow-up 20 years (1976–1996) Relative risk of MI or stroke* “Ticking clock” hypothesis: Glucose abnormalities increase CV risk After diabetes diagnosis Before diabetes diagnosis Diabetes at baseline Results from the Nurses’ Health Study indicated that women who eventually developed diabetes were at a significantly elevated risk of myocardial infarction (MI) and stroke prior to the diagnosis of diabetes, relative to women who did not develop diabetes. Hu et al found that of 117,629 female nurses free of cardiovascular (CV) disease at baseline, 1508 had diabetes at baseline, and 5894 developed diabetes during the 20 years of follow-up. For women who developed type 2 diabetes during follow-up, the adjusted relative risk of MI or stroke was 2.8 prior to the diagnosis of diabetes, and 3.7 after the diagnosis of diabetes (adjusted for age, BMI, smoking status, menopausal status, family history, and hormone replacement status). Elevated risk of CV disease began at least 15 years before the diagnosis of diabetes. This has been referred to as the “ticking clock” hypothesis. No diabetes *Adjusted n = 1508 diabetes at baseline n = 5894 new-onset diabetes Hu FB et al. Diabetes Care. 2002;25: 155

High Risk of Cardiovascular Events in Type 2 Diabetes
5 10 15 20 25 30 35 40 45 50 No diabetes Type 2 diabetes 7-year incidence of cardiovascular events (%) Slide 67. High Risk of Cardiovascular Events in Type 2 Diabetes Because of the aging of the population and an increasing prevalence of obesity and sedentary life habits, the prevalence of type 2 diabetes (90% of all cases of diabetes) is increasing [Grundy et al, 1999]. Type 2 diabetes is associated with a marked increase in the risk of cardiovascular disease. In a Finnish population-based cohort, the 7-year incidences of fatal or nonfatal MI, fatal or nonfatal stroke, and death from cardiovascular causes among 1373 nondiabetic subjects were compared with the incidences among 1059 patients with type 2 diabetes. Both the presence of diabetes and the history of a previous MI at baseline were associated with an increased incidence of cardiovascular events. In both diabetic patients and nondiabetic subjects, a history of prior MI at baseline was significantly associated with an increased incidence of MI, stroke, and cardiovascular death. Diabetic patients without prior MI had as high a cardiovascular risk as nondiabetic subjects with previous MI. The authors concluded that cardiovascular risk factors must be as aggressively treated in patients with diabetes as in nondiabetic patients with prior MI [Haffner et al, 1998]. Once patients with diabetes develop clinical coronary heart disease, they have a particularly poor prognosis. The course of acute MI in 85 patients with diabetes was compared with that in 415 nondiabetic patients. Mean follow-up was 35 months. The patients with diabetes experienced a more complicated in-hospital and post-discharge course than did the nondiabetic patients, including higher incidences of post-infarction angina, infarct extension, heart failure, and death [Stone et al, 1989]. Prior myocardial infarction Myocardial infarction Stroke Cardiovascular deaths Haffner, NEJM 1998, 156

DCCT/EDIC: Incidence of Any CVD Event
EDIC observation 0.12 Conventional treatment EDIC A1C mean 8.2% 0.10 ¯42% Risk reduction P=0.02 0.08 Cumulative incidence 0.06 0.04 0.02 DCCT/EDIC: Incidence of Any Cardiovascular Disease Outcome The Epidemiology of Diabetes Interventions and Complications (EDIC) study is a long-term observational follow-up (mean 17 years) to the Diabetes Control and Complications Trial (DCCT), which studied whether the use of intensive therapy as compared with conventional therapy affected the incidence of cardiovascular disease (CVD) in patients with type 1 diabetes. Ninety-seven percent of the original DCCT cohort joined the EDIC follow-up (N=1,394). A total of 144 cardiovascular events occurred in 83 patients during mean 17 years of follow-up, 46 among 31 patients assigned to intensive treatment and 98 among 52 patients assigned to conventional treatment. As compared with conventional treatment, intensive treatment reduced the risk of any CVD outcome by 42% (95% confidence interval, 9% to 63%; P=0.02). The authors conclude that the large reduction in the risk of cardiovascular events will improve the projected long-term health and economic benefits of intensive therapy for diabetes. DCCT/EDIC Study Research Group. N Engl J Med. 2005;353: Intensive treatment EDIC A1C mean 8.0% 0.00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 20 years Years since entry into studies DCCT=Diabetes Control and Complications Trial. EDIC=Epidemiology of Diabetes Interventions and Complications. DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:

Legacy Effect of Earlier Glucose Control
After median 8.5 years post-trial follow-up Aggregate Endpoint Any diabetes related endpoint RRR: 12% 9% P: Microvascular disease RRR: 25% 24% P: Myocardial infarction RRR: 16% 15% P: All-cause mortality RRR: 6% 13% P: RRR = Relative Risk Reduction, P = Log Rank 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Eng J Med 2008; 359

Cardiovascular Safety: Exenatide BID
Meta-analysis of clinical trials for exenatide twice daily No increased risk of CV events Relative risk (95% CI) = 0.69 ( ) versus pooled comparators Retrospective, comparative analysis of large health insurance database Exenatide-treated (n = 21754) versus non-exenatide-treated (n = ) Significantly lower risk of CV event for exenatide-treated patients Hazard ratio (95% CI) = 0.81 ( ); P = .011 Lower risk despite greater inherent CV risk due to higher rates of hyperlipidemia, hypertension, obesity, and prior CAD Exenatide meta-analysis: Shen, last sentence (no increased risk) and lines (relative risk) Liraglutide: first bullet of “update” press release Shen L, et al. Diabetes. 2009;58(suppl 1):366-OR. Best JH, et al. Presented at the ADA 70th Scientific Sesions; 712-P. 159

Cardiovascular Safety: Liraglutide
US FDA analyses of clinical trial data identified no excess risk of CV events versus comparators (active or placebo) Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial Designed to assess CV safety and satisfy FDA guidelines for T2DM treatments Scheduled to begin Autumn 2010 Exenatide meta-analysis: Shen, last sentence (no increased risk) and lines (relative risk) Liraglutide: first bullet of “update” press release FDA briefing materials – liraglutide. b2-01-FDA.pdf; Update on FDA Advisory Committee meeting on liraglutide for the treatment of type 2 diabetes. AttachmentGUID=1c87137d-806f-41bc-832a-e5a74aa86164; LEADER trial press release. 160

CV Safety With DPP-4 Inhibitors: Sitagliptin
Over 10,000 patients with T2DM, treated with sitagliptin 100 mg/day or placebo (non-exposed), up to 2 years. The patients were from trials using sitagliptin as monotherapy, or in combination with metformin, sulfonylurea, pioglitazone or insulin. Incidence rates of adverse events in the Cardiac Disorders Systems Order Class was ~4% per 100 Patient years, in both the sitagliptin and non-exposed patients. Williams-Herman D, et al.BMC Endocr Disord Apr 22;10:7.

Cardiovascular Safety in Saxagliptin Clinical Trials
Data from 8 randomized, double-blind, phase 2b/3 trialsa Major adverse cardiovascular events (MACE)b Acute cardiovascular events (ACE)c Event type Saxagliptin n (%) Comparator ACE 38 (1.1) 23 (1.8) MACE 23 (0.7) 18 (1.4) All deaths 10 (0.3) 12 (1.0) CV deaths 7 (0.2) 10 (0.8) 0.44 (0.24, 0.82) MACE ACE 0.59 (0.35, 1.00) In December 2008, the US FDA issued Guidance for Industry recommending that therapy sponsors should demonstrate that a new therapy, “…will not result in unacceptable increase in cardiovascular risk.” .[1] Because saxagliptin trials were completed prior to the Guidance was issued, post-hoc analyses of cardiovascular safety were performed. Data were presented at the 2009 ADA Scientific Sessions. [2,3] The FDA Advisor Committed determined that, based on clinical trial results, saxagliptin does not increase the risk for cardiovascular events. However, given the low rate of cardiovascular events in the studies, the FDA Advisory Committee has recommended postmarketing studies to confirm the CV safety results from the clinical trials.[2,4] Cox Proportional Hazard Ratio (95% confidence interval) a Saxagliptin exposure: n = 3356 (3758 patient-years); comparator exposure: n = 1251 (1293 patient-years). b Stroke, myocardial infarction, cardiovascular death. c Includes revascularization. Wolf R, et al. ADA 69th Scientific Sessions. Late Breaking Abstract Handout. 2009;8-LB:LB3. [1]Guidance for Industry: Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. Available at: [2] Saxagliptin gets favorable FDA panel review, but cancer concerns raised about Liraglutide. Available at: [3] Wolf R, et al. ADA 69th Scientific Sessions. Late Breaking Abstract Handout. 2009;8-LB:LB3. [4] ONGLYZA (Saxagliptin) Cardiovascular Profile Acceptable According to FDA Advisory Committee. Available at:

Summary of Incretin Actions on Different Target Tissues
Insulin secretion Glucagon secretion Gastric emptying Appetite Cardioprotection Cardiac output Insulin biosynthesis b cell proliferation b cell apoptosis Neuroprotection Glucose production Insulin sensitivity Brain Heart GI tract Liver Muscle Stomach GLP-1 The two principal incretins, GIP and GLP-1, both act on the b-cell to stimulate glucose-dependent insulin secretion and in preclinical studies, both incretins stimulate b-cell proliferation and reduce b-cell apoptosis. GLP-1 also has multiple actions on other cell types, including reduction of glucagon secretion from the islet a-cell, inhibition of food intake and gastric emptying, and regulation of cardiovascular function and contractility. Although GLP-1 action on the liver and muscle is thought to be indirect, possibly via other hormones or through the nervous system, treatment of diabetic subjects with GLP-1R agonists has also been associated with increased insulin sensitivity in peripheral tissues such as muscle and liver. Drucker D. J. Cell Metabolism 2006

Position Statementa Regarding ACCORD, ADVANCE, and VADT Results
Clinical implication = individualized goals and care General A1C goal of < 7% For microvascular disease prevention Reasonable for macrovascular risk reduction, pending more evidence A1C goals closer to normal for some patients Short diabetes duration, long life expectancy, no significant CVD Levels reached without significant adverse treatment effects Less stringent goals for some patients History of severe hypoglycemia, limited life expectancy, advanced micro- or macrovascular complications, extensive comorbid conditions, long-standing diabetes with difficulty achieving glycemic goals FXCX: Refer to – PriMed C&E Additional lines added under “General A1C goal of < 7%”: p191/c2/bullet 2 aAuthored by the American Diabetes Association, American College of Cardiology Foundation, and American Heart Association. Skyler JS, et al. Diabetes Care. 2009;32:

Risk of Hypoglycemia in Type 2 DM
Hypoglycemia associated with use of sulfonylureas and insulin. Severe hypoglycemia is clinically evident, however, mild to moderate hypoglycemia maybe asymptomatic and remain unreported. When unreported, asymptomatic hypoglycemia maybe detrimental to patients. Asymptomatic hypoglycemia maybe more prevalent in older patients. Chico A et al Diabetes Care 26: Matyka K et al Diabetes Care 20: aHypoglycemia requiring third-party assistance. Monami M, et al. Eur J Endocrinol. 2009;160: Buse JB, et al. Lancet. 2009;374:39-47.

Risk Factors and Consequences of Hypoglycemia in Type 2 Diabetes
Use of insulin secretagogues and insulin therapy Missed or irregular meals Advanced age Duration of diabetes Impaired awareness of hypoglycemia Consequences2,3 Suboptimal glycemic control Other health effects 1. Amiel SA et al. Diabet Med. 2008;25:245–254. 2. Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307. 3. Cryer PE. J Clin Invest. 2007;117:868–870.

Fear of hypoglycemia is an additional barrier to control
Hypoglycemia May Be a Barrier to Glycemic Control in Patients With Type 2 Diabetes Hypoglycemia is an important limiting factor in glycemic management and may be a significant barrier to treatment adherence Fear of hypoglycemia is an additional barrier to control A study in patients with type 2 diabetes showed increased fear of hypoglycemia as the number of mild/moderate and severe hypoglycemic events increased Amiel SA et al. Diabet Med. 2008;25:245–254.

Current Treatments Increase Risk of Hypoglycemia
p<0.05 glibenclamide vs. rosiglitazone Patients with hypoglycaemia** (%) 10 39 5 15 20 25 30 35 40 45 Rosiglitazone Metformin Glibenclamide 12 5 10 20 Glargine NPH 15 Hypoglycaemia, events/patient/year* Current treatments increase risk of hypoglycaemia Many drugs currently used for the treatment of type 2 diabetes cause hypoglycaemia Rosiglitazone 10% of patients Metformin 12% Glibenclamide 39% References Riddle et al. Diabetes Care 2003;26:3080 Kahn et al (ADOPT). NEJM 2006;355:2427–43 *All symptomatic hypoglycaemic events ** Patients self-reporting (unconfirmed) hypoglycaemia Riddle et al. Diabetes Care 2003;26:3080; Kahn et al (ADOPT). NEJM 2006;355:2427–43

Hypoglycemia Risk With GLP-1 Receptor Agonists
Meta-analysis 15 trials with exenatide BID or liraglutide versus active comparators or placebo Low risk of hypoglycemia except in combination with SUs Significantly less minor hypoglycemia with liraglutide than with exenatide in head-to-head comparison Liraglutide or exenatide + MET and/or SU Major hypoglycemiaa: 2 events in patients treated with exenatide + SU aHypoglycemia requiring third-party assistance. Monami M, et al. Eur J Endocrinol. 2009;160: Buse JB, et al. Lancet. 2009;374:39-47.

Hypoglycemia Risk With DPP-4 Inhibitors
Comparators Active Placebo-Controlled Trials Vildagliptin Monotherapy Add-on to SU/Insulin Sitagliptin DPP-4 Inhibitors Sulfonylureas Thiazolidinediones 0.01 0.10 1.0 10.0 Any Hypoglycemia (Mantel-Haenzel Odds Ratio With 95% CI)a Hypoglycemia risk similar to placebo a Logarithmic scale. Monami M, et al. Nutr Metab Cardiovasc Dis. Published online June 8, 2009; doi: /j.numecd

Age-related Decline in Renal Function in Patients with Type 2 diabetes

Dosing GLP-1 Receptor Agonists in Renal Insufficiency
Degree of Renal Insufficiency Exenatide BID Liraglutide Mild (GFR > 50 mL/min) No change Use with caution due to limited clinical experience in this population. No dose adjustment recommended. Moderate (GFR ≥ mL/min) Use caution during initiation or dose escalation Severe (GFR < 30 mL/min) Should not be used in patients with severe renal impairment or end-stage renal disease Use with caution in patients with renal transplantation FXCX notes: Exenatide: Byetta pi, sections 5.3 and 8.6 Liraglutide: Victoza pi, section 8.6 Hypovolemia statement (section 5.3): Nausea and vomiting with transient hypovolemia may worsen renal function Byetta (exenatide) [prescribing information]. Victoza (liraglutide) [prescribing information]. 172 172 172

Dosing DPP-4 Inhibitors in Renal Insufficiency
Degree of Renal Insufficiency Sitagliptin Saxagliptin Mild (GFR > 50 mL/min) 100 mg per day 5mg per day Moderate (GFR ≥ mL/min) 50 mg per day No adjustment Severe (GFR < 30 mL/min) 25 mg per day 2.5 mg per day FXCX notes: Exenatide: Byetta pi, sections 5.3 and 8.6 Liraglutide: Victoza pi, section 8.6 Hypovolemia statement (section 5.3): Nausea and vomiting with transient hypovolemia may worsen renal function 173 173 173

Saxagliptin and Sitagliptin in Elderly Patients
5 mg/day vs placebo Sitagliptin 100 mg/day vs placeboa Participants Patients ≥ 65 yearsb Monotherapy and combination therapy N = 274 Patients ≥ 65 years Monotherapy N = 206 A1C change (relative to placebo) - 0.55% - 0.7% AEs Similar to placebo Hypoglycemia None reported a Except in cases of dose adjustment for renal insufficiency. b Pooled analysis of clinical trial data. Barzilai N, et al. Diabetes. 2009;58(suppl 1):587-P. Maheux P, et al. Presented at the 2009 European Association for the Study of Diabetes Meeting. Present No. 766.

Case Studies in Oral Therapeutics for Type 2 Diabetes—Clinical Decisions and Real World Outcomes Program Chairman Charles Faiman, MD, FRCPC,MACE Past Chairman Consultant Staff Department of Endocrinology, Diabetes and Metabolism Cleveland Clinic Foundation

Case Study #1 47-year-old male with type 2 diabetes mellitus diagnosed 5 years ago, returns for a follow-up visit. He reports feeling well. For exercise, he walks his dog daily for about a mile. He feels he could “do better with his diet”; he has seen a nutritionist and diabetes educator, but says he lacks motivation.

Case Study #1 On exam he has a BMI of 36, Pulse 74, BP 130/80. Rest of the exam is normal His current meds are metformin 1000 mg bid, glyburide 10 mg bid, lisinopril 10 mg daily, simvastatin 40 mg daily, and ASA 81 mg daily. Downloaded meter reveals BG testing about once daily; BG range , average 162 mg/dl. A1C 7.8 %, serum creatinine 1.1 mg/dl , LDL-C 66 mg/dl

Case Study #1 What is your recommendation for him? Add basal insulin
Stop glyburide and start basal bolus insulin treatment Add pioglitazone (Actos) 45 mg daily Add sitagliptin (Januvia) 100 mg daily Do not change drug therapy and refer back to the diabetes educator Add exenatide (Byetta) bid

Case Study #2 67-year-old woman with DM-2, hypertension, obesity, rheumatoid arthritis and COPD presents with A1c of 7.6%. Her BMI is 34.2 and she is looking to lose weight. She tried metformin previously but did not tolerate due to side effects. Candidate for DPP-IV monotherapy Alternatives: α-glucosidase inhibitor Other options

Case Study #3 82-year-old man with hypertension, hypercholesterolemia, ischemic cardiomyopathy and NYHA class III heart failure presents with a newly diagnosed DM-2 and A1c of 7.4%. Candidate for DPP-IV monotherapy Alternatives: α-glucosidase inhibitor Other options

Case Study #4 59-year-old man with DM-2 treated with metformin, hypertension, dyslipidemia, prostate cancer and osteoporosis presents with A1c of 7.9%. He was previously taking glyburide but had several episodes of severe hypoglycemia (had to be assisted in treatment) and discontinued it 3 months ago. He has a hectic work schedule (marketing executive) and is not always able to have meals at regular times. Candidate for DPP-IV as 2nd line agent (after metformin) Alternatives: α-glucosidase inhibitor Other options

Case Study #5 52-year-old man with no past medical history presents with newly diagnosed DM-2. His A1c is 9.1%. He is adamant in refusing to consider injectable medications. Candidate for DPP-IV as 3d line agent (after metformin + sulfonylurea and / or TZD) Alternatives: α-glucosidase inhibitor Other options

Case Study #6 73-year-old African-American female - T2DM for the past 5 years PM History: GI intolerance with metformin Longstanding hypertension MI at age 65, ejection fraction 40% Meds: Glimepiride 4 mg, Aspirin 325 mg, Metoprolol 50 mg Rosuvastatin 10mg, Furosemide 20mg, Lisinopril 10mg daily Vitals: BMI 29, BP 130/80 Bloods: TCHOL 193, LDL 70, HDL 58, TG 81 FPG 127 mg/dl, A1C 7.5% Creatinine 1.4 mg/dl, GFR 49 ml/min What’s the next step in managing her diabetes?

Case Study #6 What’s the next step in managing her diabetes? The following should not be used in this patient, except one class: A. Metformin B. Sulfonylureas C. Thiazolidinediones D. Incretin mimetics/ DPP-IV inhibitors E. Insulin

Case Study #6 What are some of the major risk factors in treating Type 2 diabetic patients? 1. Cardiovascular disease 2. Renal Failure 3. Aging 4. Hypoglycemia

Oral Therapy for Type 2 Diabetes

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