INSIGHT INTO MANAGING AND TREATING TYPE 2 DIABETES ISRAEL HARTMAN MD FACE

INSIGHT INTO MANAGING AND TREATING TYPE 2 DIABETES ISRAEL HARTMAN MD FACE Type 2 Diabetes Mellitus (T2DM) Is an Epidemic The Centers for Disease Control and Prevention statistics from 2007 estimated that 23.5 million adults in the US had diabetes 10.7% of the US population aged 20 years or older 1 T2DM accounts for 90%-95% of all diagnosed cases of diabetes 1 3 Age-Adjusted Percentage of Adults With Diagnosed Diabetes in Arizona, 2007 2 Back to U.S. map AL HI MA NM SD AK ID MI NY TN AZ IL MN NC TX AR IN MS ND UT CA IA MO OH VT CO KS MT OK VA CT KY NE OR WA DE LA NV PA WV DC ME NH RI WI FL MD NJ SC WY GA 2007 Age-adjusted percent of adults with diagnosed diabetes Trends 9.4 7.6 9.3 6.6 7.5 6.5 20 years old. 1. Centers for Disease Control Web site. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf. 2. Centers for Disease Control Web site. http://apps.nccd.cdc.gov/ddt_strs2/nationaldiabetesprevalenceestimates.aspx.

Obesity Trends Among U.S. Adults BRFSS, 2005 (BMI 30, or ~ 30 lbs overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30% By the time of diabetes onset, up to 80% of beta cell function may be lost 2,3 Type 2 Diabetes Is a Complex and Progressive Metabolic Disorder History and Progression of Type 2 Diabetes 1 3 Diagnosis Adapted from Kendall DM, Bergenstal RM. 1. Kendall DM, et al. International Diabetes Center. 2005. 2. Defronzo DA. Diabetes. 2009. 3. Fehse F, et al. J Clin Endocrinol Metab. 2005. 5 β Cell mass 100% Natural History Of Pre Type 1 Diabetes Putative trigger Cellular autoimmunity Circulating autoantibodies (ICA, GAD65) Genetic predisposition Insulitis β Cell injury Loss of first phase insulin response (IVGTT) Glucose intolerance (OGTT) Pre diabetes Diabetes Clinical onset only 10% of β cells remain Time Eisenbarth GS. N Engl J Med. 1986;314:1360-1368 14

IFG and IGT Intermediate Between Normal and Diabetes Impaired Fasting Glucose (IFG) FPG 100 but <126 mg/dl Predicts increased risk of diabetes and microand macrovascular complications Impaired Glucose Tolerance (IGT) 2-h PG on OGTT 140 but <200 mg/dl Predicts increased risk of diabetes and cardiovascular disease 9 Hyperglycemia Damages Tissues Effects of hyperglycemia Glycation of proteins (eg, hemoglobin, collagen) Accumulation of sorbitol and fructose (eg, in nerves, lens) Activation of protein kinase C (eg, on vascular cells) Tissue changes Altered protein function and turnover, cytokine activation Osmotic and oxidative stress Reduced motor and sensory nerve conduction velocity Increased glomerular filtration rate and renal plasma flow 2 Making the Diagnosis of Diabetes Symptoms of diabetes plus random plasma glucose 200 mg/dl or FPG 126 mg/dl or 2-h PG during a 75-g OGTT 200 mg/dl Requires confirmation by repeat testing American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S5-S10 20

Classification of Diabetes Mellitus by Etiology Type 1 Type 2 Gestational Other specific types β-cell destruction complete lack of insulin β-cell dysfunction and insulin resistance β-cell dysfunction and insulin resistance during pregnancy Genetic defects of β-cell function Exocrine pancreatic diseases Endocrinopathies Drug- or chemical-induced Other rare forms 11 Gestational Diabetes Hyperglycemia during pregnancy usually resolves after birth Complicates ~4% of all pregnancies in the United States High risk of perinatal morbidity and mortality High risk of later type 2 diabetes in both mother and baby Diagnosed by specific glucose tolerance test methods Requires intensive dietary and glycemic management American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S88-S90 18 Two Defects Contributing to Type 2 Diabetes Insulin resistance Beta-cell dysfunction Liver Muscle tissue Adipose tissue Pancreas Beta cell Type 2 Diabetes Buchanan TA. Clin Ther. 2003;25(suppl 2):B32 B46. Kahn SE. J Clin Endocrinol Metab. 2001;86:4047 4058.

Plasma glucose (mg/dl) A1C Reflects Both Fasting and Postprandial Hyperglycemia 300 200 100 Postprandial hyperglycemia Fasting hyperglycemia Normal 0 0600 1200 1800 2400 0600 Time of day Riddle MC. Diabetes Care. 1990;13:676-686 6 Appropriate A1C Management Should Consider Both FPG and PPG Levels 14 Approximate Contribution to A1C (%) PPG FPG A1C (%) 70% 30% <7.3 53% 47% 7.3 8.4 45% 55% 8.5 9.2 FPG and PPG contributions to A1C differ as A1C levels change PPG is the major contributor to A1C in patients with A1C <7.3% FPG is the major contributor to A1C in patients with A1C 9.3% 40% 60% 9.3 10.2 30% 70% >10.2 FPG and PPG concentrations were measured in 290 patients with T2DM. Patients were divided into quintiles of A1C and these values were used to calculate the relative contribution that each made to the patient s overall diurnal hyperglycemia. The results were compared across quintiles. Significant difference was observed between FPG and PPG. Significantly different from all other quintiles. Significantly different from >10.2 quintile. All percentages are approximated. Monnier L et al. Diabetes Care. 2003;26:881-885. Nearly Half of All Adult Patients With T2DM Remain Uncontrolled on Their Current Therapy 1 15 Treated Patients with T2DM 42.9% of patients not at goal Recommended A1C A1C >7% A1C <7% 57.1% ADA 2 <7.0% AACE 3 6.5% Mean A1C=7.17% (N=491) NHANES=National Health and Nutrition Examination Survey. Data from 2003-2004 NHANES, includes all men and non-pregnant women 20 years with valid data on diabetes history and body mass index measurement (N= 4430). Participants with diabetes diagnosed at age <30 years, who were treated with insulin alone, were excluded from the analysis of determinants of glycemic control as they were likely to have type 1 diabetes. 1. Ong KL, et al. Ann Epidemiol. 2008;18:222-229. 2. Nathan DM, et al. Diabetes Care. 2009;32:193-203. 3. Rodbard HW et al. Endocr Pract. 2009;15:540-559.

Type 2 Diabetes Associated with Serious Complications Diabetic Retinopathy Leading cause of blindness in adults Stroke CV disease & stroke account for ~65% of deaths in T2D patients Cardiovascular Disease Diabetic Nephropathy Major cause of kidney failure Diabetic Neuropathy Major cause of lower extremity amputations CV = cardiovascular. National Institute of Diabetes and Digestive and Kidney Diseases. National Diabetes Statistics fact sheet: general information and national estimates on diabetes in the United States, 2005. Bethesda, MD: U.S. Department of Health and Human Services, National Institute of Health, 2005. Patients ages 20 years. Centers for Disease Control. National Diabetes Fact Sheet. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf. Accessed February 27, 2009. Relationship of A1C to Risk of Microvascular Complications Relative Risk 15 Retinopathy Nephropathy 13 11 Neuropathy Microalbuminuria 9 7 5 3 1 6 7 8 9 10 11 12 A1C (%) Adapted with permission from Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243 Who Should Be Tested for Diabetes? Consider if One or More of the Following Apply Symptoms suggesting diabetes: weight loss, hunger, urinary frequency, blurred vision Age >45 (>30 if patient has other risk factors) Prior IGT or IFG or family history of diabetes Prior gestational diabetes or baby weighing >9 lb Women with polycystic ovarian syndrome (PCOS) Obesity (BMI 25 kg/m 2 ), especially adolescents African, Latino, Asian, or Native American ancestry History of vascular disease or hypertension American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S11-S14; AACE/ACE medical guidelines. Endocr Pract. 2002;8(suppl 1):40-82 19

Type 2 Diabetes Treatment Options Utilize Different Mechanisms of Action and Target Different Primary Tissues Liver Adipose Muscle Pancreas Metformin (MET) 1 Primarily decreases hepatic glucose production Thiazolidinediones (TZDs) 2 Improve insulin sensitivity Sulfonylureas (SU) 3 Increase insulin secretion in functioning pancreatic beta cells DPP-4 Inhibitors 4 Slow inactivation of incretin hormones resulting in: increased synthesis and release of insulin from functioning pancreatic beta cells and lower glucagon secretion from pancreatic alpha cells Not intended to imply a comparison of efficacy or safety of these treatment options. Also decreases intestinal absorption of glucose and increases peripheral glucose uptake and utilization. 1. Glucophage [prescribing information]. Bristol-Myers Squibb; 2. Prescribing information for AVANDIA; 3. Amaryl (glimepiride) [prescribing information]. Aventis Pharmaceuticals; 4. Januvia TM (sitagliptin phosphate) [prescribing information]. Merck & Co., Inc. Initial Diabetes Management Patient Education Exercise Diet Glucose Monitoring Complication avoidance Be sure that the patient understands the game plan for their diabetes Dietary Recommendations Determine current BMI and ideal weight BMI = Weight (lbs) x 703 / (height in inches)^2 Normal = 20 24.9 Overweight 25 29.9 Obese 30.0 or more Ideal weight Men: 106 for first 60 inches, then 6 # each additional inch. Women: 100 for first 60 inches, then 5# each additional inch

Specify a diet Refer to a dietitian if at all possible They have more time than you do They can answer questions about specific food preferences better than you can They can schedule follow up They are usually less expensive than you A diet of 13 kcal / pound IBW will usually induce gradual weight loss Give the patient an exercise prescription Be specific Type of exercise walking, bicycling, swimming, Gazelle, weightlifting, etc How long: Ask them to do 30 minutes, you may get 20 minutes How often: 5 or more times a week Point out that exercise is effective, and less expensive than many of our medications ADA/EASD 2008 Consensus Statement Includes a GLP 1 Receptor Agonist STEP 1 At diagnosis: Lifestyle + MET If A1C 7% STEP 2 Tier 1: Well validated core therapies OR Tier 2: Less well validated therapies Lifestyle + MET + SFU CHF, chronic heart failure MET, metformin PIO, pioglitazone SFU, sulfonylurea Lifestyle + MET + basal insulin Lifestyle + MET + GLP-1 receptor agonist If hypoglycemia is particularly undesirable Lifestyle + MET and/or + promotion PIO + SFU of weight loss is a consideration Lifestyle + MET + PIO Lifestyle + MET + basal insulin STEP 3 Lifestyle + MET + intensive insulin Validation based on clinical trials and clinical judgment. Insufficient clinical use to be confident regarding safety. Adapted from Nathan DM, et al. Diabetes Care. 2008. 24

Oral Diabetes Meds Sulfonylureas Glipizide, glyburide, glimipiride, Biguanides / Metformin Thiazoladinediones Avandia, Actos α Glucosidase Inhibitors Precose, Glyset Glinides Starlix, Prandin DPP IV inhibitors Januvia, Onglyza Sulfonylureas Introduced in 1955 Inexpensive ($4 at Target/Sams/WalMart) Stimulate insulin release from pancreatic beta cell Mean absolute A1c reduction: 1 2 % Sulfonylureas Cons: Weight gain Risk of hypoglycemia K channel inhibition may worsen arrhythmia risk in patients with coronary artery disease Do not delay progression of disease

Non SU Secretagogues Starlix (nateglinide) and Prandin (repaglinide) $125/month Increase mealtime beta cell release of insulin Shorter duration of action than SU A1c Starlix 0.4 ~ 1.1 % A1c Prandin 1.7~1.9% Non SU Secretagogues Pros Short half life Less hypoglycemia than SU Starlix can be used in renal failure patients Cons Weight gain, but not as much as SU Must be taken just before meal Less long term outcome data Metformin Introduced 1962 (France) 1995 (USA) Inexpensive ($4 at Target/Sams/WalMart) Decreases hepatic glucose production primarily gluconeogenesis, probably through effects on AMP kinase Mean absolute A1c reduction: 1 2 %

Metformin Pros: Modest amount of weight loss Modest lipid lowering effect Benefit on cardiovascular risk markers As monotherapy, had lowest CV risk in UKPDS May be useful in prevention of diabetes DPP Treatment option for PCOS Metformin Cons: Gastrointestinal side effects Contraindicated in renal, liver, cardiac dysfunction because of risk of lactic acidosis AGI s Acarbose (Precose) Miglitol (Glyset) Inhibit enzyme on enterocyte brush border that breaks down complex starches Approximately $95 per month Mean absolute A1c reduction: 0.5 1% Reduces postprandial BG more than fasting Reduced risk of MI in STOP NIDDM

Thiozoladinediones (TZDs) Activate nuclear transcription factors PPARγ rosiglitazone (Avandia) & pioglitazone (Actos) Cost (full dose) $180 $213 per month Improve insulin sensitivity & glucose uptake in adipocytes and muscle Thiozoladinediones (TZDs) Pros: Durable control demonstrated for rosiglitazone (ADOPT) May delay progression of disease Improved lipid parameters ( pio > rosi ) A1c reduction of 1 2 % Rosiglitazone demonstrated to reduce IGT progression to DM by 60% (DREAM) Thiozoladinediones (TZDs) Activate nuclear transcription factors PPARγ rosiglitazone (Avandia) & pioglitazone (Actos) Cost (full dose) $180 $213 per month Improve insulin sensitivity & glucose uptake in adipocytes and muscle

Thiozoladinediones (TZDs) Cons Weight gain Edema Potential to exacerbate CHF contraindicated in Class III or IV Controversy over rosiglitazone and cardiovascular risk ADOPT: ADiabetes Outcome Progression Trial Reduced Rate of Monotherapy Failure with AVANDIA (FPG >180 mg/dl) 40 Primary Endpoint Cumulative incidence of monotherapy failure (%) 30 20 10 Risk reduction with AVANDIA: 32% over MET 63% over SU SU MET AVANDIA Patients at risk AVANDIA MET SU 0 0 1 2 3 4 5 Time (years) 1393 1397 1337 1207 1205 1114 1078 1076 958 957 950 781 844 818 617 324 311 218 The characteristics of the participants who withdrew did not differ among treatment groups. The subgroup analyses demonstrated some benefit in all subgroups. The analyses suggest that the beneficial effect of AVANDIA vs MET was unlikely to be due to a withdrawal bias. Kahn SE et al. N Engl J Med. 2006;355:2427 2443. RECORD: Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycemia in Diabetes Study Results: Primary Endpoint Time to CV Death or First Event of CV Hospitalization Cumulative Incidence (%, SE) Rosiglitazone (321 events) Metformin/SU (323 events) HR: 0.99 (95% CI 0.85, 1.16) Time (years) People at risk Rosiglitazone 2220 2086 1981 1883 1795 1720 918 156 Metformin/SU 2227 2101 1995 1895 1798 1697 908 169 Home PD et al. Lancet. 2009. http://www.thelancet.com/journals/lancet/article/piis0140-6736(09)60953-3/fulltext. Published June 5, 2009. Accessed June 6, 2009.

ROSIGLITAZONE ISSUES Neither increased or decreased risk of CV events is established. excluding trials from a meta analysis with zero events probably exaggerated risk estimates available evidence does not justify what the authors of the original meta analysis (as well as the media, the US Congress and worried patient groups decried as urgent need for comprehensive evaluations Ann Int Med 147;8:578 582 October 16, 2007 Five Long term Studies Showed No Increased Risk of Total Mortality with Rosiglitazone 1 7 Duration of Relevant Studies A Comparison of Relevant Studies ADOPT 1,2 DREAM 1,3 RECORD 1,4 ACCORD (Interim Studies) 5,6 VADT 7,8 4 6 years N=4360 patients N=5269 patients N=4447 patients N=10,251 patients 5 7 years N=1791 patients 0 1 2 3 4 5 6 Duration, years Randomized, long term prospective trials with rosiglitazone Mean duration: 41 months. Not prospectively designed to assess the safety of Randomized, long term trials that included patients on rosiglitazone rosiglitazone. Independent, non GSK sponsored studies. 1. Prescribing Information for AVANDIA; 2. Kahn SE et al. N Engl J Med. 2006;355:2427 2443; 3. DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators, Gerstein HC et al. Lancet. 2006;368:1096 1105; 4. Home PD et al. Lancet. 2009. http://www.thelancet.com/journals/lancet/article/piis0140-6736(09)60953-3/fulltext. Published June 5, 2009. Accessed June 6, 2009. 5. The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med. 2008;358:2545 2559; 6. NHLBI. http://www.nih.gov/news/health/ feb2008/nhlbi-06.htm. Accessed February 12, 2009; 7. American Diabetes Association Web site. http://www.diabetes.org/for-media/pr-intense-blood-glucose-control-yields-no-significant-effect-on-cvd-reduction.jsp. Accessed February 12, 2009; 8. Duckworth W et al. N Engl J Med. 2009;360:129 139. EXENATIDE LIRAGLUTIDE SITAGLIPTIN SAXAGLIPTIN Incretins

GLP 1 Is a Glucoregulatory Hormone With Multiple Physiological Actions Brain: Promotes satiety Food intake Pancreas α cells: Postprandial glucagon Pancreas β cells: Glucose dependent insulin secretion Liver: Hepatic glucose Stomach: Gastric emptying In animal models. Adapted from: 1. Flint A, et al. J Clin Invest. 1998. 2. Larsson H, et al. Acta Physiol Scand.1997. 3. Nauck MA, et al. Diabetologia. 1996. 4. Drucker DJ. Diabetes. 1998. 43 GLP 1 Receptor Agonists Address GLP 1 Deficiencies and Leverage the GLP 1 Effect Active GLP 1 GLP 1 receptor agonist Binds to known GLP 1 receptor DPP 4 Activated GLP 1 receptor 1 3 Inactive GLP 1 Increases glucose dependent insulin secretion Restores first phase insulin response Suppresses glucagon release Delays gastric emptying Reduces food intake 1. Nielsen LL, et al. Regul Pept. 2004. 2. Kolterman OG, et al. J Clin Endocrinol Metab. 2003. 3. Fehse F, et al. J Clin Endocrinol Metab. 2005. 44 EXENATIDE Reduces A1C With Potential Weight Loss Three 30 Week, Double Blind, Phase 3 Studies EXENATIDE 10 mcg With Metformin and/or a Sulfonylurea Change in A1C (%) Change in Weight (lb) Δ A1C (%) 0.5 0.0-0.5-1.0-1.5 +0.2% -0.8% Δ Weight (lb) 0-1 -2-3 -4-5 -1.4 lb -4.2 lb 0 2 4 6 12 18 24 30 0 2 4 6 12 18 24 30 Time (wk) Time (wk) Placebo BID (n=483) EXENATIDE 10 mcg BID (n=483) Baseline A1C=8.5% Mean ±SE; compared to placebo. P<0.0001, P=0.006. Data on file. BYETTA is not indicated for the management of obesity, and weight change was a secondary end point in clinical trials. 45

EXENATIDE Monotherapy Provided Consistent Improvement in A1C and Weight Loss 24 Week, Double Blind, Placebo Controlled Study EXENITIDE 10 mcg Monotherapy Mean A1C Reduction From Baseline Mean Weight Loss From Baseline 8.0 190 7.8 Mean A1C (%) 7.5 7.0-0.9 EXENATIDE 10 mcg BID -0.2 P<0.01 Placebo Weight (lb) 188 186 184 182-6.4 lb EXENATIDE 10 mcg BID -3.3 lb Placebo Least squares means are adjusted for screening A1C strata and baseline value of the dependent variable. BYETTA is not indicated for the management of obesity, and weight change was a secondary end point in clinical trials. 46 In addition to diet and exercise SAXAGLIPTIN 5 mg Provided Complementary A1C Reductions 47 Difference From Comparator (%) 0-0.1-0.2-0.3-0.4-0.5-0.6-0.7-0.8-0.9-1.0 Significant A1C Reduction Across Clinical Trials at 6 Months When Partnered With MET, GLY, a TZD, or as Monotherapy Add-On to MET Baseline A1C: 8.1% 0.8% P<0.0001 (n=186) Initial Combo With MET Baseline A1C: 9.4% 0.5% P<0.0001 (n=306) Add-On to the SU Glyburide Baseline A1C: 8.5% 0.7% P<0.0001 (n=250) Add-On to a TZD Baseline A1C: 8.4% P<0.0001 (n=183) Monotherapy Baseline A1C: 8.0% 0.6% 0.6% P<0.0001 (n=103) SAXAGLIPTIN Was Weight and Lipid Neutral GLY=glyburide. Please see full US Prescribing Information available at this presentation Treat to which target? AAFP Inappropriate to set a uniform target ADA in general is less than 7% Am Geriatrics Society Good functional status 7% Frail a less stringent target, such as 8% Canadian Diabetes Assn 7% or lower If it can be safely achieved <6.0% should be considered

Treat to which target? Institute for Clinical Systems < 7%, should be individualized Natl Institute for Health and Clinical Excellence Between 6.5 7.5 % on the basis of vascular risk Scottish Intercollegiate Guidelines Network around 7.0 Veterans Health Administration target should be 7.0% Treat to which target? AACE Current targets for glycemic control are: A1C <6.5% Fasting/Preprandial <110 mg/dl 2 hr Postprandial <140 mg/dl Quest Diagnostics Data Can we do it? State 2001 2006 % change Texas 7.82 7.38 5.60 USA 7.56 7.20 4.9