Treatment of Type 2 Diabetes: What Have We Learned? AACE Diabetes Algorithm. ADOPT Trial 6/13/2012

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1 Treatment of Type 2 Diabetes: What Have We Learned? Outline the clinical considerations in the selection of pharmacotherapy for type 2 diabetes, including degree of A1C lowering needed, patientspecific concerns, adverse effects, comorbidities, and contraindications Discuss the role of combination therapy and when it should be initiated based on A1C goals Discuss modes of action and clinical potential of recently introduced agents in the management of patients with type 2 diabetes: bromocriptine and colesevelam Explain the implications of recent clinical trials and meta-analyses on clinical practice decisions AACE Diabetes Algorithm Guide to therapy based on A1C level Focus on lifestyle intensification at all levels Initiation as well as maintaining therapy Important tenets: Target A1C is <6.5% Based upon associated lower risk of micro- and macrovascular complications Recommend monitoring A1C quarterly, along with fasting and postprandial blood glucose, with intensification of therapy until goal A1C is achieved Use agents with maximal efficacy associated with lowest risk of hypoglycemia Sulfonylureas are therefore much lower in algorithm Earlier use of incretin mimetics and DPP-4 inhibitors to stimulate insulin secretion without hypoglycemia ADOPT Trial No. at Risk Rosiglitazone Glyburide Kahn et al, N Engl J Med. 2006;355: Kaplan Meier estimates of the cumulative incidence of monotherapy failure at 5 years If patient had a fasting plasma glucose >180 mg/dl, treatment was considered to have failed 4 Additive Effects of Combination Therapy: A1C Changes in Selected Studies of Combination Therapy* A1C % Gly Met Gly Met Met Met Rosi *Not head-to-head trials. /- metformin. Continued monotherapy 10.0 SU 8.7 SU Pio Met Met Exe Exe Combination therapy Met Met Sit Gly = glyburide; Met = metformin; Rosi = rosiglitazone; SU = sulfonylurea; Pio = pioglitazone; Exe = exenatide; = thiazolidinedione; Sit = sitagliptin. DeFronzo R et al. N Engl J Med. 1995;333: ; Fonseca V et al. JAMA. 2000;283: ; Kipnes MS, et al. Am J Med. 2001;111:10-17; DeFronzo RA et al. Diabetes Care. 2005;28: ; Charbonnel B, et al. Diabetes Care. 2004;27: ; Rosenstock J et al. Clin Ther. 2006;28: ; Zinman B et al. Ann Intern Med. 2007;146: Sit Baseline A1C 6.5%-7.5% A1C % Monotherapy MET DPP4 AGI MET or DPP4 Glinide or SU or DPP4 MET 2-3 Mos. Dual Therapy AGI Monotherapy may be effective in this range is cornerstone of rx; first choice for monotherapy if no contraindications Consider DPP-4 if PP and FPG, if PP, if metabolic syndrome or NAFLD, AGI if PP Do not recommend secretagogue (SU or glinide) in this range due to risk of hypoglycemia, short-lived effect If monotherapy is unsuccessful, move on to dual oral rx; often need to augment reduction in PP BG to get to goal in this A1C range still the cornerstone of therapy If metformin is contraindicated, consider as foundation of rx Second component of rx is usually an incretin mimetic, DPP-4 inhibitor,, glinide, or SU, in that order May also consider metformin w/colesevelam or AGI A1C 6.5%-7.5% (cont d) MET Triple Therapy or DPP4 or DPP4 2-3 Mos. SU If dual oral rx is unsuccessful, consider triple therapy Consider 6 main rx options: MET agonist MET agonist glinide MET agonist SU MET DPP-4 MET DPP-4 glinide MET DPP-4 SU When triple oral rx fails to achieve A1C goal, insulin rx is needed Consider addition of basal, premix, prandial or basal-bolus DPP-4 inhibitors (except sitagliptin) and agonists have not been approved for use with insulin Discontinue SU or glinide if prandial insulin is initiated Consider discontinuation of due to fluid retention and weight gain AACE Algorithm for Glycemic Control, Endocr Pract. 2009;15(6):540-59; Sitagliptin Prescribing Information; Merck & Co, Inc,

2 MET Baseline A1C 7.6%-9.0% Presume monotherapy will be inadequate, and A1C % Dual Therapy 2-3 Mos. Triple Therapy MET or DPP4 SU 2-3 Mos. or DPP4 or SU or Glinide or DPP4 recommend going straight to dual oral rx. Recommended options for dual oral rx are: Met agonist Met DPP-4 inhibitor Met Met SU Met Glinide If dual oral rx is unsuccessful, may consider triple therapy Met agonist Met DPP-4 inhibitor Met agonist SU Met DPP-4 inhibitor SU Met SU Again, if triple oral rx fails to achieve A1C goal, insulin therapy is needed Baseline A1C >9.0% If patient is asymptomatic with recent onset of disease and drug naïve, may consider the following dual or triple oral rx regimens: Met agonist Met agonist SU Met DPP-4 inhibitor Met DPP-4 inhibitor SU Met Met SU Met agonist Met DPP-4 inhibitor Symptoms Drug Naive A1C > 9.0% No Symptoms Under Treatment If patient is symptomatic or is already on therapy, insulin should be initiated Once A1C has improved to <7.5%, may consider initiation of dual oral rx with tapering and possible d/c of insulin rx ME T or DPP4 or DPP4 ± SU ± Clinical Considerations Combining therapeutic agents with different modes of action may be advantageous Use insulin sensitizers such as metformin and/or thiazolidinediones as part of the therapeutic regimen in most patients unless contraindicated, or intolerance to these agents has been demonstrated, thiazolidinediones, and incretin mimetics do not cause hypoglycemia However, when used in combination with secretagogues or insulin, these medications may need to be adjusted as blood glucose levels decline Effect of Glucose-lowering Drugs on Patient Weight Therapeutic Options Sulfonylurea 1,2 3,4 Insulin 5,6 7 DPP-4 inhibitor 8 receptor agonist 9 A1C <7.0% Weight Subcutaneous fatpreventable Visceral fat 1. Malone M. Ann Pharmacother. 2005;39: Glipizide [package insert]. New York, NY; Pfizer; Pioglitazone [package insert]. Deerfield, IL: Takeda Pharmaceuticals America; Rosiglitazone [package insert]. Research Triangle Park, NC; GlaxoSmithKline; Nathan DM, et al. Diabetes Care. 2008;31(1): Holman RR. NEJM. 2007;357(17): [package insert]. Princeton NJ; Bristol Meyers Squibb; Sitagliptin [package insert]. Whitehouse Station, NJ; Merck and Co.; Drucker DJ, et al. J Clin Invest. 2007;117(1): hepatic glucose production FPG more than PPG Efficacy A1C 1%-2% Biguanides No weight gain or hypoglycemia GI side effects Lactic acidosis (rare) Renal disease; CHF Combinations available with SU,, repaglinide, and sitagliptin Characteristics of Agonists Efficacy Dosing Side effects Main risk Associated with *Dosing depends on agonist **Liraglutide only Mimic prolonged action of Decrease A1C levels 0.5% 2.0% (Depends on entry of glucose into bloodstream from gut) Once- or twice-daily injection* Nausea, vomiting, weight loss C-cell thyroid tumors**, long-term safety unknown Pancreatitis [package insert]. Princeton NJ; Bristol Myers Squibb; Nathan DM, et al. Diabetes Care. 2008;31: ; Drucker DJ, et al. Lancet. 2006;368: Exenatide [package insert]. San Diego, CA; Amylin Pharmaceuticals;

3 Characteristics of DPP-4 Inhibitors Inhibit enzymatic degradation of and GIP; glucose-dependent Efficacy Decrease A1C levels 0.6% 0.9% Dosing Once daily Side effects Headaches, nasopharyngitis Main risk Viral infection; long-term safety unknown Efficacy Sulfonylureas Glyburide, glipizide, glimepiride insulin secretion FPG PPG Moderate Inexpensive; strong short term efficacy Weight gain, hypoglycemia Avoid in severe hepatic and renal impairment Combinations available with metformin, Rosenstock J, et al. Curr Opin Endocrinol Diabetes Obes. 2007;14: Nathan DM, et al. Diabetes Care. 2008;31: Glyburide [package insert]. New York, NY; Pfizer; Glipizide [package insert]. New York, NY; Pfizer; Glimepiride [package insert]. Scoppito, Italy; Aventis Pharma S.p.A; Thiazolidinediones Pioglitazone, rosiglitazone insulin sensitivity, especially at muscle, lowers both FPG and PPG, but effect may be delayed Efficacy Moderate ( A1C 1.0%-1.5%) No hypoglycemia, no reliance on renal excretion. Fluid retention, edema, heart failure, weight gain, cost, slow onset of action, bone fractures Class III or IV CHF or hepatic impairment w/ ALT >2.5 times upper normal limits Combinations available - and sulfonylurea Synthetic Human Amylin Analog Pramlintide Amylin mimetic: PPG, suppresses glucagon secretion, slows gastric emptying, promotes satiety Efficacy Modest ( A1C 0.5%) No dosage adjustment required in renal impairment Nausea, headaches, anorexia, vomiting, abdominal pain, fatigue, dizziness, coughing, pharyngitis, risk of severe hypoglycemia with insulin Confirmed diagnosis of gastroparesis, hypoglycemia unawareness Rosiglitazone [package insert]. Research Triangle Park, NC; GlaxoSmithKline; Pramlintide [package insert]. San Diego, CA; Amylin Pharmaceuticals, Inc; Efficacy Alpha-Glucosidase Inhibitors Acarbose, miglitol Combinations available: Sulfonylurea Rate of gut polysaccharide breakdown, thereby slowing absorption Modest ( A1C 0.5%-1.0%), PPG lowering Weight-neutral, non-systemic drug, targets post-prandial glucose bloating, flatulence, diarrhea - w/slow titration, frequent dosing, cost Severe renal impairment, Diabetic ketoacidosis, malabsorption, obstruction, inflammatory bowel, or conditions aggravated by gas production. Other Therapies: Likely Effects on Hepatic and Peripheral Insulin Resistance Bromocriptine Acarbose [package insert]. Wayne, NJ; Bayer HealthCare Pharmaceuticals Inc.; Miglitol [package insert]. Wayne, NJ; Bayer HealthCare Pharmaceuticals Inc.;

4 Bromocriptine-QR (quick release) This dopamine receptor agonist is indicated as an adjunct to diet and exercise to improve glycemic control in adults with diabetes BromocriptineEffect on A1C in Combination with Other Oral Hypoglycemic Agents (OHA) Any OHA OHA SulfonylureaOHA GlyburideOHA OHA The specific mechanism by which bromocriptine mesylate improves glycemic control is not known Patients with type 2 diabetes should take bromocriptine mesylate within 2 hours of waking in the morning Bromocriptine An initial daily dose of 0.8 mg should be titrated weekly until a maximum tolerated dose of 1.6 mg to 4.8 mg is achieved Possible decreased risk for CV events with bromocriptine (p<0.0001;bromocriptine n=261; n=151) 2 - (p<0.0001;bromocriptine n=181; n=101) 3 - (p<0.0002;bromocriptine n=121; n=71) 4 - (p<0.0001;bromocriptine n=68; n=36) 5 - (p<0.0026;bromocriptine n=46; n=35) Holt RIG, et al. Diabetes, Obesity and Metabolism. 2010;12: Scranton et al, Diabetologia 2008; 51 (Suppl. 1): S Poster, presented at: EASD Rome, Italy. Cincotta et al, Diabetologia 2008; 51 (Suppl. 1): S22. Poster, presented at: EASD Rome, Italy. Bromocriptine-QR Tolerability Severe adverse events 14% 17% Nausea 7% 22% Orthostatic hypotension 0.8% 2.2% Somnolence 1.3% 4.3% Bromocriptine-QR Psychosis - may exacerbate psychotic disorders or reduce effectiveness of drugs that treat psychosis; not reported with QR formulation to date Cardiovascular Fibrosis Drug interactions (Caution combining) Safety Event rate lower in Bromocriptine-QR than placebo (1.8% vs. 3.2%) in 1-year safety study Associated with ergot-derived dopamine receptor agonists, may be less in bromocriptine-qr Other ergot-related drugs Dopamine receptor agonists or antagonists Strong inhibitors/agonists/substrates of CYP3A4 Fast-Acting Bromocriptine Safety Trial Cumulative Percent Composite CVD Endpoint HR 0.58; 95% CI, RRR=42% Bromocriptine *MI, Stroke, hospitalization unstable angina, hospitalization CHF, or coronary revasc. KM Curve: the separation in favor of Bromocriptine begins 3 months and persists through the end of the study Holt RIG, et al. Diabetes, Obesity and Metabolism. 2010;12: Gaziano M. Diabetes Care, 2010 Jul;33(7): Indicated as an adjunct to diet and exercise as dual or triple therapy to improve glycemic control in adults with type 2 diabetes Not indicated as treatment for type 1 diabetes or DKA of action uncertain : History of bowel obstruction Serum triglycerides >500 mg/dl History of hypertriglyceridemia-induced pancreatitis Effects of on A1C Levels in Add-On Therapy Trials: 0.5% Reductions Mean Change in A1C (%) GLOWS Week * Week 26 Sulfonylurea Week * -0.54* Insulin Week * * P n=>1,000 [Package Insert]. Daiichi Sankyo, Inc., Parsippany, NJ. February Zieve FJ et al. Clin Ther. 2007;29:74. Bays H et al. Presented at: AACE 16th Annual Meeting & Clinical Congress; April Abstract 204. Fonseca VA et al. Presented at: AACE 16th Annual Meeting & Clinical Congress; April Abstract 409. Goldberg RB et al. Presented at: AHA Scientific Sessions; November 2006; Chicago, IL. Poster

5 Dosage and Administration Recommended dosing with meals and a liquid: 625 mg tablets: Take 6 tablets QD OR 3 tablets BID Suspension preparation (powder mixed with water): Take 3.75 g packet QD OR g packet BID As with all LDL-C lowering agents, serum lipid levels should be monitored periodically No special considerations or dosage adjustments with hepatic impairment or renal disease LDL-C=low-density lipoprotein cholesterol in Type 2 Diabetes: Adverse Reactions * Event Description Number of Patients (%) N = 566 N = 562 Constipation 49 (8.7) 11 (2.0) Nasopharyngitis 23 (4.1) 20 (3.6) Dyspepsia 22 (3.9) 8 (1.4) Hypoglycemia 17 (3.0) 13 (2.3) Nausea 17 (3.0) 8 (1.4) Hypertension 16 (2.8) 9 (1.6) *-Controlled Clinical Studies of Add-on Combination Therapy with, Insulin, Sulfonylureas: Adverse Reactions Reported in 2% of Patients and More Commonly than in Patients Given, Regardless of Investigator Assessment of Causality. [Package Insert]. Daiichi Sankyo, Inc., Parsippany, NJ. February [Package Insert]. Daiichi Sankyo, Inc., Parsippany, NJ. February UKPDS: Benefits of Glycemic Control Every 1% decrease in A1C led to significant reductions in diabetes-related complications Effect of Intensive Control of Glucose on Cardiovascular Outcomes and Deaths in Patients with Diabetes Mellitus: A Meta-Analysis of Randomized Controlled Trials 14% Risk of myocardial infarction 21% Risk of diabetesrelated death 37% Risk of microvascular complications 43% Risk of amputation or PVD Death UKPDS PROactive ADVANCE VADT ACCORD Total N Years Patient- years 46,237 15,059 55,700 10,030 35, ,905 Control 7.9% 7.6% 7.3% 8.4% 7.5% 7.5% Intensive 7.0% 7.0% 6.8% 6.9% 6.4% 6.6% Decrease was statistically significant for all comparisons shown Stratton IM et al. BMJ. 2000;321: Probability of Non-fatal Myocardial Infarction Events with Intensive Glucose-Lowering Versus Standard Treatment Probability of Coronary Heart Disease Eventswith Intensive Glucose-Lowering Versus Standard Treatment Non-fatal myocardial infarction Coronary Heart Disease events 5

6 Probability Strokewith Intensive Glucose-Lowering Versus Standard Treatment Probability of All-cause Mortalitywith Intensive Glucose-Lowering Versus Standard Treatment Stroke All-cause mortality Recent Glycemia Trials The 3 trials: CVD outcomes Action to Control Cardiovascular Risk in Diabetes (ACCORD) Action in Diabetes and Vascular Disease Preterax and Diamicron MR Controlled Evaluation (ADVANCE) Veterans Affairs Diabetes Trial (VADT) All conducted in: Older patients ( 60 years) Patients with CVD (1/3 to 1/2 of cohorts) or 1 CVD risk factors ACCORD ADVANCE VADT Intensive Standard Intensive Standard Intensive Standard Baseline 8.1% 8.1% 7.5% 7.5% 9.4% 9.4% Final 6.4% 7.5% 6.4% 7.0% 6.9% 8.4% CVD/year 2.1% 2.3% 2.0% 2.1% 3.8% 4.9% Ray et al. Lancet. 2009;373: The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008; 358: Abraira, C, et al. J Diab Comp, 2003; Patel, A. et al. N Engl J Med, 2008;358: The 3 Trials: Severe Hypoglycemia ACCORD ADVANCE VADT Intensive Standard Intensive Standard Intensive Standard (% / year) 3.1% 1.1% 0.7% 0.4% 12.0% 4.0% Meta-Analysis: Cardiovascular Risk With Sulfonylurea Plus Results With Combination Therapy Increased composite cardiovascular risk end point (RR 1.43; 95% CI, ) All-cause mortality alone not significant Cardiovascular disease mortality alone not significant Bruno (1999) Olsson (2000) Relative Risk (95% CI) 1.04 ( ) 1.86 ( ) 0.96 ( ) 1.38 ( ) Evans (2006) (B) Evans (2006) (C) Overall 2.24 ( ) 1.86 ( ) 1.52 ( ) 1.43 ( ) Composite end point: cardiovascular hospitalization or mortality Relative risk: combination therapy vs. diet, metformin alone, or sulfonylurea alone RR = relative risk The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008; 358: Abraira, C, et al. J Diab Comp, 2003; Patel, A. et al. N Engl J Med, 2008;358: Rao AD, et al. Diabetes Care. 2008;31:

7 Higher Mortality Is Associated With Greater Exposure to Sulfonylurea There was a greater risk of death associated with higher daily doses and better adherence for patients who used glyburide (HR = 1.3; 95% CI, ), but not metformin (HR = 0.8; 95% CI, ) Monotherapy group Glyburide (n= 4138) (n = 1537) Daily Dose Deaths/1000 person-years Lower (higher) 53.4 (70.2) 41.5 (37.6) Hazard ratio Unadjusted Adjusted for age, sex, chronic disease score (CDS), and nitrate use Adjusted for age, sex, CDS, nitrate use, physician visits, and hospital admissions Monotherapy group Glyburide (n = 4138) (n = 1537) A retrospective, inception cohort study conducted in 5795 new users of oral glucose-lowering medications - Insulin or combination therapy were excluded - Mean age: 66.3 years Adherence Deaths/1000 person-years Poor (good) 49.0 (75.8) 37.7 (41.3) Hazard ratio Mean follow-up: 4.6 years - Main outcomes: all-cause mortality, death from acute ischemic event Implications for Clinical Care The lack of significant reductions in CVD events should not lead clinicians to abandon the general target A1C of <7.0% or 6.5% There is still a proven reduction in microvascular complications! Need comprehensive care for diabetes involving lipids, BP, and glycemic control Simpson SH, et al. CMAJ. 2006;174: Skyler JS, et al. J Am Coll Cardiol 2009;53: Glucose and Cardiovascular (CV) Risk If other CV risk factor control is good, there is no additional CV benefit of lowering A1C from 8.4% to 6.9% in older people with advanced DM (VADT) If other CV risk factor control is good, there may be CV harm in lowering A1C from 7.5% to 6.4% in older people with advanced DM (ACCORD), perhaps due to hypoglycemia (VADT) PROactive Study >5,000 patients in 19 European countries involving over 320 investigators Investigated effect of insulin resistance on CV morbidity and mortality in T2DM Investigated pioglitazone ability to prevent progression of macrovascular disease The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med. 2008; 358: Patel, A. et al. N Engl J Med, 2008;358: PROspective Actos Clinical Trial In macrovascular Events (PROactive) results. Accessed February Primary & Secondary Endpoints PROactive Study Primary endpoints: Time to first occurrence of any of the following events from time of randomization: All-cause mortality Stroke Leg revascularization Non-fatal MI (including silent) Major leg amputation (above the ankle) Acute coronary syndrome Cardiac intervention Secondary endpoints: Time to first occurence of any of the of the following events from randomization: Non-fatal MI Stroke All-cause mortality PROactive Study Secondary endpoints: No Significant Effect of Pioglitazone on Primary Composite CV Kaplan-Meier Event Rate Time to ACS PIO (35/1230) (54/1215) HR 95% CI P value placebo ,.035 PIO vs 0.97 Endpoints Kaplan-Meier Event Rate Time to Fatal/Nonfatal MI (excluding silent MI) PIO vs placebo PIO (65/1230) (88/1215) HR 95% CI P value , N at (139) N at (139) Risk: Risk: l l l l l l l l l l l l l l l l Time From Randomization (mo) Time From Randomization (mo) ACS=acute coronary syndromes PROactive results Web site. Available at The official PROspective Actos Clinical Trial In macrovascular Events results.com (PROactive) results website. Available at Accessed January 12, /html/analysis.htm. October 10, PROspective Actos Clinical Trial In macrovascular Events (PROactive) results. Accessed February Dormandy JA, et al. Lancet. 2005;366: