1. Slide Source: Lipids Online Slide Library www.lipidsonline.org New Approaches to Achieving Good Glycemic Control in Type 2 Diabetes: Part 2 (Other Therapies) Vivian Fonseca, MD

2. Slide Source: Lipids Online Slide Library www.lipidsonline.org Colesevelam Consistently Lowers A1C by an Additional Mean 0.5% Bays HE et al. Arch Intern Med. 2008;168:1975-1983 | Fonseca VA et al. Diabetes Care. 2008;31:1479-1484 | Goldberg RB et al. Arch Intern Med. 2008;168:1531-1540. *From baseline, placebo-adjusted ITT population, last observation carried forward (LOCF), patients on background monotherapy and combination therapy Mean Change in A1C * (%) –0.54 p<0.001 Colesevelam plus Metformin-Based Therapy Colesevelam plus Metformin-Based Therapy (n = 148) Baseline A1C = 8.1% Sulfonylurea-Based Therapy Colesevelam plus Sulfonylurea-Based Therapy (n = 218) Baseline A1C = 8.2% Insulin-Based Therapy Colesevelam plus Insulin-Based Therapy (n = 144) Baseline A1C = 8.3% –0.54 p<0.001 –0.50 p<0.001

3. Slide Source: Lipids Online Slide Library www.lipidsonline.org Colesevelam HCl: Summary of Glucose-Lowering Add-On Trials More than 1,000 patients tested (566 patients received colesevelam; total exposure 209 patient-years) in randomized, placebo- controlled trials for glucose lowering Results reflect “real-world” clinical approach – No washout of existing therapies – Added on to existing therapies Consistent, statistically significant mean reductions in A1C and LDL-C levels in all trials Not associated with weight gain

4. Slide Source: Lipids Online Slide Library www.lipidsonline.org Colesevelam HCl: Indications Reduction of elevated LDL cholesterol Indicated as an adjunct to diet and exercise to reduce elevated low-density lipoprotein cholesterol (LDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa) as monotherapy or in combination with an hydroxymethyl-glutaryl-coenzyme A (HMG- CoA) reductase inhibitor Reduction of blood glucose Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus Daiichi Sankyo. Welchol  prescribing information. Revised January 2012.

5. Slide Source: Lipids Online Slide Library www.lipidsonline.org Regulation of Seasonal and Cyclical Insulin Sensitivity (Animals) Animals switch from glucose utilization/nonutilization depending on seasons and food Hypothalamic dopaminergic and serotonergic pathways important Dopamine levels low during starvation and insulin- resistant state Decreased noradrenergic and serotonergic stimulation decreases hepatic glucose production Early morning dip in dopamine in type 2 diabetes Restoring this dopamine decreases glucose, triglycerides, and free fatty acids

6. Slide Source: Lipids Online Slide Library www.lipidsonline.org Meier AH et al. Diabetes Reviews. 1996;4:464-487. Circadian Rhythm in Diabetes Circadian neuroendocrine rhythms play a pivotal role in the development of seasonal changes in body fat stores and insulin sensitivity Glucose tolerance is greatest in the morning and declines during the day Dopamine is an important regulator of these rhythms

7. Slide Source: Lipids Online Slide Library www.lipidsonline.org Meier AH et al. Diabetes Reviews. 1996;4:464-487. Diabetes patients may have low morning levels of hypothalamic dopamine, which is thought to lead to hyperglycemia and dyslipidemia Bromocriptine resets aberrant low morning hypothalamic dopaminergic activity, which may reset neuroendocrine metabolic control Quick-Release Bromocriptine: Proposed Mechanism of Action Decreased lipolysis in adipose tissue Decreased postprandial hepatic glucose output Decreased insulin resistance

8. Slide Source: Lipids Online Slide Library www.lipidsonline.org Bromocriptine Safety Trial *MI, stroke, hospitalization for unstable angina, hospitalization for CHF, or coronary revascularization Reprinted with permission from Gaziano JM et al. Diabetes Care. 2010;33: 1503-1508. Copyright © 2010 American Diabetes Association. All rights reserved. Months Placebo Bromocriptine 5.0 4.0 3.0 2.0 1.0 0.0 012345678910111213 In a 3070-patient, 52-week safety study, bromocriptine use was not associated with increased risk for adverse CV events 1.5% of patients on bromocriptine vs. 3% on placebo had any CVD event* HR 0.60 (95% CI, 0.37 – 0.96) RRR = 40% Cumulative % with Composite CVD Endpoint*

9. Slide Source: Lipids Online Slide Library www.lipidsonline.org Quick-release and short-acting form of bromocriptine Approved for the treatment of type 2 diabetes Can be used in any drug combination Common side effects: nausea, dizziness, drop in blood pressure No long-term data available Quick-Release Bromocriptine: Summary

10. Slide Source: Lipids Online Slide Library www.lipidsonline.org Plasma insulin (pM) Plasma amylin (pM) 30 25 20 15 10 5 7 amMidnight5 pmNoon Time 600 400 200 0 Meal Time after Sustacal® meal (min) 0 5 10 15 20 -300306090120150180 Without diabetes (n=27) Type 1 (n=190) Insulin-using Type 2 (n=27) Plasma amylin (pM) Meal Reprinted with permission from Kruger D et al. Diabetes Educ. 1999; 25:389-397. Copyright © 1999 Sage Publications. All rights reserved. Insulin Amylin n=6 healthy subjects Amylin: Cosecreted with Insulin and Deficient in Diabetes

11. Slide Source: Lipids Online Slide Library www.lipidsonline.org Pramlintide An analog of amylin that overcomes the tendency of human amylin to – Aggregate, form insoluble particles – Adhere to surfaces Pharmacokinetic and pharmacodynamic properties similar to human amylin Human amylinPramlintide (analog of amylin) Amide S S A Y T N S G V N T TT T N A A A L I K S S C C Q R L N N N F G F L V H P P P Y T N S G V N T TT T N A A A L I K S S C C Q R L N N N F G F L V H Young A et al. Drug Dev Res. 1996;37:231-248 | Westermark P et al. Proc Natl Acad Sci USA. 1990;87:5036-5040.

12. Slide Source: Lipids Online Slide Library www.lipidsonline.org % Emptied per h after breakfast 0 5 10 15 20 25 Placebo 30 g Pramlintide 60 g Pramlintide Pramlintide Slows Gastric Emptying in Patients with Type 1 Diabetes Insulin + Placebo Insulin + Pramlintide Kong MF et al. Diabetologia. 1998;41:577-583.

13. Slide Source: Lipids Online Slide Library www.lipidsonline.org Change in Weight with Pramlintide Combined with Insulin in Patients with Type 2 Diabetes Reprinted with permission from Hollander PA et al. Diabetes Care. 2003;26: 784-790. Copyright © 2003 American Diabetes Association. All rights reserved. P < 0.05 for pramlintide 120 g BID vs placebo -2.0 -1.5 -0.5 0 0.5 1.0 1.5 013263952 Time (weeks) Change from baseline (kg) Placebo + insulin (n=161) Pramlintide 90 g BID + insulin (n=171) Pramlintide 120 g BID + insulin (n=166)

14. Slide Source: Lipids Online Slide Library www.lipidsonline.org Reprinted with permission from Kado S et al. Diabetes Res Clin Pract. 1998;41:49-55. Copyright © 1998 Elsevier. All rights reserved. Effects of Acarbose on Glucose and Insulin after a Meal 0 20 40 60 80 100 -300306090120150180 0 100 200 300 400 -300306090120150180 Time (min) % above baseline Glucose IncreaseInsulin Increase Meal Single-dose acarbose (baseline FPG 158 mg/dL) Without acarbose (baseline FPG 160 mg/dL) FPG=fasting plasma glucose % above baseline

15. Slide Source: Lipids Online Slide Library www.lipidsonline.org Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM): Reduction in Risk for Developing Type 2 Diabetes with Acarbose 25% risk reduction at mean 3.3 years (p=0.002) Placebo Acarbose Days after Randomization 1,3001,2001,1001,000 900800 700600 500400 3002001000 1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0.60 0.55 0.50 0.45 0.40 Cumulative Probability of Developing Diabetes Patients at risk: Reprinted with permission from Chiasson JL et al. Lancet. 2002; 359:2072-2077. Copyright © 2002 Elsevier. All rights reserved. Acarbose682655628612531523515497463447432349268212 Placebo686671655640512505497470434427414331255208

16. Slide Source: Lipids Online Slide Library www.lipidsonline.org 1,3001,2001,1001,000900800 700600 500400 3002001000 0.06 0.05 0.04 0.03 0.02 0.01 0 Probability of Any Cardiovascular Event 1,400 Placebo Acarbose p=0.04 (log-rank test) p=0.03 (Cox proportional model) Days after Randomization Reprinted with permission from Chiasson JL et al. JAMA. 2003;290:486-494. Copyright © 2003 American Medical Association. All rights reserved. Patients at risk: Acarbose682659635622608601596590577567558473376286203 Placebo686675667658643638633627615611604519424332232 49% relative risk reduction at mean 3.3 years Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM): Reduction in Risk for Cardiovascular Disease with Acarbose

17. Slide Source: Lipids Online Slide Library www.lipidsonline.org Does Pioglitazone Still Have a Place in Therapy? – YES! Early – prevention? – ACT NOW Combination with metformin – durability Insulin resistance syndrome High insulin doses – with caution CVD patients? – PROactive/BARI 2D Caveats: – Use lower doses (15–30 mg) – Stop if weight gain and edema – Assess osteoporosis risk – Risk of bladder cancer

18. Slide Source: Lipids Online Slide Library www.lipidsonline.org Long-Term Glucose Effects of Combined Glycemic Therapies Charbonnel B et al. Diabetologia. 2005;48:1093-1104. Pioglitazone Gliclazide Metformin Reduction in fasting plasma glucose at week 104, mmol/l p < 0.001p = 0.5

19. Slide Source: Lipids Online Slide Library www.lipidsonline.org Pioglitazone 2488 2373 2302 2218 2146 348 Placebo 2530 2413 2317 2215 2122 345 *Total mortality, MI, stroke, ACS, endovascular or surgical intervention in coronary or leg arteries, amputation above ankle amputation above ankle Time from Randomization (Months) 0.0 0.05 0.10 0.15 0.20 061218243036 0.25 Pioglitazone vs Placebo: HR 0.90 (95% CI 0.80–1.02); p=0.095 Placebo Pioglitazone 572/2633 514/2605 23.5% 21.0% N Events* 3-Year Estimate PROactive: Time to Composite Primary Endpoint Reprinted with permission from Dormandy JA et al. Lancet. 2005; 366:1279-1289. Copyright © 2005 Elsevier. All rights reserved. Kaplan-Meier Event * Rate Number at risk:

20. Slide Source: Lipids Online Slide Library www.lipidsonline.org Time to Fatal/Nonfatal MI (Excluding Silent MI) Kaplan-Meier Event Rate Prespecified Analysis 061218243036 Time from Randomization (Months) Time to Acute Coronary Syndrome Kaplan-Meier Event Rate Post Hoc Exploratory Analysis 061218243036 Time from Randomization (Months) –28% –37% Reprinted with permission from Erdmann E et al. J Am Coll Cardiol. 2007;49:1772-1780. Copyright © 2007 American College of Cardiology Foundation. All rights reserved. Pioglitazone (65/1230) Placebo (88/1215) Pioglitazone (35/1230) Placebo (54/1215) PROactive: Pioglitazone Reduced “Hard” Coronary Heart Disease Endpoints Pioglitazone vs Placebo: HR 0.72 (95% CI 0.52–0.99); p=0.045 Pioglitazone vs Placebo: HR 0.63 (95% CI 0.41–0.97); p=0.035

21. Slide Source: Lipids Online Slide Library www.lipidsonline.org How Can We Minimize the Side Effects of PPAR-γ Agonists? Use lower doses Avoid using in combination with insulin in high- risk patients Avoid use in patients with high risk for fractures Decrease salt and calorie intake Avoid calcium channel blockers Discontinue if patients have weight gain and edema Develop new PPAR- agonists that have fewer side effects

22. Slide Source: Lipids Online Slide Library www.lipidsonline.org BARI 2D: Outcomes by Type of Insulin Therapy and Revascularization Reprinted with permission from BARI 2D Study Group. N Engl J Med. 2009;360: 2503-2515. Copyright © 2009 Massachusetts Medical Society. All rights reserved. All-cause death (1°)Death, MI, stroke (2°) PCI/CABG Medical therapyp*p*PCI/CABG Medical therapyp*p* PCI (%) Insulin sensitization 10.210.10.6721.120.4 Insulin provision 11.410.30.5624.921.70.36 p†p†0.790.940.300.510.28 CABG (%) Insulin sensitization 13.417.10.3418.732.00.002 Insulin provision 13.915.60.6726.029.00.58 p†p†0.830.710.0660.51 *PCI/CABG vs Medical therapy. †Insulin sensitization vs. Insulin provision

23. Slide Source: Lipids Online Slide Library www.lipidsonline.org Investigational Agents for T2DM Long-acting GLP-1 receptor agonists Long-acting GLP-1 receptor agonists Sodium/glucose cotransporter (SGLT)–1 and –2 inhibitors Sodium/glucose cotransporter (SGLT)–1 and –2 inhibitors Ranolazine Ranolazine Dual (/) and pan (//) PPAR agonists Dual (/) and pan (//) PPAR agonists 11-Hydroxysteroid dehydrogenase (HSD)–1 inhibitors 11-Hydroxysteroid dehydrogenase (HSD)–1 inhibitors Fructose 1,6-bisphosphatase inhibitors Fructose 1,6-bisphosphatase inhibitors Glucokinase activators Glucokinase activators G protein–coupled receptor (GPR)–40 and –119 agonists G protein–coupled receptor (GPR)–40 and –119 agonists Protein tyrosine phosphatase (PTB)–1b inhibitors Protein tyrosine phosphatase (PTB)–1b inhibitors Carnitine palmitoyltransferase (CPT)–1 inhibitors Carnitine palmitoyltransferase (CPT)–1 inhibitors Acetyl CoA carboxylase (ACC)–1 and –2 inhibitors Acetyl CoA carboxylase (ACC)–1 and –2 inhibitors Glucagon receptor antagonists Glucagon receptor antagonists Salicylate derivatives Salicylate derivatives Immunomodulatory drugs Immunomodulatory drugs New insulins New insulins

24. Slide Source: Lipids Online Slide Library www.lipidsonline.org Summary Diabetes remains a challenging illness with multifaceted pathophysiology Current drug therapy has several limitations It is not always possible to achieve normoglycemia with current approaches Cardiovascular disease in diabetes remains a major clinical problem New treatments must address glucose lowering without hypoglycemia and weight gain and also address fundamental disease processes