Pharmacological Treatment of Type 2 Diabetes

Pharmacological Treatment of f Type 2 Diabetes Vivian Fonseca, MD

Clinical Pearls ♦ Prevention of type 2 diabetes is possible yp p ♦ Cardiovascular and microvascular complications of type 2 diabetes begin prior to y g its clinical diagnosis ♦ Monotherapy fails in the majority of patients with type 2 diabetes ih di b ♦ Effective treatment strategies should include reduction in A1C, blood pressure, and d ti i A1C bl d d cholesterol levels ♦ Improvement in cardiovascular outcomes in patients with type 2 diabetes remains a challenge

DPP: Incidence of Type 2 Diabetes 40 Placebo 30 Metformin ative incidence Lifestyle of diabetes (%) 20 Cumula 10 0 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Year *P<0.001 compared with each group Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.

DPP: Baseline Predictors of Response to Metformin Lifestyle Metformin Placebo 25 25 25 on-years 20 20 20 15 15 Cases/100 perso 15 10 10 10 5 5 5 0 0 0 95-109 110-125 25-44 45-59 ≥ 60 22 to < 30 30 to < 35 ≥ 35 (n = 2174) (n = 1060) (n = 1000) (n = 1586) (n = 648) (n = 1045) (n = 995) (n = 1194) FPG Age BMI (mg/dL) (years) (kg/m2) • Lifestyle is more effective generally than metformin or placebo • Metformin is more effective if FPG > 110 mg/dL, age < 60 years, and BMI > 30 kg/m2 • Gender, ethnicity, and 2-hour glucose were NOT predictive 2- DPP = Diabetes Prevention Program Knowler WC, et al. N Engl J Med. 2002;346:393-403.

ACT NOW: Islet-Cell Preservation May D l Onset of Type 2 Diabetes M Delay O t fT Di b t 0.30 Placebo Hazard ratio (HR) = 0.19 ( ) (95% CI, 0.09-0.39) 0.09- 0.25 P < 0.00001 6.8% per year 0.20 ard umulative haza 0.15 0.10 Pioglitazone Pi lit Cu 0.05 1.5% per year 0 0 10 20 30 40 50 Time (months) n = 602 patients (95 mg/dL ≥ FPG ≤ 125 mg/dL) Mean follow-up p p period of 2.6 y years The number needed to treat to prevent 1 case of type 2 diabetes was 3.5 patients for 1 year (development of type 2 diabetes defined as FPG > 126 mg/dL, confirmed with an OGTT) DeFronzo RA. Presented at: ADA 68th Scientific Sessions; June 2008; San Francisco, CA.

DREAM Primary Outcome:Rosiglitazone Primary Outcome Rosiglitazone .6 0. 0.1 0.2 0.3 0.4 0.5 HR = 0.40 (0.35-0.46); P<0.0001 mulative Hazard Placebo Cum Rosiglitazone 0.0 Year 0 1 2 3 4 Placebo No. at Risk 2634 2470 2150 1148 177 Placebo 2634 2470 2150 1148 177 Rosiglitazone 2635 2538 2414 1310 217 Rosiglita 2635 2538 2414 1310 217

NAVIGATOR G O 2 x 2 Factorial Design Valsartan comparison Valsartan/Nateglinide Placebo/Nateglinide (n = 2,288) (n = 2,288) Nateglinide comparison Valsartan/Placebo Placebo/Placebo (n = 2,288) (n = 2,288) Dosages Nateglinide 60 mg PO ac Valsartan 160 mg PO qd All subjects will receive a lifestyle advice program

Primary End Points: Results of Intensive Treatment in ACCORD and ADVANCE ACCORD: Primary Outcome ADVANCE: Primary Outcome 25 25 Intensive Therapy Intensive Therapy 20 20 Standard Therapy Standard Therapy Cumulative incidence (%) 15 Patients with events (%) 15 10 10 5 5 0 0 0 1 2 3 4 5 6 0 6 12 18 24 30 36 42 48 54 60 66 Years Months of Follow-up Number at Risk Number at Risk Intensive 5128 4843 4390 2839 1337 475 448 Intensive 5570 5369 5100 4867 4599 1883 Standard 5123 4827 4262 2702 1186 440 395 Standard 5569 5342 5056 4808 4545 1921 Primary Primar composite o tcome nonfatal myocardial infarction, nonfatal outcome: m ocardial infarction Primary Primar composite end point: nonfatal myocardial infarction, nonfatal point m ocardial infarction stroke, or death from cardiovascular causes stroke, death from cardiovascular causes, new or worsening Glycemia intervention stopped early for excess deaths in the intensive nephropathy, or retinopathy therapy group The hazard ratio was 0.90 (P = 0.01) for intensive compared to The hazard ratio was 0.90 (P = 0.16) for intensive compared to standard treatment. standard treatment. ACCORD Study Group. N Engl J Med. 2008;358:2545-2559. ACCORD: Action to Control Cardiovascular Risk in Diabetes ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572.

Main Findings From the ACCORD and ADVANCE Studies ACCORD ADVANCE 10,251 participants 11,140 participants Mean age: 62 years Mean age: 66 years Median duration of diabetes Mean duration of diabetes mellitus: 10 years mellitus: 8 years Mean A1C at entry: 8.3% Mean A1C at entry: 7.48% Known heart disease History of major CV event or at least 2 risk factors or at least 1 risk factor Standard: Intensive: Standard: Intensive: A1C 7.0%-7.9% A1C < 6.0% A1C, usual care A1C ≤ 6.5% Conclusion: intensive glucose lowering may Conclusion: intensive glucose lowering in cause harm in high-risk patients with type 2 high-risk patients reduces renal complications diabetes and high A1C levels by 21% (95% CI, 7%-34%) ACCORD Study Group. N Engl J Med. 2008;358:2545-2559. ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572.

VADT1 ACCORD2 ADVANCE3 (n=1700) (n=10250) (n=11140) HbA1c – Std vs. 8.4 vs. 6.9 7.5 vs. 6.5 7.3 vs. 6.5 Intensive Non-fatal MI Non-fatal stroke Non-fatal MI Non-fatal MI Primary outcome CVD death Non fatal Non-fatal stroke Non fatal Non-fatal stroke Hospitalization for CHF CVD death CVD death Revascularization Hazard Ratio for 0.87 0 87 0.90 0 90 0.94 0 94 primary outcome (0.730 – 1.04) (0.78 – 1.04) (0.84 – 1.06) (95% CI) Hazard Ratio for * 1.065 (0.801 – 1.416) 1.22 (1.01 – 1.46) 0.93 (0.83 – 1.06) mortality (95% CI) % *P=0.04 1W. Duckworth et al presented at EASD Annual Meeting, 2008; 2The ACCORD Study Group NEJM 2008;358:2545; 3The ADVANCE Collaborative Group NEJM 2008,358:2560

ACCORD VADT ADVANCE p p<0.001 p p< 0.01 p p<0.001

The VADT Trial Relationship of DM Duration and Hazard Ratio for CVD Events 1.4 1.2 1 HR for CVD 0.8 f Intensive Therapy 0.6 (p<0.0001) 0.4 04 0 3 6 9 12 15 18 21 24 DM Duration (years) Duckworth W, ADA Scientific Sessions, Symposia. June 8, 2008 .

Kaplan-Meier Curves for Four Prespecified Aggregate Clinical Outcomes Holman R et al. N Engl J Med 2008;10.1056/NEJMoa0806470

Recommendations for Adults with Diabetes Mellitus • Goals should be individualized • Certain populations (children, pregnant females, elderly) require special considerations • Set less intensive goals in patients with severe or frequent hypoglycemia (especially if ‘hypoglycemia q yp g y ( p y yp g y unawareness’ is present.) • More stringent goals (i.e. a normal A1C ≤6.0-6.5%) 6.0 6.5%) may further reduce microvascular outcomes (renal), but do not effect macrovascular outcomes (ACCORD, ADVANCE, VADT). (ACCORD ADVANCE VADT)

The ABCs of Diabetes Care A1C • ADA recommends < 7% = average glucose of 150 mg/dL mg/dL • AACE/IDF recommend ≤ 6.5% = average glucose of 135 mg/dL mg/dL Blood pressure p • < 130/80 mm Hg Cholesterol • LDL-C: < 100 mg/dL ( 70 mg/dL in very high-risk patients) LDL- mg/dL (< mg/dL high- • HDL-C: > 40 mg/dL in men and > 50 mg/dL in women HDL- mg/dL mg/dL • Non-HDL-C: ≤ 130 mg/dL (< 100 mg/dL in high-risk patients) Non-HDL- mg/dL mg/dL high- • TGs: < 150 mg/dL mg/dL g Don’t forget aspirin! ADA Standards of Medical Care in Diabetes. Diabetes Care. 2005;28(suppl 1):S4-S36. American Association of Clinical Endocrinologists. Endocr Pract. 2002;8(suppl 1):S5-S11. International Diabetes Federation. Diabetes Med. 1999;16:716-730.

Therapy for Type 2 Diabetes: Sites of Action Secretagogues Alpha-glucosidase inhibitors Stimulate insulin secretion Inhibit carbohydrate Incretins breakdown ↑ insulin secretion ↓ glucagon secretion Incretins Slow gastric emptying Metformin Thiazolidinediones Thiazolidinediones ↑ glucose metabolism ↑ glucose intake ↓ FFA output Metformin Thiazolidinediones Suppress glucose production Adapted from Saltiel AR, Olefsky JM. Diabetes. 1996:45:1661-1669. Physicians' Desk Reference®. 59th ed. Montvale, NJ:Thomson PDR; 2005. Drucker DJ. Mol Endocrinol 2003;17:161-171.

Updated ADA/EASD Consensus Algorithm STEP 1 STEP 2 STEP 3 Tier 1: Well-validated therapies Lifestyle + Metformin Lifestyle + Metformin + + Basal Insulin Intensive Insulin At Diagnosis: Lifestyle + Metformin Lifestyle + Metformin + Sulfonylureaa Tier 2: Less well-validated therapies Lifestyle + Metformin Lifestyle + Metformin + + Pioglitazone Pioglitazone + Sulfonylureaa Lifestyle + Metformin Lifestyle + Metformin + + GLP- GLP-1 agonistb Basal Insulin Reinforce lifestyle interventions at every visit and check A1C every 3 months until A1C is < 7 0% then at least every 6 months thereafter Change interventions 7.0%, thereafter. whenever A1C is ≥ 7.0%. aSulfonylureas other than glybenclamide (glyburide) or chlorpropamide. bInsufficient clinical use to be confident regarding safety. Nathan DM, et al. Diabetes Care. 2008;31:1-11.

Changing Treatment Paradigm Diet Combinations & Monotherapy of oral Insulin exercise agents Problems Glycemic targets often not met Monotherapy not effective long-term long- Treatment fails to address multiple impairments Step- Step S -wise approach tends to perpetuate “failure” f Glucose toxicity interferes with treatment response Harris, MI et al. Diabetes Care. 1999; 22: 403-408. Harris, MI et al. Diabetes Care. 1998; 21: 518-524.

Primary Objectives of Effective Management Diagnosis A1C % 9 8 7 Reduction SBP of both mm Hg micro- and macrovascular event 145 rates …by 75%! y 130 LDL mg/dL 140 100 45 50 55 60 65 70 75 80 85 90 Patient’s age American Diabetes Association. Diabetes Care. 2003:26(suppl 1):S28-S32. Gæde P et al. N Engl J Med. 2003;348:383-393.

Primary endpoint: Kaplan-Meier Estimates of the Cumulative Incidence of Monotherapy Failure Hazard ratio (95% CI) Rosiglitazone vs metformin, 0.68 (0.55–0.85); P<0.001 40 Rosiglitazone vs glyburide, 0.37 (0.30–0.45); P<0.001 Glyburide notherapy Failure 30 Cumulative Incidence of Mon Metformin 20 (%) Rosiglitazone 10 0 0 1 2 3 4 5 Years No. at risk Rosiglitazone 1393 1207 1078 957 844 324 Metformin M tf i 1397 1205 1076 950 818 311 Glyburide 1337 1114 958 781 617 218 20 Kahn SE, et al. N Engl J Med 2006;355:2427–2443.

Thiazolidinediones (TZD’s): Pioglitazone and Rosiglitazone •Mechanism of action – Enhance insulin sensitivity in muscle, adipose tissue – Inhibit hepatic gluconeogenesis – Reduced rate of beta cell dysfunction y •Safety and efficacy – Decrease A1C 1-2% – Adverse effects: edema, weight gain, anemia; peripheral fractures in women, macular edema, (MIs - rosiglitazone*) •Dosing D i – Initial dose (monotherapy): 1/2 to 2/3 maximum; dosing,1-2 x/day –M i Maximum effective dose: maximum d ff ti d i dose – Titration frequency: weeks to month(s) * Use no longer endorsed by ADA

PROactive: Reduction in Main Secondary E d P i t S d End Point Main primary composite end point: all-cause mortality, nonfatal myocardial infarction point: all- Main secondary composite end point: all-cause mortality, nonfatal point: all- (including silent MI), stroke, acute coronary syndrome, endovascular or surgical intervention in myocardial infarction, and stroke y , coronary or leg arteries, above-ankle amputation above- No. of 3-yr No. of 3-yr events estimate ARR events estimate ARR 25 Pioglitazone 514/2605 Pi lit 21.0% 21 0% 2.5% 2 5% 25 Pioglitazone 301/2605 12 3% 2 1% Pi lit 12.3% 2.1% Placebo 572/2633 23.5% Placebo 358/2633 14.4% 20 20 HR 0.90 (95% CI, 0.80-1.02) HR 0.84 (95% CI, 0.72-0.98) P = 0.095 P = 0.027 15 15 oportion of events (%) oportion of events (%) ( ( 10 10 5 5 Pro 0 Pro 0 0 6 12 18 24 30 36 0 6 12 18 24 30 36 Time from randomization (mo) Time from randomization (mo) No. at Risk: No. at Risk: Pioglitazone 2488 2373 2302 2218 2146 348 Pioglitazone 2536 2487 2435 2381 2336 396 Placebo 2530 2413 2317 2215 2122 345 Placebo 2566 2504 2442 2371 2315 390 ARR = average risk ratio PROactive = Prospective Pioglitazone Clinical Trial in Macrovascular Events Dormandy JA, et al. Lancet. 2005;366:1279-1289.

Major Pathophysiologic Defects in Type 2 Diabetes1,2 Islet-cell d f I l t ll dysfunction ti Glucagon (alpha cell) Pancreas Insulin Insulin (beta cell) resistance Hepatic glucose output Glucose uptake Hyperglycemia Muscle Liver Adipose tissue Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168. 1. Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781. 2. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254. 23

Role of Incretins in Glucose Homeostasis Ingestion of food Pancreas2,3 Glucose-dependent Glucose dependent Insulin from beta cells Glucose Release of gut (GLP-1 and GIP) uptake hormones — by Incretins1,2 muscles2,4 GI tract Blood Beta cells Active Alpha cells glucose GLP-1 & GIP Glucose production DPP-4 Glucose dependent by liver enzyme Glucagon from alpha cells (GLP-1) Inactive Inactive GLP-1 GIP DPP-4 = dipeptidyl-peptidase 4 1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913. 2. Ahrén B. Curr Diab Rep. 2003;2:365–372. 3. Drucker DJ. Diabetes Care. 2003;26:2929–2940. 4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441. 24

Physiological Actions of GLP-1 and GIP Neuroprotection Cardioprotection Appetite Cardiac output Gastric emptying GLP-1 Glucagon secretion Insulin secretion Insulin biosynthesis β cell proliferation GIP β cell apoptosis Glucose production Osteoblast Glucose Disposal Lipogenesis 25 Pratley/Cardiometabolic/16Oct08

GLP– GLP–1 Replacement Therapy in T2DM The Players • Short-acting GLP–1 receptor agonists Short- GLP– Exenatide (Amylin/Lilly) Liraglutide (Novo Nordisk) AVE0010 ( (sanofi– (sanofi–aventis) fi ti ) MKC253 Inhaled (MannKind) • Long-Acting GLP–1 receptor agonists Long- GLP– LAR– LAR–exenatide (Amylin/Lilly) Taspoglutide (R1583–Roche) (R1583– Albiglutide (Syncria®–GSK) (Syncria®– Lilly compound Conjuchem compound

Exenatide + Oral Agents Summary of A1C Changes Placebo “THE 3 AMIGOS TRIALS” TRIALS” Exenatide 5 μg 30- 30-Week, Randomized, Placebo-Controlled Placebo- Exenatide 10 μg 0.5% 0.23% 0.12% 0.08% 0 08% 8.6% 8.2% 8.5% 0% 0 5% -0.5% -0.40% Δ A1C -0.46% * * -0.55% * -0.78% -0.77% -1% -0.86% * * * Exenatide + SU Exenatide + Met (n=336) Exenatide + SU + Met -1.5% (n=377) (n=733) *P<0.01 vs placebo Buse JB et al. Diabetes Care. 2004;27:2628-2635; Defronzo RA et al. Diabetes Care. 2005;28:1092-1100; Kendall DM et al. Diabetes Care. 2005;28:1083-1091 27

Exenatide + Oral Agents Summary of Weight Changes Placebo “THE 3 AMIGOS TRIALS” TRIALS” Exenatide 5 μg 30- 30-Week, Randomized, Placebo-Controlled Placebo- Exenatide 10 μg 0.0 -0.3 -0.5 -0.6 -1.0 -0.9 -0.9 -1 5 1.5 Δ weight t (kg) -1.6 -1.6 -1.6 -1.6 -2.0 * * * * -2.5 -3.0 -2.8 * Exenatide + SU Exenatide + Met (n=336) Exenatide + SU + Met (n=377) (n=733) *P<0.05 vs placebo Buse JB et al. Diabetes Care. 2004;27:2628-2635; Defronzo RA et al. Diabetes Care. 2005;28:1092-1100; Kendall DM et al. Diabetes Care. 2005;28:1083-1091 28

Exenatide: Potential for Type 2 Diabetes Benefits B fit Limitations Li it ti • Beta Cell Effect • Nausea – Restored first-phase insulin – Mild-Moderate ~40% • Tend to subside over time • Three AMIGOs Endpoints – Severe ~5% – A1C ↓ of ~ 0.8-0.9% f – Causing Withdrawal ~3% aus ng W th rawa – A1C ≤7% in ~35-45% • Vomiting – Weight Loss 1.6-2.8 kg – 13% • Ongoing Open Label Study g g p y – Causing Withdrawal ~1% in Completers/Responders • Twice Daily Injections – Sustained A1C reductions ~1% • Cost – Sustained Weigh Loss ~3 kg • No Long-Term Controlled Study g y 29

Exenatide Added to Ongoing Therapy Improves Risk Factors P Value Parameter Change From Baseline (n = 151) Body Weight (kg) – 5.3 ± 0.5 < 0.0001 A1C (%) –08±01 0.8 0.1 < 0.0001 0 0001 Total Cholesterol (mg/dL) – 10.8 ± 3.1 0.0007 Triglycerides (mg/dL) – 44.4 ± 12.1 0.0003 LDL-C (mg/dL) – 11.8 ± 2.9 < 0.0001 HDL- HDL-C (mg/dL) + 8.5 ± 0.6 < 0.0001 Systolic Blood Pressure ( y (mm Hg) g) – 3.5 ± 1.2 0.0063 Diastolic Blood Pressure (mm Hg) – 3.3 ± 0.8 < 0.0001 Open- Open-label extension study; 527 patients using metformin and/or sulfonylurea added exenatide 5 µg BID for 4 weeks followed by 10 µg BID thereafter; 151 subjects with baseline lipid measurements completed 3.5 years of treatment Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286.

Glycemic Efficacy for JANUVIA™ (sitagliptin phosphate) Added to Patients Uncontrolled on Metformin (24-week Placebo-Adjusted)* A1C FPG 2-Hour PPG Mean Baseline A1C: 8.0% Mean Baseline: 170 mg/dL Mean Baseline: 275 mg/dL † P <0 001 <0.001 † P <0 001 <0.001 P <0 001† <0.001 0.00 0 0 § § -10 g/dL Change in A1C, % § dL -0.25 -0 25 Change in FPG, mg/d 10 -10 Change in PPG, mg n=453 n=454 -20 n=387 -0.50 -30 -20 -40 40 e ‡ -0.75 –0.7 ‡ –25 -30 -50 ‡ (95% CI: –0.8, –0.5) (95% CI: –31, –20) –51 (95% CI: –61, –41) -1.00 -60 -40 JANUVIA provided significant improvements in A1C, FPG, and 2-hr PPG vs placebo when added to patients inadequately controlled on metformin monotherapy. *In patients inadequately controlled on metformin monotherapy. †Compared with placebo plus metformin. ‡Least squares means adjusted for prior antihyperglycemic therapy status and baseline value. §Difference from placebo. 31

Emerging Therapies: Glucose- Lowering T i l With DPP 4 I hibit L i Trials DPP-4 Inhibitors Change from Baseline Prior A1C FPG Weight Dose Duration Study Treatment (%) (mg/dL) (lbs) 50 mg BID 24 wk –0.8 –14.4 –0.3 ± 0.4 Drug naive 50 mg BID 24 wk –1.1 11 –23.4 23 4 –0.3 ± 0 2 0 3 0.2 50 mg BID 24 wk –1.4 –21.6 –0.4 ± 0.1 Vildagliptin 1 Add-on to 50 mg BID 24 wk –1.0 ± 0.1 –19.8 ± 3.6 – pioglitazone Add-on to 50 mg BID 24 wk –0.6 ± 0.1 –7.2 ± 3.6 – sulfonylurea Newly 25 mg QD 26 wk –0.59 –16.4 –0.48 2 diagnosed Alogliptin g p Add-on t Add to 25 mg QD 26 wk –0.8 –19.9 – 3 pioglitazone Conclusions4: • No definite data, especially on cardiovascular outcomes, are still needed Long-term conclusions can be drawn from measurements of DPP-4 inhibitor effects on islet-cell function • 1Chia CW, et al. J Clin Endocrinol Metab. 2008;93:3703-3016. 2DeFronzo RA, et al. Presented at: ADA 68th Scientific Sessions; June 2008; San Francisco, CA. Abstract 446-P. 3Pratley R, et al. Presented at: ADA 68th Scientific Sessions; June 2008; San Francisco, CA. Abstract 478-P. 4Richter B, et al. Cochrane Database Syst Rev. 2008;2:CD006739.

Taspoglutide Dose Finding Study Summary 8 weeks study PBO vs Taspoglutide dose finding: weekly 5-10-20 mg and every 2 weeks 10-20 mg n=306 T2 DM on Metformin Baseline HbA1c 7.9% BMI 33 k / 2 kg/m2 Placeb 5 mg 10 mg 20 mg 10 mg 20 mg o QW QW QW Q2W Q2W ∆HbA1c -0.2% -1.0%* -1.2%* -1.2%* -1.0%* -1.0%* HbA1c 17% 59% 79% 81% 44% 63% ≤7% ∆Body - - -2.0kg* -2.8kg* - -1.9kg* weight (kg) *significant vs placebo Balena R et al, Diabetes 2008

Welchol™ Consistently Lowers A1C* by An Additional Mean 0.5% Welchol Plus Welchol Plus Welchol Plus Metformin-Based Sulfonylurea-Based Insulin-Based Therapy Therapy Therapy (n = 148) (n = 218) (n = 144) Baseline A1C = 8.1% Baseline A1C = 8.2% Baseline A1C = 8.3% 0 -0.1 -0.2 -0.3 Mean Change in g -0.4 A1C (%) -0.5 -0.50 -0.6 -0.54 -0.54 P <0.001 P <0.001 P <0.001 07 -0.7 -0.8 *From baseline, placebo-adjusted. Data on file, Daiichi Sankyo, Inc. ITT P Population, L l i Last Ob Observation C i d F i Carried Forward (LOCF) patients on b k d (LOCF), i background monotherapy and combination therapy. d h d bi i h

FXR: Metabolic Modulator of Post-prandial Hepatic Lipid and Glucose Metabolism Lipids BA BA synthesis Cholesterol Cyp7a1 VLDL FFA production esis Glucose e Lipogene FAS VLDL BA FXR ACC-1 Ac-CoA LPK NTESTINE Glucose Glycolysis Pyruvate BLOOD YMPH LIVER MIT Glycogenesis Glycogen LY IN B L Duran-Sandoval D. et al. J Biol Chem 2005.

JUPITER Ridker et al NEJM 2008 Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death HR 0.56, 95% CI 0.46-0.69 Placebo P < 0.00001 251 / 8901 0.08 Number Needed to Treat (NNT ) = 25 5 - 44 % 0.06 mulative Incidence 0.04 Cum Rosuvastatin 20 mg QD 142 / 8901 0.02 0.00 0 1 2 3 4 Follow-up (years) N=17,802 (No DM, LDL < 130 mg/dL, hsCRP > 2 mg/L)

Chronic Subclinical Inflammation: Part f the I P t of th Insulin Resistance Syndrome li R i t S d 1.6 16 1.4 1.2 1.0 0.8 0.6 Mean values (SE), log CRP 0.4 0.2 0 0 1 2 3 4 Number of metabolic disorders Festa. Circulation. 2000.

Chronic Inflammation Precedes Onset of Type 2 Diabetes: IRAS P=0.013 P=0.0001 P=0.0001 288 3 300 275 30 2.4 24 200 2 1.7 20 16 100 1 10 0 0 0 Fibrinogen (mg/dL) CRP (mg/L) PAI-1 (ng/mL) Diabetes No diabetes Festa A et al. Diabetes. 2002;51:1131-1137.

Two Week Trial: Salsalate (Disalcid) 4.5 g/day Baseline 2 Wk Rx Δ, % Salicylate (mg/dl) 0 19 / 28 Trough/Peak Weight (kg) 88.6 ± 22 88.4 ± 22 -0.2 NS FBG (mg/dl) 112 ± 43 91 ± 19 -19 P = 0.03 Cholesterol (mg/dl) 201 ± 49 177 ± 36 -12 P = 0.03 Triglycerides (mg/dl) 174 ± 97 105 ± 53 -40 P = 0.007 FFA (μM) 0.68 ± 0.05 0.35 ± 0.02 -49 P = 0.0006 CRP ( (mg/dl) /dl) 0.6 0.72 0 6 ± 0 72 0.31 0.46 0 31 ± 0 46 -48 48 P = 0 02 0.02 Adiponectin (mg/l) 15.5 ± 0.19 22.7 ± 0.25 +46 P < 0.01 Goldfine & Shoelson, in Press

TINSAL- TINSAL-T2D Trial Design Stage I: 14-week multicenter, double-masked, placebo-controlled dose ranging study in inadequately controlled T2D (7.0 ≤ HbA1c ≤ 9.5) Screen n=240, Randomize n=108 n=240 Placebo 3.0g 3.5g 4.0g n=27 n=27 n=27 n=27 52 Stage II: 26-week multicenter, double-masked, placebo-controlled phase III trial Screen n=564, Randomize n=282 Placebo Salsalate 3.5 g/d n=141 randomized n=141 randomized Placebo Salsalate n=113 complete n=113 complete

β β-Cell Deficiency in Diabetes: y Insulin and Amylin • Amylin – Reported in 1987 – 37-amino acid peptide – Colocated and Amylin Insulin T A T A T Q A cosecreted with insulin L N L C R F V N H C from pancreatic Amide Y T K L A F N S S β cells ll S S I G N N T S V N G Unger R, et al. In: Williams Textbook of Endocrinology. 8th ed. 1992:1273-1275.

Amylin: Cosecreted With Insulin and y Deficient in Diabetes Insulin Amylin Meal Meal Meal Meal 20 30 600 Without 25 Diabetes 15 Plasm Amylin (pM) Plasm Amylin (pM) Plasm Insulin (pM) 20 400 10 15 Insulin-Using ma ma ma Type 2 200 5 10 Type 1 0 0 5 30 -30 0 30 60 90 120 150 180 7 am 12 noon 5 pm Midnight Time Time After Sustacal® meal (min) Left graph: n=6 healthy subjects Right graph: n=27 without diabetes, Type 2 n=12, Type 1 n=190 g g p , yp , yp Kruger D, et al. Diabetes Educ 1999;25:389-397. Copyright © 1999 Sage Publications.

SUMMARY TYPE 2 DIABETES IS A COMPLEX DISEASE MULTIPLE NEW TARGETS FOR TYPE 2 DIABETES WHICH TREATMENT WILL PROVIDE VALUE?

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Pharmacological Treatment of Type 2 Diabetes

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