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A. Update on Type 2 Diabetes

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1 A. Update on Type 2 Diabetes

2 Natural History of Type 2 Diabetes
Post-meal glucose 300 IGT Diabetes Glucose (mg/dL) Fasting glucose 100 -15 -10 -5 5 10 15 20 25 Relative Function (%) 100 Insulin resistance 75 50 ß-cell 25 -15 -10 -5 5 10 15 20 25 Years of Diabetes Adapted from: International Diabetes Center (Minneapolis, Minnesota).

3 Prevalence of Diabetes in the United States: 2005 Estimates
CDC estimates that 1 in 14 Americans, 20.8 million, live with diabetes. Of these 14.6 million Americans have been diagnosed 6.2 million Americans do not know they have it The 2005 National Diabetes Fact Sheet finds that there are 20.8 million Americans with diabetes Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Available at:

4 The Prevalence of Obesity* and Diabetes Continues to Increase
1994 2004 No Data <10% 10%-14% 15%-19% 20%-24% ≥25% 1994 2004 Diabetes Missing Data <4% 4%-4.9% 5%-5.9% ≥6% *Obesity defined as BMI ≥30 or ~30 lbs overweight for 5'4" person Behavioral Risk Factor Surveillance System, Centers for Disease Control and Prevention. Available at: and Accessed January 20, 2006.

5 Type 2 Diabetes Diagnostic Criteria
American Diabetes Association (same since 1998): Symptoms of diabetes and non-fasting plasma glucose of 200 mg/dL OR By FPG (fasting plasma glucose) test Plasma glucose 126 mg/dL after 8h fast By OGTT (oral glucose tolerance test) Plasma glucose rises to at least 200 mg/dL 2 hours after swallowing 75 g anhydrous glucose dissolved in water American Diabetes Association. Diabetes Care. 2006;29:S43-S48.

6 Pre-Diabetes Diagnosis
High blood glucose (hyperglycemia) that does not meet diabetes diagnostic criteria Almost always precedes type 2 diabetes Criteria for diagnosis: Impaired Fasting Glucose (IFG) FPG test of 100 to 125 mg/dL Impaired Glucose Tolerence (IGT) OGTT test of 2h plasma glucose 140 to 199 mg/dL American Diabetes Association. Diabetes Care. 2006;29:S43-S48.

7 Type 2 Diabetes American Diabetes Association (ADA) 2006 classification: Type 2 diabetes results from a progressive insulin secretory defect on the background of insulin resistance ADA 2006 diagnosis: Fasting Plasma Glucose (FPG), or Fasting Blood Sugar (FBS), test is the preferred to diagnose diabetes in nonpregnant adults A1C (also known as glycosylated hemoglobin or HbA1c) test is not recommended for diagnosis A1C can underestimate actual blood glucose in type 2 diabetes, making negative diabetes diagnosis possible. American Diabetes Association. Diabetes Care. 2006;29:S43-S48.

8 B. 24h Glucose Monitoring

9 ADA Recommendations for Goals of Type 2 Diabetes Treatment
Measurements GOAL HbA1C (%) < 7 * Preprandial capillary plasma glucose (mg/dL) Peak postprandial plasma glucose (mg/dL) < 180 Blood pressure (mmHg) < 130/80 Lipids LDL < 100 mg/dL Triglycerides < 150 mg/dL HDL > 40 mg/dL Key concepts: A1C is primary target for glycemic control More stringent glycemic control (A1C < 6.0%) will lessen severe complications while increasing risks of hypoglycemia American Diabetes Association. Diabetes Care. 2006;29:S43-S48.

10 Lowering A1C Reduces Complications in Type 1 and Type 2 Diabetes
DCCT Kumamoto UKPDS A1C 9.1%  7.3% 9.4%  7.1% 7.9%  7.0% Retinopathy Nephropathy Neuropathy Macrovascular disease  63%  54%  60%  41%*  69%  70% Significantly improved  17%–21%  24%–33%  16%* *Not statistically significant DCCT Research Group. N Engl J Med. 1993;329: ; Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28: ; UKPDS Group. Lancet. 1998;352:

11 Glycemic Control Reduces Long-Term Risk of Macrovascular Complications
Any CV Outcome Nonfatal MI, Stroke, or Death from CVD 42% risk reduction P = 0.02 0.12 0.12 0.10 0.10 57% risk reduction P = 0.02 0.08 0.08 Cumulative Incidence 0.06 0.06 0.04 0.04 0.02 0.02 0.00 0.00 2 4 6 8 10 12 14 16 18 20 2 4 6 8 10 12 14 16 18 20 Years Since Entry Years Since Entry No. at Risk Conventional Intensive DCCT-EDIC Study Research Group. N Engl J Med 2005;353:

12 Glycemic Control Reduces Long-Term Risk of Macrovascular Complications
0.12 0.10 0.08 0.06 0.04 0.02 0.00 2 4 6 8 10 12 14 16 18 20 Years Since Entry Any CV Outcome Cumulative Incidence 42% risk reduction P = 0.02 0.12 0.10 0.08 0.06 0.04 0.00 0.02 2 4 6 8 10 12 14 16 18 20 Years Since Entry Nonfatal MI, Stroke, or Death from CVD 57% risk reduction P = 0.02 No. at Risk Conventional Intensive DCCT-EDIC Study Research Group. N Engl J Med 2005;353:

13 Continuous Blood Monitoring System
DexCom STS Continuous Glucose Monitoring System (FDA approved 2006) Indicated for detecting trends and tracking patterns in adults Intended for patients at home and in health care facilities Adjunctive device to complement information obtained from standard home glucose monitoring devices Minimed Guardian® RT Continuous Glucose Monitoring System (FDA approved 2005) Indicated for continuous or periodic monitoring of glucose in the fluid under the skin in adults to improve diabetes management Alerts if glucose falls below or rises above preset values Values intended to provide indication of when a finger stick may be required All therapy adjustments should be based on measurements from a home glucose monitor FDA Centers for Devices & Radiological Health.

14 C. Incretin Biology: Science

15 Incretin Hormones: Human Physiology
Nutrient ingestion stimulates gastrointestinal tract L-cells peptide hormone secretion in response to GLP-1: glucagon-like peptide-1 GIP: glucose-dependent insulinotropic polypeptide Incretins Modulate insulin and glucagon release from pancreatic islet cell Rapidly degraded by dipeptidyl peptidase 4 (DPP-IV) into inactive metabolites Lowered plasma GLP-1 in patients with pre-diabetes and type 2 diabetes Toft-Neilsen M, et al. J Clin Endocrinol Metab. 2001; 86: Deacon CF, et al. Diabetes 1995; 44: Drucker DJ. Gastroenterology. 2002; 122:

16 Incretin Hormones: Their Actions
Acute: Enhance glucose-dependent insulin secretion Suppress glucagon secretion Slow gastric emptying Subacute: Increase transcription of proinsulin and biosynthesis of insulin Increase expression of Glut-2 and glucokinase Chronic: Stimulate proliferation and neogenesis of β-cells from precursor ductal cells and inhibits β-cell apoptosis Drucker DJ. Mol Endocrinol 2003; 17: Farilla L, et al. Endocrinology 2002; 143:

17 GLP-1 in Type 2 Diabetes GLP-1 given a continuous subcutaneous infusion for 6 weeks resulted in: Lowered fasting plasma glucose by 77 mg/dL and mean plasma glucose by 100 mg/dL Decreased A1C percentages by 1.3% Decreased body weight by 2-3 kg Zander M, et al. Lancet. 2000;359:

18 Strategies to Increase Incretin Hormone
Subcutaneous infusion of GLP-1 and/or GIP Use pump to deliver incretin hormones continuously Long-acting GLP-1 agonists (Incretin Mimetics) Exenatide (FDA approved) Pramlintide (FDA approved) Liraglutide Blocking degradation of GLP-1 (DPP-4 Inhibitors) Sitagliptin (FDA submission) Vildagliptin (FDA submission) Saxagliptin

19 Intestinal GLP-1 Release Rapid Inactivation (> 80% of Pool)
DPP-4 Inhibitors GLP-1 Secretion and Metabolism Mixed Meal Intestinal GLP-1 Release Plasma GLP-1 Actions Renal Clearance GLP-1 (7-36) Active DPP-4 GLP-1 (9-36) Inactive X Rapid Inactivation (> 80% of Pool) Since DPP-4 rapidly breaks down GLP-1, DPP-4 inhibitors prolong the physiologic actions of GLP-1

20 C. Incretin Biology: Clinical Trials

21 Injected Incretin Mimetics Recently Approved Therapies for Type 2 Diabetes
Pramlintide (FDA approved 2005) Synthetic form of amylin, which is produced by pancreatic beta cells Injected at mealtimes lowers A1C modestly No hypoglycemia or weight gain Primary side effect is nausea, which tends to improve over time Pramlintide and insulin must be stored and injected separately Approved in type 2 diabetes for insulin-injecting patients not achieving A1C goals Exenatide (FDA approved 2005) Synthetic version of exendin-4, a hormone first isolated from lizard saliva Injected at mealtimes, lowers elevated blood glucose modestly primarily by increasing insulin secretion No increased risk of hypoglycemia unless treatment includes a sulfonylurea Modest weight loss Approved in type 2 diabetes in patients not achieving A1C goals using metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea From FDA approval letters March 17, 2005 Media Inquiries: Consumer Inquiries: 888-INFO-FDA FDA Approves New Drug to Treat Type 1 and Type 2 Diabetes The Food and Drug Administration (FDA) today approved Symlin, an injectable medicine to control blood sugar for adults with type 1 and type 2 diabetes. Symlin is to be used in addition to insulin therapy in patients who cannot achieve adequate control of their blood sugars on intensive insulin therapy alone. Symlin will be the only therapy for the treatment of type 1 diabetes other than insulin. Patients with type 2 diabetes already have several other types of oral therapies available.

22 Effects of Exenatide on Insulin and Glucagon Secretion
-1 1 2 3 4 5 6 7 8 50 100 150 200 250 300 Time (h) Serum Insulin (pmol/L) Placebo Exenatide 0.1 µg/kg Plasma Glucagon (pg/mL) 120 180 30 90 60 150 Time (min) 50 100 200 250 Placebo Exenatide 0.1 µg/kg Exenatide or Placebo Standardized Breakfast Kolterman OG, et al. J Clin Endocrinol Metab. 2003; 88:

23 Effect of Exenatide on Post-Prandial Blood Glucose
Plasma Glucose (mmol/L) 5 10 15 20 Exenatide or Placebo Standardized Breakfast 60 120 180 240 300 Time (min) Placebo Exenatide 0.1 µg/kg Kolterman OG, et al. J Clin Endocrinol Metab. 2003; 88:

24 Change in A1C seen in Exenatide in Phase 3 Clinical Trials
1. DeFronzo. Diabetes Care. 2005;28: Buse. Diabetes Care. 2004;27: Kendall. Diabetes Care. 2005;28:1083. Mean (SE): *P < 0.005 SFU 2 MET + SFU 3 MET 1 -0.4 * - 0.8 A1C (%) Baseline n 0.1 -0.4* -0.8* -0.5* -0.9* 0.2 -0.6*

25 Change in Weight in Exenatide Phase 3 Clinical Trials
Exenatide + SU + Met 3 (n=733) Exenatide + SU 1 (n=377) Exenatide + Met 2 (n=336) *P < 0.05 vs placebo 1. Buse. Diabetes Care. 2004; 27 : DeFronzo. Diabetes Care. 2005; 28 : Kendall. Diabetes Care. 2005; 28 :1083.

26 Exenatide vs. Insulin Glargine as Add-on Therapy for Type 2 Diabetes
Exenatide Group, n Insulin Glargine Group, n Hemoglobin A1C Level (%) * Exenatide Group, n Insulin Glargine Group, n Change in Body Weight (kg) Heine, R J, et al. Ann Intern Med. 2005;143:

27 Compared with native GLP-1: Phase 2 clinical trials:
Liraglutide (NN2211) Compared with native GLP-1: Has prolonged half-life of hours Phase 2 clinical trials: Insulin secretion increased Post-prandial glucagon secretion suppressed A1C decreased by % Weight loss of 0.7 – 1.2 kg Madsbad S, et al. Diabetes Care 2004; 27: Harder H, et al. Diabet Care 2004; 27:

28 Liraglutide (NN2211) vs Placebo
Dose finding study in patients with diabetes 165 patients with diet-controlled type 2 diabetes and baseline A1C % Liraglutide 0.65, 1.25, 1.9 mg Sub-Q daily vs. placebo for 14 weeks Fasting plasma glucose  16.7 mg/dL (p<0.001) A1C  1.74% (mean improvement in 3 groups, p<0.001) Reaching A1C < 7% were % of patients taking liraglutide 8% of patients taking placebo Weight change -3 kg vs. 1.2 kg (p=0.039) GI side effects were most common, highest incidence was diarrhea (19.5%) and nausea (10%) Vilsboll T, et al. ADA 2006 Annual Meeting, Abstract 115-OR

29 Sitagliptin (MK-0431)-Pioglitazone vs Placebo-Pioglitazone in Patients with Type 2 Diabetes
All treated with pioglitazone (30-50 mg/day) Baseline A1C, 7-10% First 24 weeks of treatment Sitagliptin 100 mg/day given to 353 patients Results in sitagliptin-pioglitazone patients Fasting plasma glucose  16.7 mg/dL (p<0.001) A1C  0.85% (p<0.001) 45% of patients reached A1C < 7% vs. 23% taking placebo No change in weight Slightly greater percent had hypoglycemia or any GI adverse event No information in abstract about how many patients given placebo. Addition of Sitagliptin to Pioglitazone Improved Glycemic Control with Neutral Weight Effect over 24 Weeks in Inadequately Controlled Type 2 Diabetes (T2DM) Year: 2006 Abstract Number: 556-P Authors: JULIO ROSENSTOCK, RONALD BRAZG, PAULA J. ANDRYUK, CHRISTINE MCCRARY SISK, KAIFENG LU, PETER STEIN. Institutions: Dallas, TX; Renton, WA; Rahway, NJ. Results: Thiazolidinediones are increasingly used in T2DM but may not provide sufficient glycemic control in monotherapy. This 24-wk, randomized, double-blind, placebo (PBO)-controlled study assessed the efficacy and safety of adding once-daily sitagliptin (SIT), a DPP-4 inhibitor, to patients (pts) with T2DM treated with pioglitazone (PIO) monotherapy. After a diet/exercise run-in and an 8-14 wk dose-stable period on PIO (duration according to previous therapy) and a 2-wk single-blind PBO run-in period, pts with HbA⊂1c ≥7% and ≤10% were randomized (1:1) to addition of PBO or SIT 100 mg q.d. to ongoing PIO. Mean baseline characteristics of randomized pts (N = 353) including age 56 yrs (range yrs); diabetes duration 6.1 yrs; HbA⊂1c 8.0%, FPG 167 mg/dL; BMI 31.5 kg/m⊃2 were similar between groups. Efficacy analysis was based on an all-patients-treated population using ANCOVA. After 24 wks, addition of SIT to PIO produced significant PBO-subtracted reductions in HbA⊂1c (-0.70%, p<0.001) and FPG (-17.7 mg/dL, p<0.001). SIT effects on glycemic control were maintained over the 24-wk study. Endpoint HbA⊂1c was 7.2% and 7.8% for SIT and PBO and the % of pts reaching target HbA⊂1c <7% was 45% and 23% (p<0.001), respectively. Proinsulin levels and proinsulin/insulin ratio were significantly reduced with SIT compared with PBO, suggesting improvements in Β-cell function. Sitagliptin was well tolerated with an overall incidence of AEs and of hypoglycemia similar to PBO. A slightly higher incidence of abdominal pain was observed with SIT, with no significant differences in other specific GI AEs compared to PBO. Mean body weight change was not different between SIT and PBO when added to PIO. In conclusion, in pts with T2DM with inadequate glycemic control on PIO, the addition of sitagliptin 100 mg once daily led to significant lowering of HbA⊂1c and FPG while improving some measures of Β-cell function without additional weight gain and with good tolerance over a 24-wk period. Rosenstock J, et al. ADA 2006 Annual Meeting, Abstract 556-P

30 Sitagliptin-Metformin vs Glipizide-Metformin
In New Data at One Year, JANUVIA™, an Investigational Once-Daily Medicine for Type 2 Diabetes, Demonstrated Substantial Glucose-Lowering Effect, With Significant Differences Compared to Glipizide (a Sulfonylurea) in Weight Change and Hypoglycemia In This Non-Inferiority Study, the Reduction in A1C Was Identical Between the Two Groups at 52 Weeks; Also, Patients on JANUVIA had Significant Weight Loss (vs. Weight Gain on Glipizide) and a Significantly Lower Incidence of Hypoglycemia vs. GlipizideWASHINGTON, D.C., June 13,  In a late-breaking oral presentation here today at the American Diabetes Association (ADA) 66th Annual Scientific Sessions, results from a non-inferiority study comparing JANUVIA™ (sitagliptin phosphate) to glipizide (a sulfonylurea) showed JANUVIA was non-inferior to glipizide in significantly reducing blood sugar (glucose) levels at 52 weeks when added to the regimen of patients with type 2 diabetes who had inadequate control on metformin monotherapy.  The 52-week data presented were the primary time point analysis for this study, which continues for another year (through 104 weeks). JANUVIA is Merck and Co., Inc.'s investigational once-daily medicine that, if approved, would potentially be the first in a new class of oral drugs (dipeptidyl peptidase-4 [DPP-4] inhibitors) that enhances the body's own ability to lower blood sugar (glucose) when it is elevated.  The mechanism of action of DPP-4 inhibitors is distinct from that of any currently available class of glucose-lowering agents."In the new data presented today, JANUVIA demonstrated substantial glucose-lowering effects at one year with a magnitude of A1C reduction that was non-inferior to that of glipizide.  Additionally, JANUVIA demonstrated weight loss and fewer episodes of hypoglycemia vs. glipizide," said Peter Stein, M.D., senior director, clinical research, Merck & Co., Inc.  "These are important findings for a potential new treatment for type 2 diabetes."In the per-protocol primary analysis (n= 793) of this double-blind, randomized study (N=1,172), JANUVIA 100 mg once daily (proposed registration dose) and glipizide up to 20 mg daily (maximum titrated dose) each showed significant mean reductions in A1C1  of 0.67% vs. baseline (p<0.001) in patients with mildly to moderately elevated baseline A1C levels (mean 7.5%; enrollment criteria for A1C were >6.5% and <10%).  At 52 weeks, JANUVIA achieved the pre-specified bounds for non-inferiority vs. glipizide, and similar proportions of patients achieved A1C goal (<7%) in each group (63 percent for JANUVIA vs. 59 percent for glipizide).   In the 52-week data, JANUVIA was generally well tolerated.  No significant safety concerns for JANUVIA were apparent based on review of overall incidence of adverse experiences (AEs), incidence of hypoglycemia or gastrointestinal AEs, mean changes and predefined limits of change in laboratory safety parameters and ECG data and vital signs.  Patients in the group treated with JANUVIA 100 mg once daily experienced significant weight loss (mean -1.5 kg) from baseline at 52 weeks, while patients treated with glipizide experienced significant weight gain (mean +1.1 kg) from baseline.  The between-treatment difference was statistically significant (p<0.001, JANUVIA vs. glipizide).  Additionally, patients treated with glipizide experienced a significantly higher rate of hypoglycemia (when blood sugar is too low) vs. JANUVIA (patients experiencing at least one hypoglycemic episode regardless of severity: 32.0% vs. 4.9%, respectively; p<0.001).Safety and tolerability across the clinical program The safety and tolerability of JANUVIA at once-daily doses of 100 mg and 200 mg (twice the proposed registration dose) were assessed by pooling data from two monotherapy and two add-on studies.  The overall incidence of clinical and laboratory adverse experiences was similar between JANUVIA and placebo.  The incidence of hypoglycemia was similar between JANUVIA and placebo (1.2% in 100 mg, 0.9% in 200 mg, and 0.9% in placebo) and no clinically meaningful changes compared to placebo were observed in body weight with JANUVIA in these studies.  The most common side effects(>3% and greater than placebo) reported with JANUVIA were stuffy or runny nose and sore throat; headache; diarrhea; upper respiratory infection; joint pain; and urinary tract infection (with differences ranging from 0.1% to 1.5% vs. placebo).For laboratory assessments, no clinically meaningful differences in the occurrence of pre-defined changes in laboratory values were noted.  Although not clinically meaningful, small increases in uric acid, in white cell blood count (due to a small increase in neutrophil count), and a small decrease in alkaline phosphatase were observed with JANUVIA compared with placebo. In these studies, no significant changes in vital signs or in ECG including in QTc intervals were observed.A1C goal attainment across the clinical program for JANUVIA Stein P. ADA 2006 Annual Meeting.

31 Sitagliptin vs Glipizide-Metformin
As previously stated, similar proportions of patients taking JANUVIA 100 mg vs. glipizide in the new 52-week data of an active-comparison study achieved A1C goal (<7%) (63 percent for JANUVIA vs. 59 percent for glipizide).  Additionally, JANUVIA showed significant attainment of A1C goal in other key studies reported at the ADA meeting.  Differences in percent of patients achieving A1C goal (<7%) for patients taking JANUVIA 100 mg as monotherapy vs. placebo were statistically significant (p<0.001) in a 24-week study (41 percent vs. 17 percent) and in a 12-week study in Japanese patients (58.1 percent vs percent).  Differences in percent of patients achieving A1C goal (<7%) for patients taking JANUVIA 100 mg in combination with metformin (47 percent vs. 18 percent) and with pioglitazone (45 percent vs. 23 percent) were statistically significant (p<0.001) in two 24-week studies.U.S. media and investor/analyst teleconference Merck will host an on-site briefing and teleconference for pharmaceutical investors/analysts and U.S.-based media on Tuesday, June 13, 2006, at 12:30 p.m. ET to discuss the Phase III data on JANUVIA.  Participants include Edward S. Horton, M.D., professor of medicine and vice president, Joslin Diabetes Center, and John Amatruda, M.D., vice president, clinical research, Merck & Co., Inc.   The on-site location is Room 153 in the Washington Convention Center located at 801 Mount Vernon Place NW in Washington, D.C.  The call-in number is (800) (Passcode: ).About JANUVIA JANUVIA is Merck's investigational oral, once daily DPP-4 inhibitor for the treatment of type 2 diabetes.  JANUVIA is a potent and highly selective DPP-4 inhibitor.  DPP-4 inhibitors work by enhancing a natural body system that lowers blood sugar, the incretin system.  When blood sugar is elevated, incretins work in two ways to help the body regulate high blood sugar levels: they trigger the pancreas to increase insulin and signal the liver to reduce glucose production.  DPP-4 inhibitors enhance the body's own ability to control blood sugar levels by increasing the active levels of these incretin hormones in the body, helping to decrease blood sugar levels in patients with type 2 diabetes.  The mechanism of action is distinct from any existing class of glucose lowering agents.JANUVIA has been accepted for standard review by the U.S. Food and Drug Administration (FDA). Merck expects FDA action on the New Drug Application (NDA) by mid-October.  The Company is also moving forward as planned with filings in countries outside the United States.  Also, Merck anticipates that MK-0431A, the investigational medicine combining JANUVIA with metformin for type 2 diabetes, will now be filed with the FDA in 2006 vs  About Type 2 Diabetes Type 2 diabetes is a condition in which the body has elevated blood sugar or glucose. With type 2 diabetes, the body may not make enough insulin (which helps the body use glucose), the insulin that the body produces may not work as well as it should, or the body may make too much glucose.  Patients with diabetes can develop heart disease, kidney disease, blindness, vascular or neurological problems that can lead to amputation and they can suffer increased mortality.Nearly 21 million people in the United States, or seven percent of the population, have diabetes, with type 2 diabetes accounting for 90 to 95 percent of the cases.  Approximately two-thirds of people diagnosed with type 2 diabetes have not achieved adequate control of their blood sugar levels (A1C less than seven percent as recommended by the American Diabetes Association).  It is estimated that one in three Americans born in 2000 will develop diabetes sometime during their lifetime.  There are currently more than 194 million people with diabetes worldwide, and if nothing is done to slow the epidemic, the number may exceed 333 million by 2025.About Merck Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first.  Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs.  The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them.  Merck also publishes unbiased health information as a not-for-profit service.  For more information, visit Statement This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995.  These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements.  The forward-looking statements may include statements regarding product development, product potential or financial performance.  No forward-looking statement can be guaranteed, and actual results may differ materially from those projected.  Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.  Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2005, and in its periodic reports on Form 10-Q and Form 8-K, which the company incorporates by reference. JANUVIA™ is the proposed trademark for MK-431 (sitagliptin phosphate). 1 A1C is a measure of a person's blood average blood glucose over a two- to three-month period.# # # Stein P. ADA 2006 Annual Meeting.

32 Vildagliptin (LAF237) Oral selective DDP-IV inhibitor Like sitagliptin
Prolonged half life Can be administered once daily In rat models Increased beta cell mass Enhanced endogenous incretin activity Phase 2 clinical trials Tested vildagliptin add-on therapy in patients treated with metformin, or with pioglitazone Reduces fasting BG Reduces post-prandial BG and glucagon No change to 24-hour insulin secretion American Diabetes Association 2005 Annual Meeting, Abstracts 572-P and 2192-PO Ahrén B, et al. Diabetes Care 2004; 27: Ahrén B, et al. J Clin Endocrinol Metab 2004; 89:

33 Vildagliptin vs. Placebo in Patients with Type 2 Diabetes Taking Metformin
Hemoglobin A1C (%) Ahrén B, et al. Diabetes Care 2004; 27:

34 Vildagliptin (LAF237) Monotherapy
Clinical trials with treatment naïve patients with type 2 diabetes Randomized, blinded 52 week study in 780 patients with mean baseline A1C = 8.7% Vildagliptin 50mg BID vs. metformin 1000mg BID Results: A1C  1.0% vs. 1.4% (statistically identical) Weight change: kg vs kg Incidence of GI side effects lower (22% vs. 44%) including diarrhea and abdominal pain Mild hypoglycemia <1% in both groups Dejager S, et al. ADA 2006 Annual Meeting, Abstract 120-OR

35 Vildagliptin: Superior GI Tolerability

36 Vildagliptin (LAF237) vs Rosiglitazone
Monotherapy in treatment-naïve patients with type 2 diabetes 697 patients and mean baseline A1C = 8.7% Randomized, blinded 24 week study Vildagliptin 50mg BID vs. rosiglitazone 8mg daily A1C  1.1% vs. 1.2% (non-inferior difference) Weight change: kg vs kg Changes in lipids compared to rosiglitazone: TG  9%, LDL  16%, and Total  -14% but smaller HDL  Incidence of LE edema was lower (2.5% vs. 4.9%) Mild hypoglycemia <1% in both groups Rosenstock J, et al. ADA 2006 Annual Meeting, Abstract 557-P

37 Vildagliptin (LAF237) Add on therapy to insulin
256 patients with type 2 diabetes Insulin injection > 30 units/day) baseline A1C = % Randomized, blinded 24 week study Vildagliptin 50mg BID vs. placebo Baseline insulin dose  80 units/day A1C  0.5% vs. 0.2% (p=0.022) Hypoglycemia was less frequent (33 vs. 45 patients) and less severe (0 vs. 6 severe events) Fonseca V, et al. ADA 2006 Annual Meeting, Abstract 467-P

38 A competitive, reversible DDP-IV inhibitor In healthy volunteers:
Sitagliptin (MK-0431) A competitive, reversible DDP-IV inhibitor In healthy volunteers: Single 100mg dose or 50mg daily provides >80% inhibition of DDP-IV activity for 24 hrs Increased GLP-1 plasma levels 2-fold Well tolerated - did not cause hypoglycemia Half life of 8-14 hours Primarily eliminated unchanged in the urine Herman GA, et al. Clin Pharmacol Ther 2005; 78: Bergman A, et al. Clin Therapeutics 2006; 28:

39 Sitagliptin (MK-0431) Monotherapy
741 patients with type 2 diabetes (diet controlled) and baseline A1C = 7-10% Sitagliptin 100mg or 200mg daily vs. placebo for 24 wks Fasting plasma glucose  17.1 to 21.3 mg/dL (p<0.001) A1C  0.79 to 0.94% (p<0.001) Post-meal insulin and C-peptide AUC significantly  No clinically important change in weight over time No difference in the percent who experienced hypoglycemia or any GI adverse event Aschner P, et al. ADA 2006 Annual Meeting, Abstract 1995-PO

40 Sitagliptin (MK-0431) Add on therapy to metformin
701 patients with DM type 2 on metformin 1500mg daily and baseline A1C = 7 -10% Sitagliptin 100mg daily vs. placebo for 24 weeks Fasting plasma glucose  16.9 mg/dL (p<0.001) A1C  0.67% (p<0.001) 47% of patient reached A1C < 7% vs. 18% on placebo No additional weight loss over time No difference in the percent who experienced hypoglycemia or any GI adverse event Karasik A, et al. ADA 2006 Annual Meeting, Abstract 501-P

41 D. Gaps/Obstacles in Type 2 Diabetes Therapies and Treatment Options

42 Classes of Therapies for Type 2 Diabetes
Insulin and insulin analogues Insulin secretagogues Biguanides Alpha-glucosidase inhibitors Thiazolidinediones Incretin mimetics Dipeptidyl Peptidase (DPP)-4 inhibitors FDA approval requested for sitagliptin and vildagliptin

43 Recommendations for Treatment of Type 2 Diabetes
Patients need to achieve glycemic control Patients need to be counseled on lifestyle changes by exercise and weight loss through dietary changes and calorie restriction Blood AIC should be measured Biannually in stable patients meeting glycemic goals Quarterly in patients not meeting glycemic goals or whose therapy has changed American Diabetes Association. Diabetes Care. 2006;29:S43-S48.

44 Consequences of Antihyperglycemic Therapy Use
Patients frequently Gain weight Have increased risk of hypoglycemia especially when treated with insulin and insulin secretagogue Have inadequately controlled postprandial hyperglycemia Have wide glycemic fluctuations Lack long-term glycemic control Do not understand the importance of Rigorous adherence to diet and exercise programs Frequent blood glucose monitoring

45 Weight Management Overweight and obesity Moderate weight loss
Strongly linked to the development of type 2 diabetes Can complicate management of type 2 diabetes Independent risk factor for hypertension, dyslipidemia, cardiovascular disease Moderate weight loss Improves glycemic control Reduces CVD risk Can prevent the development of type 2 diabetes Primary approach for achieving weight loss Reduction in energy intake and an increase in physical activity (therapeutic lifestyle change) Decrease of 500 –1,000 kcal/day will result in weight loss of 1–2 lb/week American Diabetes Association. Diabetes Care. 2006;29:S43-S48

46 Prevention or Delay of Type 2 Diabetes
ADA recommendations for patients with impaired glucose tolerance (IGT). They Need to be taught benefits of modest weight loss and regular physical exercise Need follow-up counseling Need to be monitored for development of type 2 diabetes Need to be counseled to lower risk of cardiovascular disease by being treated for hypertension, dyslipidemia and stopping smoking Should not be routinely treated with diabetes drugs until more information is known about cost-effectiveness American Diabetes Association. Diabetes Care. 2006;29:S43-S48.

47 Diabetes: Strategies to Achieve Optimal Glycemic Control
Development and progression of complications can be delayed by treating patients with type 2 diabetes for Obesity Glycemic control Hypertension and dyslipidemia Most patients with diabetes do not achieve treatment goals. While conventional treatments work well in some patients, in others they are associated with unmet needs including Weight gain Postprandial hyperglycemia Hypoglycemia Progressive loss of glycemic control and β-cell function and mass Newer therapies may help more patients achieve treatment goals

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