2 Natural History of Type 2 Diabetes Post-meal glucose300IGTDiabetesGlucose (mg/dL)Fasting glucose100-15-10-5510152025Relative Function (%)100Insulin resistance7550ß-cell25-15-10-5510152025Years of DiabetesAdapted 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 these14.6 million Americans have been diagnosed6.2 million Americans do not know they have itThe 2005 National Diabetes Fact Sheet finds that there are 20.8 million Americans with diabetesCenters 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 19942004No Data<10%10%-14%15%-19%20%-24%≥25%19942004DiabetesMissing Data<4%4%-4.9%5%-5.9%≥6%*Obesity defined as BMI ≥30 or ~30 lbs overweight for 5'4" personBehavioral 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/dLORBy FPG (fasting plasma glucose) testPlasma glucose 126 mg/dL after 8h fastBy OGTT (oral glucose tolerance test)Plasma glucose rises to at least 200 mg/dL 2 hours after swallowing 75 g anhydrous glucose dissolved in waterAmerican Diabetes Association. Diabetes Care. 2006;29:S43-S48.
6 Pre-Diabetes Diagnosis High blood glucose (hyperglycemia) that does not meet diabetes diagnostic criteriaAlmost always precedes type 2 diabetesCriteria for diagnosis:Impaired Fasting Glucose (IFG)FPG test of 100 to 125 mg/dLImpaired Glucose Tolerence (IGT)OGTT test of 2h plasma glucose 140 to 199 mg/dLAmerican Diabetes Association. Diabetes Care. 2006;29:S43-S48.
7 Type 2 DiabetesAmerican Diabetes Association (ADA) 2006 classification:Type 2 diabetes results from a progressive insulin secretory defect on the background of insulin resistanceADA 2006 diagnosis:Fasting Plasma Glucose (FPG), or Fasting Blood Sugar (FBS), test is the preferred to diagnose diabetes in nonpregnant adultsA1C (also known as glycosylated hemoglobin or HbA1c) test is not recommended for diagnosisA1C can underestimate actual blood glucose in type 2 diabetes, making negative diabetes diagnosis possible.American Diabetes Association. Diabetes Care. 2006;29:S43-S48.
9 ADA Recommendations for Goals of Type 2 Diabetes Treatment Measurements GOALHbA1C (%) < 7 *Preprandial capillary plasma glucose (mg/dL)Peak postprandial plasma glucose (mg/dL) < 180Blood pressure (mmHg) < 130/80Lipids LDL < 100 mg/dL Triglycerides < 150 mg/dL HDL > 40 mg/dLKey concepts:A1C is primary target for glycemic controlMore stringent glycemic control (A1C < 6.0%) will lessen severe complications while increasing risks of hypoglycemiaAmerican Diabetes Association. Diabetes Care. 2006;29:S43-S48.
10 Lowering A1C Reduces Complications in Type 1 and Type 2 Diabetes DCCTKumamotoUKPDSA1C9.1% 7.3%9.4% 7.1%7.9% 7.0%RetinopathyNephropathyNeuropathyMacrovascular disease 63% 54% 60% 41%* 69% 70%Significantly improved— 17%–21% 24%–33%— 16%**Not statistically significantDCCT 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 OutcomeNonfatal MI, Stroke, or Death from CVD42% risk reduction P = 0.020.120.120.100.1057% risk reduction P = 0.020.080.08Cumulative Incidence0.060.060.040.040.020.020.000.0024681012141618202468101214161820Years Since EntryYears Since EntryNo. at RiskConventionalIntensiveDCCT-EDIC Study Research Group. N Engl J Med 2005;353:
12 Glycemic Control Reduces Long-Term Risk of Macrovascular Complications 0.120.100.080.060.040.020.002468101214161820Years Since EntryAny CV OutcomeCumulative Incidence42% risk reduction P = 0.020.120.100.080.060.040.000.022468101214161820Years Since EntryNonfatal MI, Stroke, or Death from CVD57% risk reduction P = 0.02No. at RiskConventionalIntensiveDCCT-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 adultsIntended for patients at home and in health care facilitiesAdjunctive device to complement information obtained from standard home glucose monitoring devicesMinimed 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 managementAlerts if glucose falls below or rises above preset valuesValues intended to provide indication of when a finger stick may be requiredAll therapy adjustments should be based on measurements from a home glucose monitorFDA Centers for Devices & Radiological Health.
15 Incretin Hormones: Human Physiology Nutrient ingestion stimulates gastrointestinal tract L-cells peptide hormone secretion in response toGLP-1: glucagon-like peptide-1GIP: glucose-dependent insulinotropic polypeptideIncretinsModulate insulin and glucagon release from pancreatic islet cellRapidly degraded by dipeptidyl peptidase 4 (DPP-IV) into inactive metabolitesLowered plasma GLP-1 in patients with pre-diabetes and type 2 diabetesToft-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 secretionSuppress glucagon secretionSlow gastric emptyingSubacute:Increase transcription of proinsulin and biosynthesis of insulinIncrease expression of Glut-2 and glucokinaseChronic:Stimulate proliferation and neogenesis of β-cells from precursor ductal cells and inhibits β-cell apoptosisDrucker DJ. Mol Endocrinol 2003; 17:Farilla L, et al. Endocrinology 2002; 143:
17 GLP-1 in Type 2 DiabetesGLP-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/dLDecreased A1C percentages by 1.3%Decreased body weight by 2-3 kgZander M, et al. Lancet. 2000;359:
18 Strategies to Increase Incretin Hormone Subcutaneous infusion of GLP-1 and/or GIPUse pump to deliver incretin hormones continuouslyLong-acting GLP-1 agonists (Incretin Mimetics)Exenatide (FDA approved)Pramlintide (FDA approved)LiraglutideBlocking 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 InhibitorsGLP-1 Secretion and MetabolismMixed MealIntestinal GLP-1 ReleasePlasmaGLP-1 ActionsRenal ClearanceGLP-1 (7-36) ActiveDPP-4GLP-1 (9-36) InactiveXRapid Inactivation (> 80% of Pool)Since DPP-4 rapidly breaks down GLP-1, DPP-4 inhibitors prolong the physiologic actions of GLP-1
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 cellsInjected at mealtimes lowers A1C modestlyNo hypoglycemia or weight gainPrimary side effect is nausea, which tends to improve over timePramlintide and insulin must be stored and injected separatelyApproved in type 2 diabetes for insulin-injecting patients not achieving A1C goalsExenatide (FDA approved 2005)Synthetic version of exendin-4, a hormone first isolated from lizard salivaInjected at mealtimes, lowers elevated blood glucose modestly primarily by increasing insulin secretionNo increased risk of hypoglycemia unless treatment includes a sulfonylureaModest weight lossApproved in type 2 diabetes in patients not achieving A1C goals using metformin, a sulfonylurea, or a combination of metformin and a sulfonylureaFrom FDA approval lettersMarch 17, 2005 Media Inquiries: Consumer Inquiries: 888-INFO-FDA FDA Approves New Drug to Treat Type 1 and Type 2 DiabetesThe 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 -11234567850100150200250300Time (h)Serum Insulin (pmol/L)PlaceboExenatide 0.1 µg/kgPlasma Glucagon (pg/mL)120180309060150Time (min)50100200250PlaceboExenatide 0.1 µg/kgExenatide or PlaceboStandardized BreakfastKolterman OG, et al. J Clin Endocrinol Metab. 2003; 88:
23 Effect of Exenatide on Post-Prandial Blood Glucose Plasma Glucose (mmol/L)5101520Exenatide or PlaceboStandardized Breakfast60120180240300Time (min)PlaceboExenatide 0.1 µg/kgKolterman 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 < 0.005SFU 2MET + SFU 3MET 1-0.4*- 0.8A1C (%)Baselinen0.1-0.4*-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 placebo1. 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, nInsulin Glargine Group, nHemoglobin A1C Level (%)*Exenatide Group, nInsulin Glargine Group, nChange 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 hoursPhase 2 clinical trials:Insulin secretion increasedPost-prandial glucagon secretion suppressedA1C decreased by %Weight loss of 0.7 – 1.2 kgMadsbad 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 diabetes165 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 weeksFasting 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 liraglutide8% of patients taking placeboWeight 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 treatmentSitagliptin 100 mg/day given to 353 patientsResults in sitagliptin-pioglitazone patientsFasting plasma glucose 16.7 mg/dL (p<0.001)A1C 0.85% (p<0.001)45% of patients reached A1C < 7% vs. 23% taking placeboNo change in weightSlightly greater percent had hypoglycemia or any GI adverse eventNo 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: 2006Abstract Number: 556-PAuthors: 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 HypoglycemiaIn 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 JANUVIAStein 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 lifeCan be administered once dailyIn rat modelsIncreased beta cell massEnhanced endogenous incretin activityPhase 2 clinical trialsTested vildagliptin add-on therapy in patients treated with metformin, or with pioglitazoneReduces fasting BGReduces post-prandial BG and glucagonNo change to 24-hour insulin secretionAmerican Diabetes Association 2005 Annual Meeting, Abstracts 572-P and 2192-POAhrén 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 diabetesRandomized, blinded 52 week study in 780 patients with mean baseline A1C = 8.7%Vildagliptin 50mg BID vs. metformin 1000mg BIDResults:A1C 1.0% vs. 1.4% (statistically identical)Weight change: kg vs kgIncidence of GI side effects lower (22% vs. 44%) including diarrhea and abdominal painMild hypoglycemia <1% in both groupsDejager S, et al. ADA 2006 Annual Meeting, Abstract 120-OR
36 Vildagliptin (LAF237) vs Rosiglitazone Monotherapy in treatment-naïve patients with type 2 diabetes697 patients and mean baseline A1C = 8.7%Randomized, blinded 24 week studyVildagliptin 50mg BID vs. rosiglitazone 8mg dailyA1C 1.1% vs. 1.2% (non-inferior difference)Weight change: kg vs kgChanges 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 groupsRosenstock J, et al. ADA 2006 Annual Meeting, Abstract 557-P
37 Vildagliptin (LAF237) Add on therapy to insulin 256 patients with type 2 diabetesInsulin injection > 30 units/day)baseline A1C = %Randomized, blinded 24 week studyVildagliptin 50mg BID vs. placeboBaseline insulin dose 80 units/dayA1C 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 inhibitorIn healthy volunteers:Single 100mg dose or 50mg daily provides >80% inhibition of DDP-IV activity for 24 hrsIncreased GLP-1 plasma levels 2-foldWell tolerated - did not cause hypoglycemiaHalf life of 8-14 hoursPrimarily eliminated unchanged in the urineHerman 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 wksFasting 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 timeNo difference in the percent who experienced hypoglycemia or any GI adverse eventAschner 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 weeksFasting plasma glucose 16.9 mg/dL (p<0.001)A1C 0.67% (p<0.001)47% of patient reached A1C < 7% vs. 18% on placeboNo additional weight loss over timeNo difference in the percent who experienced hypoglycemia or any GI adverse eventKarasik 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 analoguesInsulin secretagoguesBiguanidesAlpha-glucosidase inhibitorsThiazolidinedionesIncretin mimeticsDipeptidyl Peptidase (DPP)-4 inhibitorsFDA approval requested for sitagliptin and vildagliptin
43 Recommendations for Treatment of Type 2 Diabetes Patients need to achieve glycemic controlPatients need to be counseled on lifestyle changes by exercise and weight loss through dietary changes and calorie restrictionBlood AIC should be measuredBiannually in stable patients meeting glycemic goalsQuarterly in patients not meeting glycemic goals or whose therapy has changedAmerican Diabetes Association. Diabetes Care. 2006;29:S43-S48.
44 Consequences of Antihyperglycemic Therapy Use Patients frequentlyGain weightHave increased risk of hypoglycemia especially when treated with insulin and insulin secretagogueHave inadequately controlled postprandial hyperglycemiaHave wide glycemic fluctuationsLack long-term glycemic controlDo not understand the importance ofRigorous adherence to diet and exercise programsFrequent blood glucose monitoring
45 Weight Management Overweight and obesity Moderate weight loss Strongly linked to the development of type 2 diabetesCan complicate management of type 2 diabetesIndependent risk factor for hypertension, dyslipidemia, cardiovascular diseaseModerate weight lossImproves glycemic controlReduces CVD riskCan prevent the development of type 2 diabetesPrimary approach for achieving weight lossReduction 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/weekAmerican 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). TheyNeed to be taught benefits of modest weight loss and regular physical exerciseNeed follow-up counselingNeed to be monitored for development of type 2 diabetesNeed to be counseled to lower risk of cardiovascular disease by being treated for hypertension, dyslipidemia and stopping smokingShould not be routinely treated with diabetes drugs until more information is known about cost-effectivenessAmerican 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 forObesityGlycemic controlHypertension and dyslipidemiaMost patients with diabetes do not achieve treatment goals.While conventional treatments work well in some patients, in others they are associated with unmet needs includingWeight gainPostprandial hyperglycemiaHypoglycemiaProgressive loss of glycemic control and β-cell function and massNewer therapies may help more patients achieve treatment goals