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A. Update on Type 2 Diabetes. Natural History of Type 2 Diabetes Adapted from: International Diabetes Center (Minneapolis, Minnesota). Insulin resistance.

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Presentation on theme: "A. Update on Type 2 Diabetes. Natural History of Type 2 Diabetes Adapted from: International Diabetes Center (Minneapolis, Minnesota). Insulin resistance."— Presentation transcript:

1 A. Update on Type 2 Diabetes

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

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

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 OR –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 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 GOALMeasurements GOAL Hb A1C (%) < 7 * Preprandial capillary plasma glucose (mg/dL) Peak postprandial plasma glucose (mg/dL) < 180 Blood pressure (mmHg) < 130/80 Lipids LDL 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 Retinopathy Nephropathy Neuropathy Macrovascular disease A1C  17%–21%  24%–33% —  16%* UKPDS  69%  70% Significantly improved — Kumamoto  63%  54%  60%  41%* DCCT *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: Lowering A1C Reduces Complications in Type 1 and Type 2 Diabetes 9.1%  7.3% 9.4%  7.1% 7.9%  7.0% 7.9%  7.0%

11 Glycemic Control Reduces Long-Term Risk of Macrovascular Complications DCCT-EDIC Study Research Group. N Engl J Med 2005;353: No. at Risk Conventional Intensive Years Since Entry Years Since Entry Nonfatal MI, Stroke, or Death from CVD Any CV Outcome Cumulative Incidence 42% risk reduction P = % risk reduction P = 0.02

12 Glycemic Control Reduces Long-Term Risk of Macrovascular Complications DCCT-EDIC Study Research Group. N Engl J Med 2005;353: No. at Risk Conventional Intensive Years Since Entry Any CV Outcome Cumulative Incidence 42% risk reduction P = Years Since Entry Nonfatal MI, Stroke, or Death from CVD 57% risk reduction P = 0.02

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 DPP-4 Inhibitors Since DPP-4 rapidly breaks down GLP-1, DPP-4 inhibitors prolong the physiologic actions of GLP-1 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)

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 –Primary side effect is nausea, which tends to improve over time –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

22 Effects of Exenatide on Insulin and Glucagon Secretion Plasma Glucagon (pg/mL) Time (min) Placebo Exenatide 0.1 µg/kg Exenatide or Placebo Standardized Breakfast Kolterman OG, et al. J Clin Endocrinol Metab. 2003; 88: Time (h) Serum Insulin (pmol/L) Placebo Exenatide 0.1 µg/kg

23 Effect of Exenatide on Post-Prandial Blood Glucose Plasma Glucose (mmol/L) Exenatide or Placebo Standardized Breakfast 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 < SFU 2 MET + SFU 3 MET *  A1C (%) Baseline n * -0.8* -0.5* -0.9* * -0.8*

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 Heine, R J, et al. Ann Intern Med. 2005;143: Exenatide Group, n Insulin Glargine Group, n Hemoglobin A1C Level (%) * * * * * * Exenatide Group, n Insulin Glargine Group, n Change in Body Weight (kg)

27 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 Patients –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 Rosenstock J, et al. ADA 2006 Annual Meeting, Abstract 556-P

30 Stein P. ADA 2006 Annual Meeting. Sitagliptin-Metformin vs Glipizide-Metformin

31 Stein P. ADA 2006 Annual Meeting. Sitagliptin vs Glipizide-Metformin

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 Ahrén B, et al. Diabetes Care 2004; 27: Hemoglobin A1C (%)

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: +0.3 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: -0.3 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 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 –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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