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Update 2010: Type 2 Diabetes

Update 2010: Type 2 Diabetes. Afshan Zahedi , BASc, MD, FRCP(C) Endocrinology Medical Director, Diabetes Center The Scarborough Hospital Assistant Professor of Medicine University of Toronto November 6, 2010 The 8 th Annual GTA Primary Care Symposium. Learning Objectives.

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Update 2010: Type 2 Diabetes

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  1. Update 2010: Type 2 Diabetes Afshan Zahedi, BASc, MD, FRCP(C) Endocrinology Medical Director, Diabetes Center The Scarborough Hospital Assistant Professor of Medicine University of Toronto November 6, 2010 The 8th Annual GTA Primary Care Symposium

  2. Learning Objectives Understand current limitations in the treatment of type 2 diabetes Overview of different treatments for Type 2 Diabetes - selecting the second or third OHA Role of incretin-based therapies - glucagon-like peptide-1 [GLP-1] agonists - dipeptidyl peptidase-4 [DPP-4] inhibitors Role of Insulin in Type 2 Diabetes

  3. Natural History of Type 2 Diabetes Impaired Glucose Tolerance Undiagnosed Diabetes Known Diabetes Insulin Resistance Insulin Secretion Postprandial Glucose Fasting Glucose Microvascular complications Macrovascular complications 4-7 Years Ramlo-Halsted BA, et al. Clinical Diabetes 2000;18:80-85, with permission from The American Diabetes Association

  4. ß-cell Function Progressively Declines 100 Diabetes diagnosis 80 60 β-cell function (%, HOMA) 40 20 Extrapolation of β-cell function prior to diagnosis 0 –12 –10 –8 –6 –4 –2 0 2 4 6 8 Years from diagnosis HOMA = homeostasis model assessment Lebovitz HE. Diabetes Reviews 1999;7:139 UKPDS Group. Diabetes 1995;44:1249

  5. Rate of Progression from IGT to Type 2 DM • The IDF estimates that among persons with IGT, • 40-50% will progress to • Type 2 DM within 10 years www.idf.org Fact sheet on IGT accessed Mar 10 2006

  6. Diabetes Prevention Program (DPP) n=3234 People with IGT, age 25+, BMI 24+, 2.8 yrs follow up ↓31%* ↓58%* What was done in the intensive lifestyle arm to achieve a 58% reduction in diabetes incidence? *All comparisons significant by group sequential log rank test DPP Research Group. N Engl J Med 2002;346:393-403, with permission

  7. Intensive Lifestyle Arm of the DPP Goal: Lose 7% of initial body weight Adopt a low calorie, low fat diet Exercise a minimum of 150 minutes/week How:Attend 16 diet, exercise and behaviour modification sessions taught by case managers on a one to one basis Attend monthly individual sessions + other group sessions. Results: 38% lost 7% or more of their initial body weight 58% exercised a minimum of 150 minutes/week Daily energy intake dropped by 450 kcal Fat intake dropped 6.6% DPP Research Group. N Engl J Med 2002;346:393-403

  8. The Pathophysiology of Type 2 Diabetes Includes Three Main Defects Islet Pancreas α-cell produces excess glucagon β-cell produces less insulin 1. Insulin deficiency Excess glucagon Muscle and fat Hyperglycemia Diminishedinsulin Diminishedinsulin Liver 3. Insulin resistance 2. Excess glucose output

  9. Mechanisms of Action of Currently Available Oral Hypoglycemic Agents Pancreatic β-cells Liver • Sulfonylureas, meglitinides, incretins • Stimulate insulin release Amelioration of hyperglycemia Muscle • α-glucosidase inhibitors • Retard glucose reflux into circulation • PPARs (thiazolidinediones or glitazones) • Biguanides • Insulin • Incretins • Stimulate glucose uptake • Biguanides • PPARs (thiazolidinediones or glitazones) • Insulin • Incretins • Inhibit glucose production Gut PPAR = peroxisome proliferator-activated receptor agonist Adapted from Williams G, Pickup JC, eds. Handbook of Diabetes. Blackwell Publishing; 2004 DeFronzo RA. Ann Intern Med 1999;131:281 Buse JB, et al. In: Williams textbook of endocrinology. Saunders; 2003:1427

  10. Add an agent best suited to the individual based on the advantages / disadvantages listed below (agents listed in alphabetical order) * Less hypoglycemia in the context of missed meals 2008 CDA Guidelines

  11. Choosing the next OHA • Diabetes is a progressive disease • Three goals for treatment • Slow progression of Disease • Meet Glucose targets (ie A1C < 7 %) • Prevent diabetes complications • Three factors to consider • Risk of hypoglycemia • Weight Gain • Cost and coverage

  12. ADOPT (A Diabetes Outcome Progression Trial): Study Design n=4360 pts, age 30-75, diagnosed with T2DM in the last 3 yrs, FPG 7.0 - 10.0 mmol/L, on lifestyle management alone at baseline Run-In 4 weeks Treatment Period 4-6 yrs Rosiglitazone n=1456 Completed: 917 (63%) Diet/exercise reinforcement Metformin n=1454 Completed: 903 (62%) Glyburide n=1441 Completed: 807 (56%) Clinic visits every 2 months for 1 yr, then every 3 months Randomization Study end Viberti G, et al. Diabetes Care 2002;25:1737-43 Khan SE, et al. N Engl J Med 2006;355(23):2427-43

  13. ADOPT: Durability of Glycemic Control –A1C Progression Over 5 Years Annual rate of increase in A1C (after initial 6 months): Glyburide = 0.24%* Metformin = 0.14%* Rosiglitazone = 0.07% *p<0.001 vs. rosiglitazone Khan SE, et al. N Engl J Med 2006;355(23):2427-43, with permission

  14. ADOPT: Primary Outcome Time to Monotherapy Failure Incidence of Monotherapy Failure (FPG > 10.0 mmol/L) at 5 yrs: 15% with rosiglitazone 21% with metformin 34% with glyburide Rosiglitazone vs. Metformin: 32% risk reduction* Rosiglitazone vs. Glyburide: 63% risk reduction* * p<0.001 for both comparisons Khan SE, et al. N Engl J Med 2006;355(23):2427-43, with permission

  15. ADOPT: Durability of Glycemic Control Number of Months to Exceed A1C Target of > 7% Months Khan SE, et al. N Engl J Med 2006;355(23):2427-43

  16. ADOPT Therapeutic Considerations: Weight Change Over Time Khan SE, et al. N Engl J Med 2006;355(23):2427-43, with permission

  17. Add on to Metformin: Pioglitazone vs. GliclazideChange from Baseline in A1C and FPG – 1 yr results n = 313 n = 317 FPG reduction at 52 weeks: 2.1 mmol/l (P+M) 1.6 mmol/l (G+M) [P=0.506] HbA1C reduction at 52 weeks: 0.99% (P+M) 1.01% (G+M) [P=0.837] Maximum decrease in HbA1C: 24 weeks (P+M)  maintain 16 weeks (G+M)  deteriorate at 16 weeks Maximum reduction in FPG: 16 weeks (P+M)  maintain 8 weeks (G+M)  deteriorate at 32 weeks Matthews D, et. al. Diabetes Metab Res Rev 2005; 21:167-174

  18. Initial Monotherapy with Pioglitazone or Gliclazide – A1C over Two Years n=567 People with Type 2 Diabetes, age 35-75, 2 year follow-up 9 8.5 8 7.5 7 6.5 N=289 Pioglitazone N=261 • p <0.001 • ‡ p <0.01 • † p <0.05 * N=251 Gliclazide * * N=246 Hb1c (%) N=128 N=266 * ‡ N=238 † N=140 † * N=157 † N=237 N=203 † N=271 N=246 N=237 N=259 N=268 N=237 N=175 N=147 N=198 N=154 N=267 N=232 N=230 N=269 N=262 I I I I I I I I I I I I I 0 4 8 12 16 24 32 42 52 65 78 91 104 Weeks of Treatment Tan MH, et al. Diabetes Care 2005; 28: 544-550

  19. Incretin-based Therapies glucagon-like peptide-1 [GLP-1] agonists & dipeptidyl peptidase-4 [DPP-4] inhibitors

  20. What Are Incretins? Gut peptide hormones (GLP-1 and glucose-dependent insulinotropic peptide [GIP]) Secreted in response to food ingestion Stimulate glucose-dependent insulin secretion Account for up to 60% of insulin response in healthy subjects Short half-life due to enzymatic degradation by DPP-4

  21. GLP-1 Modes of Action in Humans Upon ingestion of food: • GLP-1 is secreted from the L-cells in the intestine This in turn: • Stimulates glucose-dependent insulin secretion • Suppresses glucagon secretion • Slows gastric emptying • Reduces food intake / increases satiety Long-term effects demonstrated in animals: • Increases β-cell mass and maintains β-cell efficiency Drucker DJ. Curr Pharm Des 2001;7:1399Drucker DJ. Mol Endocrinol 2003;17:161

  22. The family of incretin-based therapies Incretin-based therapies GLP-1 Receptor Agonists GLP-1 enhancers DPP – IV Inhibitors Human GLP-1 Analogues Exendin-based Therapies

  23. GLP-1 Secretion and Inactivation Meal Intestinal GLP-1 release GLP-1 t½ = 1 to 2 min ActiveGLP-1 DPP-4 GLP-1 inactive (>80% of pool) GLP-1 = glucagon-like peptide–1; DPP-4= dipeptidyl-peptidase–4 Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131.

  24. GLP-1 Homology 100 80 60 43% 40 8.6% 20 0 Liraglutide1 Exenatide + Metformin2 Percentage of patients with increase in antibodies 97% amino acid homology to human GLP-1 Improved PK: albumin binding through acylation; heptamer formation There was no blunting of efficacy by liraglutide antibodies Slow absorption from subcutis Resistant to DPP-4 Long plasma half-life (T½=13 h) 53% amino acid homology to human GLP-1 Study duration: liraglutide 26 weeks; exenatide 30 weeks 1. LEAD 1, 2, 3, 4, 5 meta-analysis of antibody formation. Data on file 2. DeFronzo et al. Diabetes Care 2005;28:1092

  25. Incretin Therapies Glycemic Control

  26. DPP-4 Inhibitor A1C With Sitagliptin Monotherapy Placebo Sitagliptin 100 mg qd (n = 238) Sitagliptin 200 mg qd (n = 250) 8.6 8.4 8.2 8.0 7.8 7.6 7.4 7.2 7.0 0 6 12 18 24 100 mg qd vs placebo = -0.79%* 200 mg qd vs placebo = -0.94%* A1C (%) Weeks *Difference in LS mean change from baseline vs placebo at Week 24;p< 0.001 Aschner P, et al. Diabetes Care 2006;29:2632

  27. A1C Reduction With LiraglutideMonotherapy 0.4 0.2 0.0 -0.2 -0.4 -0.6 -0.51 A1C change from baseline (%) -0.8 -0.84* -1.0 -1.14* -1.2 *p < 0.001 vs Glimepiride -1.4 -1.6 Liraglutide 1.2 mg Liraglutide 1.8 mg Glimepiride (SU) Garber A, et al. Lancet 2008 Sep 24 [Epub]

  28. A1C Reductions with Liraglutide + Metformin + metformin 0.4 0.2 0.1 0.0 -0.2 -0.4 -0.6 A1C change from baseline (%) -0.8 -1.0 -1.0† -1.0 -1.0† -1.2 -1.4 -1.6 Placebo Liraglutide 1.2 mg Liraglutide 1.8 mg Glimepiride (SU) †p<0.05 versus placebo; Nauck, et al. Diabetes Care, accepted for publication Liraglutide is not yet available in Canada

  29. A1C Reductions with Liraglutide + SU, +Met/TZD or +Met/SU + SU + met + TZD + met + SU 0.23 -0.24 -0.44 -0.54 -1.08‡§ -1.09 -1.13‡§ -1.33¶ -1.48 -1.48 Placebo Liraglutide 1.2 mg Liraglutide 1.8 mg Rosiglitazone (TZD) Glargine ‡p<0.0001 versus placebo; §p<0.0001 versus rosiglitazone; ¶p=0.0015 versus glargine 0.4 0.2 0.0 -0.2 -0.4 A1C change from baseline (%) -0.6 -0.8 -1.0 -1.2 -1.4 -1.6 Marre, et al. Diabetes 2008;57(suppl 1):A4; Zinman b, et al. Diabetologia 2008;51(suppl 1):Poster 898;Russell-Jones, et al. Diabetes 2008;57(suppl 1):A159 Liraglutide is not yet available in Canada

  30. Most common adverse reactions associated with Incretin-based agents in Phase III Trials *Not yet approved in Canada Sitagliptin Canadian Product Monograph, 2008; FDA. US prescribing information. 2008;FDA. Information for healthcare professionals exenatide. 2008; Garber A, et al. Lancet 2009.

  31. Nausea with Liraglutide Proportion of subjects with nausea by week and treatment; safety population1 • Patient withdrawals due to nausea were infrequent (2-4%)1 • In a separate study, the average patient rating of gastrointestinal adverse event severity was a maximum of 2 on a seven-point scale2 • Garber A, et al. Lancet 2009 • Horowitz M, et al. Diabetes Obes Metab. 2008;10(7):593-6. Liraglutide is not yet available in Canada

  32. Beyond glycemic control with incretin-based agents

  33. Non-significant Weight Reduction with Sitagliptin added to Patients Uncontrolled on Metformin Body Weight 0.0 -0.2 (n = 86) (n = 77) LS mean change from baseline -0.4 p = 0.954 vs placebo -0.6 Sitagliptin 100 mg Placebo -0.8 0 6 12 18 Weeks Excluding data after initiation of glycemic rescue Raz I, et al. Curr Med Res 2008;24:537

  34. Sustained Weight Reduction Over 52 Weeks With Liraglutide • Waist circumference was reduced from baseline by 3.0 cm with liraglutide 1.8 mg • Waist circumference increased by 0.4 cm with glimepiride (p< 0.0001) * * Glimepiride 4 mg/day Liraglutide 1.2 mg/day Liraglutide 1.8 mg/day *p< 0.0001 for change from baseline Garber A, et al. Lancet 2008 Sep 24 [Epub]

  35. Liraglutide Improves β-cell Function Baseline 56.4% 70.6% 45.5% 56.3% 0.48 0.45 0.42 0.45 p= 0.0313 p= 0.0033 Change in proinsulin:insulin HOMA (%) Liraglutide 1.8 mg Liraglutide 1.2 mg Rosi-glitazone Placebo Liraglutide 1.8 mg Liraglutide 1.2 mg Rosi-glitazone Placebo Mean ± 2SE Study NN2211-1436 Marre, et al. Diabetes 2008;57(suppl 1):A4

  36. GLP-1 Agonists versus DPP-4 Inhibitors *Not yet approved in Canada, + Blonde et al. Poster presented at CDA 2008

  37. Liraglutide Victoza

  38. Liraglutide Indications - Canada Once-daily administration for the treatment of adults with type 2 diabetes to improve glycemic control in combination with: Metformin, when diet and exercise plus maximal tolerated dose of metformin do not achieve adequate glycemic control Metformin and a sulfonylurea, when diet and exercise plus dual therapy with metformin and a sulfonylurea do not achieve adequate glycemic control Liraglutide should not be used in type 1 diabetes, pregnancy and pediatric population Victoza Product Monograph, Novo Nordisk Canada Inc., 2010.

  39. What about TZDs?

  40. Rosiglitazone • CHMP (Committee of the European regulatory agency): All rosiglitazone-containing medicines should be suspended across the EU – the benefit of Rosiglitazone do not outweigh its risks • In US – all rosiglitazone containing medicine will remain available with additional safety labelling and restrictions of use. FDA requires a risk evaluation programme.

  41. Rosiglitazone • Canada – rosiglitazone will be available, with the same safety labelling and restrictions • GSK – will not promote rosiglitazone in any country including Canada • Pioglitazone will continue to be available with no change in its status compare to previous

  42. Type 2 Diabetes - OHA • Start with Metformin if no contraindications • Avoid early use of SU • DDP4 inhibitors and GLP1 analogs can be used as second line of therapy • pioglitazone and acarbose are other options • Insulin should be used at any point in the therapy if glucose targets are not met

  43. Type 2 DM & Insulin

  44. Type 2 DM - Insulin • Role for insulin early in disease • Beta cell glucose toxicity • Relieve symptoms rapidly • Failure of combination of oral agents • Contraindication to oral agents • Renal failure • Dropping CrCl.

  45. Types of insulin • Bolus (meal): • Rapid acting – Humalog, Novorapid, Apidra • Short acting – Regular or Toronto • Basal: • Lantus, Levemir • Novolin NPH, Humulin N • Pre- mix: • Analog mix - NovoMix 30Humalog Mix 25 & Humalog Mix 50 • Regular mix - 30/70, 40/60, 50/50,

  46. BG Pattern Diet Lifestyle Insulin Fitting the Insulin Regimen to thePatient High fasting, with minimal glucose rise throughout day Small regular meals -MDI reluctant -Needs orals Basal-Only Insulin Premixed QD or BID Any fasting glucose, with glucose rises during the day Large suppers & small lunches -MDI reluctant -Consistent daily routine Any glucose pattern Match any diet -Erratic schedule -Motivated to achieve tight control Basal Bolus [MDI] Adapted from Hirsch I. Clinical Diabetes 2005; 23(2):78-86

  47. The Relative Contribution of Glucose control as one strives for a better A1c3* FPG PPG 30% 50% 60% 55% 70% Contribution (%) 70% 50% 45% 40% 30% <7.3 7.3 to 8.4 8.5 to 9.2 9.3 to 10.2 >10.2 A1c Range (%) * 290 non-insulin and non-acrabose- using patients with type 2 diabetes for at least 6 months. Plasma glucose concentrations were determined at fasting (8:00 AM) and postprandial and post absorptive (11:00 AM, 2:00 PM and 5:00 PM). 3. Adapted from Monnier L, et al. Diabetes Care. 2003;26:881-885.

  48. The INSIGHT Trial • A 24-week, randomized, open-label, parallel-group study conducted at 19 specialist sites and 34 sites led by family physicians. • Patients were randomized to receive either insulin glargine added to their current oral therapy with an insulin self-titration protocol (n=206) or physician-managed intensification of oral glucose-lowering therapy with no added insulin (n=199). • Patients in the OADs-only group were conventionally managed by their physicians. Gerstein HC, et al. Diabet Med 2006;23(7):736–42.

  49. Results • Patients receiving glargine achieved greater glycemic control than those on OADs only: • 1.68 times more likely to achieve two consecutive AIC 6.5% • Achieved lower FPG • Reported greater treatment satisfaction • No difference in the rate of hypoglycemia Gerstein HC, et al. Diabet Med 2006;23(7):736–42.

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