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Type 2 Diabetes Glitazones and other antidiabetic agents, cardiovascular prevention

Type 2 Diabetes Glitazones and other antidiabetic agents, cardiovascular prevention. Bernard Charbonnel Endocrinology and Diabetes Department Nantes University Hospital France. High BP. Lipids.

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Type 2 Diabetes Glitazones and other antidiabetic agents, cardiovascular prevention

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  1. Type 2 Diabetes Glitazones and other antidiabetic agents, cardiovascular prevention Bernard Charbonnel Endocrinology and Diabetes Department Nantes University Hospital France

  2. High BP Lipids Control of hyperglycaemia is critical to the goal of reducing the risk of complications of diabetes Within a multifactorial intervention Hyperglycaemia High BP Cardiovascular disease Microangiopathy Neuropathy eye kidney

  3. Thanks to an intensive early multifactorial therapy : an impressive trend to a decrease in mortality over time UKPDS 33 Conventionnal Deaths/year/100 patients UKPDS 33 Intensive ADVANCE Blood glucose standard 1.87 ADVANCE Blood Glucose Intensive ACCORD Blood Glucose Intensif 1.79 ACCORD Blood Glucose standard 1.74 1.62 1.43 1.14

  4. Type 2 Diabetes treatment : a stepwise approach An ordered sequence of lifestyle modification, oral monotherapy, oral combination therapy, and finally insulin (with or without oral drugs) Insulin Oral agents + insulin Combination of oral agents Oral agent Nutrition and exercise Diabetes progression / Treatment failure = HbA1c >7%

  5. Type 2 Diabetes is a progressive disease UKPDS : HbA1c deteriorates over time Increasingly intensive therapies are required to maintain glucose control over time

  6. ADOPT : a comparison of 3 monotherapies as initial treatments N Engl J Med 2006;355:2427-43

  7. ADOPT : Differences in the efficacy between the 3 main anti-diabetic oral agents

  8. Sulfonylureas : A rapid and good efficacy, but not sustained

  9. Glitazones : a sustainable effect, the most powerful drug on the long term

  10. Chicago Study: JAMA, Nov 2006 The better glycemic durability on glitazones : a class effect, demonstrated for pioglitazone as well SU Pio

  11. Type 2 Diabetes is a major cardiovascular risk factor Type 2 Diabetes : the burden of cardio-vascular complications 50% of the diabetic patients die from an heart attack 60% of patients in intensive care cardiology units have some kind of glucose intolerance and 1/4 are diabetics High prevalence of strokes in diabetic patients

  12. The main large Outcome Studies for Blood Glucose lowering strategies UKPDS PROactive ACCORD ADVANCE VADT

  13. The main large Outcome Studies for Blood Glucose lowering strategies UKPDS PROactive ACCORD ADVANCE VADT ± positive negative

  14. ACCORD, AVANCE, VADT Intensive vs standard anti-diabetic treatment In patients > 60 years old and > 10 years diabetes duration 80% on insulin + oral agents

  15. ACCORD: Primary Outcome and Death from any Cause Discontinued at mean 3.5 yrs: increased death from any cause Intensive 257 / 5128 (5%), Standard 203 / 5123 (4%), HR 1.22 (p=0.04) Primary outcome * Death from any cause Relative risk : 1.22 Hypoglycemia ? *Non fatal myocardial infarction, non fatal stroke, CV death The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;10.1056/NEJMoa0802743

  16. ADVANCE (Gliclazide-based regimen) Cardio-vascular primary end-point : negative (Non fatal myocardial infarction, non fatal stroke, CV death)

  17. DietaryRun-in Randomisation1977-1991 Trial end1997 Intensive 2,729Intensivewith sulfonylurea/insulin 744Diet failureFPG >15 mmol/l P Conventional 5,102Newly-diagnosedtype 2 diabetes 4209 1,138 (411 overweight)Conventionalwith diet P Intensive 342 (all overweight)Intensivewith metformin 149Diet satisfactoryFPG <6 mmol/l UKPDS : Glucose Interventional Trial Mean age 54 years(IQR 48–60)

  18. ukpds UKPDS: Myocardial Infarction and CV death fatal or non fatal myocardial infarction, sudden death 573 of 3867 patients (15%) 30% Conventional Intensive p=0.052 20% % of patients with an event 10% Risk reduction 16% for 0.9% decrease in HbA1C 0% 0 3 6 9 12 15 Years from randomisation

  19. Post-Trial Monitoring: Patients 1997# in survivor cohort 2002 2007# with final year data 2,118Sulfonylurea/Insulin 1,010Sulfonylurea/Insulin Clinic Questionnaire P Clinic Questionnaire 880 Conventional 379 Conventional P Clinic Questionnaire 279 Metformin 136 Metformin Mean age62±8 years Mortality 44% (1,852)Lost-to-follow-up 3.5% (146)

  20. Myocardial Infarction Hazard Ratio (fatal or non-fatal myocardial infarction or sudden death) Intensive (SU/Ins) vs. Conventional glucose control HR (95%CI)

  21. All-cause Mortality Hazard Ratio Intensive (SU/Ins) vs. Conventional glucose control HR (95%CI)

  22. Legacy Effect of Earlier Glucose Control After median 8.5 years post-trial follow-up Aggregate Endpoint19972007 Any diabetes related endpoint RRR:12%9% P:0.0290.040 Microvascular disease RRR:25%24% P:0.00990.001 Myocardial infarction RRR: 16% 15% P:0.0520.014 All-cause mortality RRR: 6% 13% P:0.440.007 RRR = Relative Risk Reduction, P = Log Rank

  23. The expectations for TZDs (Glitazones) : a lot of potential anti-atherogenic effects in experimental and observational studies reduced risk of thrombus formation Decreased blood glucose Improved lipid profile improved endothelial function reduced risk of plaque rupture anti-inflammatory effects reduced LDL oxidation reduced foam cell formation Incrased cholesterol efflux Plutzky J, et al. J Diabetes Complications 2002; 16:401–405.

  24. Do clinical studies in man support the experimental or observational cardioprotective effects of glitazones ? Yes for clinical studies using surrogate end-points

  25. Chicago Study To evaluate the effect of pioglitazone vs glimepiride on changes in Carotid Intima Media Thickness (CIMT), a well established predictor of cardiovascular disease. in 242 patients with type 2 DM. Chicago is a positive study : Over an 18-month treatment period, pioglitazone slowed progression of CIMT compared with glimepiride (for a similar HbA1c decrease)

  26. EEM Area LumenArea JAMA. 2008;299(13):1561-1573 Determining the Atheroma Area : withIVUS, coronary intravascular ultrasonography EEM : external elastic membrane cross-sectional area and LUMEN : the luminal crosssectional area. (EEM Area — Lumen Area)

  27. EEM Area LumenArea Intravascular Ultrasound(IVUS) • Insight into plaque anatomy • Measures atheroma volume • Invasive procedure; limited to patients who require coronary angiography for a clinical indication Atheroma Area : EEM Area — Lumen Area J Clin Pract. 2007;61:951-962.

  28. * *patients who required coronary angiography JAMA. 2008;299(13):1561-1573

  29. PERISCOPE Primary Endpoint :Change in Percent Atheroma Volume (%) P < 0.001 For a similar HbA1c P = 0.002 P = 0.44 Glimepiride Pioglitazone

  30. HbA1c Levels during the Trial HbA1c (%) Weeks after Randomization

  31. Periscope : Changes in Biochemical Parameters HDL-cholesterol LDL-cholesterol 16.0% 6.9% 6.6% P <0.001 P = 0.69 4.1% hs C-reactive Protein Triglycerides 0.6% -18.0% P <0.001 P <0.001 -15.3% -44.9%

  32. Do clinical studies in man support the experimental or observational cardioprotective effects of glitazones ? Yes for clinical studies using surrogate end-points, either for rosiglitazone or pioglitazone What about large scale outcome studies ?

  33. TZDs and CVD : only one large published outcome study PROactive Study EASD, September 2005

  34. PROactive Study Design In 5238 diabetic patients with prior cardio-vascular disease Pioglitazone + existing therapy Existing therapy Forced titration up to 45 mg/day diet and glucose-lowering agents, antihypertensives, lipid-altering agents, antithrombotic agents, other cardiovascular drugs… Placebo + existing therapy Patient management throughout study to be according to the 1999 International Diabetes Federation (Europe) Guidelines

  35. Baseline Characteristics : Patients with a severe macrovascular disease Previous stroke n=984 19% 662 82 Previous MI n=2445 47% 763 145 95 Other macrovascular criteria n=3649* 1505 1904 • revascularisation of the coronary or the leg arteries • acute coronary syndrome • other evidence of coronary artery disease Number of entry criteria 2 : 48 % * - including 1043 (20%) with peripheral arterial obstructive disease

  36. 0.25 N events: 3-year estimate: placebo 572 / 2633 23.5% 0.20 pioglitazone 514 / 2605 21.0% 0.15 0.10 0.05 0.0 Time to Primary Composite Endpoint* Kaplan-Meier event rate Risk reduction : 10 % HR 95% CI p value pioglitazone 0.904 0.802, 1.018 0.0951 vs placebo N at Risk: 5238 5018 4786 4619 4433 4268 693 (228) 0 6 12 18 24 30 36 Time from randomisation (months) *Death, non-fatal myocardial infarction (including silent MI), stroke, major leg amputation, acute coronary syndrome, coronary or leg revascularisation

  37. Numbers of 1st Events Contributing to the Primary Composite Endpoint difference between placebo and pioglitazone n events : placebo 572 pioglitazone 514 Number of events

  38. N events: 3-year estimate: placebo 358 / 2633 14.4% pioglitazone 301 / 2605 12.3% Time to : Death, MI or Stroke Secondary composite endpoint prespecified as « principal » 0.15 0.10 Risk reduction : 16 % 0.05 HR 95% CI p value pioglitazone 0.841 0.722, 0.981 0.0273 vs placebo 0.0 N at Risk: 5238 5102 4991 4877 4752 4651 786 (256) 0 6 12 18 24 30 36 Time from randomisation (months)

  39. Factors Possibly Contributing to the Beneficial Effect of Pioglitazone HbA1c -0.5% HDL-C  +8.9% Blood pressure  -3 mmHg LDL / HDL  -5.3% Triglycerides  -13.2% CRP not measured Insulin sensitivity not evaluated vs placebo

  40. The Rosiglitazone controversy The Nissen‘s meta-analysis bombshell NEJM, mai 2007 Conclusions : Rosiglitazone is associated with an increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes

  41. 14291 patients in 4 major (but not cardio-vascular outcome) trials S. Singh et al : JAMA Sept 2007 Increased mortality on Rosi : not found in this meta-analysis Increased risk of MI on Rosi : suggested in this meta-analysis

  42. TZDs and cardiovascular prevention : the debate in 2009 • Is rosiglitazone bad for the heart ? • a suspicion, • but no validated evidence • 2. Is it good ? • probably no. • Is Pio different from Rosi • (no class-effect) ? • probably yes

  43. 1 2 3 Pioglitazone-SPECIFIC TARGET GENES Rosiglitazone-SPECIFIC TARGET GENES Pioglitazone-SPECIFIC BIOLOGICAL RESPONSE Rosiglitazone-SPECIFIC BIOLOGICAL RESPONSE Which rationale for no class-effect for TZDs : The SPPARM concept Pioglitazone Rosiglitazone PPAR PPAR COFACTORS PPAR PPAR COMMON TARGET GENES COMMON RESPONSE Glucose homeostasis

  44. No TZDs class-effect for the lipid profile on treatment NEJM, 2004

  45. No TZDs class-effect for the lipid profile on treatment NEJM, 2004

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