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Cardiovascular risk of Glucose-Lowering Drugs

1. Cardiovascular risk of Glucose-Lowering Drugs. Josep Redon. MD, PhD, FAHA Scientific Director Research Foundation and Research Institute INCLIVA. University of Valencia. Long-term CV and non-CV mortality in patients with type 2 diabetes.

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Cardiovascular risk of Glucose-Lowering Drugs

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  1. 1 Cardiovascular risk of Glucose-Lowering Drugs Josep Redon. MD, PhD, FAHA Scientific Director Research Foundation and Research Institute INCLIVA. University of Valencia

  2. Long-term CV and non-CV mortality in patients with type 2 diabetes Standardised mortality rates (SMR) for menand women with type 2 diabetes 6 8 4 10 0 2 Increased risk of mortality *Follow-up from 1974-2005 for all-cause mortality and 1974-2004 for cardiovascular and non-cardiovascular mortality **p<0.01 for difference between men and women Allemann S, et al. Swiss Med Wkly. 2009;139(39-40):576-83.

  3. Potential contributors to accelerate atherosclerosis and CV disease in Diabetes Type 1 DM Late-onset central obesity and IR Hyperglycemia Nephropathy Type 2 DM Central obesity and IR Dyslipidemia* Low-HDL Increased TGRL-C Postpandrial lipemia Proimflamatory state* Procoagulant state* * Relate toinsulin-resistance Redon J et al. (submitted).

  4. CV riskreductionwithmultipleinterventiontherapy in type 2 DM Gaede et al. N Engl J Med 2008 358:580-91

  5. Factorswhichcontributetothe final CV risk in diabetes Glucose Lowering Drug

  6. 6 Interaction between Patient Characteristics Glucose Control Level and CV Risk Reduction

  7. Impact of intensive therapy of glucose control in CV events in type 1 diabetes: DCCT study DCCT/EDIC N Engl J Med 2008;353:2643-2653

  8. Impact of intensive glucose control in CV events in diabetes

  9. Impact of intensive glucose control in CV events in diabetes

  10. Meta-analisis of RCT in macrovascular events with intensive glucose control: Main results Ray KK et al Lancet 2009;373:1765-1772

  11. Meta-analisis of RCT in macrovascular events with intensive glucose control: Main results Tumbull FM et al. Diabetologica 2009;52:2288-2298

  12. Hypoglycemia frequently occurs in intensive glucose control treatment

  13. Disease duration and CV risk events in intensive glucose control therapy (VADT) Duckworth et al. N Engl J Med 2009;360:129-139

  14. HbA1c goals and CV risk

  15. 15 Glucose-lowering drugs and CV risk

  16. Glucosemetabolismabnormalities in type 2 diabetes and treatment approaches

  17. Risk of all-cause mortality as a function of HbA1cand kind of treatment in T2DM Adjusted HR for all-cause mortality by HbA1c deciles ** 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 ** ** † † ** * ** ** ** HR (95% CI) * 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 HbA1c (%) HbA1c (%) Insulin-based regimens (n=20,005) Metformin plus sulphonylureas (n=27,965) Adjusted for age, sex, smoking status, total cholesterol, cardiovascular risk and general morbidity *Truncated at lower quartile; †Truncated at upper quartile **p<0.01 vs the reference group (decile 4; median HbA1c 7.5) Currie CJ, et al. Lancet 2010 ;375:481-9

  18. Risk of CV fatal and non-fatalevents in T2DM treated with metformin or SU Roumie CL et al. Ann InternMed 2012; 157: 601-610.

  19. Risk of CV fatal and non-fatalevents in T2DM with or withoutpreviousMI No Prior MI Prior MI MI, Stroke, and Cardiovascular Death MI, Stroke, and Cardiovascular Death 1 1.22 (1.30, 1.46) 0.03 0.71 (0.52, 1.99) 0.04 1.10 (0.85, 1.41) 0.5 1.54 (1.12, 2.10) 0.008 1.44 (1.01, 2.05) 0.04 1.10 (0.67, 1.82) 0.69 Metformin Metformin 1 1.29 (1.20, 1.39) 1.18 (1.02, 1.36) 1.16 (1.04, 1.29) 1.24 (1.09, 1.40) 1.17 (1.03, 1.33) 0.87 (0.49, 1.54) Glimepiride Glimepiride Gliclazide Gliclazide Glibenclamide Glibenclamide Glipizide Glipizide Tolbutamide Tolbutamide Repaglinide Repaglinide 0 1 2 0 1 2 Hazard Ratios (95% confidence intervals) Hazard Ratios (95% confidence intervals) Schramm TK et al. Eur Heart J. 2011; 32:1900–1908.

  20. Impact of different oral glucose-lowering drugs on CV risk of T2DM All cause mortality 2.0 Increased risk of allcause mortality 1.5 1.0 Hazard ratio (95% Cl) (log scale) Decreased risk of all cause mortality 0.5 Other combinations† vs metformin 1st generation sulphonylureas vs metformin 2nd generation sulphonylureas vs metformin All rosiglitazone* vs metformin All pioglitazone* vs metformin All rosiglitazone*vs all pioglitazone* n = 6053, 1st generation sulphonylureas; n= 58,095, 2nd generation sulphonylureas; n= 8442, rosiglitazone; n = 9640, rosiglitazone combination; n = 3816, pioglitazone monotherapy or combination; n = 37,253, other drugs or combinations; n = 68,181, metformin *Any therapy (monotherapy and combinations) †Other drugs and combinations of any oral antidiabetes drugs excluding rosiglitazone and pioglitazone Tzoulaki et al BMJ 2009;339:b4731

  21. Impact of different oral glucose-lowering drugs on CV risk of T2DM Myocardial infarction 2.0 1.5 Increased risk of MI 1.0 Hazard ratio (95% Cl) (log scale) Decreased risk of MI 0.5 Other combinations† vs metformin 1st generation sulphonylureas vs metformin 2nd generation sulphonylureas vs metformin All rosiglitazone* vs metformin All pioglitazone* vs metformin All rosiglitazone*vs all pioglitazone* n = 6053, 1st generation sulphonylureas; n= 58,095, 2nd generation sulphonylureas; n= 8442, rosiglitazone; n = 9640, rosiglitazone combination; n = 3816, pioglitazone monotherapy or combination; n = 37,253, other drugs or combinations; n = 68,181, metformin *Any therapy (monotherapy and combinations) †Other drugs and combinations of any oral antidiabetes drugs excluding rosiglitazone and pioglitazone Tzoulaki et al BMJ 2009;339:b4731

  22. Impact of different oral glucose-lowering drugs on CV risk of T2DM Congestive heart failure 2.0 1.5 Increased risk of CHF 1.0 Hazard ratio (95% Cl) (log scale) Decreased risk of CHF 0.5 Other combinations† vs metformin 1st generation sulphonylureas vs metformin 2nd generation sulphonylureas vs metformin All rosiglitazone* vs metformin All pioglitazone* vs metformin n = 6053, 1st generation sulphonylureas; n= 58,095, 2nd generation sulphonylureas; n= 8442, rosiglitazone; n = 9640, rosiglitazone combination; n = 3816, pioglitazone monotherapy or combination; n = 37,253, other drugs or combinations; n = 68,181, metformin *Any therapy (monotherapy and combinations) †Other drugs and combinations of any oral antidiabetes drugs excluding rosiglitazone and pioglitazone Tzoulaki et al BMJ 2009;339:b4731

  23. Factorsrelatedtotheimpact of differentglucose-loweringdrugson CV risk

  24. Comparative risk of hypoglycemia with glucose-lowering drugs 0.00 (−0.01-0.01) 3 (1557) 0.02 (−0.02-0.05) 5 (1495) 0.03 (0.00-0.05) 6 (2238) 0.04 (0.00-0.09) 8 (2026) 0.08 (0.00-0.16) 3 (1028) 0.09 (0.03-0.15) 5 (1921) 0.11 (0.07-0.14) 8 (1948) 0.14 (0.07-0.21) 9 (1987) Hypoglycemia Drug 1 less risk of hypoglycemia Drug 1 greater risk of hypoglycemia Pooled effect (95% CI) Studies (participants) METvs MET + TZD SU vsREPAG GLIB vs other SU SU vs MET SU + TZD vs SU SU vs TZD SU + MET vs SU SU + MET vs MET 0 0.05 0.1 0.15 0.2 Weighted absolute risk difference • Bolen S, et al. Ann Intern Med. 2007; 147: 386-399.

  25. Meta-analysis of effect of antidiabetes therapies on hypoglycaemia Hypoglycemia Relative risk (RR; 95% CI) of hypoglycaemia versus placebo No. trials RR (95% CI) 19 All drugs 1.43 (0.89 to 2.30) 3 SUs 2.63 (0.76 to 9.13)** 2 Glinides 7.92 (1.45 to 43.21) 2 TZDs 2.04 (0.50 to 8.23) 2 AGIs 0.60 (0.08 to 4.55) DPP-4 inhibitors 8 0.67 (0.30 to 1.50) GLP-1 analogues 2 0.94 (0.42 to 2.12) 6 8 4 44 0 2 Increased risk of hypoglycaemia vs placebo Decreased risk of hypoglycaemia vs placebo *I2=50-75%; **I2≥75% I2>50% was considered to represent important statistical heterogeneity SU, sulphonylurea; TZD, thiazolidinediones; AGI, -glucosidase inhibitor; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1 Phung OJ, et al. JAMA 2010;303(14):1410-8

  26. Risk of hypoglycaemiawithglucose-loweringdrugs Hypoglycemia

  27. Meta-analysis of effect of antidiabetes therapies on weight change Changes in body weight Weighted mean difference (WMD) in change from baseline in body weight (kg) versus placebo TZDs SUs Glinides All drugs DPP-4inhibitors AGIs GLP-1 analogues 1 4 1 2 3 2 2 12 No. trials 2 1 0 -1 ** WMD (mean; 95% CI) vs placebo * -2 -3 *I2=50-75%; **I2≥75% I2>50% was considered to represent important statistical heterogeneity SU, sulphonylurea; TZD, thiazolidinediones; AGI, -glucosidase inhibitor; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1 Phung OJ, et al. JAMA 2010;303(14):1410-8

  28. Risk of weightgainwithglucose-loweringdrugs Changes in body weight

  29. Bloodpressurereductionwithglucose-loweringdrugs Effect on other CVRF

  30. Differentimpact of rosiglitazone and pioglitazone in CV risk Specific molecule effect Erdmann E et al. CurrCardiologyRev 2009;5:155-165

  31. Differentimpact of rosiglitazone and pioglitazone in lipidprofile Specific molecule effect Aljada et al. PPAR Research 2009

  32. Differentimpact of rosiglitazone and pioglitazone in gene expression Specific molecule effect Erdmann E et al. CurrCardiologyRev 2009;5:155-165

  33. Sitagliptine (DDP-4 inhibitor) improves endothelial function and reduce atherosclerosis Matsubara J et al. J Am Coll Cardiol 2012;59:265–76

  34. Lireglutide (GLP-1) reduces vascular inflammatory markers Forst T et al. Diabetic Med 2012

  35. Gliptins and CV risk factors in type 2 diabetes.

  36. Ussher JR and Drucker DJ. Endocrine Reviews 2012; 33: 187-215.

  37. Ongoing trials of CV outcomes with several classic and new glucose-lowering drugs

  38. Ongoing trials of CV outcomes with several classic and new glucose-lowering drugs

  39. To take home Diabetes is a high CV risk condition Hypoglycemia and side effects of the glucose-lowering drugs can blunt the CV risk reduction HbA1c should be tailored to the individual patient New molecular targets expand potential CV and renal protection The potential impact of new glucose-lowering agents in CV risk should be explored in the forthcoming studies

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