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Lowering sugars in diabetes – a cardiovascular waste of time?

Lowering sugars in diabetes – a cardiovascular waste of time?. Hamish Courtney Regional Endocrine Centre Royal Victoria Hospital Belfast. OASIS Study: Total Mortality. Diabetes/CVD (n = 1148). RR=2.88 (2.37–3.49). Diabetes/No CVD (n = 569). No Diabetes/CVD (n = 3503).

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Lowering sugars in diabetes – a cardiovascular waste of time?

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  1. Lowering sugars in diabetes – a cardiovascular waste of time? Hamish Courtney Regional Endocrine Centre Royal Victoria Hospital Belfast

  2. OASIS Study: Total Mortality Diabetes/CVD (n = 1148) RR=2.88 (2.37–3.49) Diabetes/No CVD (n = 569) No Diabetes/CVD (n = 3503) No Diabetes/No CVD (n = 2796) RR=1.99 (1.52–2.60) Event Rate RR=1.71 (1.44–2.04) RR=1.00 3 6 9 12 15 18 21 24 Months Malmberg K et al. Circulation 2000;102:1014-1019.

  3. Estimates of Diabetes Prevalence in World Regions Estimated prevalence (millions) 2000 1995 2025 Africa Americas EasternMediterranean Europe SoutheastAsia WesternPacific WHO Report 1997. World Health Organization. Geneva;1997.

  4. How low can you go.....safely?

  5. UKPDS United Kingdom Prospective Diabetes Study

  6. Main Randomisationn=4209 (82%) 342 allocated to metformin 3867 Conventional Policy30% (n=1138) Intensive Policy70% (n=2729) Insulinn=1156 Sulphonylurean=1573 UKPDS

  7. HbA1c

  8. UKPDS Microvascular Endpoints

  9. OASIS Study: Total Mortality Diabetes/CVD (n = 1148) RR=2.88 (2.37–3.49) Diabetes/No CVD (n = 569) No Diabetes/CVD (n = 3503) No Diabetes/No CVD (n = 2796) RR=1.99 (1.52–2.60) Event Rate RR=1.71 (1.44–2.04) RR=1.00 3 6 9 12 15 18 21 24 Months Malmberg K et al. Circulation 2000;102:1014-1019.

  10. 5 p<0.0001 Hazard ratio 1 14% change per 1% change in HbA1c 0 . 5 0 5 6 7 8 9 1 0 1 1 Updated mean HbA1c UKPDS 35. BMJ 2000; 321: 405-12 Fatal and Non-Fatal Myocardial Infarction

  11. 30 20 10 0 UKPDS and myocardial infarction Conventional Intensive p=0.06 % of patients with MI Risk reduction 16% (CI 95%: 0-29%) 0 3 6 9 12 15 Years after randomisation UKPDS 33 Lancet. 1998;352:837-853

  12. 0 UKPDS and myocardial infarction 40 Conventional (896) Chlorpropamide (619) Glibenclamide (615) 30 Insulin (911) % of patients with MI 20 10 CvGv IP =0.66 15 0 3 6 9 12 Years after randomisation

  13. Myocardial Infarction Mv Cp=0.010 Mv Ip=0.12

  14. University Group Diabetes Program (UGDP) North-American multicentre study Duration: 8 years (1961-1969) 1027 patients randomised into 5 groups Placebo - diet Tolbutamide - fixed dosage 1.5 g/d Phenformin - fixed dosage 100 mg/d Insulin - fixed dosage Insulin - adjusted dosage Klimt et al. Diabetes. 1970;19(suppl 2):747-783

  15. UGDP Meinert et al. Diabetes. 1970;19(suppl 2):789-830

  16. Intensive glycaemic control Does intensive glycaemic control reduce cardiovascular outcomes in T2DM? - ACCORD - ADVANCE - VADT - UKPDS follow up

  17. ACCORD Glycaemic intervention Intensive (HbA1c <6%) vs Standard (HbA1c 7.0-7.9%) Primary end point nonfatal MI, stroke or cardiovascular death

  18. Glycaemic Control N Engl J Med 2008;358:2545-2559

  19. ACCORD: Glucose-lowering drugs Patients (%) Intensive therapy(n = 5128) Standard therapy(n = 5123) Metformin 94.7 86.9 SU 86.6 73.8 Thiazolidinedione 91.7 58.3 α-Glucosidase inhibitor 23.2 5.1 Incretin 17.8 4.9 Insulin 77.3 55.4 N Engl J Med 2008;358:2545-2559

  20. ACCORD Primary Outcome N Engl J Med 2008;358:2545-2559

  21. ADVANCE Glycaemic intervention Intensive using gliclazide (HbA1c <6.5%) vs Standard (HbA1c to local guidelines) Primary end point composite macrovascular and microvascular events

  22. ADVANCE: Glucose-lowering drugs • ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.

  23. ADVANCE: primary macrovascular outcome CV death, MI, stroke 25 20 HR 0.94 (0.84-1.06)P = 0.32 Standard control 15 Cumulative incidence (%) 10 Intensive control 5 0 0 6 12 18 24 30 36 42 48 54 60 66 Follow-up (months) • ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.

  24. ADVANCE: all-cause mortality 25 20 HR 0.93 (0.83-1.06)P = 0.28 Standard control 15 Cumulative incidence (%) 10 Intensive control 5 0 0 6 12 18 24 30 36 42 54 60 66 48 Follow-up (months) • ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.

  25. ADVANCE: primary microvascular outcome New/worsening nephropathy, retinopathy 25 20 HR 0.86 (0.77-0.97)P = 0.01 Standard control 15 Cumulative incidence (%) 10 Intensive control 5 0 0 6 12 18 24 30 36 42 48 54 60 66 Follow-up (months) • ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.

  26. VADT Glycaemic intervention Intensive (HbA1c <6.0%) vs Standard (HbA1c to local guidelines) Primary end point composite macrovascular event

  27. VADT Duckworth W et al. N Engl J Med 2009;360:129-139

  28. VADT Duckworth W et al. N Engl J Med 2009;360:129-139

  29. Reasons? Drugs used?

  30. ACCORD: Glucose-lowering drugs Patients (%) Intensive therapy(n = 5128) Standard therapy(n = 5123) Metformin 94.7 86.9 SU 86.6 73.8 Thiazolidinedione 91.7 58.3 α-Glucosidase inhibitor 23.2 5.1 Incretin 17.8 4.9 Insulin 77.3 55.4 N Engl J Med 2008;358:2545-2559

  31. Reasons? Drugs used? Increase in hypoglycaemia? Increase in weight? Too rapid reduction in HbA1c?

  32. Glycaemic Control N Engl J Med 2008;358:2545-2559

  33. Reasons? Drugs used? Increase in hypoglycaemia? Increase in weight? Too rapid reduction in HbA1c? Chance?

  34. 30 20 10 0 UKPDS and myocardial infarction Conventional Intensive p=0.06 % of patients with MI Risk reduction 16% (CI 95%: 0-29%) 0 3 6 9 12 15 Years after randomisation UKPDS 33 Lancet. 1998;352:837-853

  35. UKPDS resultspresented Post-Trial Changes in HbA1c Mean (95%CI)

  36. Intervention TrialMedian follow-up 10.0 years Intervention Trial + Post-trial monitoringMedian follow-up 16.8 years RR=0.88 (0.79-0.99) P=0.029 Conventional Sulfonylurea/Insulin Conventional Sulfonylurea/Insulin Any Diabetes-related Endpoint

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

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

  39. Aggregate Endpoint19972007 Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040 Microvascular disease RRR: 25% 24% P:0.0099 0.001 Myocardial infarction RRR: 16% 15% P:0.052 0.014 All-cause mortality RRR: 6% 13% P:0.44 0.007 RRR = Relative Risk Reduction, P = Log Rank Legacy Effect of Earlier Glucose Control

  40. ACCORD/ADVANCE 25 20 N Engl J Med 2008;358:2545-2559 Standard control 15 Cumulative incidence (%) 10 Intensive control 5 0 0 6 12 18 24 30 36 42 48 54 60 66 Follow-up (months) • N Engl J Med. 2008;358:2560-72.

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