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  • 1. Managing micro- and macrovascular risk in T2DM Lars Rydén
  • 2. Photo: Lennart Nilsson SCANPIX
  • 3. Lars Rydén MD, Dr h.c., FESC, FACC, FAHA Declaration of interest  Advisory board / speaker     AstraZeneca BMS Roche Sanofi  Research support        Swedish Heart–Lung Foundation Karolinska Institutet Stockholm County Council AFA Insurance Swedish Medical Assembly AstraZeneca Roche
  • 4. The first attempt to develop a glucose-lowering drug Frederic G. Banting (1891 – 1941) “Diabetus Ligate pancreatic ducts of dogs. Keep dogs alive till acini degenerate leaving islets. Try to isolate the internal secretion of these to relieve glycosurea.” Banting FG. Edin Med J. 1929;36:1-18.
  • 5. The first patient treated with insulin  The Banting & Best experiment, 1921  Ligated the pancreatic duct inducing digestive cell necrosis  Homogenized and filtered the remaining parts of pancreas  Kept the pancreatectomized dog, Marjorie, alive several months by injections of the isolated substance "isletin" Banting FG, Best CH, Macleod JJR. Am J Physiol. 1922;59:479. Best, Banting, and one of the dogs
  • 6. The first (human) patient treated with insulin Leonard Thompson (1908 – 1935) Dying from diabetes, he was the first human to get the extract in January 1922 Survived until the age of 27. Banting FG, Best CH, Macleod JJR. Am J Physiol. 1922;59:479.
  • 7. A much-acknowledged contribution The 1923 Nobel prize in medicine or physiology was awarded to FREDERICK GRANT BANTING JOHN JAMES RICKARD MACLEOD “for the discovery of insulin.” Banting shared his prize money with Charles Best while Mcleod shared his with James Collip
  • 8. T1DM – insulin
  • 9. Impact of insulin on microvascular complications in T1DM Decrease in retinopathy with 2% ∆ in HbA1c Percentage of patients 60 Conventional treatment Mean reduction 76% (95% CI, 62 – 85%) P < 0.001 50 40 30 20 Intensive treatment 10 0 0 1 2 3 4 5 6 7 8 9 Follow-up (years) Conventional Intensive 375 342 220 202 DCCT Research Group. N Engl J Med. 1993;329:977-986. 79 78 52 49
  • 10. Impact of insulin on macrovascular complications in T1DM Cumulative incidence of predefined cardiovascular events in the Diabetes Control and Complications Trial (DCCT–EDIC) Cumulative incidence of nonfatal MI, stroke or death from CVD 0.06 57% risk reduction in non-fatal MI, stroke or CVD death (intensive vs. conventional; P = 0.02) Conventional treatment 0.04 Intensive treatment 0.02 0.00 0 1 2 3 4 5 6 7 8 9 DCCT (intervention period) Years since entry At risk Intensive 705 Conventional 721 10 11 12 13 14 15 16 17 18 19 20 21 EDIC (observational follow-up) 686 694 640 637 DCCT/EDIC Study Research Group. N Engl J Med. 2005; 353:2643-2653. 118 96 Years
  • 11. T2DM – a variety of drugs GI Pancreas Sulphonylurea Incretins Incretins α-glucosidase inhibitors Liver Metformin Insulin Insulin Glucose Metformin Thiazolidinediones Thiazolidinediones Muscle and adipose tissue
  • 12. Insulin in T2DM – why?  Restores insulin deficit in dysglycemia  Improved buffering of glucose changes by reducing the need for pancreatic insulin  Reduces toxic pro-oxidant effects of hyperglycemia  Anti-inflammatory, vasodilatory & antithrombotic effects  Improves endothelial repair & dysfunction
  • 13. Impact of glucose-lowering drugs on vascular endpoints in T2DM UKPDS. Lancet. 1998;352:837-853.
  • 14. Impact of glucose-lowering drugs on vascular endpoints in T2DM Randomized to intensive or conventional therapy (N = 4,209) SU or insulin (n = 2,729) Conventional (primarily diet) (n = 1,138) Metformin (n = 342) Available follow-up (n = 2,118) Available follow up (n = 880) Available follow up (n = 239) UKPDS. Lancet. 1998;352:837-853.
  • 15. Impact of intensive glucose lowering on microvascular complications Decrease in microvascular complications with 0.9% ∆ in HbA1c 50 Mean reduction 76% (95% CI, 62 – 85%) P < 0.001 40 30 20 10 0 30% 30 Conventional 60 Intensive 0 1 2 3 4 5 6 7 Follow-up (years) 8 Percentage of patients with event % of patients with an event Percentage of patients Decrease in retinopathy with 2% ∆ in HbA1c Conventional Intensive p=0.0099 20% 20 P = 0.0099 Conventional 10% 10 RiskIntensive reduction 25% (95% CI: 7% to 40%) 0% 0 9 DCCT Research Group. N Engl J Med. 1993;329:977-986. 0 0 3 6 9 12 3 6 9 12 Years from randomisation 15 15 Years from randomization UKPDS. Lancet. 1998;352:837-853.
  • 16. Impact of glucose-lowering drugs on macrovascular endpoints in T2DM Glycaemic control and macrovascular disease: Beneficial start UKPDS. Lancet. 1998;352:837-853.
  • 17. Impact of glucose-lowering drugs on macrovascular endpoints in T2DM UKPDS – 10-year follow-up Glycemic control (HbA1c) during follow up Between group difference in HbA1c lost after the first years Holman RR, et al. N Engl J Med. 2008;359:1577-1589.
  • 18. Impact of glucose-lowering drugs on macrovascular endpoints in T2DM UKPDS – 10-year follow-up All-cause mortality Sulphonylurea–insulin Holman RR, et al. N Engl J Med. 2008;359:1577-1589. Metformin
  • 19. Impact of glucose-lowering drugs on macrovascular endpoints in T2DM UKPDS – patient characteristics UKPDS. Lancet. 1998;352:837-853.
  • 20. Impact of glucose-lowering drugs on macrovascular endpoints in T2DM UKPDS – patient characteristics Medication Diuretic BP lowering ASA Lipid-lowering UKPDS. Lancet. 1998;352:837-853. % 13 12 1.5 0.3
  • 21. Impact of glucose-lowering drugs on macrovascular endpoints in T2DM The PROACTIVE study: pioglitazone vs. placebo as add-on therapy 1° endpoint: death, MI/ACS, stroke, leg amputation, coronary or leg revascularization 20 Pioglitazone (514 events) 15 10 5 Proportion of events (%) Proportion of events (%) 25 10% RRR HR (95% CI) = 0.90 (0.80 –1.02) Placebo P = 0.095 (572 events) 25 2° endpoint: death, MI or stroke 20 Placebo (358 events) 16% RRR HR (95% CI) = 0.84 (0.72 – 0.98) P = 0.027 15 10 Pioglitazone (301 events) 5 0 0 0 6 12 18 24 30 36 0 12 18 24 30 36 Time from randomization Time from randomization Number at risk Number at risk Pioglitazone Placebo 6 2,488 2,530 2,373 2,413 2,302 2,317 2,218 2,215 2,146 2,122 348 345 Dormandy JA, et al. Lancet. 2005;366:1279-1289. Pioglitazone Placebo 2,536 2,566 2,487 2,504 2,435 2,442 2,381 2,371 2,336 2,315 396 390
  • 22. Impact of glucose-lowering drugs on macrovascular endpoints in T2DM Glycaemic control and macrovascular disease: Beneficial start, subsequent doubts ACCORD ADVANCE VADT
  • 23. Impact of glucose-lowering drugs on macrovascular endpoints in T2DM  T2DM at high risk (CVD or risk factors); N = 10,251  Glycaemic control  Intensive HbA1c < 6.0% vs. conventional HbA1c 7.0 – 7.9%  Impact on cardiovascular morbidity and mortality Primary outcome until end of study Death from any cause until end of study HR (95% CI) = 0.91 (0.81 – 1.03) Standard 80 10 60 Intensive 0 40 0 1 2 3 4 5 6 7 8 20 0 100 20 0 Participants with events (%) Participants with events (%) 100 HR (95% CI) = 1.19 (1.03 – 1.38) 20 Intensive 80 10 Standard 60 40 0 0 1 2 3 4 5 6 7 8 20 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 Years since randomization Years since randomization The ACCORD Study Group. N Engl J Med. 2011;364:818-828.
  • 24. Impact of glucose-lowering drugs on macrovascular endpoints in T2DM The ACCORD Study Group. N Engl J Med. 2011;364:818-828.
  • 25. Impact of intensive glucose-lowering on macrovascular complications in T2DM Meta-analysis of five major trials UKPDS, PROACTIVE, ADVANCE, VADT, ACCORD Nonfatal MI OR (95% CI) = 0.83 (75 – 0.93) All-cause mortality OR (95% CI) = 1.02 (0.87 – 1.19) Mean HbA1c difference intensive vs. standard = 0.9% Ray KK, et al. Lancet. 2009;373:1765-1772.
  • 26. Impact of intensive glucose-lowering on macrovascular complications in T2DM Meta-analysis of four major trials UKPDS, ADVANCE, VADT, ACCORD Turnbull FM, et al. Diabetologia. 2009;52:2288-2298.
  • 27. Impact of insulin on macrovascular complications in T2DM (and IGT) In high-risk people with IFG, IGT or early diabetes, does insulin replacement therapy targeting fasting normoglycemia (< 5.3 mM or 95 mg/dL) with insulin glargine, reduce CV outcomes more than standard approaches to dysglycemia? ORIGIN Trial Investigators. N Engl J Med. 2012;367:319-328.
  • 28. Impact of insulin on macrovascular complications in T2DM (and IGT) 8.0 FPG (mmol/L) 7.5 6.9 7.0 6.5 Glargine IQR 5.7 – 7.9 Standard 6.6 6.8 6.9 6.0 5.5 5.0 5.2 4.5 5 4.0 0 1 2 5.1 5 IQR 4.4 – 5.8 3 4 5.1 5.2 5.2 5.3 Penultimate 5 6 Year ORIGIN Trial Investigators. N Engl J Med. 2012;367:319-328. 7 End
  • 29. Impact of insulin on macrovascular complications in T2DM (and IGT) Fasting glucose at study end Insulin 5.3 mmol/L Standard care 6.8 mmol/L ORIGIN Trial Investigators. N Engl J Med. 2012;367:319-328.
  • 30. Safety of glucose-lowering drugs in T2DM Potential problem Avoid or reconsider Weight gain SUs, glinides, TZDs, insulin Gastrointestinal Biguanides, α-glucosidase inhibitors Hypoglycemia SUs, glinides, insulin Kidney dysfunction Biguanides, SUs Hepatic dysfunction Glinides, TZDs, biguanides, α-glucosidase inhibitors Cardiovascular concerns Biguanides, TZDs Rydén L, et al. Eur Heart J. 2007;28:88-136.
  • 31. Safety of glucose-lowering drugs Pio- and rosiglitazone and heart failure Odds ratio (95%CI) Rosi Pio Total Favours 1 TZD Hernandez AV, et al. Am J Cardiovasc Drugs. 2011;11:115-128. 2 Placebo 4
  • 32. Safety of glucose-lowering drugs Rosiglitazone and CVD events Nissen SE, Wolski K. N Engl J Med. 2007;356:2457-2471.
  • 33. Safety of glucose-lowering drugs Rosiglitazone and CVD events Nissen SE, Wolski K. N Engl J Med. 2007;356:2457-2471.
  • 34. Strict demands on cardiovascular safety of glucose-lowering drugs U.S. Food and Drug Administration FDA News FOR IMMEDIATE RELEASE December 17, 2008 Consumer Inquiries: 888-INFO-FDA FDA Announces New Recommendations on Evaluating Cardiovascular Risk in Drugs Intended to Treat Type 2 Diabetes The U.S. Food and Drug Administration recommended today that Manufacturers developing new drugs and biologics for type 2 diabetes provide evidence that the therapy will not increase the risk of such cardiovascular events as a heart attack. The recommendation is part of a new guidance for industry that applies to all diabetes drugs currently under development.
  • 35. Safety of glucose-lowering drugs: rosi- vs. pioglitazone  Systematic review and meta-analysis of 16 observational studies comparing risk of cardiovascular outcomes for  Rosiglitazone (N = 429,000) and  Pioglitazone (N = 381,000) in patients with T2DM during 105 days – 7 years Loke YK, et al. BMJ. 2011;342:d1309.
  • 36. Safety of glucose-lowering drugs: rosi- vs. pioglitazone Myocardial infarction Loke YK, et al. BMJ. 2011;342:d1309. Heart failure Overall mortality
  • 37. Safety of glucose-lowering drugs: rosi- vs. pioglitazone The TIDE Trial Investigators. Diabetologia. 2012;55:36-45.
  • 38. Safety of glucose-lowering drugs: rosi- vs. pioglitazone The TIDE Trial Investigators. Diabetologia. 2012;55:36-45.
  • 39. Insulin – potential drawbacks Smith U, Gale AM. Diabetologia. 2009;52:1699-1708.
  • 40. Insulin – potential drawbacks Hemkens LG, et al. Diabetologia. 2009;52:1732-1744. Jonasson JM, et al. Diabetologia. 2009;52:1745-1754.
  • 41. Impact of insulin on cancer in T2DM Glargine n (%) Rate Standard n (%) Rate HR (95%CI) P Cancer death 0.94 (0.77 – 1.15) 0.52 189 (3.0) 0.51 201 (3.2) 0.54 Any cancer 1.00 (0.88 – 1.13) 0.97 476 (7.6) 1.32 477 (7.6) 1.32 Lung 1.21 (0.87 – 1.67) 0.27 80 (1.3) 0.22 66 (1.1) 0.18 Colon 1.09 (0.79 – 1.51) 0.61 76 (1.2) 0.21 70 (1.1) 0.19 Breast 1.01 (0.60 – 1.71) 0.95 28 (0.4) 0.08 28 (0.4) 0.08 Prostate 0.94 (0.70 – 1.26) 0.70 88 (2.1) 0.36 89 (2.2) 0.38 Melanoma 0.88 (0.44 – 1.75) 0.71 15 (0.2) 0.04 17 (0.3) 0.05 Other 0.95 (0.80 – 1.14) 0.59 233 (3.7) 0.64 245 (3.9) 0.67 Any skin 1.02 (0.78 – 1.33) 0.88 110 (1.8) 0.30 108 (1.7) 0.29 1 ORIGIN Trial Investigators. N Engl J Med. 2012;367:319-328. 10
  • 42. Safety of glucose-lowering drugs Pioglitazone and bladder cancer Kaiser Permanente diabetes registry On pioglitazone 193,099 30,173 HR for bladder cancer Overall Treated > 24 months Lewis JD, et al. Diabetes Care. 2011;34:916-922. 1.2 (95% CI, 0.9 – 1.5) 1.5 (95% CI, 1.03 – 2.0)
  • 43. Effects of established glucose-lowering drugs on cardiovascular risk Some reflections  Strict glycaemic control in the presence of multifactorial therapy (lipids, blood pressure etc) less rewarding!  The impact of glycaemic control perhaps more apparent if instituted in early dysglycaemia?  Are patients without apparent CVD more sensitive to glycaemic control?  Legacy effect may be important – is follow up still too short?  Hypoglycaemia and weight gain do not fully explain lack of effect!  Some glucose-lowering drugs may cause harm alone or when combined!  Insulin safe at least if given to strict glycaemic targets
  • 44. Which patients are we studying? Mortality in DIGAMI 2 25 ♦ ♦ Percent 20 2-year mortality 18.4% Predicted mortality 22.3% ♦ ♦ 15 Total study mortality 21.3% 10 5 0 0 200 400 600 800 Follow-up time (days) Malmberg K, Rydén L, et al. Eur Heart J. 2005;26:650-661. 1,000 1,200
  • 45. Which patients are we studying? Events in ACCORD and ADVANCE related to DIGAMI 2 ACCORD ADVANCE Standard Intensive Years of follow-up Cumulative incidence (%) Patients with events (%)  F/u median 3.4 years  1° outcome: MI, stroke, CV death  F/u median 5 years  1° outcome: major macro- and microvascular events Standard Intensive HR (95% CI) = 0.90 (0.82 – 0.98) P = 0.01 Months of follow-up ADVANCE Collaborative Group. N Engl J. Med. 2008;358:2560-2572. ACCORD Study Group. N Engl J Med. 2008;358:2545-2559.
  • 46. Effects of established glucose-lowering drugs on cardiovascular risk From the Swedish PCI registry STEMI + DM Mortality (%) 25 NSTEMI + DM 20 STEMI – no DM Stable AP + DM 15 NSTEMI – no DM 10 Stable AP – no DM 5 0 0 1 2 3 4 5 6 Years after PCI Norhammar A, et al. EuroIntervention. 2010;5:891-897. doi:10.4244/.
  • 47. Effects of established glucose-lowering drugs on cardiovascular risk One-year mortality (%) One-year mortality following MI: Sweden 1994 – 2010 Diabetes No diabetes Norhammar A, et al. Heart. 2007;93:1577-1583; SWEDEHEART 2011 Annual Report. www.ucr.uu.se/swedeheart/.../178-swedeheart-annual-report-2011-english
  • 48. Effects of established glucose-lowering drugs on cardiovascular risk One-year mortality (%) One-year mortality following MI: Sweden 1994 – 2010 One-year mortality DIGAMI 2 ♦ Diabetes No diabetes Norhammar A, et al. Heart. 2007;93:1577-1583; SWEDEHEART 2011 Annual Report. www.ucr.uu.se/swedeheart/.../178-swedeheart-annual-report-2011-english
  • 49. Effects of multifactorial treatment of T2DM on cardiovascular risk Proportionate contribution of treatment components applying UKPDS risk score in STENO–2 intensive arm HbA1c 13% Blood pressure 11% Smoking 3% Courtesy: P. Gaede. Lipids 73% Total cholesterol 48% HDL-cholesterol 25%
  • 50. T2DM – more than hyperglycaemia Dysglycaemia Oxidative stress AGEs oxLDL PAF-acetylhydrolase Endothelial dysfunction vWF tPA antigen Adhesion molecules ET–1, NO β-cell dysfunction Insulin resistance T2DM/CVD GH system Hypercoagulability IGF–I IGFBP–1 IBFBP–3 PAI–1 Fibrinogen Antithrombin activity Inflammation hsCRP IL–1 IL–6 TNF–α MMPs CD40–lig PAI–1 Adipokines Dyslipidemia Small dense LDL HDL FFAs Triglycerides ApoB, ApoA–1
  • 51. Targets for the balanced PPAR α/γ agonist aleglitazar Dyslipidemia ↑ HDL 21% ↓ Triglycerides 43% ↓ LDL 10% Shift to fewer and larger particles! Glycemic control ↓ HbA1c 0.85% ↓ FPG 2.16 mmol/L ↓ HOMA–IR 35% Henry RR, et al. Lancet. 2009;374:126-135. Inflammation and thrombolysis/ fibrinolysis ↓ hs-CRP 40% ↓ Fibrinogen 10% ↓ PAI–1 6% Hypertension ↓ Blood pressure 1 – 3 mmHg
  • 52. Effects of GLP–1 on various tissues Baggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157.
  • 53. Trials with GLP–1 analogs and DPP–4 inhibitors OR (95%CI) Monami M. et al. Curr Med Res Opin. 2011;27:57-64.
  • 54. Trials with GLP–1 analogs and DPP–4 inhibitors Ongoing trials with CV endpoints Acronym Type Drug Leader Exscel ELIXA SAVOR–TIMI 53 TECOS CAROLINA EXAMINE GLP–1 GLP–1 GLP–1 DPP–4 inhibitor DPP–4 inhibitor DPP–4 inhibitor DPP–4 inhibitor Liraglutide Exenatide Lixisenatide Saxagliptin Sitagliptin Linagliptin Alogliptin Monami M. et al. Curr Med Res Opin. 2011;27:57-64. OR (95%CI)
  • 55. Effects of established glucose-lowering drugs on cardiovascular risk Conclusions  Strict glycaemic control protects from microvascular complications  Glucose target in established T2DM remains uncertain  Available drugs may be less well suited for cardioprotection  Individualized multifactorial management important
  • 56. Effects of established glucose-lowering drugs on cardiovascular risk  Conclusions  Strict glycaemic control protects from ies t eg microvascular complications stra ntrol  Glucose target and co ls in established T2DM t oo olic remains uncertain ab New o-met  Available drugs may d!!!less well suited c be !! glu ede or f for cardioprotection ne  Individualized multifactorial management important