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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. Banting FG. Edin Med J. 1929;36:1-18. 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
5. Best, Banting, and one of the dogs 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.
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. Decrease in retinopathy with 2% Δ in HbA1c Impact of insulin on microvascular complications in T1DM DCCT Research Group. N Engl J Med. 1993;329:977-986. Conventional treatment Intensive treatment Mean reduction 76% (95% CI, 62 – 85%) P < 0.001 Percentage of patients Follow-up (years) Conventional 375 220 79 52 Intensive 342 202 78 49 0 1 2 3 4 5 6 7 8 9 50 60 30 40 10 20 0
10. Cumulative incidence of predefined cardiovascular events in the Diabetes Control and Complications Trial (DCCT–EDIC) Years since entry At risk Intensive 705 686 640 118 Conventional 721 694 637 96 Impact of insulin on macrovascular complications in T1DM 57% risk reduction in non-fatal MI, stroke or CVD death (intensive vs. conventional; P = 0.02) Intensive treatment Cumulative incidence of nonfatal MI, stroke or death from CVD Conventional treatment 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Years 0.06 0.04 0.02 0.00 DCCT (intervention period) EDIC (observational follow-up) DCCT/EDIC Study Research Group. N Engl J Med. 2005; 353:2643-2653.
11. Liver Pancreas Muscle and adipose tissue Insulin Insulin Sulphonylurea Incretins Metformin Thiazolidinediones α-glucosidase inhibitors Incretins Metformin Thiazolidinediones Glucose GI T2DM – a variety of drugs
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. 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) Impact of glucose-lowering drugs on vascular endpoints in T2DM UKPDS. Lancet. 1998;352:837-853.
15. Impact of intensive glucose lowering on microvascular complications Decrease in retinopathy with 2% Δ in HbA1c Follow-up (years) Conventional Intensive Mean reduction 76% (95% CI, 62 – 85%) P < 0.001 Percentage of patients 0 1 2 3 4 5 6 7 8 9 50 60 30 40 10 20 0 p=0.0099 0% 10% 20% 30% 0 3 6 9 12 15 % of patients with an event Years from randomisation Intensive Conventional Risk reduction 25% (95% CI: 7% to 40%) Percentage of patients with event Years from randomization 0 3 6 9 30 10 20 0 12 15 P = 0.0099 Conventional Intensive Decrease in microvascular complications with 0.9% Δ in HbA1c DCCT Research Group. N Engl J Med. 1993;329:977-986. UKPDS. Lancet. 1998;352:837-853.
16. Impact of glucose-lowering drugs on macrovascular endpoints in T2DM UKPDS. Lancet. 1998;352:837-853. Glycaemic control and macrovascular disease: Beneficial start
17. 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. Impact of glucose-lowering drugs on macrovascular endpoints in T2DM
18. UKPDS – 10-year follow-up All-cause mortality Holman RR, et al. N Engl J Med. 2008;359:1577-1589. Impact of glucose-lowering drugs on macrovascular endpoints in T2DM Sulphonylurea–insulin Metformin
19. UKPDS – patient characteristics Impact of glucose-lowering drugs on macrovascular endpoints in T2DM UKPDS. Lancet. 1998;352:837-853.
20. UKPDS – patient characteristics Impact of glucose-lowering drugs on macrovascular endpoints in T2DM UKPDS. Lancet. 1998;352:837-853. Medication % Diuretic 13 BP lowering 12 ASA 1.5 Lipid-lowering 0.3
21. The PROACTIVE study: pioglitazone vs. placebo as add-on therapy 1° endpoint: death, MI/ACS, stroke, leg amputation, coronary or leg revascularization 2° endpoint: death, MI or stroke Impact of glucose-lowering drugs on macrovascular endpoints in T2DM Dormandy JA, et al. Lancet. 2005;366:1279-1289. Number at risk Pioglitazone 2,488 2,373 2,302 2,218 2,146 348 Placebo 2,530 2,413 2,317 2,215 2,122 345 5 10 15 25 0 6 20 0 12 18 24 30 36 Pioglitazone (514 events) 10% RRR HR (95% CI) = 0.90 (0.80 –1.02) P = 0.095 Placebo (572 events) Time from randomization Proportion of events (%) 5 10 15 25 0 6 20 0 12 18 24 30 36 Pioglitazone (301 events) Placebo (358 events) Time from randomization Proportion of events (%) 16% RRR HR (95% CI) = 0.84 (0.72 – 0.98) P = 0.027 Number at risk Pioglitazone 2,536 2,487 2,435 2,381 2,336 396 Placebo 2,566 2,504 2,442 2,371 2,315 390
22. Glycaemic control and macrovascular disease: Beneficial start, subsequent doubts ACCORD ADVANCE VADT Impact of glucose-lowering drugs on macrovascular endpoints in T2DM
23. 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 0 20 40 60 80 100 0 20 40 60 80 100 0 10 20 0 10 20 Years since randomization Years since randomization Participants with events (%) Participants with events (%) HR (95% CI) = 1.19 (1.03 – 1.38) HR (95% CI) = 0.91 (0.81 – 1.03) Primary outcome until end of study Death from any cause until end of study Standard Intensive Intensive Standard The ACCORD Study Group. N Engl J Med. 2011;364:818-828. 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
24. The ACCORD Study Group. N Engl J Med. 2011;364:818-828. Impact of glucose-lowering drugs on macrovascular endpoints in T2DM
25. Nonfatal MI OR (95% CI) = 0.83 (75 – 0.93) All-cause mortality OR (95% CI) = 1.02 (0.87 – 1.19) Meta-analysis of five major trials UKPDS, PROACTIVE, ADVANCE, VADT, ACCORD Mean HbA1c difference intensive vs. standard = 0.9% Impact of intensive glucose-lowering on macrovascular complications in T2DM Ray KK, et al. Lancet. 2009;373:1765-1772.
26. Impact of intensive glucose-lowering on macrovascular complications in T2DM Turnbull FM, et al. Diabetologia. 2009;52:2288-2298. Meta-analysis of four major trials UKPDS, ADVANCE, VADT, ACCORD
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) 6.9 5.2 5 5 5.1 5.1 5.2 5.2 5.3 6.9 6.6 6.8 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 0 1 2 3 4 5 6 7 End Year FPG (mmol/L) Glargine Standard Penultimate IQR 4.4 – 5.8 IQR 5.7 – 7.9 ORIGIN Trial Investigators. N Engl J Med. 2012;367:319-328.
29. Fasting glucose at study end Insulin 5.3 mmol/L Standard care 6.8 mmol/L Impact of insulin on macrovascular complications in T2DM (and IGT) 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. 1 2 4 Favours TZD Placebo Rosi Pio Total Odds ratio (95%CI) Safety of glucose-lowering drugs Hernandez AV, et al. Am J Cardiovasc Drugs. 2011;11:115-128. Pio- and rosiglitazone and heart failure
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. U.S. Food and Drug Administration Strict demands on cardiovascular safety of glucose-lowering drugs 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 Loke YK, et al. BMJ. 2011;342:d1309. Overall mortality Heart failure Myocardial infarction
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. Glargine Standard HR (95%CI) P n (%) Rate n (%) Rate 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 Impact of insulin on cancer in T2DM 1 10 ORIGIN Trial Investigators. N Engl J Med. 2012;367:319-328.
42. Safety of glucose-lowering drugs Pioglitazone and bladder cancer Lewis JD, et al. Diabetes Care. 2011;34:916-922. Kaiser Permanente diabetes registry 193,099 On pioglitazone 30,173 HR for bladder cancer Overall 1.2 (95% CI, 0.9 – 1.5) Treated > 24 months 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. 2-year mortality 18.4% Predicted mortality 22.3% 5 10 15 20 25 0 200 400 600 Follow-up time (days) ♦ ♦ ♦ ♦ Total study mortality 21.3% 800 1,000 1,200 Which patients are we studying? Malmberg K, Rydén L, et al. Eur Heart J. 2005;26:650-661. Percent 0 Mortality in DIGAMI 2
45. Which patients are we studying? ACCORD §  F/u median 3.4 years §  1° outcome: MI, stroke, CV death ADVANCE §  F/u median 5 years §  1° outcome: major macro- and microvascular events ADVANCE Collaborative Group. N Engl J. Med. 2008;358:2560-2572. ACCORD Study Group. N Engl J Med. 2008;358:2545-2559. Events in ACCORD and ADVANCE related to DIGAMI 2 Years of follow-up Months of follow-up Patients with events (%) Cumulative incidence (%) Standard Intensive Standard Intensive HR (95% CI) = 0.90 (0.82 – 0.98) P = 0.01
46. Effects of established glucose-lowering drugs on cardiovascular risk Norhammar A, et al. EuroIntervention. 2010;5:891-897. doi:10.4244/. 20 25 15 10 5 0 Mortality (%) 0 1 2 3 4 5 6 Years after PCI STEMI + DM NSTEMI + DM STEMI – no DM Stable AP + DM NSTEMI – no DM Stable AP – no DM From the Swedish PCI registry
47. One-­‐year  mortality  (%)   Effects of established glucose-lowering drugs on cardiovascular risk 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 One-year mortality following MI: Sweden 1994 – 2010
48. Effects of established glucose-lowering drugs on cardiovascular risk ♦ One-year mortality DIGAMI 2 Diabetes No diabetes One-­‐year  mortality  (%)   One-year mortality following MI: Sweden 1994 – 2010 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 Courtesy: P. Gaede. Smoking 3% Blood pressure 11% HbA1c 13% Total cholesterol 48% Lipids 73% HDL-cholesterol 25% Proportionate contribution of treatment components applying UKPDS risk score in STENO–2 intensive arm
50. T2DM/CVD Inflammation hsCRP IL–1 IL–6 TNF–α MMPs CD40–lig PAI–1 Adipokines Dyslipidemia Small dense LDL HDL FFAs Triglycerides ApoB, ApoA–1 Hypercoagulability PAI–1 Fibrinogen Antithrombin activity GH system IGF–I IGFBP–1 IBFBP–3 Dysglycaemia β-cell dysfunction Insulin resistance Oxidative stress AGEs oxLDL PAF-acetylhydrolase Endothelial dysfunction vWF tPA antigen Adhesion molecules ET–1, NO T2DM – more than hyperglycaemia
51. Inflammation and thrombolysis/ fibrinolysis ↓ hs-CRP 40% ↓ Fibrinogen 10% ↓ PAI–1 6% Hypertension ↓ Blood pressure 1 – 3 mmHg Glycemic control ↓ HbA1c 0.85% ↓ FPG 2.16 mmol/L ↓ HOMA–IR 35% Dyslipidemia ↑ HDL 21% ↓ Triglycerides 43% ↓ LDL 10% Shift to fewer and larger particles! Targets for the balanced PPAR α/γ agonist aleglitazar Henry RR, et al. Lancet. 2009;374:126-135.
52. Effects of GLP–1 on various tissues Baggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157.
53. OR (95%CI) Trials with GLP–1 analogs and DPP–4 inhibitors Monami M. et al. Curr Med Res Opin. 2011;27:57-64.
54. OR (95%CI) Ongoing trials with CV endpoints Acronym Type Drug Leader GLP–1 Liraglutide Exscel GLP–1 Exenatide ELIXA GLP–1 Lixisenatide SAVOR–TIMI 53 DPP–4 inhibitor Saxagliptin TECOS DPP–4 inhibitor Sitagliptin CAROLINA DPP–4 inhibitor Linagliptin EXAMINE DPP–4 inhibitor Alogliptin Trials with GLP–1 analogs and DPP–4 inhibitors Monami M. et al. Curr Med Res Opin. 2011;27:57-64.
55. 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 Effects of established glucose-lowering drugs on cardiovascular risk
56. §  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 New tools and strategies for gluco-metabolic control needed!!!!! Effects of established glucose-lowering drugs on cardiovascular risk