Benefits of intensive multiple risk factor intervention

1. Benefits of intensive multiple risk factor intervention

2. Potential benefits of multifactorial approaches Adherence to multiple therapies is more likely if initiated simultaneously Early aggressive therapy targeting multiple risk factors could potentially have a major impact on CVD prevention Chapman RH et al. Arch Intern Med. 2005;165:1147-1152. Wald NJ, Law MR. BMJ. 2003;326:1419.

3. MRFIT: CVD mortality by diabetes status and number of baseline risk factors Stamler J et al. Diabetes Care 1993;16:434-443

4. Evidence base for multiple risk factor intervention: the STENO-2 study FPG (mmol/L) HbA1C (%) SBP (mmHg) DBP (mmHg) Tot-C (mmol/L) LDL-C (mmol/L) TG (mmol/L) Conventional –1.0 +0.2 –3 –8 +0.2 –0.3 +0.1 Intensive –2.9 –0.5 –14 –12 –1.1 –1.2 –0.5 p <0.001 <0.001 <0.001 0.006 <0.001 <0.001 0.015 Gaede P et al. NEJM2003;348:383-93

5. STENO-2 study: Clinical outcomes Cardiovascular disease Autonomic neuropathy Retinopathy Nephropathy 0 0.2 0.4 0.6 0.8 1.0 Hazard ratio and 95% CI Gaede P et al. NEJM2003;348:383-93

6. Intensive Risk Management in Patients With Diabetes 60 P = 0.007 Conventional Therapy 50 Hazard ratio = 0.47 (95 percent CI., 0.24 to 0.73; P = 0.008) 40 Primary Composite End Point* (%) 30 20 Intensive therapy 10 24 36 48 0 12 60 72 84 96 Months of Follow-up *From nonfatal MI, CABG, PCI, nonfatal stroke, amputation, or surgery for PAD . STENO-2 study: Residual CV risk Gaede P, et al. NEJM 2003; 348: 383-93

7. Risk factors for coronary artery disease Stepwise selection of major risk factors for 280 coronaryartery disease events in 2,693 UKPDS patients followed for 10 years • Potentially modifiable p • LDL cholesterol <0.0001 • HDL cholesterol 0.0001 • HbA1C 0.0022 • Systolic blood pressure 0.0065 • Smoking 0.056 Age and gender were also significant risk factors but not body mass index, fasting plasma insulin, waist/hip ratio or microalbuminuria Turner RC et al. BMJ 1998;316:823-8

8. Summary • Type 2 diabetes is characterised by a complex and evolving pathophysiology • Most patients die from a cardiovascular cause, but microvascular complications are also important • Integrated strategies to control multiple risk factors are crucial to improve patient outcomes

9. Lipidmodification Lifestyle intervention Optimal CV risk Reduction ? Glucose lowering BPlowering Approaches to CVD prevention in diabetes

10. The prevention of CV complications: a complex and multifactorial problem CV complications start to develop early in disease course Complications are usually already present at diagnosis Patients routinely underestimate their own CV risk The problem Patients pick and choose which pills to take Abnormal insulin sensitivity, haemostasis, BP, vascular function, weight, lipids, all drive adverse outcomes Dysfunctional microcirculation andmacrocirculation

11. Frequently used therapies in diabetes

12. IDEAL Benefit of intensive vs moderate lipid lowering in stable CAD ASCOT-LLABenefit in high-risk HTN regardless of baseline LDL-C CARDSBenefit in DM ALLHAT-LLTNeutral effect in HTN with mild lipid lowering 4DNeutral effect in ESRD 2002 2003 2004 2005 HPS Benefit in CVD and DM regardless of baseline LDL-C PROVE IT-TIMI 22Early and late benefit of intensive vs moderate lipid lowering in ACS TNTBenefit of intensive vsmoderate lipid loweringin stable CAD A to ZLate benefit of intensive vs moderate lipid lowering in ACS Primary prevention Secondary prevention (ACS) Secondary prevention (stable CAD) Key findings from recent lipid-lowering trials

13. Cause of death Events (%) Treatment(n = 45,054) Control(n = 45,002) Treatment better Controlbetter Vascular causes: 3.4 4.4 CHD 0.81 0.6 0.91 Stroke 0.6 0.6 0.95 Other vascular 0.7 Any non-CHD vascular 1.2 1.3 0.93 Any vascular 4.7 5.7 0.83 Nonvascular causes: 2.4 2.4 1.01 Cancer Respiratory 0.2 0.3 0.82 0.1 Trauma 0.1 0.89 Other/unknown 1.1 1.2 0.87 Any nonvascular 3.8 4.0 0.95 8.5 Any death 9.7 0.88 0.5 1.0 1.5 Relative risk Statins reduce all-cause death: Meta-analysis of 14 trials CTT Collaborators. Lancet. 2005;366:1267-78

14. Benefits of aggressive LDL-C lowering in diabetes Primary event rate (%) Aggressive lipid-lowering better Aggressive lipid-lowering worse Difference in LDL-C(mg/dL) Treatment Control P TNT Diabetes, CHD ASCOT-LLA Diabetes, HTN CARDS Diabetes, no CVD HPS All diabetes Diabetes, no CVD 13.8 9.2 5.8 9.4 9.3 17.9 11.9 9.0 12.6 13.5 0.026 0.036 0.001 <0.0001 0.0003 22* 35† 46† 39† 39† 0.75 0.77 0.63 0.73 0.67 0.5 0.7 0.9 1 1.7 Relative risk * Atorvastatin 10 vs 80 mg/day † Statin vs placebo Shepherd J et al. Diabetes Care 2006; Sever PS et al. Diabetes Care 2005; HPS Collaborative Group. Lancet 2003; Colhoun HM et al. Lancet 2004.

15. CARDS: cumulative hazard for any CVD endpoint 20 15 10 5 0 0 1 2 3 4 4.75 Relative Risk = -32% (95% CI -45, -15) p=0.001 Placebo 189 events Atorvastatin 134 events Cumulative Hazard (%) Years 1334 1275 Placebo 1410 992 621 287 1428 1372 1337 Atorva 1040 663 306 Colhoun H.M. et.al. Lancet 2004; 364: 685-696

16. Key findings from recent BP-lowering trials INVESTCCB + ACEIequivalent to -blocker + diuretic in hypertension + CAD ASCOT-BPLABenefit of CCB + ACEI vs -blocker + diureticin high-risk hypertension without CAD ALLHATBenefit regardless of drug class VALUEImportanceof promptBP control 2002 2003 2004 2005 CAMELOTEvidence for  BP goal in hypertension+ CAD -blocker meta-analysisIncreased risk of stroke vs other antihypertensives

17. p=0.04 All-causemortality No diabetes Diabetes p=0.02 No diabetes CV mortality Diabetes p=0.01 No diabetes CV events Diabetes Favours treatment 0 -0.5 0.5 Adjusted hazard ratio Greater benefit from hypertension control in type 2 diabetes: Syst-Eur study p values comparediabetic vs. non-diabetic Tuomilehto J et al. N Engl J Med 1999;340:677-84

18. Risk reductions from intervention studies in type 2 diabetes Clinical Outcomes Diabetes-related deaths (%) All-cause mortality (%) All MI (%) Fatal MI (%) All stroke (%) Fatal stroke (%) Follow-up (years) UKPDS Captopril Atenolol n=1148 32 18 21 28 44 58 8.4 HOPE Ramipril n=3577 37 24 22 - 33 - 4.5 HOT Felodipine Aspirin n=1501 67 43 51 - 30 - 3.8 4S Simva-statin n=202 36 43 55 - 62 - 5.4 UKPDS Group. BMJ 1998; 317: 713-20; HOT Study Group. Lancet 1998; 351(9118): 1755-62; 4S Group. Lancet 1994; 344: 1383-89; HOPE study investigators. Lancet 2000; 355; 253-59.

19. Targets for glycaemic control ADA (USA)1 IDF (Europe)2 AACE (USA)3 HbA1C (%) < 7 < 6.5 < 6.5 FPG (mmol/L) < 6.7 (120)* < 6.0 (110)* < 6.0 (110)* *mg/dL 1American Diabetes Association. Diabetes Care 1999; 22(Suppl 1):S1-S114; 2European Diabetes Policy Group. Diabetic Medicine 1999;16:716-30; 3American Association of Clinical Endocrinologists. Endocrine Pract (2002) 8(Suppl. 1):40-82

20. Risk reduction in UKPDS 75 An intensive glucose control policy HbA1c 7.0 % vs 7.9 % reduces risk of • any diabetes-related endpoints 12% p=0.030 • microvascular endpoints 25% p=0.010 • myocardial infarction 16% p=0.052 A tight BP control policy 144 / 82 vs 154 / 87 mmHg reduces risk of • any diabetes-related endpoint 24% p=0.005 • microvascular endpoint 37% p=0.009 • stroke 44% p=0.013 Stratton IM et al. Diabetologia 2006; 1761-9

21. n = 1704 overweight, with diabetes; n = 342 metformin group Aggregate endpoints Favors metforminor intensive Favors usual care P* All-cause mortality Metformin Intensive Myocardial infarction Metformin Intensive Stroke Metformin Intensive 0.02 0.12 0.08 0 1 2 Relative risk(95% CI) *Metformin vs other intensive therapy (sulfonylurea or insulin) UKPDS 34: Intensive glucose control and CV protection UKPDS Group. Lancet. 1998;352:854-65.