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. FPG (mmol/L) HbA 1C (%) 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 0.006 <0.001 0.015 Gaede P et al. NEJM 2003;348:383-93 Evidence base for multiple risk factor intervention: the STENO-2 study

5. Hazard ratio and 95% CI Cardiovascular disease Autonomic neuropathy Retinopathy Nephropathy 00.20.40.60.81.0 Gaede P et al. NEJM 2003;348:383-93 STENO-2 study: Clinical outcomes

6. Gaede P, et al. NEJM 2003; 348: 383-93 STENO-2 study: Residual CV risk

7. Risk factors for coronary artery disease Potentially modifiablep  LDL cholesterol<0.0001  HDL cholesterol 0.0001  HbA 1C 0.0022  Systolic blood pressure 0.0065  Smoking 0.056 Stepwise selection of major risk factors for 280 coronary artery disease events in 2,693 UKPDS patients followed for 10 years 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. Approaches to CVD prevention in diabetes Lipid modification Lifestyle intervention BP lowering Glucose lowering Optimal CV risk Reduction ?

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

11. Drug Therapy Primary Indication Statins Dyslipidaemia Antihypertensives Blood pressure Oral antidiabetics Glucose control Long-acting insulins Glucose control Frequently used therapies in diabetes

12. Key findings from recent lipid- lowering trials 200220032004 2005 HPS Benefit in CVD and DM regardless of baseline LDL-C ASCOT-LLA Benefit in high-risk HTN regardless of baseline LDL-C CARDS Benefit in DM TNT Benefit of intensive vs moderate lipid lowering in stable CAD ALLHAT-LLT Neutral effect in HTN with mild lipid lowering PROVE IT-TIMI 22 Early and late benefit of intensive vs moderate lipid lowering in ACS Primary prevention Secondary prevention (ACS) Secondary prevention (stable CAD) 4D Neutral effect in ESRD A to Z Late benefit of intensive vs moderate lipid lowering in ACS IDEAL Benefit of intensive vs moderate lipid lowering in stable CAD

13. Statins reduce all-cause death: Meta-analysis of 14 trials CTT Collaborators. Lancet. 2005;366:1267-78 Cause of death 3.4 0.81 0.91 0.95 0.93 Vascular causes: Stroke Other vascular Any vascular Any non-CHD vascular 0.6 1.2 4.7 2.4 0.2 0.1 1.1 3.8 8.5 9.7 4.0 1.2 0.1 0.3 2.4 5.7 1.3 0.7 0.6 4.4 Nonvascular causes: Cancer Respiratory 0.83 1.01 0.82 0.89 0.87 0.95 0.88 Trauma Other/unknown Any nonvascular Any death Events (%) Treatment (n = 45,054) Control (n = 45,002) Treatment better Control better 1.51.00.5 CHD Relative risk

14. Benefits of aggressive LDL-C lowering in diabetes 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. Difference in LDL-C (mg/dL) Aggressive lipid- lowering better Aggressive lipid- lowering worse 0.026 0.036 0.001 <0.0001 0.0003 Primary event rate (%) 17.9 11.9 9.0 12.6 13.5 Control 13.8 9.2 5.8 9.4 9.3 Treatment 0.63 0.67 0.73 P TNT Diabetes, CHD ASCOT-LLA Diabetes, HTN CARDS Diabetes, no CVD HPS All diabetes Diabetes, no CVD * Atorvastatin 10 vs 80 mg/day † Statin vs placebo Relative risk 0.70.910.5 1.7 0.77 22* 35 † 46 † 39 † 0.75

15. CARDS: cumulative hazard for any CVD endpoint Relative Risk = -32% (95% CI -45, -15) p=0.001 Years 306 287 663 621 1040 992 1337 1275 1372 1334 Atorva Placebo 1428 1410 Placebo 189 events Atorvastatin 134 events Cumulative Hazard (%) 0 5 10 15 20 012344.75 Colhoun H.M. et.al. Lancet 2004; 364: 685-696

16. Key findings from recent BP-lowering trials 2002200320042005 ALLHAT Benefit regardless of drug class INVEST CCB + ACEI equivalent to  -blocker + diuretic in hypertension + CAD VALUE Importance of prompt BP control ASCOT-BPLA Benefit of CCB + ACEI vs  -blocker + diuretic in high-risk hypertension without CAD CAMELOT Evidence for  BP goal in hypertension + CAD  -blocker meta- analysis Increased risk of stroke vs other antihypertensives

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

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

20. Risk reduction in UKPDS 75 An intensive glucose control policy HbA 1c 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. UKPDS 34: Intensive glucose control and CV protection UKPDS Group. Lancet. 1998;352:854-65. n = 1704 overweight, with diabetes; n = 342 metformin group Favors metformin or intensive Favors usual care All-cause mortality Metformin Intensive Myocardial infarction Metformin Intensive Stroke Metformin Intensive 0.02 0.12 0.08 Aggregate endpointsP* 012 *Metformin vs other intensive therapy (sulfonylurea or insulin) Relative risk (95% CI)