1. Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner TA, Pedersen TR, Kjekshus J, Pyorala K for the 4S Group Reduced Coronary Events in Simvastatin-Treated Subjects with CHD and Diabetes or Impaired Fasting Glucose: Subgroup Analyses in the Scandinavian Simvastatin Survival Study Arch Intern Med 1999;159:2661-2667

2. Expanded 4S Diabetes Analysis Diabetes Mellitus by HistoryDiabetes Mellitus by History –202 Subjects (Original 4S Diabetes Subgroup) FG > 126 mg/dl, but No History of DiabetesFG > 126 mg/dl, but No History of Diabetes –281 Subjects Impaired Fasting Glucose (FG 110-125 mg/dl)Impaired Fasting Glucose (FG 110-125 mg/dl) –678 Subjects Normal (FG < 110 mg/dl)Normal (FG < 110 mg/dl) –3,237 Subjects Haffner SM, et al. Arch Intern Med 1999;159:2661-2667

3. Rationale & Goals Rationale New ADA Diagnostic Criteria for DM (FG > 126 mg/dl)New ADA Diagnostic Criteria for DM (FG > 126 mg/dl) New Category of IFG (FG 110-125 mg/dl)New Category of IFG (FG 110-125 mg/dl)Goals Confirm previous dataConfirm previous data Perform analysis of 4S subjects with IFGPerform analysis of 4S subjects with IFG Haffner SM, et al. Arch Intern Med 1999;159:2661-2667

4. Baseline Characteristics NormalIFGDM-FGDM - Hx n3237678281202 Age59595960 Male (%)80848978 SBP138139141147 Tot-C261261261259 LDL-C189189186189 HDL-C46454444 TG130137142153 FG95117136175 Haffner SM, et al. Arch Intern Med 1999;159:2661-2667

5. Percent Change in Lipids and Lipoproteins in 4S Haffner SM, et al. Arch Intern Med 1999;159:2661-2667

6. Incidence of Major CHD Events by Glucose Status in the 4S Placebo Group NFG(n=1631)IFG(n=335)DM-FG(n=135)DM-history(n=97) Baseline Glucose Status Haffner SM, et al. Arch Intern Med 1999;159:2661-2667

7. 4S ~ Major Coronary Heart Disease Events RR = 0.68 0.62 0.58 p value = <0.001 0.003 0.001 n = 1631/1606 335/343 232/251 Haffner SM, et al. Arch Intern Med 1999;159:2661-2667

8. 4S & Revascularizations RR = 0.67 0.57 0.52 p value = <0.001 0.01 0.005 n = 1631/1606 335/343 232/251 Haffner SM, et al. Arch Intern Med 1999;159:2661-2667

9. 4S ~ Total Mortality RR = 0.72 0.57 0.79 p value = 0.005 0.02 0.34 n = 1631/1606 335/343 232/251 Haffner SM, et al. Arch Intern Med 1999;159:2661-2667

10. IFG Subjects (n=678) 0.00.20.40.60.81.01.21.4 Relative Risk MCE Revascularization Tot Mortality CHD Mortality p=0.003 p=0.009 p=0.02 p=0.007 0.62 0.57 0.57 0.45 Haffner SM, et al. Arch Intern Med 1999;159:2661-2667

11. Diabetic Subjects (n=483) 0.00.20.40.60.81.01.21.4 Relative Risk MCE Revascularization Tot Mortality CHD Mortality p=0.001 p=0.005 p=0.34 p=0.26 0.58 0.52 0.79 0.72 Haffner SM, et al. Arch Intern Med 1999;159:2661-2667

12. Major CHD Events Major CHD Events NFG Simvastatin NFG Placebo IFG Simvastatin IFG Placebo DM Simvastatin DM Placebo Arch Intern Med 1999;159:2661-2667

13. Effects of Simvastatin on Major Coronary Events by Glucose Status Stratified by Level of Lipid Parameters Arch Intern Med 1999;159:2661-2667

14. Absolute and Relative Risk Benefit of Simvastatin Therapy by Glucose Status for Major Coronary Events NFGIFGDM Simvastatin group, No. (%) 299/1606 (18.6) 67/343 (19.5) 59/251 (23.5) Placebo group, No. (%) 428/1631 (26.2) 102/335 (30.5) 87/232 (37.5) Relative risk 0.680.620.58 P relative risk<0.0010.0030.001 Absolute benefit (Kaplan-Meier year 6 estimate) 8.02/100 cases 12.11/100 cases 13.85/100 cases 6 estimate) 8.02/100 cases 12.11/100 cases 13.85/100 cases Number needed to treat1287 Haffner SM, et al. Arch Intern Med 1999;159:2661-2667

15. Summary - Diabetes Mellitus Higher event rate in diabetes group, by history, compared to other groupsHigher event rate in diabetes group, by history, compared to other groups In combined DM group (by history and fasting glucose):In combined DM group (by history and fasting glucose): –Major Coronary Events were reduced by 42% (p=0.001) –Revascularizations were reduced by 48% (p=0.005) Total and coronary mortality were reduced, but reductions not significant due to small sample sizeTotal and coronary mortality were reduced, but reductions not significant due to small sample size Haffner SM, et al. Arch Intern Med 1999;159:2661-2667

16. Summary - Impaired Fasting Glucose Reduced total mortality by 43% (p=0.02)Reduced total mortality by 43% (p=0.02) Reduced coronary mortality by 55% (p=0.007)Reduced coronary mortality by 55% (p=0.007) Reduced major coronary events by 38% (p=0.003)Reduced major coronary events by 38% (p=0.003) Reduced the need for revascularization procedures by 43% (p=0.009)Reduced the need for revascularization procedures by 43% (p=0.009) Haffner SM, et al. Arch Intern Med 1999;159:2661-2667

17. ConclusionsConclusions This analysis confirms and extends the benefit of cholesterol lowering with simvastatin in an expanded cohort of patients with diabetes and overt CHDThis analysis confirms and extends the benefit of cholesterol lowering with simvastatin in an expanded cohort of patients with diabetes and overt CHD CHD patients with impaired fasting glucose (FG 110 to 125 mg/dL) benefit from treatment with simvastatin by significant & substantial reductions in total and coronary mortality, major CHD events and revascularizations.CHD patients with impaired fasting glucose (FG 110 to 125 mg/dL) benefit from treatment with simvastatin by significant & substantial reductions in total and coronary mortality, major CHD events and revascularizations. Haffner SM, et al. Arch Intern Med 1999;159:2661-2667