Baseline characteristics of HPS participants by prior diabetes Notes: none

HPS: Baseline lipids (mmol/L) and apolipoproteins (g/L) by prior diabetes Notes: Average lipid levels (mmol/L) at baseline in those with and without diagnosed diabetes.

HPS: Baseline lipids (mg/dL) and apolipoproteins (g/L) by prior diabetes Notes: Average lipid levels (mg/dL) at baseline in those with and without diagnosed diabetes.

HPS: FACTORIAL TREATMENT COMPARISONS Notes: Participants were randomly allocated to receive simvastatin or matching placebo tablets, with the average duration of treatment being 5 years. In addition, using a "2x2 factorial design", half of the patients in each of these groups were randomly allocated to receive vitamins and half were allocated placebo capsules. Assessment of cholesterol-lowering therapy involves comparing the 10,000 allocated active statin versus the 10,000 allocated placebo statin.

HPS: Mean (SE) differences in lipids during follow-up by diabetes Notes: Intention-to-treat comparisons (simvastatin minus placebo) of lipid levels during follow-up in those with and without diabetes. Missing data imputed from initial pretreatment screening values.

SIMVASTATIN: MAJOR CORONARY EVENTS and STROKE by prior DIABETES PLACEBO Rate ratio & 95% CI STATIN better PLACEBO better Vascular event & disease group (10269) (10267) Major coronary events Diabetes 279 377 (9.4%) (12.6%) No diabetes 619 835 (8.5%) (11.5%) All patients 898 1212 (8.7%) (11.8%) 27% SE 4 reduction (2P<0.00001) Strokes 149 193 (5.0%) (6.5%) 295 392 (4.0%) (5.4%) 444 585 (4.3%) (5.7%) 25% SE 5 0.4 0.6 0.8 1.0 1.2 1.4 Notes: Similar proportional reductions are seen both in those with and without diabetes in major coronary events (non-fatal myocardial infarction or coronary death) and in strokes (fatal or non-fatal stroke).

SIMVASTATIN: REVASCULARISATIONS and MAJOR VASCULAR EVENTS by prior DIABETES SIMVASTATIN PLACEBO Rate ratio & 95% CI STATIN better PLACEBO better Vascular event & disease group (10269) (10267) Revascularisations Diabetes 260 309 (8.7%) (10.4%) No diabetes 679 896 (9.3%) (12.3%) All patients 939 1205 (9.1%) (11.7%) 24% SE 4 reduction (2P<0.00001) Major vascular events 601 748 (20.2%) (25.1%) 1432 1837 (19.6%) (25.2%) ALL PATIENTS 2033 2585 (19.8%) 24% SE 3 0.4 0.6 0.8 1.0 1.2 1.4 Notes: Similar proportional reductions in major coronary events, strokes and revascularisation seen in those with and without diabetes yields a very clear effect on the first occurrence of any of these “major vascular events”. The extreme statistical significance of the reduction in the rate of first major vascular event (Z score =9.3), and the large number of events on which it is based, allows reliable assessment of the effects of treatment in various different circumstances.

SIMVASTATIN: MAJOR VASCULAR EVENT by YEAR in DIABETIC PATIENTS Year SIMVASTATIN PLACEBO Rate ratio & 95% CI of follow-up (2978) (2985) STATIN better PLACEBO better 1 143 (4.8%) 141 (4.7%) 2 110 (3.9%) 150 (5.3%) 3 109 (4.0%) 172 (6.5%) 4 101 (3.9%) 138 (5.6%) 5+ 138 (5.7%) 147 (6.4%) 22% SE 5 ALL FOLLOW-UP During the first year after randomisation in participants with diabetes there was little apparent effect of simvastatin allocation on the incidence of first major vascular event, but by year 2 there was a highly significant reduction with similar proportional benefits seen in each separate subsequent year (even though by the end of year 3 about one-sixth of simvastatin allocated participants had stopped their study treatment and about one-sixth of placebo allocated participants had started statin therapy). 601 (20.2%) 748 (25.1%) reduction (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4

SIMVASTATIN: MAJOR VASCULAR EVENTS by YEAR in DIABETIC PATIENTS Years of follow-up PLACEBO SIMVASTATIN Benefit/1000(SE) -1(6) 13(8) 34(9) 47(10) 51(15) 58(48) Logrank p<0.00001 1 2 3 4 5 6 10 15 20 25 30 People suffering events (%) Notes: Life-table plot of the effects of simvastatin allocation on percentage of diabetic patients having a first major vascular event suggests that benefits increase with longer duration of treatment and follow-up.

SIMVASTATIN: MAJOR VASCULAR EVENTS by PRIOR DISEASE & prior DIABETES PLACEBO Rate ratio & 95% CI STATIN better PLACEBO better Prior disease & diabetes (10269) (10267) CHD Diabetes 325 381 (33.4%) (37.8%) No diabetes 1134 1460 (19.8%) (25.7%) Other CVD 141 171 (25.6%) (32.9%) 287 362 (24.4%) No CVD 135 196 (9.3%) (13.5%) ALL PATIENTS 2033 2585 (25.2%) 24% SE 3 reduction (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4 Notes: There were similar proportional reductions in risk of major vascular events in those with and without diabetes irrespective of prior vascular disease. CHD = any coronary heart disease at entry, CVD = any cardiovascular disease at entry.

SIMVASTATIN: MAJOR VASCULAR EVENTS by SEX & prior DIABETES SIMVASTATIN PLACEBO Rate ratio & 95% CI STATIN better PLACEBO better Sex & diabetes (10269) (10267) Male Diabetes 471 580 (22.8%) (27.8%) No diabetes 1195 1555 (21.1%) (27.6%) Female 130 168 (14.2%) (18.6%) 237 282 (14.6%) (17.2%) ALL PATIENTS 2033 2585 (19.8%) (25.2%) 24% SE 3 reduction (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4 Notes: There were similar proportional reductions in risk of major vascular events in men and women, both with and without diabetes.

SIMVASTATIN: MAJOR VASCULAR EVENTS by AGE & prior DIABETES SIMVASTATIN PLACEBO Rate ratio & 95% CI STATIN better PLACEBO better Age & diabetes (10269) (10267) <65 y Diabetes 263 341 (15.7%) (20.1%) No diabetes 568 750 (17.6%) (23.1%)  65 y 338 407 (25.9%) (31.6%) 864 1087 (21.3%) (26.9%) ALL PATIENTS 2033 2585 (19.8%) (25.2%) 24% SE 3 reduction (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4 Notes: There were similar proportional reductions in risk of major vascular events in those with and without diabetes at different ages.

SIMVASTATIN: MAJOR VASCULAR EVENTS by LDL CHOLESTEROL & prior DIABETES PLACEBO Rate ratio & 95% CI STATIN better PLACEBO better LDL cholesterol & diabetes (10269) (10267) <3.0 mmol/L Diabetes 191 252 (15.7%) (20.9%) No diabetes 407 504 (18.8%) (22.9%)  3.0 mmol/L 410 496 (23.3%) (27.9%) 1025 1333 (20.0%) (26.2%) ALL PATIENTS 2033 2585 (19.8%) (25.2%) 24% SE 3 reduction (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4 Notes: There were similar proportional reductions in risk of major vascular events irrespective of various lipid values at baseline, both in those with and those without diabetes.

SIMVASTATIN: MAJOR VASCULAR EVENTS by TRIGLYCERIDES & prior DIABETES PLACEBO Rate ratio & 95% CI STATIN better PLACEBO better Triglycerides & diabetes (10269) (10267) <2.0 mmol/L Diabetes 270 364 (16.8%) (22.8%) No diabetes 831 1068 (18.9%) (24.1%)  2.0 mmol/L 331 384 (27.6%) 601 769 (20.8%) (27.1%) ALL PATIENTS 2033 2585 (19.8%) (25.2%) 24% SE 3 reduction (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4 Notes: There were similar proportional reductions in risk of major vascular events irrespective of various lipid values at baseline, both in those with and those without diabetes.

SIMVASTATIN: MAJOR VASCULAR EVENTS by HDL CHOLESTEROL & prior DIABETES PLACEBO Rate ratio & 95% CI STATIN better PLACEBO better HDL cholesterol & diabetes (10269) (10267) <0.9 mmol/L Diabetes 288 356 (25.9%) (31.1%) No diabetes 530 708 (21.1%) (29.3%)  0.9 mmol/L 313 392 (16.8%) (21.3%) 902 1129 (18.9%) (23.2%) ALL PATIENTS 2033 2585 (19.8%) (25.2%) 24% SE 3 reduction (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4 Notes: There were similar proportional reductions in risk of major vascular events irrespective of various lipid values at baseline, both in those with and those without diabetes.

SIMVASTATIN: MAJOR VASCULAR EVENTS by ApoB/ApoA1 ratio & prior DIABETES SIMVASTATIN PLACEBO Rate ratio & 95% CI STATIN better PLACEBO better ApoB/ApoA1 ratio & diabetes (10269) (10267) <1.0 mmol/L Diabetes 301 382 (16.9%) (21.6%) No diabetes 717 899 (18.3%) (22.9%)  1.0 mmol/L 300 366 (25.2%) (30.1%) 715 937 (21.3%) (27.9%) ALL PATIENTS 2033 2585 (19.8%) 24% SE 3 reduction (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4 Notes: There were similar proportional reductions in risk of major vascular events irrespective of various lipid or apolipoprotein ratios at baseline, both in those with and those without diabetes.

SIMVASTATIN: MAJOR VASCULAR EVENTS by DURATION OF DIABETES Duration (years) SIMVASTATIN PLACEBO Rate ratio & 95% CI (10269) (10267) STATIN better PLACEBO better <6 203 (18.9%) 247 (23.0%)  6 <13 201 (20.8%) 241 (25.6%)  13 197 (21.0%) 259 (26.7%) No diabetes 1432 (19.6%) 1837 (25.2%) 24% SE 3 ALL PATIENTS 2033 (19.8%) 2585 (25.2%) Notes: There were similar proportional reductions in risk of major vascular events irrespective of the duration of diabetes. reduction (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4

SIMVASTATIN: MAJOR VASCULAR EVENTS by TYPE OF DIABETES SIMVASTATIN PLACEBO Rate ratio & 95% CI STATIN better PLACEBO better Type of diabetes (10269) (10267) Type 1 43 53 (13.7%) (17.5%) Type 2 558 695 (20.9%) (25.9%) No diabetes 1432 1837 (19.6%) (25.2%) ALL PATIENTS 2033 2585 (19.8%) 24% SE 3 reduction (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4 Notes: There were similar proportional reductions in risk of major vascular events in those with type 1 as well as type 2 diabetes. However, with only 615 patients having type 1 diabetes, there were only small numbers suffering an event and the confidence intervals around the estimate are wide.

SIMVASTATIN: MAJOR VASCULAR EVENTS by HbA1c PLACEBO Rate ratio & 95% CI STATIN better PLACEBO better HbA1c (%) (10269) (10267) <7.0 294 360 (18.3%) (22.6%)  7.0 301 373 (27.5%) No diabetes 1432 1837 (19.6%) (25.2%) ALL PATIENTS 2033 2585 (19.8%) 24% SE 3 reduction (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4 Notes: There were similar proportional reductions in risk of major vascular events irrespective of the glycaemic control at entry among those with diagnosed diabetes.

SIMVASTATIN: HbA1c (% ± SE) among a sample with DIABETES at entry Notes: HbA1C was measured at entry in those with diagnosed diabetes and in a random sample of 1087 after an average of 4.6 years of follow-up. There was no evidence that allocation to simvastatin had any effect on glycaemic control in these patients.

SIMVASTATIN: Development of DIABETES in patients not known to have diabetes at entry Notes: There was no evidence that allocation to simvastatin reduced the incidence of new diabetes during the trial.

SIMVASTATIN: Change in blood CREATININE (µmol/l ± se) from baseline to 4 years Notes: Creatinine was measured at baseline and in samples collected after an average of 4.6 years of follow-up. Plasma creatinine increased during follow-up, but the increase was significantly smaller among those allocated simvastatin compared with placebo.

HPS: Effects of SIMVASTATIN on first and all major vascular events in those with and without diabetes Notes: Continued treatment reduced the rate not just of the first occurrence of a major vascular event but also of subsequent events. The absolute reductions in the number of major vascular events avoided per 1000 people are more than 50% greater than the number of people per 1000 who avoided such events, both among those with or without diabetes.

Occlusive arterial disease alone Both arterial disease and diabetes Absolute effects of simvastatin allocation on 5-year rates of first major vascular event Risk reductions (SE): Proportional 32.9% (9.1) 24.5% (3.1) 18.4% (5.7) Absolute/1000 44 (12) 62 (8) 66 (21) P-value 0.0003 <0.0001 0.002 40 Diabetes alone Occlusive arterial disease alone Both arterial disease and diabetes 9% 13% 20% 25% 31% 36% S P 30 20 10 S=simvastatin-allocated P=placebo-allocated Proportion with first major vascular event (%) Notes: Similar proportional benefits were observed with allocation to simvastatin among people in different baseline disease categories. The larger absolute benefit seen among participants with diabetes alone may reflect the play of chance on the proportional reduction observed just in that relatively small subgroup. By contrast, estimates of the absolute benefit derived from the more reliably determined overall reduction of one quarter, would suggest that a 1 mmol/L LDL reduction would produce an absolute risk reduction of 30 per 1000 in patients with diabetes alone.

HPS: Conclusions for people with diabetes Lowering LDL cholesterol by 1 mmol/L (40 mg/dL) reduces the risk of major vascular events by about one-quarter during 5 years of treatment Similar proportional reductions in risk among people with or without diabetes ― irrespective of age, sex, vascular disease or lipid levels Continued statin treatment prevents not only first but also subsequent major vascular events Notes: none