What did the Heart Protection Study find about daily simvastatin 40 mg lowering low‑density lipoprotein cholesterol and reducing major vascular events across all subgroups (men, women, with or without prior cardiovascular disease, and diabetics)?

Heart Protection Study: LDL-Cholesterol Management Summary

The Heart Protection Study demonstrated that simvastatin 40 mg daily reduces major vascular events by 24% across all patient subgroups—including men, women, diabetics, and those with or without prior cardiovascular disease—regardless of baseline LDL-cholesterol levels, even when LDL-C was below 100 mg/dL. 1, 2

Trial Design and Dose

• 20,536 high-risk adults (aged 40-80 years) were randomized to simvastatin 40 mg daily versus placebo for a mean follow-up of 5 years 1, 2
• The trial achieved an average LDL-C reduction of 1.0 mmol/L (approximately 39 mg/dL), representing a 25-30% decrease from baseline 1, 3, 2
• Baseline population included patients with coronary disease (65%), diabetes (29%), cerebrovascular disease (16%), and peripheral arterial disease (33%) 4, 2

Mortality and Major Cardiovascular Outcomes

• All-cause mortality was reduced by 13% (p=0.0003), with 1,328 deaths in the simvastatin group versus 1,507 in placebo 1
• Coronary death rate decreased by 18% (587 vs 707 deaths; p=0.0005) 1
• Major vascular events (composite of MI, coronary death, stroke, or revascularization) were reduced by 24% (19.8% vs 25.2%; p<0.0001) 1, 2
• Nonfatal MI plus coronary death fell by 27% (p<0.0001) 1
• Stroke (fatal or nonfatal) was reduced by 25% (4.3% vs 5.7%; p<0.0001) 1
• Cardiovascular revascularization procedures decreased by 24% (p<0.0001) 1

Universal Benefit Across All Subgroups

Baseline LDL-Cholesterol Levels

The critical finding: benefit was consistent regardless of baseline LDL-C, including patients with very low cholesterol levels. 1

• Relative risk reductions were similar for patients with baseline LDL-C ≥135 mg/dL, <116 mg/dL, or <100 mg/dL 1
• Even among 3,421 patients (17%) with baseline LDL-C below 100 mg/dL, simvastatin produced significant benefit 4, 2
• Among patients with both low LDL-C (<116 mg/dL) and low CRP (<1.25 mg/L), major vascular events were reduced by 27% (p<0.0001) 5

Important caveat: LDL-C was measured directly (non-fasting) at baseline, yielding a mean of 131 mg/dL; if calculated by the Friedewald equation (standard clinical practice), baseline LDL-C would have been approximately 150-155 mg/dL—about 15% higher 1, 3

Sex and Age

• Similar event reductions occurred in both men and women, despite women comprising only 18% of the study population 1
• Benefit was consistent in participants under and over 70 years of age at entry 1

Diabetes Subgroup Analysis

Among 5,963 diabetic patients (29% of cohort), simvastatin produced particularly robust benefits: 1

• First-event rates for major coronary events, strokes, and revascularizations were reduced by approximately 25%, similar to non-diabetic patients 1
• In 2,912 diabetic patients without diagnosed coronary or other occlusive arterial disease, simvastatin reduced risk by approximately one-third (33%) 1
• Among 2,426 diabetic participants with baseline LDL-C <116 mg/dL, event rates were 27% lower on simvastatin 1
• In diabetic patients without vascular disease and with LDL-C <116 mg/dL, a marginally significant 30% risk reduction was observed 1

Cardiovascular Disease Subtypes

• Benefit extended to patients without diagnosed coronary disease who had cerebrovascular disease, peripheral artery disease, or diabetes 1
• Among 3,280 patients with prior cerebrovascular disease, simvastatin reduced major vascular events by 20% (p=0.001), though stroke recurrence itself was not significantly reduced 1, 6
• In 6,748 patients with peripheral arterial disease, simvastatin reduced major vascular events by 22% (p<0.0001) and peripheral vascular events by 16% 1, 7

Safety Profile

No significant adverse effects were reported over 5 years of treatment: 1

• No significant increase in myopathy (annual excess risk approximately 0.01%) 2
• No increase in cancer incidence 1
• No increase in hospitalization for any other non-vascular cause 1
• No significant increase in hemorrhagic stroke overall (51 simvastatin vs 53 placebo; rate ratio 0.95; p=0.8) 6

Common pitfall to avoid: The SPARCL trial (atorvastatin 80 mg in stroke patients) showed increased hemorrhagic stroke risk (2.3% vs 1.4%), but HPS with simvastatin 40 mg did not demonstrate this effect 1

Clinical Significance and Implications

• The benefit was not significant during the first year, but became highly significant by the end of the second year and remained so throughout follow-up 2, 6
• Absolute risk reduction: Simvastatin prevented approximately 63 major vascular events per 1,000 patients with PAD and 50 per 1,000 without pre-existing PAD over 5 years 7
• After accounting for 85% compliance in the simvastatin group and 17% statin use in placebo group, actual use of simvastatin 40 mg daily would likely reduce event rates by approximately one-third 2, 6

The HPS established that statin benefit depends primarily on overall cardiovascular risk rather than baseline lipid levels alone, fundamentally changing the paradigm for statin therapy initiation. 1, 3, 2