The Effects of Lowering LDL Cholesterol With Statin Therapy in People at Low Risk of Vascular Disease: Meta-Analysis of Individual Data From 27 Randomized Trials

Study Questions:

What is the net effect of statins in people at low risk of vascular events?

Methods:

This meta-analysis included individual participant data from 22 trials of statin versus control (n = 134,537; mean low-density protein [LDL] cholesterol difference 1.08 mmol/L; median follow-up 4.8 years) and five trials of more versus less statin (n = 39,612; difference 0.51 mmol/L; 5.1 years). Major vascular events were major coronary events (i.e., nonfatal myocardial infarction or coronary death), strokes, or coronary revascularizations. Participants were separated into five categories of baseline 5-year major vascular event risk on control therapy (no statin or low-intensity statin) (<5%, ≥5% to <10%, ≥10% to <20%, ≥20% to <30%, ≥30%); in each, the rate ratio (RR) per 1.0 mmol/L LDL cholesterol reduction was estimated.

Results:

Reduction of LDL cholesterol with a statin reduced the risk of major vascular events (RR, 0.79; 95% confidence interval [CI], 0.77-0.81; per 1.0 mmol/L reduction), largely irrespective of age, sex, baseline LDL cholesterol or previous vascular disease, and of vascular and all-cause mortality. The proportional reduction in major vascular events was at least as big in the two lowest risk categories as in the higher risk categories (RR per 1.0 mmol/L reduction from lowest to highest risk: 0.62 [99% CI, 0.47-0.81], 0.69 [99% CI, 0.60-0.79], 0.79 [99% CI, 0.74-0.85], 0.81 [99% CI, 0.77-0.86], and 0.79 [99% CI, 0.74-0.84]; trend p = 0.04), which reflected significant reductions in these two lowest risk categories in major coronary events (RR, 0.57; 99% CI, 0.36-0.89; p = 0.0012, and 0.61, 99% CI, 0.50-0.74; p < 0.0001) and in coronary revascularizations (RR, 0.52; 99% CI, 0.35-0.75; and 0.63, 99% CI, 0.51-0.79; both p < 0.0001). For stroke, the reduction in risk in participants with 5-year risk of major vascular events lower than 10% (RR per 1.0 mmol/L LDL cholesterol reduction, 0.76; 99% CI, 0.61-0.95; p = 0.0012) was also similar to that seen in higher risk categories (trend, p = 0.3). In participants without a history of vascular disease, statins reduced the risks of vascular (RR per 1.0 mmol/L LDL cholesterol reduction, 0.85; 95% CI, 0.77-0.95) and all-cause mortality (RR, 0.91; 95% CI, 0.85-0.97), and the proportional reductions were similar by baseline risk. There was no evidence that reduction of LDL cholesterol with a statin increased cancer incidence (RR per 1.0 mmol/L LDL cholesterol reduction, 1.00; 95% CI, 0.96-1.04), cancer mortality (RR, 0.99; 95% CI, 0.93-1.06), or other nonvascular mortality.

Conclusions:

The authors concluded that in individuals with low risk of major vascular events, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1,000 over 5 years.

Perspective:

The present study suggests that reduction of LDL cholesterol with statin therapy significantly reduced the risk of major vascular events in individuals with 5-year risk lower than 10% even in those with no previous history of vascular disease, diabetes, or chronic kidney disease. Although there was no evidence of any increased risk of death from nonvascular causes or of cancer in those at low risk, several known or potential hazards of statin therapy need to be considered when estimating the net effects of statin therapy in people at lowest risk. Overall data suggest that any long-term effects of any small excesses in hemorrhagic strokes and in diagnoses of diabetes are not associated with long-term effects on major vascular events that are sufficiently large to outweigh the persistent benefits of statin therapy. The current analysis confirms that statins are indeed both effective and safe for people with low risk of major vascular events and that recommendations regarding their use in these individuals may need to be reassessed.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Risk, Stroke, Neoplasms, Myocardial Infarction, Follow-Up Studies, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Vascular Diseases, Cholesterol, Cardiovascular Diseases, Confidence Intervals, Diabetes Mellitus, Renal Insufficiency, Chronic


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