Association Between LDL-C Reduction and Effects of Statin Treatment

Mar 15, 2022
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Authors:
Byrne P, Demasi M, Jones M, et al.
Citation:
Evaluating the Association Between Low-Density Lipoprotein Cholesterol Reduction and Relative and Absolute Effects of Statin Treatment: A Systematic Review and Meta-Analysis. JAMA Intern Med 2022;Mar 14:[Epub ahead of print].
Summary By:
Melvyn Rubenfire, MD, FACC

Quick Takes

  • In this meta-analysis of about 120,000 participants in 21 heterogeneous statin trials, the absolute benefits of statins are modest for both primary and secondary prevention. There was not a clear relationship between absolute reduction in LDL-C and all-cause mortality. Use of the data to inform patients may be more harmful than good.
  • The results are in conflict with the many studies, which have shown that the use of statin and nonstatin therapies that increase LDL-C receptor activity to reduce LDL-C are associated with similar relative reduction of major cardiovascular events per change in LDL-C.
  • The 20% risk reduction per 40 mg/dL decrease in LDL-C from statin and nonstatin treatments was derived from a meta-analysis conducted by the Cholesterol Treatment Trialists’ (CTT) Collaboration, which had individual LDL-C data from 170,000 participants in 26 randomized trials not available in this meta-analysis.
  • The all-cause mortality in the CTT study was reduced by 10% per 40 mg/dL in LDL-C reflecting the decrease in death due to coronary heart disease and other cardiac causes with no effect on deaths due to stroke. And there were no significant effects of death from cancer and no increase in cancer incidence even at low LDL-C levels.

Study Questions:

What is the association between absolute reduction in low-density lipoprotein cholesterol (LDL-C) levels by statin therapy and all-cause mortality, myocardial infarction (MI), and stroke?

Methods:

Meta-analyses and a meta-regression were performed of large randomized clinical trials from January 1966–June 2021 designed to assess the effect of statins versus placebo or usual care on cardiovascular outcomes and reported absolute change in LDL-C.

Results:

Twenty-one trials with at least 1,000 participants were included of which 33% were primary prevention, 29% secondary, and 38% combined. Trial size ranged from 1,255–20,536 patients with follow-up average 4.4 years (range 1.9-6.1 years). Achieved LDL-C differences ranged from 17–68 mg/dL. Meta-analyses showed reductions in the absolute risk was 0.6% for all-cause mortality, 0.7% for MI, and 0.3% for stroke in primary prevention and 0.9%, 2.2%, and 0.7%, respectively, in secondary prevention. The relative risk reduction was 13% for all-cause mortality, 38% for MI, and 24% for stroke in primary prevention and 14%, 27%, and 13%, respectively, in secondary prevention. A meta-regression exploring the potential mediating association of the magnitude of statin-induced LDL-C reduction with outcomes was inconclusive.

Conclusions:

Absolute risk reductions of treatment with statins in terms of all-cause mortality, MI, and stroke are modest compared with the relative risk reductions. A conclusive association between absolute reductions in LDL-C levels and individual clinical outcomes was not established, and these findings underscore the importance of discussing absolute risk reductions when making informed clinical decisions with individual patients.

Perspective:

The concept of the physician discussing absolute risk reduction and relative risk reduction for each of several cardiovascular events for primary or secondary prevention with each patient may have merit. But in fact, the physician cannot predict the risk of events for individual patients for either primary or secondary prevention. What percent of patients who are statin eligible by the guidelines would take a medication with a 5-10% risk of muscle aches, about 5-10 per 1,000 risk for diabetes, and 5-10 per 10,000 risk for hemorrhagic stroke with <1 in 100 chance of having the wanted effect? Including studies through a 50-year period during which cardiovascular risk factors and nonlipid treatments have changed and the intensity of statins have changed has a profound effect on meta-analysis.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Vascular Medicine, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Cholesterol, LDL, Diabetes Mellitus, Dyslipidemias, Heart Disease Risk Factors, Hemorrhagic Stroke, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipids, Myocardial Infarction, Primary Prevention, Risk Factors, Risk Reduction Behavior, Secondary Prevention, Stroke, Vascular Diseases


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