Dublin, Ireland—The development of atherosclerosis is believed to be linked to the accumulation of LDL-C in vessel walls. Based on that, most guidelines call for aggressive lowering of LDL-C levels with statins (3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors).

A new international study published in the Journal of the American Medical Association Internal Medicine calls into question the conventional wisdom that the lower the LDL-C level, the better.

Irish researchers from RCSI University of Medicine in Dublin and colleagues performed a meta-analysis to try to determine the association between statin-induced reductions in LDL-C levels and the absolute and relative reductions in individual clinical outcomes, such as all-cause mortality, myocardial infarction (MI), or stroke.

Reviewing 21 randomized clinical trials in primary and secondary prevention that examined the efficacy of statins in reducing total mortality and cardiovascular outcomes, the study team uncovered significant heterogeneity, but also reductions, in the absolute risk of 0.8% for all-cause mortality, 1.3% for MI and 0.4% for stroke in those randomized to treatment with statins compared with control. That translated to relative risk reductions of 9%, 29%, and 14%, respectively.

The authors cautioned that a meta-regression was inconclusive regarding the association between the magnitude of statin-induced LDL-C reduction and all-cause mortality, MI, or stroke.

“The study results suggest that the absolute benefits of statins are modest, may not be strongly mediated through the degree of LDL-C reduction, and should be communicated to patients as part of informed clinical decision-making as well as to inform clinical guidelines and policy,” the study concluded.

Among the goals of the meta-analysis was to facilitate shared decision-making between clinicians and patients and inform clinical guidelines and policy, according to the authors who searched PubMed and Embase to identify eligible trials from January 1987 to June 2021.

Meta-analyses showed reductions in the absolute risk of 0.8% (95% CI, 0.4%-1.2%) for all-cause mortality, 1.3% (95% CI, 0.9%-1.7%) for MI, and 0.4% (95% CI, 0.2%-0.6%) for stroke in those randomized to treatment with statins, with associated relative risk reductions of 9% (95% CI, 5%-14%), 29% (95% CI, 22%-34%), and 14% (95% CI, 5%-22%), respectively. A meta-regression exploring the potential mediating association of the magnitude of statin-induced LDL-C reduction with outcomes was inconclusive.

The researchers noted that many trials looking at the use of statins to lower LDL used relative risk reduction (RRR) measures. “Reported RRRs in composite outcomes may be associated with reductions in potentially subjective outcomes, such as revascularization or hospitalization, the frequency of which may depend on opinions or preferences of the attending physician, rather than more objective outcomes (e.g., all-cause mortality, myocardial infarction [MI], or stroke), leading to misleading impressions of the effect of treatment,” they explained. “Hence, an analysis focusing on hard, singular endpoints (total mortality, MI, and stroke) is less susceptible to bias.”

The problem is, the authors added, “Reporting the reduction in cardiovascular outcomes as RRR without reporting the corresponding absolute risk reduction (ARR) has the potential to inflate the clinical importance of an intervention and may exaggerate trivial associations.”

The meta-analysis used studies assessing ARRs and RRRs from treatment with statins in hard outcomes, such as all-cause mortality, MI, and stroke, as well as exploring the association between LDL-C reduction and statin treatment effects.

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