Patients with familial hypercholesterolemia (FH) were found to get more clinical benefits than those with coronary artery disease (CAD) for comparable reductions in low-density lipoprotein cholesterol (LDL-c) concentrations, according to a study published in Atherosclerosis.

A total of 4444 patients (mean age, 58 years; 80% men) with established CAD and hypercholesterolemia not receiving lipid-lowering therapies were recruited for this study. Patients with LDL-c ≥ 4.9 mmol/L who also had premature CAD and a history of CAD, were considered as having FH. Patients were randomly assigned at a 1:1 ratio to receive simvastatin (20 mg daily; n=2221) or placebo (n=2223) and were assessed for major coronary events (MCE) or death at a median follow-up of 5.4 years.

Of participants receiving simvastatin, 37% had their dose increased to 40 mg due to high cholesterol (ie, LDL-c >5.2 mmol/L) at 3 or 6 months.

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Participants receiving simvastatin vs placebo had reductions in total cholesterol, LDL-c (38% after 1 year; 34-35% at 5 years), and triglycerides, and increased high-density lipoprotein cholesterol (P <.0001 for all).

Participants receiving simvastatin vs placebo with low and high baseline LDL-c concentrations (ie, <4.9 and ³4.9 mmol/L, respectively) had a reduced risk for: major coronary events (MCE) at the follow-up (low LDL-c: hazard ratio [HR], 0.67; 95% CI, 0.56-0.80; P <.0001; high LDL-c: HR, 0.65; 95% CI, 0.55-0.78; P <.0001), cardiovascular death (low LDL-c: HR, 0.69; 95% CI, 0.50-0.95; P =.0231; high LDL-c: HR, 0.58; 95% CI, 0.37-0.92; P =.0008), and coronary heart disease death (low LDL-c: HR, 0.63; 95% CI, 0.45-0.89; P =.079; high LDL-c: HR, 0.53; 95% CI, 0.38-0.74; P =.0001).

Patients with high LDL-c were stratified into 4 groups: no premature CAD or family history or CAD (n=926), premature CAD without family history of CAD (n=469), no premature CAD but with family history of CAD (n=617), and both premature and family history of CAD (n=152).

Patients with FH who received simvastatin had the greatest reduction in risk for MCE (-13.2%; HR, 0.45; 95% CI, 0.22-0.92; P =.0297) and all-cause mortality (-6.6%; HR, 0.16; 95% CI, 0.03-0.97; P =.0464) compared with all other groups.

Study limitations include the fact that it was a post-hoc analysis of a randomized clinical trial, and was not prespecified in the original study design.

“[I]n individuals with CAD, those with an LDL-C ≥4.9 mmol/L and FH phenotype appear to associate greater relative and absolute benefits from LDL-C reduction than individuals with LDL-C ≥4.9 mmol/L without FH phenotype from the same magnitude of LDLC lowering,” concluded the study authors.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Vallejo-Vaz A J, Packard C J, Ference B A, et al. LDL-cholesterol lowering and clinical outcomes in hypercholesterolemic subjects with and without a familial hypercholesterolemia phenotype: Analysis from the secondary prevention 4S trial. Atherosclerosis. 2021;320:1-9. doi:10.1016/j.atherosclerosis.2021.01.003