Clinical Benefits of Lipid-Lowering Therapy in CAD With vs Without Familial Hypercholesterolemia

familial hypercholesterolemia
Patients with familial hypercholesterolemia were found to get more clinical benefits than those with CAD for comparable reductions in LDL-c.

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.

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