Risk factors for atherosclerotic cardiovascular disease in individuals with heterozygous familial hypercholesterolemia: a systematic review and meta-analysis.

Familial hypercholesterolemia (FH) is a highly prevalent monogenic disorder characterized by elevated low-density lipoprotein-cholesterol (LDL-C) levels and premature atherosclerotic cardiovascular disease (ASCVD). The risk factors associated with cardiovascular events in this population vary considerably among studies. This systematic review aims to identify the key risk factors predicting cardiovascular events in patients with a confirmed genetic diagnosis of heterozygous FH (PROSPERO, CRD42022304273). Cochrane Library, Embase, MEDLINE, Scopus, UpToDate and other literature databases were searched from inception to June 2023. Records were eligible if they included studies reporting risk factors for ASCVD endpoints in adult patients with a genetic diagnosis of FH. A meta-analysis was performed using MetaEasy. A total of 21 studies were identified, involving 23,613 individual participants and 3489 prevalent cardiovascular events. The sex distribution was 47.2% male and 52.8% female. Most of the studies were conducted in European populations, representing 90.5% of the total. The meta-analysis found associations between ASCVD and hypertension (effect size 0.414; 95% CI: 0.346-0.482), male sex (0.334; 0.213-0.456), smoking (0.324; 0.203-0.445), lipoprotein(a) (0.219; 0.127-0.312), age (0.212; 0.161-0.264), body mass index (0.108; 0.028-0.188), triglycerides (0.084; 0.057-0.111) and LDL-C (0.015; 0.002-0.028). This is the first systematic review and meta-analysis demonstrating that hypertension, male sex, smoking, lipoprotein(a), age, body mass index, triglycerides and LDL-C are significantly and independently associated with ASCVD in genetically confirmed patients with heterozygous FH. These data can inform risk stratification models and optimise therapy in such patients.