Major adverse cardiovascular events in homozygous familial hypercholesterolaemia: a systematic review and meta-analysis

Abstract

Aims Homozygous familial hypercholesterolaemia (HoFH) is a genetic condition characterized by extremely elevated levels of low-density lipoprotein cholesterol and premature atherosclerotic cardiovascular disease and death. Due to its rarity, accurate assessment of cardiovascular outcomes associated with HoFH and how they have changed over time has been challenging. The goal of this study was to assess the prevalence and age-of-onset of major adverse cardiovascular events (MACE) among patients with HoFH. Methods and results We searched MEDLINE, EMBASE, Pubmed, Cochrane Central Register of Controlled Trials, Scopus, Africa-Wide, Google Scholar, Open Grey, and various clinical trial registries from inception to February 2020 to identify studies reporting on MACE in HoFH patients. We determined the pooled prevalence and mean age-of-onset of MACE outcomes individually using a random effects inverse variance model. We identified 94 studies that met our eligibility criteria. Myocardial infarction and coronary revascularization were common with a prevalence of 15.1% [95% confidence interval (95% CI) 10.7–20.0] and 28.3% (95% CI 22.5–34.3), respectively. The mean age-of-onset was 24.5 (95% CI 19.2–29.8) years for myocardial infarction and 32.2 (95% CI 26.6–37.8) years for revascularization. Sub-group analyses based on the year of publication revealed significant delays in the onset of MACE outcomes post-1990 compared to pre-1990. Egger’s regression suggested possible bias, likely due to small study effects. Conclusions Atherosclerotic cardiovascular disease is common among HoFH patients and occurs at a young age. Age-of-onset of myocardial infarction was delayed by more than a decade from pre-1990 to post-1990, likely attributable to widespread use of statins and other therapies, reflecting substantial progress in the management of this rare but severe disorder.

Inclisiran—A Revolutionary Addition to a Cholesterol-Lowering Therapy

“…The safety and efficacy of inclisiran were also assessed in patients with homozygous familial hypercholesterolemia (HoFH) in the ORION-5 study [ 95 , 96 ]. The disease, as a consequence of mutations in LDLR , APOB , or PCSK9 genes inherited from both parents, is characterized by extremely elevated LDL-C levels and, subsequently, high risk for premature cardiovascular diseases [ 97 , 98 ]. Participants who met the inclusion criteria were randomly assigned to receive either a dose of 300 milligrams of inclisiran or a placebo.…”

Current Treatment Options in Homozygous Familial Hypercholesterolemia

“…However, the effect of all these conventional agents is not sufficient to achieve adequate LDL-C reduction, and more effective add-on LLTs are required in most cases. Moreover, a recent meta-analysis of 94 studies conducted on HoFH patients showed that the age-onset of major adverse cardiovascular events has been delayed 11 years in the post-1990 compared to the pre-1990 era, but the prevalence of ASCVD has not changed, emphasizing the need for new treatment approaches on top of conventional LLT [ 17 ].…”

Sex Differences in Diagnosis, Treatment, and Cardiovascular Outcomes in Homozygous Familial Hypercholesterolemia

“…Variants in 3 of the causal genes— LDLR , APOB , and PCSK9 —display autosomal semidominant inheritance, while variants in the LDLRAP1 gene underlie a rare recessive form of HoFH . The cumulative LDL-C burden is substantial from birth onwards, giving rise to a very high risk of premature atherosclerotic cardiovascular disease (ASCVD) . Patients with HoFH may already experience an ASCVD event before reaching adulthood or before the condition is diagnosed and treatment can be initiated .…”