Sex differences in treatment of familial hypercholesterolaemia: a meta-analysis

Abstract

Background and aims: Familial hypercholesterolaemia (FH) is a highly prevalent monogenic disorder characterized by elevated LDL cholesterol (LDL-C) levels and premature atherosclerotic cardiovascular disease. Sex disparities in diagnosis, lipid-lowering therapy, and achieved lipid levels have emerged worldwide, resulting in barriers to care in FH. A systematic review was performed to investigate sex-related disparities in treatment, response, and lipid target achievement in FH (PROSPERO, CRD42022353297).

Methods: MEDLINE, Embase, The Cochrane library, PubMed, Scopus, PsycInfo, and grey literature databases were searched from inception to 26 April 2023. Records were eligible if they described sex differences in the treatment of adults with FH.

Results: Of 4432 publications reviewed, 133 met our eligibility criteria. In 16 interventional clinical trials (eight randomized and eight non-randomized; 1840 participants, 49.4% females), there were no differences between males and females in response to fixed doses of lipid-lowering therapy, suggesting that sex was not a determinant of response. Meta-analysis of 25 real-world observational studies (129 441 participants, 53.4% females) found that females were less likely to be on lipid-lowering therapy compared with males (odds ratio .74, 95% confidence interval .66-.85). Importantly, females were less likely to reach an LDL-C < 2.5 mmol/L (odds ratio .85, 95% confidence interval .74-.97). Similarly, treated LDL-C levels were higher in females. Despite this, male sex was associated with a two-fold greater relative risk of major adverse cardiovascular events including myocardial infarction, atherosclerotic cardiovascular disease, and cardiovascular mortality.

Conclusions: Females with FH were less likely to be treated intensively and to reach guideline-recommended LDL-C targets. This sex bias represents a surmountable barrier to clinical care.

Keywords: Atherosclerotic cardiovascular disease; Familial hypercholesterolaemia; Females; Lipid-lowering treatment; Sex differences; Systematic review.

Structured Graphical Abstract

Sex differences in the treatment of familial hypercholesterolaemia: a systematic review and meta-analysis. CI, confidence interval; CVD, cardiovascular disease; FH, familial hypercholesterolaemia; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy; MACE, major adverse cardiovascular events; OR, odds ratio; PCSK9, proprotein convertase subtilisin/kexin type 9; RR, risk ratio.

Figure 1

Preferred Reporting Items for Systematic reviews and Meta-Analyses flow chart of studies included in the systematic review of sex differences in the treatment of familial hypercholesterolaemia. *Seven studies were describing both data on sex differences in the treatment of familial hypercholesterolaemia and cardiovascular disease outcomes in patients with treated familial hypercholesterolaemia. FH, familial hypercholesterolaemia

Figure 2

Mean LDL cholesterol percent reduction in clinical trials included in the systematic review. Asterisks denote studies where participants received progressive escalations of therapy to reach maximal doses. CI, confidence interval; PCSK9, proprotein convertase subtilisin/kexin type 9

Figure 3

Meta-analysis of sex differences in treatment with lipid-lowering therapies in observational studies. Squares represent study-level odds ratios; horizontal lines represent 95% confidence intervals; large square represents pooled odds ratio derived under the random-effects model. CI, confidence interval

Figure 4

Sex differences in LDL cholesterol reductions in males and females in observational studies included in the systematic review of sex differences in the treatment of familial hypercholesterolaemia with lipid-lowering therapies. Panel (A) depicts sex differences in mean LDL cholesterol reduction (mmol/L) reported in observational studies. Panel (B) depicts sex differences in mean LDL cholesterol reduction (%) from baseline levels reported in observational studies. CI, confidence interval; SD, standard deviation

Figure 5

Absolute LDL cholesterol reductions (mmol/L) in males and females in observational studies included in the systematic review of sex differences in the treatment of familial hypercholesterolaemia. This figure depicts difference in means of LDL cholesterol from baseline to follow-up measurements reported in observational data. Squares represent mean differences; horizontal lines show 95% confidence intervals. Area of the square is proportional to the inverse variance of the estimate. Diamonds represent pooled estimates with 95% confidence intervals derived under the random-effects model. Solid vertical line indicates null effect. Test of subgroup differences refers to variations in the difference of means between male and female subgroups; P-values <.1 are considered significant. CI, confidence interval; SD, standard deviation

Figure 6

Meta-analyses of sex differences in LDL cholesterol reduction target attainment. Panel (A) depicts sex differences in attainment of ≥50% reductions in LDL cholesterol. Panel (B) depicts sex differences in attainment of an LDL <2.5 mmol/L. Panel (C) depicts sex differences in attainment of an LDL <1.8 mmol/L. Small squares indicate study-level estimates of sex differences in treatment (odds ratios); large squares represent pooled odds ratio derived under random-effects models; horizontal lines represent 95% confidence intervals; vertical dashed line represents null effect. CI, confidence interval

Figure 7

Risk of major adverse cardiovascular events in males vs. females with familial hypercholesterolaemia. This figure depicts pooled estimates (circles) with 95% confidence intervals (horizontal lines) for comparisons of the risk of major adverse cardiovascular events in males vs. females with familial hypercholesterolaemia. All pooled estimates are derived using inverse-variance weighting incorporating random-effects. ASCVD, atherosclerotic cardiovascular diseases; CHD, coronary heart disease; CI, confidence interval; CV, cardiovascular; MACE, major adverse cardiovascular events; MI, myocardial infarction; PVD, peripheral vascular disease