Familial Hypercholesterolemia and CVD risk factors

Genetic inability to clear LDL-particles leads to familial hypercholesterolemia. Persistent high serum LDLc and total-cholesterol are major cumulative risk factors for premature cardiovascular disease.

The article identifies other independent risk factors contributing to CVD in these patients. Such factors are male sex, smoking, hypertension, diabetes, elevated Lp(a), and family history of CVD.

Obviously, the modifiable contributors; hypertension, smoking and diabetes need to be managed aggressively.


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J. Clinical Lipidology


January 2019


  • Several clinical risk factors were associated with increased CVD in HeFH.

  • Major modifiable risk factors account for more than 25% of CVD risk.

  • An LDLc > 154 mg/dL was associated with 1 in 3 CVD cases (33%).



Current data from individual studies present conflicting evidence about the relationship between risk factors and cardiovascular disease (CVD) in heterozygous familial hypercholesterolemia (HeFH).



We conducted a systematic review and meta-analysis to quantify the association between various CVD risk factors and CVD in FH.



We searched MEDLINE, EMBASE, Global Health, the Cochrane Library, and PubMed for English-language studies reporting adjusted-associations between cardiovascular, behavioral, or clinical risk factors and CVD with ≥ 100 participants.

We calculated pooled odds ratios (ORs) with 95% confidence intervals (CIs) for selected risk factors with random-effects meta-analysis, from which we derived attributable risk estimates.



We identified 27 studies representing 41,831 unique participants and 6629 CVD events. The following were found to be significant CVD risk factors in HeFH:

  • Age (OR: 1.07, p<0.05)

  • Male sex (OR: 1.95, p<0.05)

  • Hypertension (OR: 2.11, p<0.05),

  • Diabetes (OR: 1.95, p<0.05),

  • BMI (OR: 1.04, p<0.05)

  • Smoking (OR: 1.71, p<0.05)

  • Elevated lipoprotein(a) (OR: 1.90, p<0.05),

  • Low HDLc (OR: 1.39, p<0.05)

  • Family history of CVD (OR: 1.83, p<0.05)

Smoking, hypertension, and diabetes accounted for more than 25% of CVD risk in FH individuals, whereas LDLc > 154 mg/dL accounted for 1 in 3 CVD cases.

Meta-regression analyses found associations between LDLc (P = .045) and TOTc (P < .001) and CVD. Results were broadly consistent in sensitivity analyses.



Several clinical risk factors are significantly and independently associated with CVD risk in patients with FH and should be targeted for modification. These data can also inform the selection of variables for prediction models to aid in risk stratifying patients.