Statins in Familial Hypercholesterolemia: Consequences for Coronary Artery Disease and All-Cause Mortality.

Besseling J1, Hovingh GK1, Huijgen R1, Kastelein JJ2, Hutten BA3.
  • 1Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
  • 2Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands. Electronic address:
  • 3Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, the Netherlands.



A statin-induced reduction of coronary artery disease (CAD) events and mortality has not been adequately quantified in patients with heterozygous familial hypercholesterolemia (FH).


This study estimated the relative risk reduction for CAD and mortality by statins in heterozygous FH patients.


The authors included all adult heterozygous FH patients, identified by the Dutch screening program for FH between 1994 and 2013, who were free of CAD at baseline. Hospital, pharmacy, and mortality records between 1995 and 2015 were linked to these patients. The primary outcome was the composite of myocardial infarction, coronary revascularization, and death from any cause. The effect of statins (time-varying) was determined using a Cox proportional hazard model, while correcting for the use of other lipid-lowering therapy, thrombocyte aggregation inhibitors, and antihypertensive and antidiabetic medication. The authors applied inverse-probability-for-treatment weighting (IPTW) to account for differences at baseline between statin users and never-users.


The authors obtained medical records of 2,447 patients, of whom 888 were excluded on the basis of age


In patients with heterozygous FH, moderate- to high-intensity statin therapy lowered the risk for CAD and mortality by 44%. This is essential information in all cost-effectiveness studies of this disorder, such as when evaluating reimbursement of new lipid-lowering therapies. Copyright © 2016 American College of Cardiology Foundation.

KEYWORDS: intensity; inverse-probability-of-treatment-weighting; lipid lowering

PMID: 27417002




Familial hypercholesterolemia, a hereditary disorder of low-density lipoprotein (LDL) cholesterol metabolism, affects 1 in 250 persons and is characterized by increased levels of LDL cholesterol.1–3 Patients with heterozygous familial hypercholesterolemia are at 3-4 fold higher risk for coronary artery disease (CAD) and tend to develop CAD on average ten years earlier in life than unaffected persons.3,4 Statins lower LDL cholesterol in patients with heterozygous familial hypercholesterolemia5 approximately to the same extent as in the general population.6 In the latter, the average relative risk reduction of statins for CAD is estimated to be 22% per mmol/L.6,7 This estimate is, however, unknown in heterozygous familial hypercholesterolemia patients, since it is considered unethical to withhold treatment from these patients. Randomized controlled trials are therefore not available.


There is a clear need to know to what extent statins reduce the risk for CAD and how large the residual CAD risk is in these patients because new classes of LDL cholesterol lowering therapy (e.g. antibodies to proprotein convertase subtilisin/kexin type 2 [PCSK9]) will be evaluated for approval in heterozygous familial hypercholesterolemia patients who do not reach treatment targets despite statin therapy. The objective of current study was therefore to estimate the relative risk reduction for CAD and mortality by statins in heterozygous familial hypercholesterolemia patients.


In our large cohort of patients with heterozygous familial hypercholesterolemia, we found that medium- to high intensity statin therapy was associated with a relative risk reduction of approximately 44% for the primary prevention of CAD and all-cause mortality. Furthermore, a non-significant positive association between off-treatment LDL cholesterol levels and relative risk reduction was observed.


The efficacy of statin therapy in patients with familial hypercholesterolemia was previously evaluated in a retrospective cohort study.14 The authors of this study reported a relative risk reduction of 76% which is much higher than the relative reduction of 44% in our study. The main reason for this discrepancy might be found in the high untreated LDL cholesterol levels of their study population as compared to our study population (309 mg/dL versus 213 mg/dL). In fact, prior studies have shown that the higher the baseline LDL cholesterol, the greater the relative risk reduction with statin therapy.15,16 The latter is consistent with our other findings as well. Furthermore, the baseline LDL cholesterol level in our study is similar to that in large population based cohorts of patients with heterozygous familial hypercholesterolemia (200 to 236 mg/dL).17,18 We therefore deem the relative risk reduction of 44% to be applicable to heterozygous familial hypercholesterolemia patients in general.


In line with the association between baseline LDL cholesterol level and the extent of relative risk reduction is the lower hazard ratio of statin use for CAD and all-cause mortality in LDLR mutation carriers, compared to APOB mutation carriers. However, caution is warranted since the confidence intervals of these hazard ratios are wide and include 1.00 and the p-value for interaction is far from significant. Nonetheless, it might be suggested that LDLR mutation carriers profit more from statin use, based on their higher baseline LDL cholesterol level and therefore their absolute LDL cholesterol reduction.


In absolute terms, the lifetime risk for first CAD event in untreated patients with heterozygous familial hypercholesterolemia is estimated to be 103/100,000 person-years in the Netherlands.19 In theory, statins would lower this risk by 44% to 58/100,000 person-years. This is certainly an improvement, but a substantial residual risk remains in these patients compared to CAD event rates in their unaffected family members (29/100,000 person-years).19


Clinical relevance

The increased risk for premature CAD in heterozygous familial hypercholesterolemia, in conjunction with its high prevalence of around 1:2501,3,20, has an important impact on public health. Moreover, it is estimated that 80% of these patients will not reach LDL cholesterol levels below 100 m/dL despite efficacious therapy.21 Currently, new lipid lowering modalities, such as PCSK9 inhibitors, are evaluated by authorities for reimbursement for these patients. An important aspect in this decision is the potential for the prevention of CAD events by statins at a population level, and therefore it is important to quantify the residual CAD risk in statin treated patients. The relative risk reduction by statins is key information in this estimation. In fact, it is fundamental information in all cost-effectiveness studies in this disorder, for example when evaluating screening programs.22,23


In conclusion, medium to high intensity statin therapy lowers the risk of CAD and all-cause mortality by approximately 44% in patients with heterozygous familial hypercholesterolemia. 



  1. Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur. Hear. J. 2014;36(9):560-5.
  2. Hovingh GK, Davidson MH, Kastelein JJP, O’Connor AM. Diagnosis and treatment of familial hypercholesterolaemia. Eur. Heart J. 2013;34(13):962-71.
  3. Benn M, Watts GF, Tybjærg-Hansen A, Nordestgaard BG. Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217. Eur. Heart J. 2016:ehw028. doi:10.1093/eurheartj/ehw028.
  4. Huijgen R, Kindt I, Defesche JC, Kastelein JJP. Cardiovascular risk in relation to functionality of sequence variants in the gene coding for the low-density lipoprotein receptor: a study among 29,365 individuals tested for 64 specific low-density lipoprotein-receptor sequence variants. Eur. Heart J. 2012;33(18):2325-30.
  5. Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001;357(9256):577-81.
  6. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366(9493):1267-78.
  7. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376(9753):1670-81.
  8. van Herk-Sukel MPP, van de Poll-Franse L V., Lemmens VEPP, et al. New opportunities for drug outcomes research in cancer patients: The linkage of the Eindhoven Cancer Registry and the PHARMO Record Linkage System. Eur. J. Cancer 2010;46(2):395-404.
  9. RIVM. Classification of Medical Interventions version 2.6. 2005. Available at: Accessed June 30, 2015.
  10. World Health Organization. International Classification of Procedures in Medicine. Geneva; 1978.
  11. Cole SR, Hernán MA. Adjusted survival curves with inverse probability weights. Comput. Methods Programs Biomed. 2004;75(1):45-49.
  12. Xu S, Ross C, Raebel M a, Shetterly S, Blanchette C, Smith D. Use of stabilized inverse propensity scores as weights to directly estimate relative risk and its confidence intervals. Value Heal. 2010;13(2):273-7.
  13. Pan W. Akaike’s information criterion in generalized estimating equations. Biometrics 2001;57(1):120-5.
  14. Versmissen J, Oosterveer DM, Yazdanpanah M, et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 2008;337:a2423.
  15. Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? BMJ 1994;308(6925):367-372.
  16. Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. J. Am. Coll. Cardiol. 2004;44(3):720-32.
  17. Besseling J, Kindt I, Hof M, Kastelein JJP, Hutten BA, Hovingh GK. Severe heterozygous familial hypercholesterolemia and risk for cardiovascular disease: A study of a cohort of 14, 000 mutation carriers. Atherosclerosis 2014;233(1):219-23.
  18. Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG. Familial hypercholesterolemia in the danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. JCEM 2012;97(11):3956-64.
  19. Huijgen R, Versmissen J, Oosterveer DM, et al. Cascade Screening for Familial Hypercholesterolemia: Prevention of Coronary Artery Disease in a Large Cohort of FH Heterozygotes. Amsterdam; 2012.
  20. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: Guidance for clinicians to prevent coronary heart disease. Eur. Heart J. 2013;34(45):3478-90a.
  21. Pijlman A, Huijgen R, Verhagen SN, et al. Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands. Atherosclerosis 2010;209(1):189-94.
  22. Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil HAW. Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia. BMJ 2002;324(7349):1303.
  23. Nherera L, Marks D, Minhas R, Thorogood M, Humphries SE. Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies. Heart 2011;97(14):1175-81.
  24. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N. Engl. J. Med. 2008;359(21):2195-2207.
  25. Cannon CP, Blazing M a., Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N. Engl. J. Med. 2015:150603140057001. doi:10.1056/NEJMoa1410489.