Survival in HoFH and Treatment Level of Serum Cholesterol

Study Questions:

What is the relationship between survival and level of on-treatment serum cholesterol in homozygous familial hypercholesterolemia (HoFH) in the modern era of lipid-lowering therapy (statin + novel from 1990 through 2014)?

Methods:

The study was conducted in South Africa and the United Kingdom in 133 previously statin-naive HoFH patients. The cohort was divided into quartiles according to their on-treatment levels of serum cholesterol and quartiles, which were compared for the occurrence of any death, cardiovascular death, and major adverse cardiovascular events (MACE) between the quartiles during 25 years of follow-up, using Cox and competing risks regression analysis. Criteria for the diagnosis of HoFH were confirmation of two mutant alleles at the low-density lipoprotein receptor (LDLR) or LDL receptor adaptor protein (LDL-RAP) 1 loci (95%) or an untreated LDL cholesterol (LDL-C) ≥500 mg/dl, and cutaneous or tendon xanthomas before the age of 10 years.

Results:

Mean age at baseline was about 15 years and 31 years at the time of death or 2014, and did not differ between quartiles. Baseline pretreatment mean LDL-C ranged from 575 mg/dl in Quartile 1 to 737 mg/dl in Quartile 4. Mean percent reduction in cholesterol was 58% in Quartile 1, 29% in Quartiles 2 and 3 combined, and 10% in Quartile 4. Total fatal MACE over the 25-year follow-up was 6.1% in Quartile 1, 25.4% in Quartile 2+3, and 51.5% in Quartile 4. Patients in Quartile 4, with an on-treatment serum cholesterol >583 mg/dl, had a hazard ratio of 11.5 for any death compared with those in Quartile 1, with on-treatment cholesterol of <312.7 mg/dl. Those in Quartiles 2 and 3 combined, with on-treatment cholesterol of 313-583 mg/dl had a hazard ratio of 3.6 compared with Quartile 1. These differences were statistically significant (p < 0.001) and remained so after adjustments for confounding factors (p = 0.04). Significant differences between quartiles were also evident for cardiovascular deaths and MACE.

Conclusions:

These findings provide unequivocal evidence that the extent of reduction of serum cholesterol achieved by a combination of therapeutic measures, including statins, ezetimibe, lipoprotein apheresis, and evolocumab, is a major determinant of survival in HoFH.

Perspective:

This is the first large outcome study that provides conclusive evidence that treatment of HoFH, a genetic disorder found early in life, should be treated as aggressively as possible at any age. Despite the availability of the above agents, only a few will reach the target LDL-C of <135 mg/dl in children and <100 mg/dl in adults, or <70 mg/dl in those at highest risk. Novel treatments are very expensive. In our adult lipid clinic, the best treatment(s) is the combination of the highest tolerated dose of statins, ezetimibe, the PCSK9 inhibitor evolocumab, and oral lomitapide, the microsomal triglyceride transfer protein inhibitor. LDL apheresis is effective, but requires weekly treatments, which lead to complications in a high percentage of patients.


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