Making the Case for Early Statins in Familial Hypercholesterolemia

Patrice Wendling

October 16, 2019

Starting statin therapy during childhood in patients with familial hypercholesterolemia (FH) has beneficial effects on atherosclerotic progression and reduces cardiovascular events including death, a 20-year follow-up study indicates.

The cumulative incidence of cardiovascular events at age 39 years was 1% among patients with FH who began taking statins during childhood, compared with 26% among their affected parents for whom statins were only available much later in life.

None of the young adults who received statins during childhood died from cardiovascular disease (CVD) during follow-up, whereas 7% of affected parents died before age 40, all from myocardial infarction, Ilse Luirink, MD, University of Amsterdam, the Netherlands, and colleagues report today in the New England Journal of Medicine.

Patients with FH develop severely elevated low-density lipoprotein cholesterol (LDL-C) levels from birth onward, placing them at high risk for premature CVD. Statins are the preferred drug therapy and both the European Atherosclerosis Society consensus panel and American College of Cardiology/American Heart Association guidelines for FH advocate initiating statins at 8 to 10 years of age. Follow-up data on outcomes in treated children into adulthood, however, are lacking, the authors note.

To address this evidence gap, the investigators sent questionnaires to and performed physical examinations in 184 of 214 patients with FH and 77 of 95 unaffected siblings available for follow-up about 20 years after participation in a 2-year randomized trial evaluating pravastatin in the late 1990s. A single experienced sonographer assessed carotid intima-media thickness (c-IMT), a validated marker of future CV risk, during the initial trial and follow-up study. FH was genetically confirmed in 98% of patients, who began taking statins at an average age of 14 years.

At follow-up, 22% of patients and 34% of siblings were current smokers; their average age was 31 years. Self-reported adherence to lipid-lowering therapy was 79% among patients with FH, with 84% of those reportedly taking at least 80% of their medication in the month before the assessment.

Lipids and c-IMT

Mean LDL-C levels among the patients fell 32% from a baseline of 237.3 mg/dL to 160.7 mg/dL at follow-up. That compares with an LDL-C increase of 24% over the same period among their unaffected siblings (from 99.0 to 121.9 mg/dL), the authors reported.

Total cholesterol levels followed a similar pattern among patients (from 300.6 to 232.6 mg/dL) and their siblings (from 166.9 to 201.5 mg/dL), while high-density lipoprotein levels increased slightly in both groups (47.8 to 53.3 mg/dL and 54.8 to 56.3 mg/dL, respectively).

Notably, only 37 patients with FH (20%) reached the LDL-C treatment target of less than 100 mg/dL, and only eight of these reached an LDL-C of less than 70 mg/dL.

Despite this modest percentage, results show that patients with FH had a greater c-IMT at baseline than their unaffected siblings (mean, 0.446 mm vs 0.439 mm; adjusted difference, 0.012 mm; 95% confidence interval (CI), 0.002 - 0.021) but similar mean thickness after 20 years (0.555 mm vs 0.551 mm; adjusted difference, 0.008 mm; 95% CI, 0.009 - 0.026).

Given that most patients were taking statins throughout follow-up, "…we deduced that starting statin treatment in childhood had beneficial effects on atherosclerotic vascular disease in participants in the present study, even when guideline goals were not always achieved. If corroborated, such findings would underscore the current pediatric guidelines, which recommend starting treatment from the age of 8 years or 10 years, with less stringent targets than those for adults," Luirink and colleagues write.

The Younger the Better

The authors observe that LDL cholesterol hypothesis is no longer a hypothesis but a fact, and that Mendelian randomization studies have shown that the consequences of LDL-C with respect to atherosclerotic disease are determined not only by absolute LDL-C levels but also the cumulative exposure of the arterial wall to LDL-C. "Altogether, this makes a strong case for not only 'the lower the better' but also for 'the younger the better.' "

Jennifer Robinson, MD, MPH, an FH expert and director of the Preventive Intervention Center at the University of Iowa, Iowa City, said the results are a "call to action," particularly for family physicians, who tend to follow the US Preventive Services Task Force, which says there's insufficient evidence to treat children with FH with statins.

"Generic statins are cost savings even in low-risk people and they're perfectly safe; they have the same side effects as placebo," she said. "So there's absolutely no reason to not be treating people. It's really, I think, almost a crime to not be treating these FH children and young adults, given the amount of knowledge we already have and then the addition of this study."

"I feel pretty strongly about it," she added. "I think it's sort of become immoral at some point to deny therapy when you have such overwhelming evidence."

FH is the most common genetic disorder in the world that is fatal but curable, yet 80% of patients with FH go undiagnosed, Robinson observed. While novel therapies like proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may be needed to achieve acceptable LDL-C levels in patients with FH who have additional risk factors or existing CVD, all patients with FH should receive statins as initial treatment.

"There's all sorts of science to be done like how intensively to treat, how early should you treat, but the issue of putting kids on moderate-intensity statins and the adults on high-intensity statins is incontrovertibly supported by the evidence," she said.

In the study, treatment included a statin-only in 82 patients; a statin plus ezetimibe in 53; a statin, ezetimibe, and a PCSK9 inhibitor in 4; and combination therapy with cholestagel in 4. The most commonly prescribed statin was rosuvastatin 40 mg (n = 28), followed by atorvastatin 40 mg (n = 26), rosuvastatin 20 mg (n = 21), and simvastatin 40 mg (n = 15).

Four patients discontinued statin therapy because of side effects. No episodes of rhabdomyolysis or other serious adverse events were reported and no significant differences in liver-function tests were observed between patients with FH and their unaffected siblings, according to the authors.

"It really, I think, strikes hard at everything that lipid guidelines writers around the world have been saying recently, which is, in FH in particular but really in anybody felt to be at significant risk from LDL, LDL treatment needs to start early," Milan Gupta, MD, McMaster University, Hamilton, Ontario, who was not involved with the study, told | Medscape Cardiology.

The only "sobering point from this paper," he said, is that even though roughly 80% of patients had been taking statins for 20 years, only 20% were at even a liberal LDL target of less than 100 mg/dL or 2.6 mmol/L and a really "dismal percent" were at the more aggressive target.

"That's a glass half-empty, glass half-full argument because you could say if we can get these patients to target earlier in life, we could potentially even further reduce bad things from happening," Gupta said. "But the glass half-full approach says, regardless of whether they hit target or not, on average, this patient population seems to have a remarkably good prognosis."

The study was supported by a grant from the AMC Foundation. Kastelein reports personal fees from Amgen, CSL Behring, Esperion, Gemphire, Madrigal, The Medicines Company, AstraZeneca/Omthera, Staten Biotechnology, and Regeneron outside the submitted work. Robinson reports consulting for and research grants from The Medicines Company, Amgen, Sanofi, Pfizer, AstraZeneca, and Merck. Gupta reports speaking and advisory board honorarium from Amgen and Sanofi and research funding from The Medicines Company.

N Engl J Med. 2019;381;1547-1556. Abstract

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