Greater benefit of statin therapy in those with inherited high LDL, suggests 4S

Introduction and methods

News - May 28, 2019

More statin benefit in people with likely genetic vulnerability to high levels of bad cholesterol: new analysis from the Scandinavian Simvastatin Survival Study (4S)

Presented at EAS 2019 in Maastricht, The Netherlands, by Antonio J. Vallejo-Vaz (Imperial College, London, UK).

Individuals with familial hypercholesterolemia (FH) are at high risk of coronary events, such as heart attack, as a consequence of their long-term exposure to high LDL-c levels. The absolute CV risk of these individuals is therefore higher than in people who develop hypercholesterolemia during adult life, but who do not have a clinical history suggestive of FH.

The ‘Scandinavian Simvastatin Survival Study’ or 4S study was the first landmark trial to demonstrate the benefit of statin treatment in patients with established heart disease and high cholesterol levels (between 5.5-8.0 mmol/L or about 200-300 mg/dL) on a lipid-lowering diet. As this benefit depends on absolute cardiovascular risk, baseline LDL-C level and the absolute reduction in LDL-C levels, this suggests that patients with likely FH who have longer lifetime exposure to high LDL-C levels may gain more from LDL-C lowering with a statin.

In the current analysis of 4S data, individuals were categorized according to baseline LDL-c (<4.9 mmol/L or ≥4.9 mmol/L) and those with high LDL-c levels were further divided based on the presence or absence of (premature) CAD in the individual and/or a family history of CAD, suggestive of inherited high cholesterol.

Main results

  • After one year, LDL-c lowering in people with baseline LDL-c ≥4.9 mmol/L showed 35% (P=0.002) reduction in the risk of major coronary events, and 32% (P=0.059) reduction in all-cause mortality.
  • Absolute risk reduction was greater in those with LDL-c ≥4.9 mmol/L than in those with levels <4.9 mmol/L. Those with LDL-c ≥4.9 mmol/L and an FH phenotype, showed absolute reductions of 6.5% of the risk of all-cause death, 5.3% in the risk of CV death, 5.3% in the risk of coronary death and 13.2% in the risk of coronary events.
  • In individuals with elevated LDL-c and an FH phenotype, the reduction in risk with statin treatment was even greater: they showed 84% (P=0.046) reduction of all-cause mortality, and 55% (P=0.030) reduction of the risk of major coronary events.
  • Individuals with high LDL-c and either a personal or family history of premature heart disease appeared to derive a similar benefit from statin therapy as those without clinical history of premature heart disease.


A new analysis of the 4S data shows that people with characteristics suggestive of FH, i.e. the combination of high LDL-c, premature heart disease and a family history of heart disease, gain greater clinical benefit from statin therapy. In these patients, statin therapy lowered the risk of all-cause mortality by more than 80%, and the risk of recurrent MI was halved. This is the first randomized trial evidence in secondary prevention that suggests that statin therapy reduces CVD events in those with an FH phenotype.

Our reporting is based on the information provided at the EAS 2019 congress

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