Individuals at high genetic risk have greater benefit from statins
Polygenic Risk Score Identifies Subgroup with Higher Burden of Atherosclerosis and Greater Relative Benefit from Statin Therapy in the Primary Prevention Setting
Statins lower relative risk by approximately 20% per 1.0 mmol/L of LDL-c. This is consistent across nearly all subgroups defined by clinical and biochemical measures [1,2], however two studies (ASCOT-LLA and JUPITER) recently reported that those at high genetic risk experienced greater relative risk reduction from statin therapy compared with all others [3,4]. This risk was defined by the 27-SNP polygenic risk score for coronary heart disease (CHD) .
Using WOSCOPS trial data, this study aimed to confirm this observation by an expanded 57-SNP polygenic risk score, as well as to assess whether the burden of subclinical coronary atherosclerosis is greater among those at high genetic risk. Genetic data were available in 4 892 men. Results from the ASCOT-LLA and JUPITER trial (6 978 and 8 769 individuals, respectively) were used for meta-analysis. The CARDIA and BioImage observational cohorts were used to explore the potential greater clinical benefit of statins in those at high genetic risk.
- After adjustment for traditional cardiovascular risk factors, those receiving placebo and at high genetic risk were at increased risk for a first CHD event (HR 1.62, 95% CI 1.29-2.05, P<0.001).
- One SD increase in polygenic risk score was associated with 25% increased risk of incident CHD of placebo-treated WOSCOPS patients (HR 1.25, 95% CI 1.20-1.35, P<0.001).
- Mean LDL-c at baseline was 192 mg/dL (SD 17.5) and 192 mg/dL (SD 17.3) among those at high genetic risk and all others, respectively.
- Among high genetic risk participants, statin therapy reduced risk for a first CHD event by 44% (HR 0.56, 95% CI 0.40-0.78, P<0.001), whereas this was 24% among all others (HR 0.76, 95% CI 0.63-0.92, P=0.004).
- Absolute risk was 7.9% (95% CI 3.4-12.4%) and 2.7% (95% CI 0.7-4.7%) for high genetic participants and all participants, respectively (P heterogeneity 0.04).
- The number needed to treat was 13 in high genetic risk participants and 38 among all others.
- Achieved LDL-c reduction was similar between groups (22.9 and 22.2% for high genetic risk group and all others respectively).
- Meta-analysis using ASCOT-LLA and JUPITER data showed statin therapy reduced risk for a first CHD event by 46% (HR 0.54, 95% CI 0.41-0.71, P<0.001) and by 26% among all others (HR 0.74, 95% CI 0.63-0.86, P<0.001). Absolute risk reduction was 3.6% (95% CI 2.0-5.1%) and 1.3% (95% CI 0.6-1.9%) respectively. Number needed to treat was 28 and 80 respectively.
- CARDIA data showed that every SD increase in polygenic risk score (57 SNPs) was equal to a multivariable adjusted odd ratio for coronary arterial calcification of 1.32 (95% CI 1.04-1.68, P=0.02). BioImage data showed that every SD increase in polygenic risk score resulted in 9.7% (95% CI 2.2-17.8%, P=0.01) in carotid artery plaque burden.
Although levels of LDL-c reduction were comparable, men with a high genetic risk derived a greater relative benefit from statin therapy. Furthermore, an expanded 57-SNP score was associated with subclinical atherosclerosis in two vascular beds. High genetic risk may identify individuals eligible to statins to prevent a first myocardial infarction event who otherwise would not be considered for treatment based on clinical criteria. This hypothesis can be tested in more contemporary cohorts with sizable proportions of statin-ineligible patients.