👤 Mie Balling

Lipid-lowering therapy is typically initiated at high low-density lipoprotein(LDL) cholesterol marked by elevated apolipoprotein B(apoB). We tested the hypothesis that elevated apoB alternatively due to high remnant cholesterol confers equally high risk of atherosclerotic cardiovascular disease(ASCVD) but less initiation of lipid-lowering therapy, compared to elevated apoB due to high LDL cholesterol. From the Copenhagen General Population Study, 94 299 lipid-lowering therapy naïve adults without a history of ASCVD were included in 2003-2015. Discordance groups were formed by median levels of remnant cholesterol, LDL cholesterol and apoB. In the national Danish health registries, individuals were followed for a prescription of lipid-lowering therapy and for incident ASCVD until December 2021. During a median follow-up of 12 years, 9269 developed ASCVD. Compared to individuals with concordant low values of remnant cholesterol, apoB, and LDL cholesterol, those with high remnant cholesterol and high apoB but low LDL cholesterol had a hazard ratio(HR) of 1.45 (95% confidence interval: 1.34-1.56) for ASCVD and an odds ratio(OR) of 3.0 (2.5-3.6) for starting lipid-lowering therapy within one year. Correspondingly, those with low remnant cholesterol but high apoB and high LDL cholesterol had a HR of 1.20 (1.11-1.30) for ASCVD and an OR of 5.1 (4.3-5.9) for starting lipid-lowering therapy. In a primary prevention setting, elevated apoB due to high remnant cholesterol confers high risk of ASCVD but less initiation of lipid-lowering therapy compared to elevated apoB due to high LDL cholesterol, representing a guideline-based limitation and an unmet medical need. Show less

Randomized clinical trials of remnant cholesterol lowering drugs show 50 % and 80 % reduction in remnant cholesterol with apolipoprotein C3 (APOC3) and angiopoietin-like 3 (ANGPTL3) inhibitors. However, how many of atherosclerotic cardiovascular disease(ASCVD) cases that could be prevented lowering remnant cholesterol by these therapies is unknown. The aim of the study was to estimate the potential of APOC3 and ANGPTL3 inhibitors to reduce the ASCVD burden through lowering of remnant cholesterol. Of 98,311 individuals from the Copenhagen General Population Study without ASCVD at study entry 8,506 were statin users and 89,805 were statin non-users. Cause-specific Cox regression was used to model rates of ASCVD and non-cardiovascular death conditional on remnant cholesterol and risk factors. Based on these models the potential 10-year absolute risk reduction of ASCVD in individuals with remnant cholesterol >1 mmol/L (>39 mg/dL) for 15 %, 30 %, 50 %, and 80 % lower remnant cholesterol was predicted. The predicted average 10-year absolute risk of ASCVD was 20 % for statin users and 11 % for statin non-users with remnant cholesterol >1 mmol/L (>39 mg/dL). The predicted 10-year absolute risk reduction of ASCVD in individuals with remnant cholesterol >1 mmol/L (>39 mg/dL) for 50 % and 80 % lower remnant cholesterol were 2.7 % (95 % confidence interval: 2.2-3.2 %), and 4.1 % (3.4-4.8 %) for statin users and 1.4 % (1.3-1.5 %), and 2.1 % (2.0-2.3 %) for statin non-users. We have shown that significant ASCVD risk reductions are expected for remnant cholesterol lowering drugs in at-risk populations, if intervention trials with novel remnant cholesterol lowering drugs show expected reductions in remnants in large cardiovascular outcomes trials. Show less