Meta- analysis of lowering apolipoprotein B with mortality and cardiovascular outcomes across various lipid lowering therapies

Introduction: Apolipoprotein B (apoB) concentration is reflective of the total burden of atherogenic lipoprotein particles, including low-density lipoprotein (LDL). Hypothesis: Association between apoB lowering and cardiovascular (CV) outcomes might vary across different classes of lipid-lowering therapies. Methods: Data bases of PubMed, Cochrane and EMBASE were searched through 2018 to select randomized controlled trials of lipid lowering therapies which reduce apoB by upregulating LDL receptor (LDL-R) expression (ezetimibe, PCSK9 inhibitors, bile acid séquestrants) or interventions which reduce apoB independent of LDL-R (CETP inhibitor, fibrates, niacin, n-3 fatty acids), with sample size >1000 patients and follow-up of >1 yr. The meta-regression and meta-analyses were constructed using a random effects model. The primary and secondary outcomes were all-cause mortality and major adverse CV events (MACE), respectively. Results: In 29 trials (332,912 patients), meta-regression showed relative risks (RR) of 0.95 for all-cause mortality (95% CI 0.92-0.99; Figure) and 0.93 (0.88-0.98) for CV mortality per 10 mg/dL decrease in apoB by all interventions combined. Reduction in all-cause mortality was only found for statins (0.92 [0.86-0.98]). For MACE, the RR per 10 mg/dL reduction in apoB was 0.93 (0.90-0.97) for all therapies combined, but varied by type of therapies; with both statin (0.88 [0.83-0.93]) and non-statin therapies (0.96 [0.94-0.99]) which clear apoB by upregulating LDL-R showing significant reductions; whereas, interventions which lower apoB independent of LDL-R did not demonstrate this effect (1.02 [0.81-1.30]). Conclusions: Reduction in apoB resulted in mortality and CV risk reduction. While both statin and established non-statin therapies (PCSK9 inhibitor and ezetimibe) reduced CV risk per decrease in apoB, interventions which reduce apoB independent of LDL-R were not associated with CV benefit.