Outcomes trials
Meta-analysis of 332,912 patients: lowering apoB only cuts cardiovascular risk when it works through the LDL receptor, not via CETP inhibitors or fibrates (Eur J Prev Cardiol 2020)
Original title: Association of lowering apolipoprotein B with cardiovascular outcomes across various lipid-lowering therapies: Systematic review and meta-analysis of trials
A systematic review and meta-analysis pooled 29 randomised controlled trials (332,912 patients, follow-up at least 1 year) of therapies that lower apolipoprotein B (apoB), comparing those that clear apoB particles by upregulating the LDL receptor (statins, ezetimibe, PCSK9 inhibitors, bile acid sequestrants) against those that lower apoB independent of the LDL receptor (CETP inhibitors, fibrates, niacin, omega-3 fatty acids). Across all interventions combined, every 10 mg/dL reduction in apoB was associated with a relative risk of 0.95 for all-cause mortality and 0.93 for cardiovascular mortality, though the all-cause mortality benefit was limited to statins. For major adverse cardiovascular events, LDL-receptor-mediated therapies showed a significant reduction per 10 mg/dL apoB decrease (statins 0.88, non-statin 0.96), while therapies lowering apoB independently of the LDL receptor, including CETP inhibitors, showed no significant benefit (relative risk 1.02, 95% CI, 0.81 to 1.30). The authors conclude the mechanism by which apoB is lowered matters, not just the magnitude, offering a mechanistic explanation for why CETP inhibitors have failed to reduce cardiovascular events despite lowering apoB.
Original abstract
Aims: The effect of therapeutic lowering of apolipoprotein B (apoB) on mortality and major adverse cardiovascular events is uncertain. It is also unclear whether these potential effects vary by different lipid-lowering strategies.
Methods: A total of 29 randomized controlled trials were selected using PubMed, Cochrane Library and EMBASE through 2018. We selected trials of therapies which ultimately clear apolipoprotein B particles by upregulating low-density lipoprotein receptor (LDL-R) expression (statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, bile acid sequestrants) or therapies which reduce apolipoprotein B independent of LDL-R (cholesteryl ester transfer protein inhibitor, fibrates, niacin, omega-3 fatty acids) with sample size of ≥1000 patients and follow-up of ≥1 year. The meta-regression and meta-analyses were constructed using a random effects model.
Results: In 332,912 patients, meta-regression analyses showed relative risks of 0.95 for all-cause mortality (95% confidence interval 0.92-0.99) and 0.93 (0.88-0.98) for cardiovascular mortality for every 10 mg/dL decrease in apolipoprotein B by all interventions combined. Reduction in all-cause mortality was limited to statins (0.92 (0.86-0.98)). For MACE, the relative risk per 10 mg/dL reduction in apolipoprotein B was 0.93 (0.90-0.97) for all therapies combined, with both statin (0.88 (0.83-0.93)) and non-statin therapies (0.96 (0.94-0.99)). which clear apolipoprotein B by upregulating LDL-R showing significant reductions; whereas interventions which lower apolipoprotein B independent of LDL-R did not demonstrate this effect (1.02 (0.81-1.30)).
Conclusion: While both statin and established non-statin therapies (PCSK9 inhibitor and ezetimibe) reduced cardiovascular risk per decrease in apolipoprotein B, interventions which reduce apolipoprotein B independently of LDL-R were not associated with cardiovascular benefit.
the classLDL and apoBoutcomes trials
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.