Association of lowering apolipoprotein B with cardiovascular outcomes across various lipid-lowering therapies: Systematic review and meta-analysis of trials

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.

Investigations on the clinical utility of apolipoprotein B measurement: A research priority

“…1 Reduction in all-cause mortality per decrease in apoB was found only with statins. 1 Results are interesting in light of the scientific debate on the best treatment strategy for atherogenic dyslipidaemia, a condition in which circulating LDL particles are small and dense and therefore measurement of LDL-cholesterol may underestimate cardiovascular risk because the particles are depleted of part of their cholesterol content. 2 The residual risk that remains in these patients on statin treatment has fuelled the debate about considering apoB as a treatment target.…”

“…Michel R Langlois 1,2 In this issue of the European Journal of Preventive Cardiology, Khan et al present their results of a large scale systematic review and meta-analysis (including >330,000 patients from 29 lipid-lowering trials) on the association of decrease in apolipoprotein B (apoB) concentration with all-cause mortality and cardiovascular outcomes across different lipid-lowering drug classes. 1 They found that statins and other therapies which clear apoB by upregulating low-density lipoprotein (LDL)-receptor expression reduce cardiovascular risk proportional to the decrease in apoB concentration, whereas interventions which lower apoB independent of LDL-receptor did not demonstrate this association. 1 Reduction in all-cause mortality per decrease in apoB was found only with statins.…”

“…1 They found that statins and other therapies which clear apoB by upregulating low-density lipoprotein (LDL)-receptor expression reduce cardiovascular risk proportional to the decrease in apoB concentration, whereas interventions which lower apoB independent of LDL-receptor did not demonstrate this association. 1 Reduction in all-cause mortality per decrease in apoB was found only with statins. 1 Results are interesting in light of the scientific debate on the best treatment strategy for atherogenic dyslipidaemia, a condition in which circulating LDL particles are small and dense and therefore measurement of LDL-cholesterol may underestimate cardiovascular risk because the particles are depleted of part of their cholesterol content.…”

“…It is derived solely by associations with reported apoB data in the original trials and, when data were not reported, estimated apoB concentrations. 1 At present, there is no direct evidence of clinical utility of apoB measurements. The European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) has defined key characteristics for a diagnostic biomarker -analytical performance, clinical performance, clinical effectiveness and cost-effectiveness -to become a medically useful test.…”

“…3 Use of apoB would be cost-effective if the test provided information to guide therapy to reduce the healthcare costs related to cardiovascular disease in the population. The study by Khan et al 1 and previous meta-analyses [6][7][8] lead to the assumption that apoB measurements would enable to identify, treat and follow up individuals who could benefit from lipid-lowering therapies. In a previous metaanalysis of seven statin trials, it was estimated that one-standard deviation decreases of LDL-cholesterol and apoB concentrations would yield expected risk reductions of 30% and 39%, respectively, suggesting that benefit would be greater if therapy were targeted to apoB rather than to LDL-cholesterol.…”