Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta‐Analysis of 35 Randomized Controlled Trials

Abstract

BackgroundWe sought to examine the efficacy and safety of 2 PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors: alirocumab and evolocumab.Methods and ResultsWe performed a systematic review and meta‐analysis of randomized controlled trials comparing treatment with and without PCSK9 inhibitors; 35 randomized controlled trials comprising 45 539 patients (mean follow‐up: 85.5 weeks) were included. Mean age was 61.0±2.8 years, and mean baseline low‐density lipoprotein cholesterol was 106±22 mg/dL. Compared with no PCSK9 inhibitor therapy, treatment with a PCSK9 inhibitor was associated with a lower rate of myocardial infarction (2.3% versus 3.6%; odds ratio [OR]: 0.72 [95% confidence interval (CI), 0.64–0.81]; P<0.001), stroke (1.0% versus 1.4%; OR: 0.80 [95% CI, 0.67–0.96]; P=0.02), and coronary revascularization (4.2% versus 5.8%; OR: 0.78 [95% CI, 0.71–0.86]; P<0.001). Overall, no significant change was observed in all‐cause mortality (OR: 0.71 [95% CI, 0.47–1.09]; P=0.12) or cardiovascular mortality (OR: 1.01 [95% CI, 0.85–1.19]; P=0.95). A significant association was observed between higher baseline low‐density lipoprotein cholesterol and benefit in all‐cause mortality (P=0.038). No significant change was observed in neurocognitive adverse events (OR: 1.12 [95% CI, 0.88–1.42]; P=0.37), myalgia (OR: 0.95 [95% CI, 0.75–1.20]; P=0.65), new onset or worsening of preexisting diabetes mellitus (OR: 1.05 [95% CI, 0.95–1.17]; P=0.32), and increase in levels of creatine kinase (OR: 0.84 [95% CI, 0.70–1.01]; P=0.06) or alanine or aspartate aminotransferase (OR: 0.96 [95% CI, 0.82–1.12]; P=0.61).ConclusionsTreatment with a PCSK9 inhibitor is well tolerated and improves cardiovascular outcomes. Although no overall benefit was noted in all‐cause or cardiovascular mortality, such benefit may be achievable in patients with higher baseline low‐density lipoprotein cholesterol.

Use of multivariable Mendelian randomization to address biases due to competing risk before recruitment

“…More methods of obtaining valid MR estimates when using invalid instruments are required. [38] on IHD, stroke and AF using Mendelian randomization applied to the CARDIoGRAMplusC4D 1000 Genomes based GWAS of IHD [39], UK Biobank summary statistics from SAIGE for IHD and stroke [42], MEGASTROKE [40] for stroke and a study by Nielsen et al [41] for AF and the effects of statins and PCSK9 inhibitors on the same outcomes from meta-analysis of RCTs [30,32,36,37] Estimates from…”

“…AF may also be a consequence of IHD. Statins also appear to have a greater effect on overall survival than PCSK9 inhibitors [30,32,36,37]. As such, bearing in mind Figures 1d and 1e, greater bias would be expected when using MR to assess effects of harmful exposures on stroke and AF than on IHD, for studies with participants recruited at older ages and possibly more for genetically predicted statins than PCSK9 inhibitors.…”

Efficacy and safety of alirocumab among individuals with diabetes mellitus and atherosclerotic cardiovascular disease in the ODYSSEY phase 3 trials

“…These findings are consistent with those of the ODYSSEY DM‐INSULIN trial27 and previous sub‐analyses that revealed no effect of alirocumab on glycaemic parameters31, 33, 45 or no increase in new‐onset DM compared with controls 45. Furthermore, in a recent meta‐analysis of 15 randomized controlled trials with PCSK9 inhibitors, including alirocumab, there was no increase in glycaemic parameters in those without DM or pre‐existing DM (crude rate, 5.6% vs 5.9%; odds ratio, 1.05 [95% confidence interval, 0.95‐1.17], P = .32, I2 = 0%, heterogeneity P = .86) 46. More evidence has recently become available from the ODYSSEY OUTCOMES trial, involving 18 924 patients with recent acute coronary syndrome, using alirocumab vs placebo, with exposure for up to 5 years (median exposure, 2.8 years) 29…”

Tapping the RNA world for therapeutics

“…As they compete to treat the same diseases, it will become clearer which of these strategies offers better therapeutics. Examples are the approved ASO mipomersen and PCSK9 mAbs versus the siRNA-based drug incli-siran, now in phase 3 trials, all three designed to lower cholesterol by targeting the same enzyme 69,105,106 , and the Ionis ASO inotersen versus Alnylam patisiran, both targeting TTR to treat amyloidosis (J. Gollob (Alnylam), personal communication and ref. 107 ).…”