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Effetti degli inibitori del PCSK9 sul quadro lipidico e sugli eventi clinici. Una meta-analisi
Sono ormai tanti i lavori pubblicati sugli inibitori di PCSK9 (Proprotein convertase subtilisin-kexin type 9) e non poteva mancare una meta-analisi che facesse il punto della situazione sia per quanto riguarda gli effetti metabolici, sia quelli clinici. Sono stati presi in considerazione 17 studi randomizzati e controllati per un totale di 13.083 pazienti e tutti sono stati concordi nel dimostrare che anticorpi monoclonali, somministrati a varie dosi e ogni 2 o 4 settimane determinano un'ulteriore riduzione del colesterolo LDL di circa il 58% quando aggiunti alla usuale terapia ipocolesterolemizzante con statine, ezetimibe o ambedue. Come atteso, all'effetto di riduzione del colesterolo LDL seguono effetti clinici di rilievo che si possono riassumere in una riduzione significativa della mortalità totale, una tendenza verso la diminuzione degli eventi e della morte cardiovascolare. Siamo solo agli inizi della storia, le premesse sono positive, ma andranno verificate nel lungo termine, soprattutto per quanto riguarda gli eventi clinici. Unico neo è l'aumento del rischio di deterioramento neurocognitivo.
The impact of proprotein convertase subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: a network meta-analysis
Patel RS, Ghasemzadeh N, Eapen DJ, Sher S, Arshad S, Ko YA, Veledar E, Samady H, Zafari Lipinski MJ, Benedetto U, Escarcega RO, Biondi-Zoccai G, Lhermusier T, Baker NC, Torguson R, Brewer HB Jr, Waksman R
Eur Heart J 2016;37:536-545b
AIMS: We performed a network meta-analysis of randomized controlled trials (RCTs) in patients with primary hypercholesterolaemia to compare the impact of proprotein convertase subtilisin-kexin type 9 serine protease (PCSK9) inhibitors with placebo and ezetimibe on lipid levels and outcomes.
METHODS AND RESULTS: MEDLINE/PubMed, Cochrane CENTRAL, and ClinicalTrials.gov were searched for RCTs assessing PCSK9 inhibitors vs. other therapies in patients with primary hypercholesterolaemia. Network meta-analysis with both a frequentist approach and a Bayesian framework was performed to directly and indirectly compare PCSK9 inhibition on lipid levels with ezetimibe and placebo. Odds ratios with 95% confidence intervals (OR [95% CIs]) were generated with random-effects models to compare outcomes. Our meta-analysis included 17 RCTs with 13 083 patients that were randomized to PCSK9 inhibitors (n = 8250), placebo (n = 3957), ezetimibe (n = 846), or PCSK9 inhibitors and ezetimibe (n = 30). The mean age was 59 ± 10, 52% were male, 34% had coronary artery disease, 51% had hypertension, 19% had diabetes mellitus, baseline LDL of 122 ± 36 mg/dL, total cholesterol of 199 ± 39 mg/dL, and HDL of 51 ± 14 mg/dL. inhibitors significantly reduced LDL cholesterol by 57% relative to placebo (P < 0.001) and 36.1% relative to ezetimibe (P < 0.001). Proprotein convertase subtilisin-kexin type 9 serine protease inhibitors reduced the incidence of all-cause mortality [OR 0.43 (95% CI 0.22-0.82), P = 0.01] but was associated with an increased incidence of neurocognitive adverse events [OR 2.34 (95% CI 1.11-4.93), I(2) = 4%, P = 0.02] when compared with placebo.
CONCLUSION: Proprotein convertase subtilisin-kexin type 9 serine protease inhibition significantly improved lipid profiles and reduced the incidence of all-cause mortality compared with placebo but had a higher rate of neurocognitive adverse events. Thus, PCSK9 inhibitor therapy may serve as an alternative for patients with statin intolerance and for those who do not respond to other lipid reduction therapy.
