Sabatine MS, et al. - The clinicians aimed to examine the efficacy and safety of evolocumab by diabetes status and the effect of evolocumab on glycaemia and risk of developing diabetes in this prespecified analysis of FOURIER. Among patients with and without diabetes, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition with evolocumab significantly reduced cardiovascular risk. Evolocumab did not increase the risk of new-onset diabetes, nor did it worsen glycaemia. These data proposed evolocumab use in patients with the atherosclerotic disease was efficacious and safe in patients with and without diabetes.

Methods

• FOURIER was a randomised trial of evolocumab (140 mg every 2 weeks or 420 mg once per month) vs placebo given to 27,564 patients with atherosclerotic disease who were on statin therapy, followed up for a median of 2·2 years.
• The clinicians examined the effect of evolocumab on cardiovascular events by diabetes status at baseline, defined on the basis of patient history, clinical events committee review of medical records, or baseline HbA_1c of 6·5% (48 mmol/mol) or greater or fasting plasma glucose (FPG) of 7·0 mmol/L or greater, in this prespecified analysis.
• A composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularization was the primary endpoint.
• A composite of cardiovascular death, myocardial infarction, or stroke was the key secondary endpoint.
• Furthermore, they evaluated the effect of evolocumab on glycaemia, and on the risk of new-onset diabetes among patients without diabetes at baseline.
• They measured HbA_1c at baseline then every 24 weeks and FPG at baseline, week 12, week 24, and every 24 weeks thereafter.
• Potential cases of new-onset diabetes were adjudicated centrally.
• They examined the effects on glycaemia and diabetes risk in patients with prediabetes (HbA_1c 5·7–6·4% [39–46 mmol/mol] or FPG 5·6–6·9 mmol/L) at baseline, in a post-hoc analysis.

Results

• A total of 11,031 patients (40%) had diabetes and 16,533 (60%) did not have diabetes (of whom 10,344 had prediabetes and 6,189 had normoglycaemia), at study baseline.
• In patients with and without diabetes at baseline, evolocumab significantly reduced cardiovascular outcomes consistently.
• The hazard ratios (HRs) were 0·83 (95% CI 0·75–0·93; p=0·0008) for patients with diabetes and 0·87 (0·79-0·96; p=0·0052) for patients without diabetes (p_interaction=0·60) were included as the primary composite endpoint.
• The HRs were 0·82 (0·72–0·93; p=0·0021) for those with diabetes and 0·78 (0·69–0·89; p=0·0002) for those without diabetes (p_interaction=0·65) comprised of the key secondary endpoint.
• In patients without diabetes at baseline (HR 1·05, 0·94-1·17), evolocumab did not increase the risk of new-onset diabetes, including in those with prediabetes (HR 1·00, 0·89-1·13).
• In patients with diabetes, prediabetes, or normoglycaemia, levels of HbA_1c and FPG were similar between the evolocumab and placebo groups over time.
• The proportions of patients with adverse events were 78·5% (4,327 of 5,513 patients) in the evolocumab group and 78·3% (4,307 of 5,502 patients) in the placebo group, among patients with diabetes at baseline.
• The proportions of adverse events were 76·8% (6,337 of 8,256 patients) in the evolocumab group and 76·8% (6,337 of 8,254 patients) in the placebo group, among patients without diabetes at baseline.