Abstract
Aims/hypothesisThe study aimed to examine the efficacy of 12 weeks of monthly evolocumab or placebo in lowering LDL-cholesterol (LDL-C) in individuals with type 2 diabetes and hypercholesterolaemia or mixed dyslipidaemia and on a maximum-tolerated statin of at least moderate intensity.MethodsFor this randomised, placebo-controlled outpatient study, eligible individuals were ≥18 years old with type 2 diabetes, HbA1c <10% (86 mmol/mol), had been on stable pharmacological therapy for diabetes for ≥6 months and were taking a maximum-tolerated statin dose of at least moderate intensity. Lipid eligibility criteria varied by history of clinical cardiovascular disease. Participants were randomised 2:1 to evolocumab 420 mg s.c. or placebo. Randomisation was performed centrally via an interactive web-based or voice recognition system. Allocation was concealed using the centralised randomisation process. Treatment assignment was blinded to the sponsor study team, investigators, site staff and patients throughout the study. Co-primary endpoints were mean percentage change in LDL-C from baseline to week 12 and to the mean of weeks 10 and 12. Additional endpoints included LDL-C <1.81 mmol/l, LDL-C reduction ≥50% and other lipids. Exploratory analyses included percentage changes in fasting and post mixed-meal tolerance test (MMTT) lipoproteins and lipids, glucose metabolism variables and inflammatory biomarkers.ResultsIn total, 421 individuals were randomised and analysed, having received evolocumab (280 participants) or placebo (141 participants) (mean [SD] age 62 [8] years; 44% women; 77% white). Evolocumab decreased LDL-C by 54.3% (1.4%) at week 12 (vs 1.1% [1.9%] decrease with placebo; p < 0.0001) and by 65.0% (1.3%) at the mean of weeks 10 and 12 (vs 0.8% [1.8%] decrease with placebo; p < 0.0001); it also decreased non-HDL-cholesterol (HDL-C) by 46.9% (1.3%) at week 12 (vs 0.6% [1.8%] decrease with placebo) and by 56.6% (1.2%) at the mean of weeks 10 and 12 (vs 0.1% [1.6%] decrease with placebo). Evolocumab significantly improved levels of other lipids and allowed more participants to reach LDL-C <1.81 mmol/l or a reduction in LDL-C levels ≥50%. After an MMTT (120 min), there were favourable changes (p < 0.05; nominal, post hoc, no multiplicity adjustment) in chylomicron triacylglycerol (triglycerides), chylomicron cholesterol, VLDL-C and LDL-C. Evolocumab had no effect on glycaemic variables and was well tolerated.Conclusions/interpretationIn statin-treated individuals with type 2 diabetes and hypercholesterolaemia or mixed dyslipidaemia, evolocumab significantly reduced LDL-C and non-HDL-C. Favourable changes (p < 0.05) were observed in postprandial levels of chylomicrons, VLDL-C and LDL-C.Trial registrationClinicalTrials.gov NCT02739984FundingThis study was funded by Amgen Inc.Data availabilityQualified researchers may request data from Amgen clinical studies. Complete details are available at www.amgen.com/datasharing.
Highlights
The prevalence of diabetes mellitus has increased progressively worldwide over the past several decades [1, 2], and diabetes mellitus is associated with an increased risk for cardiovascular disease (CVD) morbidity and mortality [3, 4]
The secondary objectives were to assess the effects of 12 weeks of treatment with monthly evolocumab compared with monthly placebo on: (1) change in LDL-C from baseline and the percentage change in non-HDL-C, apolipoprotein B (ApoB), total cholesterol, lipoprotein(a) (Lp(a)), triacylglycerol, HDL-C and VLDL cholesterol (VLDL-C); (2) percentage of participants achieving LDL-C
Persistent elevations in LDL-C and nonHDL-C may derive from insufficient LDL-C-lowering efficacy with moderate- to high-intensity statins, lack of statin titration in individuals with diabetes mellitus taking a low- to moderate-intensity statin who are not titrated to a highintensity dosage [7] or statin-associated adverse events (AEs) [11]
Summary
The prevalence of diabetes mellitus has increased progressively worldwide over the past several decades [1, 2], and diabetes mellitus is associated with an increased risk for cardiovascular disease (CVD) morbidity and mortality [3, 4]. Individuals with diabetes mellitus who experience an acute myocardial infarction (MI) are at higher risk for recurrent cardiovascular events and mortality compared with their counterparts without diabetes mellitus [3, 4], and require an aggressive treatment approach [5,6,7]. In the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial (ClinicalTrials.gov NCT01764633), the use of evolocumab 140 mg every 2 weeks or 420 mg once every month was associated with similar reductions in both LDL-C levels and the risk of incident cardiovascular events in individuals with or without diabetes [8]. The evolocumaB efficAcy aNd safeTy IN type 2 diabetes mellitus on backGround statin therapy (BANTING) study (NCT02739984) aimed to examine the efficacy of a 12 week regimen of s.c. evolocumab 420 mg once monthly compared with placebo in lowering LDL-C and improving other lipid levels in individuals with type 2 diabetes and hypercholesterolaemia or mixed dyslipidaemia taking maximally tolerated background statin therapy of at least moderate intensity
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