S-EPMC6175384 - Efficacy and safety of alirocumab among individuals with diabetes mellitus and atherosclerotic cardiovascular disease in the ODYSSEY phase 3 trials. - OmicsDI

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

ABSTRACT: AIMS:Individuals with both diabetes mellitus (DM) and atherosclerotic cardiovascular disease (ASCVD) are at very high risk of cardiovascular events. This post-hoc analysis evaluated efficacy and safety of the PCSK9 inhibitor alirocumab among 984 individuals with DM and ASCVD pooled from 9 ODYSSEY Phase 3 trials. MATERIALS AND METHODS:Changes in low-density lipoprotein cholesterol (LDL-C) and other lipids from baseline to Week 24 were analysed (intention-to-treat) in four pools by alirocumab dosage (150 mg every 2 weeks [150] or 75 mg with possible increase to 150 mg every 2 weeks [75/150]), control (placebo/ezetimibe) and background statin usage (yes/no). RESULTS:At Week 24, LDL-C changes from baseline in pools with background statins were -61.5% with alirocumab 150 (vs -1.0% with placebo), -46.4% with alirocumab 75/150 (vs +6.3% with placebo) and -48.7% with alirocumab 75/150 (vs -20.6% with ezetimibe), and -54.9% with alirocumab 75/150 (vs +4.0% with ezetimibe) without background statins. A greater proportion of alirocumab recipients achieved LDL-C < 70 and < 55 mg/dL at Week 24 vs controls. Alirocumab also resulted in significant reductions in non-high-density lipoprotein cholesterol, apolipoprotein B and lipoprotein(a) vs controls. Alirocumab did not appear to affect glycaemia over 78-104 weeks. Overall safety was similar between treatment groups, with a higher injection-site reaction frequency (mostly mild) with alirocumab. CONCLUSION:Alirocumab significantly reduced LDL-C and other atherogenic lipid parameters, and was generally well tolerated in individuals with DM and ASCVD.

SUBMITTER: Ganda OP

PROVIDER: S-EPMC6175384 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Ganda Om P OP Plutzky Jorge J Sanganalmath Santosh K SK Bujas-Bobanovic Maja M Koren Andrew A Mandel Jonas J Letierce Alexia A Leiter Lawrence A LA

Diabetes, obesity & metabolism 20180702 10

<h4>Aims</h4>Individuals with both diabetes mellitus (DM) and atherosclerotic cardiovascular disease (ASCVD) are at very high risk of cardiovascular events. This post-hoc analysis evaluated efficacy and safety of the PCSK9 inhibitor alirocumab among 984 individuals with DM and ASCVD pooled from 9 ODYSSEY Phase 3 trials.<h4>Materials and methods</h4>Changes in low-density lipoprotein cholesterol (LDL-C) and other lipids from baseline to Week 24 were analysed (intention-to-treat) in four pools by ...[more]

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Project description:BACKGROUND:Individuals with diabetes often have high levels of atherogenic lipoproteins and cholesterol reflected by elevated low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and LDL particle number (LDL-PN). The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events. We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778). METHODS:In DM-DYSLIPIDEMIA, individuals with T2DM and mixed dyslipidemia (non-HDL-C???100 mg/dL; n?=?413) were randomized to open-label alirocumab 75 mg every 2 weeks (Q2W) or usual care (UC) for 24 weeks, with UC options selected before stratified randomization. In DM-INSULIN, insulin-treated individuals with T2DM (LDL-C???70 mg/dL; n?=?441) were randomized in a double-blind fashion to alirocumab 75 mg Q2W or placebo for 24 weeks. Study participants also had a glycated hemoglobin?<?9% (DM-DYSLIPIDEMIA) or?<?10% (DM-INSULIN). Alirocumab dose was increased to 150 mg Q2W at week 12 if week 8 LDL-C was???70 mg/dL (DM-INSULIN) or non-HDL-C was???100 mg/dL (DM-DYSLIPIDEMIA). Lipid reductions and safety were assessed in patients with ASCVD from these studies. RESULTS:This analysis included 142 DM-DYSLIPIDEMIA and 177 DM-INSULIN participants with ASCVD, including 95.1% and 86.4% with coronary heart disease, and 32.4% and 49.7% with microvascular diabetes complications, respectively. At week 24, alirocumab significantly reduced LDL-C, non-HDL-C, ApoB, and LDL-PN from baseline versus control. This translated into a greater proportion of individuals achieving non-HDL-C?<?100 mg/dL (64.6% alirocumab/23.8% UC [DM-DYSLIPIDEMIA]; 65.4% alirocumab/14.9% placebo [DM-INSULIN]) and ApoB?<?80 mg/dL (75.1% alirocumab/35.4% UC and 76.8% alirocumab/24.8% placebo, respectively) versus control at week 24 (all P?<?0.0001). In pooling these studies, 66.4% (alirocumab) and 67.0% (control) of individuals reported treatment-emergent adverse events. The adverse event pattern was similar with alirocumab versus controls. CONCLUSIONS:Among individuals with T2DM and ASCVD who had high non-HDL-C/LDL-C levels despite maximally tolerated statin, alirocumab significantly reduced atherogenic cholesterol and LDL-PN versus control. Alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov. NCT02642159. Registered 30 December 2015 and Clinicaltrials.gov. NCT02585778. Registered 23 October 2015.

Project description:Type 2 diabetes mellitus (T2DM) is often associated with mixed dyslipidaemia, where non-high-density lipoprotein cholesterol (non-HDL-C) levels may more closely align with cardiovascular risk than low-density lipoprotein cholesterol (LDL-C). We describe the design and rationale of the ODYSSEY DM-DYSLIPIDEMIA study that assesses the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, versus lipid-lowering usual care in individuals with T2DM and mixed dyslipidaemia at high cardiovascular risk with non-HDL-C inadequately controlled despite maximally tolerated statin therapy. For the first time, atherogenic cholesterol-lowering with a PCSK9 inhibitor will be assessed with non-HDL-C as the primary endpoint with usual care as the comparator.DM-DYSLIPIDEMIA is a Phase 3b/4, randomised, open-label, parallel group, multinational study that planned to enrol 420 individuals. Main inclusion criteria were T2DM and mixed dyslipidaemia (non-HDL-C ?100 mg/dl [?2.59 mmol/l], and triglycerides ?150 and <500 mg/dl [?1.70 and <5.65 mmol/l]) with documented atherosclerotic cardiovascular disease or ?1 additional cardiovascular risk factor. Participants were randomised (2:1) to alirocumab 75 mg every 2 weeks (Q2W) or lipid-lowering usual care on top of maximally tolerated statin (or no statin if intolerant). If randomised to usual care, investigators were able to add their pre-specified choice of one of the following to the patient's current statin regimen: ezetimibe, fenofibrate, omega-3 fatty acids or nicotinic acid, in accordance with local standard-of-care. Alirocumab-treated individuals with non-HDL-C ?100 mg/dl at week 8 will undergo a blinded dose increase to 150 mg Q2W at week 12. The primary efficacy endpoint is non-HDL-C change from baseline to week 24 with alirocumab versus usual care; other lipid levels (including LDL-C), glycaemia-related measures, safety and tolerability will also be assessed. Alirocumab will be compared to fenofibrate in a secondary analysis.Recruitment completed with 413 individuals randomised in 14 countries worldwide. Results of this trial are expected in the second quarter of 2017.ODYSSEY DM-DYSLIPIDEMIA will provide information on the efficacy and safety of alirocumab versus lipid-lowering usual care in individuals with T2DM and mixed dyslipidaemia at high cardiovascular risk using non-HDL-C as the primary efficacy endpoint. Trial registration NCT02642159 (registered December 24, 2015).

Project description:AimsGuidelines recommend targeting non-high-density lipoprotein cholesterol to reduce cardiovascular risk. We assessed the impact of baseline triglycerides on non-high-density lipoprotein cholesterol goal attainment in 10 phase 3 trials with alirocumab versus control (n = 4983).MethodsTrials were grouped into four pools based on alirocumab dose (75-150 mg every 2 weeks), control (placebo/ezetimibe) and statin use. Baseline triglyceride quintiles were built within each pool. Non-high-density lipoprotein cholesterol goal attainment (very high risk: <100 mg/dl; moderate/high risk: <130 mg/dl), low-density lipoprotein cholesterol goal attainment (very high risk: <70 mg/dl; moderate/high risk: <100 mg/dl) and changes from baseline in lipid parameters were assessed at Week 24 among baseline triglyceride quintiles.ResultsHigher baseline triglycerides were associated with a worse cardiovascular risk profile. Low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol increased with higher triglycerides, but the magnitude in non-high-density lipoprotein cholesterol was three- to four-fold higher compared with the increase in low-density lipoprotein cholesterol. Non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol percentage reductions from baseline with alirocumab were similar regardless of baseline triglycerides. A greater proportion of alirocumab-treated patients attained non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol goals compared with placebo or ezetimibe. Unlike low-density lipoprotein cholesterol goal attainment, non-high-density lipoprotein cholesterol goal attainment significantly declined with increasing baseline triglycerides (p < 0.05 for trend tests). A single standard deviation increase in baseline log(triglycerides) was significantly associated with lower odds ratios of attaining non-high-density lipoprotein cholesterol goals in the different pools and treatment (alirocumab/placebo/ezetimibe) groups, unlike low-density lipoprotein cholesterol goal attainment.ConclusionIndividuals with increased triglycerides have higher non-high-density lipoprotein cholesterol levels and lower rates of non-high-density lipoprotein cholesterol goal attainment (unlike low-density lipoprotein cholesterol goal attainment). Alirocumab improves non-high-density lipoprotein cholesterol goal attainment in this population. These results highlight the impact of triglycerides on non-high-density lipoprotein cholesterol and the need for novel therapies targeting triglyceride-related pathways.