Efficacy and safety of alirocumab in insulin-treated patients with type 1 or type 2 diabetes and high cardiovascular risk: Rationale and design of the ODYSSEY DM–INSULIN trial

AimsThe coadministration of alirocumab, a PCSK9 inhibitor for treatment of hypercholesterolaemia, and insulin in diabetes mellitus (DM) requires further study. Described here is the rationale behind a phase-IIIb study designed to characterize the efficacy and safety of alirocumab in insulin-treated patients with type 1 (T1) or type 2 (T2) DM with hypercholesterolaemia and high cardiovascular (CV) risk.MethodsODYSSEY DM–INSULIN (NCT02585778) is a randomized, double-blind, placebo-controlled, multicentre study that planned to enrol around 400 T2 and up to 100 T1 insulin-treated DM patients. Participants had low-density lipoprotein cholesterol (LDL-C) levels at screening ≥ 70 mg/dL (1.81 mmol/L) with stable maximum tolerated statin therapy or were statin-intolerant, and taking (or not) other lipid-lowering therapy; they also had established CV disease or at least one additional CV risk factor. Eligible patients were randomized 2:1 to 24 weeks of alirocumab 75 mg every 2 weeks (Q2W) or a placebo. Alirocumab-treated patients with LDL-C ≥ 70 mg/dL at week 8 underwent a blinded dose increase to 150 mg Q2W at week 12. Primary endpoints were the difference between treatment arms in percentage change of calculated LDL-C from baseline to week 24, and alirocumab safety.ResultsThis is an ongoing clinical trial, with 76 T1 and 441 T2 DM patients enrolled; results are expected in mid-2017.ConclusionThe ODYSSEY DM–INSULIN study will provide information on the efficacy and safety of alirocumab in insulin-treated individuals with T1 or T2 DM who are at high CV risk and have hypercholesterolaemia not adequately controlled by the maximum tolerated statin therapy.     

High-Density Lipoprotein Particle Subfractions in Heart Failure With Preserved or Reduced Ejection Fraction

Background

Circulating high-density lipoprotein particle (HDL-P) subfractions impact atherogenesis, inflammation, and endothelial function, all of which are implicated in the pathobiology of heart failure (HF).

Clinical- and cost-effectiveness of LDL particle-guided statin therapy: A simulation study

We used the Archimedes Model, a mathematical simulation model (Model) to estimate the clinical- and cost-effectiveness of using LDL particle concentration (LDL-P) as an adjunct or alternative to LDL cholesterol (LDL-C) to guide statin therapy. LDL-P by NMR has been shown to be a better measure of cardiovascular disease (CVD) risk than LDL-C, and may therefore be a better gauge of the need for and response to statin treatment. Using the Model, we conducted a virtual clinical trial comparing the use of LDL-C alone, LDL-P alone, and LDL-C and LDL-P together to guide treatment in the general adult population, and in high-risk, dyslipidemic subpopulations. In the general population, the 5-year major adverse cardiovascular event (MACE) relative risk reduction (RRR) of LDL-P alone compared to the control arm (LDL-C alone) was 5.0% (95% CI, 4.7–5.3; p < .0001); using both LDL-C and LDL-P (dual markers) led to 3.0% RRR compared to the control arm (95% CI, 2.8–3.3; p < .0001). For individuals with diabetes, the RRR was 7.3% (95% CI, 6.4–8.2; p < .0001) for LDL-P alone and 6.9% for dual markers (95% CI, 6.1–7.8; both, p < .0001).     

Beyond low-density lipoprotein cholesterol: defining the role of low-density lipoprotein heterogeneity in coronary artery disease

Recent clinical trials in patients with coronary artery disease (CAD) provide evidence that low-density lipoprotein cholesterol (LDL-C) levels should be lowered even further to prevent recurrent CAD. However, despite more aggressive interventions for lowering LDL-C levels, the majority of CAD events go undeterred, perhaps related to the fact that intervention was not started earlier in life or that LDL-C levels represent an incomplete picture of atherogenic potential. Nevertheless, LDL-C remains the contemporary standard as the primary goal for aggressive LDL reduction. If triglycerides are >200 mg/dl, the measurement of non-high-density lipoprotein cholesterol (HDL-C) is recommended. Measurement of apolipoprotein (apo)B has been shown in nearly all studies to outperform LDL-C and non-HDL-C as a predictor of CAD events and as an index of residual CAD risk. This is because apoB reflects the total number of atherogenic apoB-containing lipoproteins and is a superior predictor of the number of low-density lipoprotein particles (LDL-P). Estimates of LDL-P and size can also be made by nuclear magnetic resonance spectroscopy, density gradient ultracentrifugation, and gradient gel electrophoresis. Although a number of studies show that such estimates predict CAD, LDL-P, and size often accompany low HDL-C and high triglyceride levels, and therefore such additional lipoprotein testing has not been recommended for routine screening and follow-up. Because apoB is a superior predictor of LDL-P, we recommend that apoB and the apoB/apoA-I ratio be determined after measurement of LDL-C, non-HDL-C, and the ratio of total cholesterol/HDL-C to better predict CAD and assess efficacy of treatment.