AimsTo investigate the efficacy and safety of alirocumab in participants with type 2 (T2D) or type 1 diabetes (T1D) treated with insulin who have elevated LDL cholesterol levels despite maximally tolerated statin therapy.MethodsParticipants at high cardiovascular risk with T2D (n = 441) or T1D (n = 76) and LDL cholesterol levels ≥1.8 mmol/L (≥70 mg/dL) were randomized 2:1 to alirocumab:placebo administered subcutaneously every 2 weeks, for 24 weeks' double‐blind treatment. Alirocumab‐treated participants received 75 mg every 2 weeks, with blinded dose increase to 150 mg every 2 weeks at week 12 if week 8 LDL cholesterol levels were ≥1.8 mmol/L. Primary endpoints were percentage change in calculated LDL cholesterol from baseline to week 24, and safety assessments.ResultsAlirocumab reduced LDL cholesterol from baseline to week 24 by a mean ± standard error of 49.0% ± 2.7% and 47.8% ± 6.5% vs placebo (both P < .0001) in participants with T2D and T1D, respectively. Significant reductions were observed in non‐HDL cholesterol (P < .0001), apolipoprotein B (P < .0001) and lipoprotein (a) (P ≤ .0039). At week 24, 76.4% and 70.2% of the alirocumab group achieved LDL cholesterol <1.8 mmol/L in the T2D and T1D populations (P < .0001), respectively. Glycated haemoglobin and fasting plasma glucose levels remained stable for the study duration. Treatment‐emergent adverse events were observed in 64.5% of alirocumab‐ vs 64.1% of placebo‐treated individuals (overall population).ConclusionsAlirocumab produced significant LDL cholesterol reductions in participants with insulin‐treated diabetes regardless of diabetes type, and was generally well tolerated. Concomitant administration of alirocumab and insulin did not raise any safety concerns (NCT02585778).

AimTo compare alirocumab, a proprotein convertase subtilisin‐kexin type 9 inhibitor, with usual care (UC) in individuals with type 2 diabetes (T2DM) and mixed dyslipidaemia not optimally managed by maximally tolerated statins in the ODYSSEY DM‐DYSLIPIDEMIA trial (NCT02642159).Materials and MethodsThe UC options (no additional lipid‐lowering therapy; fenofibrate; ezetimibe; omega‐3 fatty acid; nicotinic acid) were selected prior to stratified randomization to open‐label alirocumab 75 mg every 2 weeks (with increase to 150 mg every 2 weeks at week 12 if week 8 non‐HDL cholesterol concentration was ≥2.59 mmol/L [100 mg/dL]) or UC for 24 weeks. The primary efficacy endpoint was percentage change in non‐HDL cholesterol from baseline to week 24.ResultsThe randomized population comprised 413 individuals (intention‐to‐treat population, n = 409; safety population, n = 412). At week 24, the mean non‐HDL cholesterol reductions were superior with alirocumab (−32.5% difference vs UC, 97.5% confidence interval −38.1 to −27.0; P < .0001). Overall, 63.6% of alirocumab‐treated individuals were maintained on 75 mg every 2 weeks. Alirocumab also reduced LDL cholesterol (−43.0%), apolipoprotein B (−32.3%), total cholesterol (−24.6%) and LDL particle number (−37.8%) at week 24 vs UC (all P < .0001). Consistent with the overall trial comparison, alirocumab reduced non‐HDL cholesterol to a greater degree within each UC stratum at week 24. The incidence of treatment‐emergent adverse events was 68.4% (alirocumab) and 66.4% (UC). No clinically meaningful effect on glycated haemoglobin, or change in number of glucose‐lowering agents, was seen.ConclusionsIn individuals with T2DM and mixed dyslipidaemia on maximally tolerated statin, alirocumab showed superiority to UC in non‐HDL cholesterol reduction and was generally well tolerated.

AimThis sub‐analysis of the ODYSSEY COMBO II study compared the effects of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in high cardiovascular risk patients with or without diabetes mellitus (DM) receiving maximally tolerated statin therapy.Methods COMBO II was a 104‐week, double‐blind study (n = 720) enrolling patients with documented atherosclerotic cardiovascular disease (ASCVD) and baseline LDL‐C ≥70 mg/dL (1.8 mmol/L), and patients without documented ASCVD at high cardiovascular risk with LDL‐C ≥100 mg/dL (2.6 mmol/L). Patients receiving maximally tolerated statin therapy were randomized (2:1) to alirocumab 75 mg every 2 weeks (Q2W; 1 mL subcutaneous injection) or oral ezetimibe 10 mg daily. Alirocumab dose was increased to 150 mg Q2W (also 1 mL) at Week 12 if Week 8 LDL‐C was ≥70 mg/dL.ResultsHistory of DM was reported in 31% (n = 148) of patients on alirocumab and 32% (n = 77) of patients on ezetimibe. At Week 24, alirocumab consistently reduced LDL‐C from baseline in patients with (−49.1%) or without DM (−51.2%) to a significantly greater extent than ezetimibe (−18.4% and −21.8%, respectively). Occurrence of treatment‐emergent adverse events was similar between groups. Efficacy results at 104 weeks were similar to those at 24 weeks.ConclusionsOver a 104‐week double‐blind study period, alirocumab provided consistently greater LDL‐C reductions than ezetimibe, with similar LDL‐C results in patients with or without DM. Safety of alirocumab was similar regardless of baseline DM status.

1 Phencyclidine (PCP) is widely used as an animal model of schizophrenia. The aim of this study was to better understand the role of nitric oxide (NO) in the mechanism of action of PCP and to determine whether positive NO modulators may provide a new approach to the treatment of schizophrenia. 2 The eects of the NO donor, sodium nitroprusside (SNP), were studied in PCP-treated rats. Following drug administration, behavioural changes and the expression of c-fos, a metabolic marker of functional pathways in the brain, were simultaneously monitored. 3 Acute PCP (5 mg kg 71 , i.p.) treatment induced a complex behavioural syndrome, consisting of hyperlocomotion, stereotyped behaviours and ataxia. Treatment with SNP (2 ± 6 mg kg 71 , i.p.) by itself produced no eect on any behaviour studied but completely abolished PCP-induced behaviour in a dose-and time-dependent manner. 4 PCP had dierential regional eects on c-fos expression in rat brain, suggesting regionally dierent patterns of neuronal activity. The most prominent immunostaining was observed in the cortical regions. Pre-treatment with SNP blocked PCP-induced c-fos expression at doses similar to those that suppress PCP-induced behavioural eects. 5 These results implicate the NO system in the mechanism of action of PCP. The fact that SNP abolished eects of PCP suggests that drugs targeting the glutamate-NO system may represent a novel approach to the treatment of PCP-induced psychosis and schizophrenia.

Analysis of 10 phase 3 ODYSSEY trials, alirocumab (ALI) vs. placebo or ezetimibe. • Median lipoprotein(a) [Lp(a)] reductions: ALI (21.4-25.6%) vs. control (0.0-2.5%).• Adjusted by baseline characteristics, 12% RRR in MACE per 25% reduction in Lp(a); p = 0.0254. • Adjusted by LDL-C reductions, RRR was not significant; hazard ratio = 0.89, p = 0.0780. • Fully adjusted RRR significant if baseline Lp(a) ≥ vs. < 50 mg/dL; p-interaction 0.0549. A R T I C L E I N F O Keywords: PCSK9 Alirocumab lipoprotein(a) Low-density lipoprotein cholesterol Cardiovascular risk Cholesterol-lowering drugs A B S T R A C TBackground and aims: Elevated lipoprotein(a) [Lp(a)] levels are considered a causal factor for cardiovascular disease. In phase 3 ODYSSEY trials, alirocumab reduced levels of low-density lipoprotein cholesterol (LDL-C) and Lp(a), with concomitant reductions in the risk of major adverse cardiovascular events (MACE). We assessed whether lower on-study and greater percentage reductions in Lp(a) are associated with a lower risk of MACE. Methods: Post-hoc analysis of data pooled from 10 phase 3 ODYSSEY trials comparing alirocumab with control (placebo or ezetimibe) in patients (n = 4983) with cardiovascular disease and/or risk factors, and hypercholesterolemia despite statin/other lipid-lowering therapies. Results: Median (Q1, Q3) baseline Lp(a) levels were 23.5 (8.0, 67.0) mg/dL. Median Lp(a) changes from baseline with alirocumab were −25.6% vs. −2.5% with placebo (absolute reductions 6.8 vs. 0.5 mg/dL) in placebocontrolled trials, and −21.4% vs. 0.0% with ezetimibe (4.5 vs. 0.0 mg/dL) in ezetimibe-controlled trials. During follow-up (6699 patient-years), 104 patients experienced MACE. A 12% relative risk reduction in MACE per 25% reduction in Lp(a) (p=0.0254) was no longer significant after adjustment for LDL-C changes: hazard ratio per 25% reduction: 0.89 (95% confidence interval, 0.79-1.01; p=0.0780). In subgroup analysis, the association between Lp(a) reduction and MACE remained significant in a fully adjusted model among participants with baseline Lp(a) ≥50 mg/dL (p-interaction vs. Lp(a) < 50 mg/dL: 0.0549). Conclusions: In this population, Lp(a) reductions were not significantly associated with MACE independently of LDL-C reductions. Reducing the risk of MACE by targeting Lp(a) may require greater reductions in Lp(a) with more potent therapies and/or higher initial Lp(a) levels.