Aim
To assess the lipid‐lowering efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in people with hypercholesterolaemia and prediabetes at baseline ...vs people with normoglycaemia at baseline in a pooled analysis of 10 ODYSSEY phase III trials.
Methods
People classified as having prediabetes had baseline HbA1c ≥39 mmol/mol (5.7%) and <48 mmol/mol (6.5%), or two baseline fasting plasma glucose values ≥5.6 mmol/l (100 mg/dl) but no more than one fasting plasma glucose value ≥7.0 mmol/l (126 mg/dl), or had specific terms reported in their medical history; people diagnosed with diabetes at baseline were excluded, and the remainder were classified as having normoglycaemia. Participants received alirocumab or control (placebo/ezetimibe) for 24–104 weeks, with maximally tolerated statin in most cases. The primary efficacy endpoint was LDL cholesterol reductions from baseline to week 24 in the intention‐to‐treat population using the mixed‐effect model with a repeated measures approach.
Results
Reductions in LDL cholesterol from baseline to week 24 with alirocumab were 44.0–61.8% (prediabetes group) and 45.8–59.5% (normoglycaemia group). In both subgroups, LDL cholesterol reductions were generally similar in those with and without baseline triglycerides ≥1.7 mmol/l (150 mg/dl). Alirocumab was not associated with changes in HbA1c or fasting plasma glucose over time in either subgroup (up to 24 months' follow‐up). Adverse event rates were generally similar in those with and without prediabetes.
Conclusions
Over a mean follow‐up of 24–104 weeks, alirocumab treatment resulted in significant LDL cholesterol reductions from baseline that were similar in participants with prediabetes and those with normoglycaemia at baseline, with no effect on glycaemia and a safety profile similar to that of the control.
What's new?
With statins being associated with an increased risk of diabetes (especially in individuals with risk factors for diabetes) and recent studies linking PCSK9 to glucose homeostasis, there is much interest in whether PCSK9 inhibitors affect diabetes risk.
We assessed the efficacy/safety of alirocumab, a PCSK9 inhibitor, vs control over a mean follow‐up of 24–104 weeks in people with hypercholesterolaemia and prediabetes vs people with normoglycaemia at baseline from 10 ODYSSEY phase III trials.
Our findings show alirocumab is generally well tolerated and significantly reduced LDL cholesterol levels to similar extents in individuals with prediabetes and those with normoglycaemia without any changes in measures of glycaemic control.
Aim
To evaluate the safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab according to diabetes mellitus status.
Methods
Safety data from 14 trials (8–104‐week ...durations) were analysed by treatment (alirocumab or placebo/ezetimibe control) and diabetes status (yes/no, defined by medical history). Adverse event data were assessed using descriptive statistics and Cox models.
Results
Of the 5234 trial participants, 1554 (29.7%) had diabetes. Overall, treatment‐emergent adverse events were similar in the alirocumab and control groups, except for more frequent local injection site reactions with alirocumab. Fewer people with diabetes experienced local injection site reactions alirocumab, 3.5%, control, 2.9%; hazard ratio 1.24 (95% CI 0.68–2.25) than those without diabetes alirocumab, 7.5%; control, 4.9%; hazard ratio 1.51 (95% CI 1.13–2.01). Those with diabetes reported a greater number of serious adverse events (alirocumab, 19.4%; control, 19.7%) than those without diabetes (alirocumab, 14.5%; control, 13.5%). In people with diabetes, major adverse cardiac events occurred in 2.7% of alirocumab‐treated people control, 3.3%; hazard ratio 0.74 (95% CI 0.41–1.35); in those without diabetes, 1.8% of alirocumab‐treated people had major adverse cardiac events control, 1.7%; hazard ratio 0.95 (95% CI 0.56–1.62). Overall, no increase in HbA1c or fasting plasma glucose vs control treatment groups was observed, regardless of diabetes status.
Conclusion
This pooled analysis across 14 trials demonstrated similar safety for alirocumab vs control treatment, irrespective of diabetes status, except for more frequent local injection site reactions with alirocumab. People with diabetes reported fewer local injection site reactions than those without diabetes.
What's new?
People with diabetes are at high cardiovascular risk and may require additional lipid‐lowering beyond statins. PCSK9 inhibitors provide additional LDL cholesterol reductions, but their safety has not been fully evaluated by diabetes status.
Our pooled analysis of 14 phase 2/3 trials is the largest safety assessment of the PCSK9 inhibitor alirocumab in terms of study participant numbers (n = 5234), comparing those with vs without diabetes at baseline over 8–104 weeks of treatment.
Our findings show comparable safety for alirocumab vs control, irrespective of diabetes status, except for more frequent local injection site reactions with alirocumab; people with diabetes reported fewer local injection site reactions than those without. No clinically significant changes in glycaemic variables (fasting plasma glucose and HbA1c) were observed in people with or without diabetes, regardless of treatment with alirocumab or control.
The authors studied the psychosocial adjustment of pediatric liver transplant (LT) recipients reaching adulthood. The study comprised phone interviews of 116 volunteers aged 17–33 years. Results were ...compared to those for healthy peers and 65 patients who were eligible for inclusion but did not participate. Participants’ median age at LT was 6 years and the median period since LT was 15 years. Of the 116 participants, 76% considered their quality of life as good or very good. Seventy‐five patients (65%) were attending schools, 27 of whom were 2 years or more below the age‐appropriate level. Of the remaining 41 patients, 26 had a job and 15 were unemployed. Poor compliance with medications was reported by 52 patients (45%). Alcohol consumption was lower than in the reference population (p < 0.001). Anxiety, loneliness and negative thoughts were expressed by 53, 84 and 47% of the participants, respectively. Thirteen patients (11%) were being cared for by psychologists or psychiatrists. The 65 nonparticipants had greater psychological problems than the participants, and a lower educational level. In conclusion, after LT in early life, most patients displayed psychological vulnerability during early adulthood. The educational level of patients was lower than that of theirs peers.
Investigation of the current life‐style of 116 young adults aged 17 years or more who had undergone LT in childhood, showed that most appeared at particular risk for delays in autonomy, and exhibited psychological disturbances that might partly account for lower performances at school than healthy peers. See editorial by Heneghan on page 1505.
Abstract Aims The 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. Methods ODYSSEY 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. Results This is an ongoing clinical trial, with 76 T1 and 441 T2 DM patients enrolled; results are expected in mid-2017. Conclusion The 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.
Nonsteroidal anti‐inflammatory drugs (NSAIDs), other than aspirin, are to some extent metabolized by cytochrome P450 2C9 (CYP2C9). The CYP2C9 359Leu (CYP2C9*3) loss‐of‐function allele could be a risk ...factor for acute upper gastrointestinal bleeding (AUGIB) related to the use of NSAIDs other than aspirin. To test this hypothesis, we performed a prospective, multicenter, case–case study in patients hospitalized for AUGIB related to the use of NSAIDs. A total of 131 patients had been treated with aspirin and 57 patients had been treated with an NSAID other than aspirin (non‐ASP). In the aspirin group, 12 patients (9.2%) had the CYP2C9 359Leu allele as compared with 19 (33.3%) in the non‐ASP group (odds ratio (OR) = 5.0; 95% confidence interval 2.2–11.1, P < 0.0001). In a multivariate analysis, CYP2C9 359Leu remained associated with the non‐ASP group (OR = 7.2 (2.6–20.3), P = 0.0002) even though 40% of these patients were under treatment with antiulcer drugs at the time of admission. Therefore the results of the study support the hypothesis that the CYP2C9 359Leu allele is a robust risk factor for AUGIB related to the use of NSAIDs other than aspirin.
Clinical Pharmacology & Therapeutics (2010) 87 6, 693–698. doi: 10.1038/clpt.2010.33
The aim of this study was to determine the influence of amiodarone on the pharmacokinetics of simvastatin and pravastatin in humans. This was a prospective, crossover, randomized, open‐label study ...performed in 12 healthy volunteers comparing the pharmacokinetics of a single oral dose of simvastatin (40 mg) or pravastatin (40 mg) taken alone and after 3 days of amiodarone (400 mg/day). Amiodarone increased simvastatin acid AUC (area under the plasma concentration–time curve)0–24 h, peak plasma concentration (Cmax), and t1/2 by 73% (P=0.02), 100% (P=0.02), and 48% (P=0.06), respectively, whereas it did not significantly alter pravastatin pharmacokinetics. Point estimates and 90% confidence intervals for simvastatin acid, simvastatin lactone, and pravastatin AUC0–24 h were 154% (109–216%), 155% (109–227%), and 86% (63–118%), respectively. If amiodarone and a statin have to be simultaneously prescribed, pravastatin should be preferred to simvastatin in order to avoid a drug interaction.
Clinical Pharmacology & Therapeutics (2007) 81, 679–684. doi:10.1038/sj.clpt.6100098; published online 14 February 2007
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