Aim: To evaluate the efficacy, safety, and pharmacokinetics (PK) of inclisiran in Japanese patients with high cardiovascular risk and elevated low-density lipoprotein cholesterol (LDL-C).Methods: ...ORION-15 was a phase 2, double-blind, placebo-controlled randomized trial. Patients with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH), were randomized to inclisiran sodium 100, 200, or 300 mg, or placebo and dosed subcutaneously on Days 1, 90, and 270. The primary endpoint was the percentage change from baseline to Day 180 to demonstrate the superiority of inclisiran vs. placebo. Patients who consented to the PK substudy had additional study procedures for blood collection and safety assessment. Results: Overall, 312 patients (mean age, 63.6 years; male, 74.4%; baseline LDL-C, 114.0 mg/dL) were randomized. Baseline characteristics were well balanced among the groups. At Day 180, inclisiran at all doses demonstrated significant LDL-C and proprotein convertase subtilisin/kexin type 9 (PCSK9) reductions (p＜0.0001 for both), which showed a dose–response relationship. The greatest reductions (LDL-C, 65.3%; PCSK9, 79.2%) were with inclisiran sodium 300 mg. At Day 180, ＞86% of the patients receiving inclisiran achieved the Japan Atherosclerosis Society 2017 lipid management targets compared to 8.9% for placebo. The mean (SD) plasma half-life for inclisiran was 6.8 (2.0)–7.6 (0.8) h. The incidence of adverse events with inclisiran was similar to that with placebo.Conclusion: Inclisiran sodium 100, 200, and 300 mg demonstrated clinically meaningful and statistically significant LDL-C and PCSK9 reductions at Day 180, which were consistent over 12 months. Inclisiran was effective and well tolerated in Japanese patients with hypercholesterolemia, including HeFH.
1 Service of Endocrinology, Department of Medicine, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada; and 2 Pfizer Inc., New York, New York
The aim of this review is to ...explore the dysregulation of adrenocortical secretions as a major contributor in the development of obesity and insulin resistance. Disturbance of adipose tissue physiology is one of the primary events in the development of pathologies associated with the metabolic syndrome, such as obesity and type 2 diabetes. Several studies indicate that alterations in metabolism of glucocorticoids (GC) and androgens, as well as aldosterone in excess, are involved in the emergence of metabolic syndrome. Cross talk among adipose tissue, the hypothalamo-pituitary complex, and adrenal gland activity plays a major role in the control of food intake, glucose metabolism, lipid storage, and energy balance. Perturbation of this cross talk induces alterations in the regulatory mechanisms of adrenocortical steroid synthesis, secretion, degradation, and/or recycling, at the level of the zonae glomerulosa (aldosterone), fasciculata (GC and GC metabolites), and reticularis (androgens and androgen precursors DHEA and DHEAS). As a whole, these adrenocortical perturbations contribute to the development of metabolic syndrome at both the paracrine and systemic level by favoring the physiological dysregulation of organs responsive to aldosterone, GC, and/or androgens, including adipose tissue.
adrenal gland; adipocytes; angiotensin II; adrenocorticotropic hormone; adrenal steroids
Address for reprint requests and other correspondence: N. Gallo-Payet, Service of Endocrinology, Faculty of Medicine, Université de Sherbrooke, 3001, 12th Ave. North, Sherbrooke, QC, Canada J1H 5N4 (e-mail: Nicole.Gallo-Payet{at}USherbrooke.ca )
Abstract Objectives To determine the long-term effects of changing the amount or source of dietary carbohydrate on quality of life (QOL), symptoms and dietary satisfaction in people with type 2 ...diabetes. Methods Subjects with diabetes treated by diet alone (n=162) were randomly assigned to high-carbohydrate/high-glycemic-index (HGI) diets; high-carbohydrate/low-glycemic-index (LGI) diets; or lower-carbohydrate/high-monounsaturated-fat (LC) diets for 1 year. We measured QOL at baseline and at study's end, and we measured symptoms and dietary satisfaction quarterly. Results The HGI, LGI and LC diets contained, respectively, 47±1, 52±1 and 40±1% energy carbohydrate; 30±1, 27±1 and 40±1% fat with GI 64±0.4, 55±0.4 and 59±0.4. Significantly more participants reported increased flatulence on LGI than on LC and HGI diets at 3 months (41%, 19%, 14%; p<0.05), but not at 12 months (29%, 17%, 17%; ns). Abdominal distension was more severe (46% vs. 14%, 19%; p<0.05), and headache less severe (8% vs. 22%, 23%; p<0.05) on LGI than on both other diets. Increased appetite was more severe on LC (33%) than on HGI diets (14%, p<0.05). Joint/limb pains were less severe on LGI (16%) than HGI (28%) diets. LC elicited more severe gloomy thoughts (23%) than LGI (4%; p<0.05) but greater dietary-satisfaction (70%; p<0.05) than LGI (40%) and HGI (48%) diets. For all diets, glycated hemoglobin (A1C) levels increased less in those who gained less weight, had less increased appetite and were more satisfied with the enjoyment obtained from eating. Conclusions Each diet elicited increased severity of 1 or more symptoms than the other diets. Although overall dietary satisfaction was greater on the 40% carbohydrate diet than on the 50% carbohydrate diet, the LGI diet was no less satisfying than the HGI diet. Changes in appetite and dietary satisfaction may influence body weight and glycemic control, or vice-versa.
Homozygous familial hypercholesterolemia is a genetic disease characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C) and a high risk of premature cardiovascular events. ...The proof-of-concept study ORION-2 (A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia) showed that inclisiran, a small interfering RNA that prevents production of the hepatic PCSK9 protein (proprotein convertase subtilisin/kexin type 9), could lead to durable reductions in LDL-C levels when added to statins and ezetimibe in patients with homozygous familial hypercholesterolemia.
ORION-5 was a phase 3, 2-part, multicenter study in 56 patients with homozygous familial hypercholesterolemia and elevated LDL-C levels despite maximum tolerated doses of LDL-C-lowering therapies with or without lipoprotein apheresis. Patients eligible for part 1 (double-blind, 6 months) were randomized 2:1 to receive either 300 mg of inclisiran sodium (equivalent to 284 mg of inclisiran) or placebo. Placebo-treated patients from part 1 were transitioned to inclisiran in part 2 (open-label, 18 months). The primary end point was the percentage change in LDL-C levels from baseline to day 150.
The mean age of the patients was 42.7 years, and 60.7% were women. The mean baseline LDL-C levels were 294.0 mg/dL and 356.7 mg/dL in the inclisiran and placebo groups, respectively. The placebo-corrected percentage change in LDL-C level from baseline to day 150 was -1.68% (95% CI, -29.19% to 25.83%;
=0.90), and the difference was not statistically significant between the inclisiran and placebo groups. The placebo-corrected percentage change in PCSK9 levels from baseline to day 150 was -60.6% with inclisiran treatment (
<0.0001); this was sustained throughout the study, confirming the effect of inclisiran on its biological target of PCSK9. No statistically significant differences between the inclisiran and placebo groups were observed in the levels of other lipids and lipoproteins (apolipoprotein B, total cholesterol, and non-high-density lipoprotein cholesterol). Adverse events and serious adverse events did not differ between the inclisiran and placebo groups throughout the study.
Inclisiran treatment did not reduce LDL-C levels in patients with homozygous familial hypercholesterolemia despite substantial lowering of PCSK9 levels. Inclisiran was well-tolerated, and the safety findings were consistent with previously reported studies and the overall safety profile.
URL: https://www.clinicaltrials.gov; Unique identifier: NCT03851705.
Whether long-term treatment with the twice-yearly, siRNA therapeutic inclisiran, which reduces hepatic production of proprotein convertase subtilisin/kexin type 9 (PCSK9), results in sustained ...reductions in LDL cholesterol with an acceptable safety profile is not known. The aim of this study was to assess the effect of long-term dosing of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol.
ORION-3 was a 4-year open-label extension study of the placebo-controlled, phase 2 ORION-1 trial, conducted at 52 sites across five countries. Patients with prevalent atherosclerotic cardiovascular disease or high-risk primary prevention and elevated LDL cholesterol despite maximally tolerated statins or other LDL-lowering treatments, or with documented statin intolerance, who had completed the ORION-1 trial were eligible. Patients receiving inclisiran in ORION-1 received twice-yearly 300 mg subcutaneous inclisiran sodium throughout ORION-3 (inclisiran-only arm), whereas patients receiving placebo in ORION-1 first received subcutaneous evolocumab 140 mg every 2 weeks until day 360 thereafter transitioning to inclisiran twice-yearly for the remainder of ORION-3 study (switching arm). The primary efficacy endpoint was the percentage change in LDL cholesterol with inclisiran from the start of ORION-1 through to day 210 of the open label extension phase in the inclisiran-only arm (approximately 570 days of total inclisiran exposure in the modified intention-to-treat population). Secondary and exploratory endpoints included changes in LDL-C cholesterol and PCSK9 concentrations levels up to day 1440 (4 years) in each arm, and safety. ORION-3 is registered with ClinicalTrials.gov, NCT03060577.
Of the original ORION-1 cohort of 497 patients, 290 of 370 patients allocated to drug continued into the inclisiran-only arm and 92 of 127 patients allocated to placebo entered the switching-arm in the ORION-3 extension study conducted between March 24, 2017, and Dec 17, 2021. In the inclisiran-only arm, LDL cholesterol was reduced by 47·5% (95% CI 50·7–44·3) at day 210 and sustained over 1440 days. The 4-year averaged mean reduction of LDL-C cholesterol was 44·2% (95% CI: 47·1–41·4), with reductions in PCSK9 ranging from 62·2% to 77·8%. Adverse events at the injection site were reported in 39 (14%) of 284 patients in the inclisiran-only arm and 12 (14%) of 87 patients in the switching arm. The incidence of treatment-emergent serious adverse events possibly related to the study drug was 1% (three of 284) in the inclisiran-only arm and 1% (one of 87) in the switching arm.
Twice-yearly inclisiran provided sustained reductions in LDL cholesterol and PCSK9 concentrations and was well tolerated over 4 years in the extension study. This is the first prospective long-term study to assess repeat hepatic exposure to inclisiran.
Novartis Pharma.
Objective
To provide an update on glycaemic control in European patients with type 2 diabetes based on data from the nine‐country, cross‐sectional PANORAMA study (NCT00916513).
Design
Post‐hoc ...analysis to report the number of patients achieving/not achieving glycaemic goal (HbA1c <7%).
Patients
Patients were randomly or consecutively selected from physician practices in nine countries. Eligible patients were aged ≥40 years, diagnosed with type 2 diabetes >1 year prior to study entry, and had an available medical record of >1 year.
Measurements
All data were collected at a single visit, including HbA1c measurement using a common device (A1CNow®). Bivariate and multivariate analyses were used to investigate factors associated with not reaching glycaemic goal.
Results
Of 5817 patients enrolled (aged 65·9 ± 10·4 years, 53·7% male), 37·4% had an HbA1c ≥7%; (range 25·9% in The Netherlands to 52·0% in Turkey). In adjusted multivariate analyses, higher individual glycaemic target, younger age, poor physician‐reported patient adherence to lifestyle/medication, longer diabetes duration, increasing treatment regimen complexity and physician‐reported patient's unwillingness to intensify treatment were associated with not achieving goal. However, bivariate analyses also found gender, socioeconomic factors, body mass index, rate of complications and hypoglycaemia to be associated with not achieving goal.
Conclusions
In PANORAMA, 37·4% of patients enrolled were not at glycaemic goal. Factors relating to patient characteristics, physician selection of individualized HbA1c target and diabetes itself (longer duration, more complex treatment) were strongly associated with not achieving goal. Further studies are warranted to explore these associations and evaluate strategies for improving glycaemic control.
Inclisiran is a small interfering RNA agent to lower low-density lipoprotein cholesterol.
The purpose of this study was to provide reliable evidence to date on the long-term safety profile of ...inclisiran.
This post hoc analysis comprised patients treated with 300 mg inclisiran sodium or placebo in the completed (ORION-1, -3, -5, -9, -10, and -11) and ongoing (ORION-8) trials. Exposure-adjusted incidence rates and Kaplan-Meier estimates of cumulative incidence of reported treatment-emergent adverse events (TEAE), abnormal laboratory measurements, and incidence of antidrug antibodies were analyzed.
This analysis included 3,576 patients treated with inclisiran for up to 6 years and 1,968 patients treated with placebo for up to 1.5 years, with 9,982.1 and 2,647.7 patient-years of exposure, respectively. Baseline characteristics were balanced between groups. Kaplan-Meier analyses showed that TEAEs that were serious or led to discontinuation; hepatic, muscle, and kidney events; incident diabetes; and elevations of creatine kinase or creatinine accrued at a comparable rate between groups for up to 1.5 years, with similar trends continuing for inclisiran beyond this period. Numerically fewer major cardiovascular events reported as TEAEs occurred with inclisiran during this period. Treatment-induced antidrug antibodies were uncommon with inclisiran (4.6%), with few of these persistent (1.4%) and not associated with greater incidence of TEAEs leading to study drug discontinuation or serious TEAEs.
Long-term treatment with inclisiran was well tolerated in a diverse population, without new safety signals, supporting the safety of inclisiran in patients with dyslipidemia.
Aim: To evaluate the efficacy, safety, and pharmacokinetics (PK) of inclisiran in Japanese patients with high cardiovascular risk and elevated low-density lipoprotein cholesterol (LDL-C). Methods: ...ORION-15 was a phase 2, double-blind, placebo-controlled randomized trial. Patients with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH), were randomized to inclisiran sodium 100, 200, or 300 mg, or placebo and dosed subcutaneously on Days 1, 90, and 270. T he primary endpoint was the percentage change from baseline to Day 180 to demonstrate the superiority of inclisiran vs. placebo. Patients who consented to the PK substudy had additional study procedures for blood collection and safety assessment. Results: Overall, 312 patients (mean age, 63.6 years; male, 74.4%; baseline LDL-C, 114.0 mg/dL) were randomized. Baseline characteristics were well balanced among the groups. At Day 180, inclisiran at all doses demonstrated significant LDL-C and proprotein convertase subtilisin/kexin type 9 (PCSK9) reductions (p＜0.0001 for both), which showed a dose-response relationship. The greatest reductions (LDL-C, 65.3%; PCSK9, 79.2%) were with inclisiran sodium 300 mg. At Day 180, ＞86% of the patients receiving inclisiran achieved the Japan Atherosclerosis Society 2017 lipid management targets compared to 8.9% for placebo. The mean (SD) plasma half-life for inclisiran was 6.8 (2.0)-7.6 (0.8) h. The incidence of adverse events with inclisiran was similar to that with placebo. Conclusion: Inclisiran sodium 100, 200, and 300 mg demonstrated clinically meaningful and statistically significant LDL-C and PCSK9 reductions at Day 180, which were consistent over 12 months. Inclisiran was effective and well tolerated in Japanese patients with hypercholesterolemia, including HeFH.
Data describing the long-term efficacy, safety, and tolerability of inclisiran are limited. This was explored in ORION-8, an open-label extension study of preceding Phase 2 and Phase 3 ...placebo-controlled and open-label extension trials.
Adults with ASCVD, ASCVD risk equivalent, or HeFH received open-label inclisiran every 180 days (after completion of the parent trial) until Day 990, followed by an end-of-study (EOS) visit at Day 1080 or ≥90 days after last dose. Study endpoints included proportion of patients achieving pre-specified LDL-C goals (ASCVD: <1.8 mmol/L <70 mg/dL; ASCVD risk equivalent: <2.6 mmol/L <100 mg/dL), percentage and absolute changes in LDL-C at EOS, and safety of inclisiran.
Of 3274 patients included in the analysis, 2446 (74.7%) were followed until EOS. Mean age was 64.9±9.9 years, 82.7% (n=2709) had ASCVD, and mean baseline LDL-C was 2.9±1.2 mmol/L. Mean cumulative exposure to inclisiran (including parent trials) was 3.7 years; maximum exposure was 6.8 years. With inclisiran, 78.4% (95% CI: 76.8, 80.0) of patients achieved pre-specified LDL-C goals and mean percentage LDL-C reduction was -49.4% (95% CI: -50.4, -48.3). No attenuation of LDL-C lowering over time was observed. Treatment-emergent adverse events at the injection site (all mild or moderate) occurred in 5.9% of inclisiran-treated patients. Inclisiran-associated anti-drug antibodies were infrequent (5.5%) and had no impact on the efficacy or safety of inclisiran. No new safety signals were identified.
In the largest and longest follow-up to date, inclisiran demonstrated sustained and substantial LDL-C lowering with a favourable long-term safety and tolerability profile. ClinicalTrials.gov identifier: NCT03814187.
