Dataset Information

Statin tolerability: In defence of placebo-controlled trials.

ABSTRACT: Statin intolerance is a barrier to effective lipid-lowering treatment. A significant number of patients stop prescribed statins, or can take only a reduced dose, because of adverse events attributed to the statin, and are then considered statin-intolerant.Examination of differences between statin and placebo in withdrawal rates due to adverse events - a good measure of tolerability - in statin cardiovascular outcome trials in patients with advanced disease and complex medical histories, who may be more vulnerable to adverse effects. The arguments commonly used to dismiss safety and tolerability data in statin clinical trials are examined.Rates of withdrawal due to adverse events in trials in patients with advanced disease and complex medical histories are consistently similar in the statin and placebo groups. We find no support for arguments that statin cardiovascular outcome trials do not translate to clinical practice.Given the absence of any signal of intolerance in clinical trials, it appears that statin intolerance in the clinic is commonly due to the nocebo effect causing patients to attribute background symptoms to the statin. Consistent with this, over 90% of patients who have stopped treatment because of an adverse event can tolerate a statin if re-challenged. Consequently, new agents, including monoclonal antibodies to proprotein convertase subtilisin/kexin type 9, will be useful when added to statin therapy but should rarely be used as a statin substitute.

SUBMITTER: Tobert JA

PROVIDER: S-EPMC4847124 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Statin tolerability: In defence of placebo-controlled trials.

Tobert Jonathan A JA Newman Connie B CB

European journal of preventive cardiology 20150828 8

<h4>Background</h4>Statin intolerance is a barrier to effective lipid-lowering treatment. A significant number of patients stop prescribed statins, or can take only a reduced dose, because of adverse events attributed to the statin, and are then considered statin-intolerant.<h4>Methods</h4>Examination of differences between statin and placebo in withdrawal rates due to adverse events - a good measure of tolerability - in statin cardiovascular outcome trials in patients with advanced disease and ...[more]

PMID: 26318980

Similar Datasets

Project description:IntroductionIn the management of postoperative acute moderate-to-severe pain, opioids remain an important component. However, conventional opioids have a narrow therapeutic index and are associated with dose-limiting opioid-related adverse events (ORAEs) that can result in worse patient outcomes. Oliceridine, a new intravenous µ-opioid receptor agonist, is shown in nonclinical studies to be biased for G protein signaling (achieving analgesia) with limited recruitment of β-arrestin (associated with ORAEs). In two phase 3 randomized controlled studies of patients with moderate-to-severe acute pain following hard or soft tissue surgery, in which analgesia was measured using Sum of Pain Intensity Differences (SPID) from baseline over 48 and 24 h (SPID-48 and -24 respectively, oliceridine at demand doses of 0.1, 0.35, or 0.5 mg was highly effective compared to placebo, with a favorable safety profile compared to morphine. This exploratory analysis was conducted to determine whether the safety benefits seen with oliceridine persisted when adjusted for equal levels of analgesia compared to morphine.MethodsPresence of at least one treatment-emergent ORAE (based on Medical Dictionary for Regulatory Activities [MedDRA]-coded events: hypoxemia, nausea, vomiting, sedation, pruritus, or dizziness) was used as the composite safety endpoint. A logistic regression model was utilized to compare oliceridine (pooled regimens) versus morphine, after controlling for analgesia (using SPID-48 or SPID-24 with pre-rescue scores carried forward 6 h). This analysis excluded patients receiving placebo and was repeated for each study and for pooled data.ResultsAt a given level of SPID-48 or SPID-24, patients receiving oliceridine were less likely to experience the composite safety endpoint. Although not statistically significant at the 0.05 level in the soft tissue model, the odds ratio (OR) showed a consistent numerical trend for oliceridine, being approximately half that observed with morphine in both the hard (OR 0.499; 95% confidence interval [CI] 0.255, 0.976; p = 0.042) and soft (OR 0.542; 95% CI 0.250, 1.175; p = 0.121) tissue studies. Results from the pooled data were consistent with those observed in the individual studies (OR 0.507; 95% CI 0.304, 0.844; p = 0.009).ConclusionFindings from this exploratory analysis suggest that at comparable levels of analgesia, patients receiving oliceridine were less likely to experience the composite safety endpoint consisting of ORAEs compared to patients treated with morphine. Oliceridine Exhibits Improved Tolerability Compared to Morphine at Equianalgesic Conditions: Exploratory Analysis from Two Phase 3 Randomized Placebo and Active Controlled Trials- A Video (MP4 99188 kb).

Project description:BackgroundErenumab, a fully human monoclonal antibody that targets the calcitonin gene-related peptide receptor, has demonstrated efficacy and safety in the prevention of episodic and chronic migraine. There exists an unmet need to establish the safety of erenumab in older individuals, in view of existing multiple comorbidities, polypharmacy, and age-related physiological changes. This pooled analysis of five large migraine-prevention studies examined the safety of erenumab stratified across age groups, particularly in older populations.MethodsPooled and age-stratified analysis of safety data from the 12-week double-blind treatment phase (DBTP) of five randomized, placebo-controlled Phase 2 and 3 studies of erenumab in participants with episodic or chronic migraine across the age groups < 40 years, 40-49 years, 50-59 years, and ≥ 60 years was completed. The safety of erenumab across age groups was determined by assessing safety endpoints including treatment-emergent adverse events (AEs), serious AEs, and events leading to study drug discontinuation.ResultsOverall, 3345 participants across five studies were randomized to receive either placebo (n = 1359), erenumab 70 mg (n = 1132) or erenumab 140 mg (n = 854); 3176 (94.9%) completed the DBTP, and 169 (5.1%) discontinued, mainly due to participant decision (110; 3.3%). Overall, 1349 (40.6%), 1122 (33.8%), and 850 (25.6%) participants received at least one dose of placebo, erenumab 70 mg, and erenumab 140 mg, respectively. Incidence of treatment-emergent AEs was similar across all age groups for both doses of erenumab (70 mg or 140 mg) and placebo (< 40 years, 44.0% vs 44.4%; 40-49 years, 42.5% vs 49.2%; 50-59 years, 46.5% vs 41.6%; ≥ 60 years, 43.8% vs 59.4%). Incidence of treatment-emergent serious AEs overall, and stratified by age groups for both doses and placebo was low (< 40 years, 0.9% vs 1.2%; 40-49 years, 1.7% vs 1.9%; and 50-59 years, 1.6% vs 1.1%), with no serious AEs reported in participants aged ≥ 60 years. No deaths were reported.ConclusionsErenumab (70 mg or 140 mg) exhibited a similar safety profile compared with placebo across age groups in individuals with episodic or chronic migraine, with no increased emergence of events due to age. Erenumab was well tolerated in older participants with multiple comorbidities, polypharmacy, and age-related physiological changes.Trial registration numberClinicalTrials.gov Identifiers: NCT02066415, NCT02456740, NCT02483585, NCT03096834, NCT03333109.

Project description:Oncostatin M (OSM) has been implicated in the pathophysiology of rheumatoid arthritis (RA) through its effect on inflammation and joint damage. GSK315234 is a humanised anti-OSM Immunoglobulin G1 (IgG1) monoclonal antibody (mAb). This 3-part study examines the safety, tolerability and efficacy of GSK315234 in patients with active RA.This was a 3-part (Parts A, B and C), multicenter study. Part A and Part B were randomised, double-blind, placebo-controlled, Bayesian adaptive dose finding studies to investigate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of single (Part A) and 3 repeat (Part B) intravenous infusions of GSK315234 in patients with active RA on a background of methotrexate (MTX). Part C was a single dose, randomised, single-blind, placebo-controlled study to assess subcutaneously administered GSK315234 to patients with active RA on a background of MTX.The primary endpoint of the study was mean change in DAS28 at Day 28 in Part A and Day 56 in Part B and C. All patients receiving at least one dose of GSK315234 were included in safety analysis. In Part A, there were statistically significant differences in DAS28 between 3 mg/kg and placebo at Day 56, 84 and 91. There was also a statistically significant difference in DAS28 between 0.3 mg/kg, 3 mg/kg and 10 mg/kg, as compared to placebo, at Day 84. Although these changes were small and occurred late, they supported progression to Part B and C to determine the therapeutic potential of GSK315234. For Part B, no significant difference was observed between 6 mg/kg and placebo. For Part C, a statistically significant difference in DAS28 was observed at Day 40, Day 84 and Day 100 between the 500 mg subcutaneous group, as compared to placebo. No significant findings were observed at any of the time points for EULAR response criteria, ACR20, ACR50 or ACR70. An exploratory analysis of clinical, pharmacokinetic and pharmacodynamics data suggests the lack of efficacy may be due to moderate binding affinity and rapid off-rate of GSK315234 as compared to the higher affinity OSM receptor causing a protein carrier effect prolonging the half life of OSM due to accumulation of the OSM/antibody complex in the serum and synovial fluid.Our data highlighted the importance of binding affinity and off-rate effect of a mAb to fully neutralize the target and how this may influence its efficacy and potentially worsen disease activity. Using an anti-OSM mAb with high affinity should test this hypothesis and examine the potential of OSM as a therapeutic target in RA.ClinicalTrials.gov no: NCT00674635.

Project description:BackgroundExenatide twice daily is a first-in-class glucagon-like peptide receptor agonist approved for the treatment of type 2 diabetes. The objective of this analysis was to evaluate the safety profile of exenatide twice daily and to compare its profile with that of a pooled comparator (placebo and insulin) in patients with type 2 diabetes.MethodsData from 19 completed, randomized, controlled clinical trials of exenatide twice daily (5 μg and 10 μg) were pooled and analyzed; the pooled data included 5594 intent-to-treat patients who were followed for 12-52 weeks. Incidence rates, exposure-adjusted incidence rates, and 95% confidence intervals around risk differences between groups were calculated.ResultsBaseline demographics and exposure time were comparable between groups (exenatide, N = 3261; pooled comparator, N = 2333; mean exposure time 166-171 days). Transient, mild- to-moderate nausea was the most frequent adverse event with exenatide (36.9% versus 8.3% in the pooled comparator). The incidence of hypoglycemia (minor or major) with concomitant sulfonylurea (exenatide 26.5%, pooled comparator 20.7%) was higher than that without sulfonylurea (exenatide 3.1%, pooled comparator 2.7%) in all groups. Serious adverse events, discontinuations due to serious adverse events, and deaths were reported with similar frequency in the exenatide and pooled comparator groups. Composite exposure-adjusted incidence rates were not statistically different between groups for pancreatitis, renal impairment, or major adverse cardiac events; there was a difference in incidence rates for benign thyroid neoplasm (0.3% versus 0%).ConclusionOverall, this analysis, representing over 1500 patient-years of exposure, demonstrated that exenatide twice daily was safe and generally well tolerated in patients with type 2 diabetes. The incidence of most adverse events, including serious adverse events, was similar in both exenatide-treated and comparator-treated patients. The most distinct differences between groups were in gastrointestinal-related adverse events, which is consistent with other therapies within the glucagon-like peptide class.

Dataset Information

Statin tolerability: In defence of placebo-controlled trials.

Publications

Statin tolerability: In defence of placebo-controlled trials.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets