A meta-analysis comparing short-term weight and cardiometabolic changes between olanzapine/samidorphan and olanzapine.
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SUBMITTER: Srisurapanont M
PROVIDER: S-EPMC8027382 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and hypothesesWeight gain and adverse cardiometabolic effects often limit the clinical utility of olanzapine. In ENLIGHTEN-2, combining olanzapine with the opioid receptor antagonist samidorphan (OLZ/SAM) mitigated olanzapine-associated weight gain. These analyses tested the hypothesis that OLZ/SAM would be associated with reduced adverse cardiometabolic effects compared with olanzapine.Study designThis phase 3 double-blind study randomized adults with schizophrenia to OLZ/SAM or olanzapine for 24 weeks. Post hoc analyses assessed changes from baseline to week 24 in cardiometabolic risk parameters, including body mass index (BMI), risk of developing obesity (BMI ≥30 kg/m2) or metabolic syndrome, waist circumference, along with mean and potentially clinically significant changes in blood pressure, glucose, and lipids.ResultsAfter 24 weeks' treatment, compared with olanzapine, OLZ/SAM was associated with smaller least-squares mean (LSM) changes from baseline in systolic blood pressure (LSM difference, -2.63 mm Hg; 95% CI: -4.78, -0.47), diastolic blood pressure (LSM difference, -0.75 mm Hg; 95% CI: -2.31, 0.80), and BMI (LSM difference, -0.65 kg/m2; 95% CI: -1.01, -0.28). OLZ/SAM treatment was also associated with reduced risk of shifting from normal blood pressure to stage 1/2 hypertension (odds ratio [OR], 0.48; 95% CI: 0.24, 0.96), becoming obese (OR, 0.52; 95% CI: 0.32, 0.82), and developing metabolic syndrome (OR, 0.55; 95% CI: 0.31, 0.99) compared with olanzapine. No treatment group differences were noted for risk of hyperglycemia or hyperlipidemia.ConclusionsOLZ/SAM treatment was associated with lower risk of worsening cardiometabolic risk factors related to obesity, hypertension, and metabolic syndrome relative to olanzapine. NCT02694328, https://clinicaltrials.gov/ct2/show/NCT02694328.
| S-EPMC10016392 | biostudies-literature
Project description:BackgroundOlanzapine, regarded as one of the most efficacious antipsychotic medications for the treatment of schizophrenia, is associated with a high risk of weight gain and metabolic dysfunction. ALKS 3831, a clinical candidate for treatment of schizophrenia, is a combination of olanzapine and samidorphan, an opioid receptor antagonist. The addition of samidorphan is intended to mitigate weight gain and the metabolic dysregulation associated with the use of olanzapine.MethodsNon-clinical studies were conducted to assess the metabolic effects of olanzapine and samidorphan alone and in combination at clinically relevant exposure levels.ResultsChronic olanzapine administration in male and female rats shifted body composition by increasing adipose mass, which was accompanied by an increase in the rate of weight gain in female rats. Co-administration of samidorphan normalized body composition in both sexes and attenuated weight gain in female rats. In hyperinsulinemic euglycemic clamp experiments conducted prior to measurable changes in weight and/or body composition, olanzapine decreased hepatic insulin sensitivity and glucose uptake in muscle while increasing uptake in adipose tissue. Samidorphan appeared to normalize glucose utilization in both tissues, but did not restore hepatic insulin sensitivity. In subsequent studies, samidorphan normalized olanzapine-induced decreases in whole-body glucose clearance following bolus insulin administration. Results from experiments in female monkeys paralleled the effects in rats.ConclusionsOlanzapine administration increased weight gain and adiposity, both of which were attenuated by samidorphan. Furthermore, the combination of olanzapine and samidorphan prevented olanzapine-induced insulin insensitivity. Collectively, these data indicate that samidorphan mitigates several metabolic abnormalities associated with olanzapine in both the presence and the absence of weight gain.
| S-EPMC6764014 | biostudies-literature
Project description:Background and objectivesObesity precedes and is strongly linked to the development of type 2 diabetic nephropathy in most patients, yet little is known about the effects of weight reduction on this disease. This study aimed to establish proof of concept for the hypothesis that weight reduction ameliorates diabetic nephropathy.Design, setting, participants, & measurementsSix obese individuals with advanced diabetic nephropathy (estimated GFR <40 ml/min per 1.73 m(2), urine albumin excretion >30 mg/d) currently taking a renin-aldosterone axis inhibitor underwent a 12-week very low calorie ketogenic weight reduction diet with encouragement of exercise between March and September 2012. Albuminuria and other parameters of kidney health were the main outcome measures.ResultsThere was a 12% reduction in weight (median 118.5 versus 104.3 kg, P=0.03). The intervention was associated with a 36% reduction in albuminuria that did not reach statistical significance (2124 versus 1366 mg/24 h, P=0.08) and significant reductions in the filtration markers serum creatinine (3.54 versus 3.13 mg/dl, P<0.05) and cystatin C (2.79 versus 2.46 mg/l, P<0.05). Improvements were also noted for the diabetes markers fasting glucose (166 versus 131 mg/dl, P<0.05), fasting insulin (26.9 versus 10.4 μU/ml, P<0.05), and insulin resistance (9.6 versus 4.2, P=0.03). Physical function, general health, and the number of diabetes medications also showed statistically significant signs of improvement.ConclusionsAfter a short-term intensive weight reduction intervention in patients with advanced diabetic nephropathy, improvements were observed in markers of glomerular filtration, diabetes status, and risk factors for kidney disease progression, as well as other general indicators of health and well-being.
| S-EPMC3817909 | biostudies-literature
Project description:A combination of the antipsychotic olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM) is intended to provide the antipsychotic efficacy of olanzapine while mitigating olanzapine-associated weight gain. As cytochrome P450 (CYP) 1A2 and CYP3A4 are the major enzymes involved in metabolism of olanzapine and samidorphan, respectively, physiologically-based pharmacokinetic (PBPK) modeling was applied to predict any drug-drug interaction (DDI) potential between olanzapine and samidorphan or between OLZ/SAM and CYP3A4/CYP1A2 inhibitors/inducers. A PBPK model for OLZ/SAM was developed and validated by comparing model-simulated data with observed clinical study data. Based on model-based simulations, no DDI between olanzapine and samidorphan is expected when administered as OLZ/SAM. CYP3A4 inhibition is predicted to have a weak effect on samidorphan exposure and negligible effect on olanzapine exposure. CYP3A4 induction is predicted to reduce both samidorphan and olanzapine exposure. CYP1A2 inhibition or induction is predicted to increase or decrease, respectively, olanzapine exposure only.
| S-EPMC7020312 | biostudies-literature
Project description:Body weight in lower animals and humans is highly stable despite a very large flux in energy intake and expenditure over time. Conversely, the existence of higher-than-average variability in weight may indicate a disruption in the mechanisms responsible for homeostatic weight regulation.In a sample chosen for weight-gain proneness, we evaluated whether weight variability over a 6-mo period predicted subsequent weight change from 6 to 24 mo.A total of 171 nonobese women were recruited to participate in this longitudinal study in which weight was measured 4 times over 24 mo. The initial 3 weights were used to calculate weight variability with the use of a root mean square error approach to assess fluctuations in weight independent of trajectory. Linear regression analysis was used to examine whether weight variability in the initial 6 mo predicted weight change 18 mo later.Greater weight variability significantly predicted amount of weight gained. This result was unchanged after control for baseline body mass index (BMI) and BMI change from baseline to 6 mo and for measures of disinhibition, restrained eating, and dieting.Elevated weight variability in young women may signal the degradation of body weight regulatory systems. In an obesogenic environment this may eventuate in accelerated weight gain, particularly in those with a genetic susceptibility toward overweight. Future research is needed to evaluate the reliability of weight variability as a predictor of future weight gain and the sources of its predictive effect. The trial on which this study is based is registered at clinicaltrials.gov as NCT00456131.
| S-EPMC4625595 | biostudies-literature
Project description:BackgroundClinically significant weight gain has been reported during treatment with atypical antipsychotics. It has been suggested that weight changes in patients treated with olanzapine may be associated with increased appetite.MethodsData were used from adult patients for whom both appetite and weight data were available from 4 prospective, 12- to 24-week clinical trials. Patients' appetites were assessed with Eating Behavior Assessment (EBA, Study 1), Platypus Appetite Rating Scale (PARS, Study 2), Eating Inventory (EI, Study 3), Food Craving Inventory (FCI, Study 3), and Eating Attitude Scale (EAS, Study 4).ResultsIn Studies 1 (EBA) and 4 (EAS), patients who reported overall score increases on appetite scales, indicating an increase in appetite, experienced the greatest overall weight gains. However, in Studies 2 (PARS) and 3 (EI, FCI), patients who reported overall score increases on appetite scales did not experience greater weight changes than patients not reporting score increases. Early weight changes (2-4 weeks) were more positively correlated with overall weight changes than early or overall score changes on any utilized appetite assessment scale. No additional information was gained by adding early appetite change to early weight change in correlation to overall weight change.ConclusionsEarly weight changes may be a more useful predictor for long-term weight changes than early score changes on appetite assessment scales.Clinical trials registrationThis report represents secondary analyses of 4 clinical studies. Studies 1, 2, and 3 were registered at http://clinicaltrials.gov/ct2/home, under NCT00190749, NCT00303602, and NCT00401973, respectively. Study 4 predates the registration requirements for observational studies that are not classified as category 1 observational studies.
| S-EPMC2945973 | biostudies-literature
Project description:A combination of olanzapine and samidorphan was recently approved by the US Food and Drug Administration for the treatment of patients with schizophrenia or bipolar I disorder. Population pharmacokinetic models for olanzapine and samidorphan were developed using data from 11 clinical studies in healthy subjects or patients with schizophrenia. A 2-compartment disposition model with first-order absorption and elimination and a lag time for absorption adequately described concentration-time profiles of both olanzapine and samidorphan. Age, sex, race, smoking status, and body weight were identified as covariates that impacted the pharmacokinetics of olanzapine. A moderate effect of body weight on samidorphan pharmacokinetics was identified by the model but was not considered clinically meaningful. The effects of food, hepatic or renal impairment, and coadministration with rifampin on the pharmacokinetics of olanzapine and samidorphan, as estimated by the population pharmacokinetic analysis, were consistent with findings from dedicated clinical studies designed to evaluate these specific covariates of interest. Food intake did not have a clinically relevant effect on the pharmacokinetics of olanzapine or samidorphan. Consistent with the known metabolic pathways for olanzapine (primarily via uridine 5'-diphospho-glucuronosyltransferase-mediated direct glucuronidation and cytochrome P450 [CYP]-mediated oxidation) and for samidorphan (predominantly mediated by CYP3A4), coadministration of olanzapine and samidorphan with rifampin, a strong inducer of CYP3A4 and an inducer of uridine 5'-diphospho-glucuronosyltransferase enzymes, significantly decreased the systemic exposure of both olanzapine and samidorphan. Severe renal impairment or moderate hepatic impairment resulted in a modest increase in olanzapine and samidorphan exposure.
| S-EPMC8596792 | biostudies-literature
Project description:BackgroundPatients with first-episode psychosis or early-phase schizophrenia are susceptible to olanzapine-associated weight gain and cardiometabolic dysregulation. This meta-analysis characterized weight and metabolic effects observed during olanzapine treatment in randomized clinical trials in this vulnerable patient population.MethodsPubMed, EMBASE, and Dialog were searched for randomized controlled trials (RCTs) reporting weight or cardiometabolic outcomes associated with olanzapine treatment in first-episode psychosis or early-phase schizophrenia. Random-effects meta-analysis and meta-regression were conducted using R v4.0.5.ResultsOf 1203 records identified, 26 RCTs informed the analyses. The meta-analytic mean (95% CI) weight gain was 7.53 (6.42-8.63) kg in studies (n = 19) that reported weight gain with olanzapine treatment. Stratified by duration, the mean (95% CI) weight gain was significantly higher in studies >13 weeks in duration than in those lasting ≤13 weeks: 11.35 (10.05-12.65) vs 5.51 (4.73-6.28) kg, respectively. Despite between-study variability, increases from baseline in most glycemic and lipid parameters were generally small in studies of both ≤13 and >13 weeks. There were no correlations, however, between weight gain and metabolic parameter changes when stratified by study duration.ConclusionsIn RCTs enrolling patients with first-episode psychosis or early-phase schizophrenia, olanzapine was consistently associated with weight gain that was greater in studies lasting >13 weeks compared with those of ≤13 weeks. Metabolic changes observed across studies suggest that RCTs may underestimate metabolic sequelae vs real-world treatment observations. Patients with first-episode psychosis or early-phase schizophrenia are vulnerable to olanzapine-associated weight gain; strategies minimizing olanzapine-associated weight gain should be carefully considered.
| S-EPMC10388390 | biostudies-literature
Project description:While more than 50% of smokers make a serious quit attempt each year, less than 10% quit permanently. Evidence from studies of adolescent smoking and other substances of abuse suggest that alternative reinforcers, a construct of Behavioral Economic Theory, may contribute to the likelihood of smoking cessation in adults. This study examined the behavioral economics of smoking cessation within a smoking cessation clinical trial and evaluated how depressive symptoms and behavioral economic variables are associated with smoking cessation.A sample of 469 smokers, enrolled in an effectiveness trial that provided counseling and 8 weeks of 21 mg nicotine patches, was analyzed. Alternative reinforcers (substitute and complementary reinforcers) and depressive symptoms were examined in relation to 7-day point prevalence abstinence, verified with breath carbon monoxide, 8 weeks after the quit date.Controlling for covariates associated with cessation (nicotine dependence, age of smoking initiation, patch adherence), participants who were abstinent at week 8 showed significantly higher substitute reinforcers at all time-points, compared to those who were smoking (p's<.05). Participants who were abstinent at week 8 showed lower complementary reinforcers and depressive symptoms at all time-points, compared to those who were smoking, but significant differences were confined to week 8 (p's<.01). There was no significant interaction between alternative reinforcers and depressive symptoms across the 8 weeks on week 8 abstinence.These results support continued examination of Behavioral Economic Theory in understanding adult smoking cessation in order to inform future treatments and guidelines.
| S-EPMC4030632 | biostudies-literature
Project description:IntroductionWomen with gestational diabetes mellitus (GDM) have a 30% to 70% risk for developing type 2 diabetes and are at increased risk for cardiovascular disease. Little is known about how anthropometric changes in the first postpartum year modify cardiometabolic risk factors.MethodsWe randomly assigned women in the Balance After Baby study to an intervention group consisting of participation in a web-based lifestyle program or to a control group in which no program was offered. We measured weight, height, waist circumference, blood pressure, lipids, insulin, adiponectin, interleukin-6, and high-sensitivity C-reactive protein, and we conducted 2-hour oral glucose tolerance tests at 6 weeks, 6 months, and 12 months postpartum. We evaluated whether women assigned to the intervention had improved cardiometabolic risk markers compared with the control group. We then conducted a post-hoc analysis, pooling the 2 groups to compare changes in weight and waist circumference with changes in cardiometabolic risk factors.ResultsWomen in the intervention group did not significantly improve cardiometabolic risk markers compared with women in the control group. We noted a large overlap of weight change and change in waist circumference between groups. In our post-hoc analysis pooling groups, changes in diabetes and cardiovascular risk factors were significantly correlated with changes in weight and waist circumference. The strongest associations were observed for fasting insulin, HOMA, and fasting glucose.ConclusionAnthropometric changes in weight and waist circumference in women with recent GDM may affect cardiometabolic risk factors, even in the first postpartum year. Our study demonstrates the importance of the postpartum year as an opportunity to decrease future risk for diabetes and cardiovascular disease in women with a history of GDM.
| S-EPMC6513485 | biostudies-literature