Reduction in Multiple Cardiometabolic Risk Factors With Combined Olanzapine/Samidorphan Compared With Olanzapine: Post Hoc Analyses From a 24-Week Phase 3 Study

Abstract

Background and hypotheses: Weight 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 design: This 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.

Results: After 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.

Conclusions: OLZ/SAM treatment was associated with lower risk of worsening cardiometabolic risk factors related to obesity, hypertension, and metabolic syndrome relative to olanzapine. NCT02694328, https://ichgcp.net/clinical-trials-registry/NCT02694328.

Keywords: 3-carboxamido-4-hydroxynaltrexone; dyslipidemia; hyperglycemia; hypertension; metabolic syndrome; schizophrenia.

© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.

Figures

Fig. 1.

By visit least-squares mean change from baseline in (A) body mass index,a (B) systolic blood pressure,b and (C) diastolic blood pressureb in ENLIGHTEN-2. aBased on an analysis of covariance approach using multiple imputation for missing post-baseline assessments. The model included treatment, race, and age group as factors and the baseline value as a covariate. LSM difference (95% CI) of OLZ/SAM versus olanzapine in BMI: −0.65 kg/m2 (−1.01, −0.28). bBased on an analysis of covariance or logistic regression approach using multiple imputation for missing post-baseline assessments. The model included treatment group as a factor and the baseline value as a covariate. LSM difference (95% CI) for OLZ/SAM versus olanzapine in BP: systolic BP: −2.63 mm Hg (−4.78, −0.47); diastolic BP: −0.75 mm Hg (−2.31, 0.80). BMI, body mass index; BP, blood pressure; HbA1c, glycosylated hemoglobin; LDL, low-density lipoprotein; LSM, least-squares mean; MetS, metabolic syndrome; OLZ/SAM, combination of olanzapine and samidorphan

Fig. 2.

Proportions of patients without metabolic syndrome at baseline who developed metabolic syndrome or any component criterion of metabolic syndrome.a,b, aOdds ratio (95% CI) for the development of MetS during treatment with OLZ/SAM vs olanzapine, at the last on-treatment assessment, in those without MetS at baseline: 0.55 (0.31, 0.99). bThe proportion of patients who developed metabolic syndrome or who developed individual metabolic syndrome parameter criteria were compared using a logistic regression model based on observed data at the patients’ last on-treatment assessments. The model included treatment, race (black, non-black), and age group (<30 years, ≥30 years) as factors, and baseline body mass index as covariate. HDL, high-density lipoprotein; MetS, metabolic syndrome; OLZ/SAM, combination of olanzapine and samidorphan.

Fig. 3.

Cardiometabolic parameter risk differences with OLZ/SAM compared with olanzapine.a aThe odds ratio (95% CI) for developing obesity (BMI ≥30 kg/m2) with use of OLZ/SAM versus olanzapine was 0.52 (0.32, 0.82). Risk differences for shifts in metabolic laboratory parameters were based on sustained potentially clinically significant shifts (ie, the parameters met shift criteria at the last 2 on-treatment assessments). BMI, body mass index; HbA1c, glycosylated hemoglobin; LDL, low-density lipoprotein; OLZ/SAM, combination of olanzapine and samidorphan; WCF, waist circumference.