Insulin and glucose metabolism with olanzapine and a combination of olanzapine and samidorphan: exploratory phase 1 results in healthy volunteers

Abstract

A combination of olanzapine and samidorphan (OLZ/SAM) received US Food and Drug Administration approval in May 2021 for the treatment of adults with schizophrenia or bipolar I disorder. OLZ/SAM provides the efficacy of olanzapine, while mitigating olanzapine-associated weight gain. This exploratory study characterized the metabolic profile of OLZ/SAM in healthy volunteers to gain mechanistic insights. Volunteers received once-daily oral 10 mg/10 mg OLZ/SAM, 10 mg olanzapine, or placebo for 21 days. Assessments included insulin sensitivity during an oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, other measures of glucose/lipid metabolism, and adverse event (AE) monitoring. Treatment effects were estimated with analysis of covariance. In total, 60 subjects were randomized (double-blind; placebo, n = 12; olanzapine, n = 24; OLZ/SAM, n = 24). Olanzapine resulted in hyperinsulinemia and reduced insulin sensitivity during an OGTT at day 19, changes not observed with OLZ/SAM or placebo. Insulin sensitivity, measured by hyperinsulinemic-euglycemic clamp, was decreased in all treatment groups relative to baseline, but this effect was greatest with olanzapine and OLZ/SAM. Although postprandial (OGTT) glucose and fasting cholesterol concentrations were similarly increased with olanzapine or OLZ/SAM, other early metabolic effects were distinct, including post-OGTT C-peptide concentrations and aspects of energy metabolism. Forty-nine subjects (81.7%) experienced at least 1 AE, most mild or moderate in severity. OLZ/SAM appeared to mitigate some of olanzapine’s unfavorable postprandial metabolic effects (e.g., hyperinsulinemia, elevated C-peptide) in this exploratory study. These findings supplement the body of evidence from completed or ongoing OLZ/SAM clinical trials supporting its role in the treatment of schizophrenia and bipolar I disorder.

Olanzapine-Samidorphan for Schizophrenia: A Systematic Review and Meta-Analysis

“…The trials have documented the good tolerability of OLZSAM and indicated that the incidence of adverse events with either OLZSAM or OLZ is comparable. 26-28,30,31 Haddad et al also had documented that OLZSAM exhibited fewer adverse effects than OLZ, and the same has been substantiated by Jawad et al, as they observed that in short-term studies, the addition of the µ-opioid receptor antagonist did not alter the safety profile of the OLZ. 15,20 Interestingly, we observed that the incidences of various adverse events were either high in the OLZ group or the OLZSAM group.…”

“…36 Even though we wished to include trials of high quality, two of them (Toledo et al and Silverman et al) had a high risk of bias, thus affecting the results. 28,31 On the whole, the certainty of evidence generated in this meta-analysis for the selected endpoints was of moderate to high quality, except for the incidence of weight gain, headache, dry mouth, and any adverse event, wherein the certainty ranged from low to very low (Tables 2 and 3), which again can be attributed to these two trials having a high risk of bias. Furthermore, the overall certainty was reduced as the sample size required to achieve optimal information was inadequate in these trials.…”

“…Two of these trials were found to be at high risk as per the RoB2 tool. 28,31 Toledo et al had a high risk due to bias arising from improper randomization process and inadequate addressing of missing data; on the other hand, in Silverman et al, the randomization process could have been more precise.…”

“…The usual pattern of the demographic distribution of schizophrenia could be observed in the studies included in this analysis, with males being more commonly affected than females (even though two trials had included only healthy volunteers, especially one having exclusively male healthy volunteers) and black people being more afflicted. 28,31,[33][34][35] The mean age of recruited patients in the studies was ~40 years; however, as no information about the age at which schizophrenia was first diagnosed was available, it is dubious to comment whether the schizophrenia indeed developed in preadolescence or post-adolescence age. 36 Even though we wished to include trials of high quality, two of them (Toledo et al and Silverman et al) had a high risk of bias, thus affecting the results.…”

“…The possible justification for these findings is that two of the included studies 28,31 had recruited a small number of healthy individuals. In contrast, other studies recruited patients with schizophrenia, contributing to heterogeneity.…”