Blood sugar levels and body weight rise sharply during the first 90 days after starting second-generation antipsychotics, particularly among women and patients taking olanzapine, new research suggested.

In a large observational study of adults with severe mental illness, A1c levels increased about 14 times faster and weight increased about nine times faster during the first 3 months of treatment than before treatment initiation.

Changes in weight and A1c did not always move in parallel, suggesting that monitoring weight alone may miss early metabolic abnormalities, the researchers said.

“The main practical message is about the timing and breadth of metabolic monitoring: clinicians should assess both weight and glycemia at baseline and again at around 12 weeks, rather than using weight change as a proxy for glycemic risk,” investigator Juan Carlos Bazo-Alvarez, PhD, of University College London, London, England, told Medscape Medical News.

The findings were published online on October 14 in The Lancet Psychiatry.

Early Metabolic Changes

Although second-generation antipsychotics contribute to excess cardiometabolic morbidity in people with severe mental illness, the timing of early glycemic changes and their relationship to weight gain have been less clear.

To investigate, researchers analyzed electronic health records from 96,849 adults (mean age, 37 years; 55% men) with severe mental illness who received at least two oral antipsychotic prescriptions within 90 days in England between 2000 and 2023. Individuals with preexisting type 2 diabetes were excluded.

They compared changes in A1c and weight during the 2 years before treatment initiation, the first 90 days after initiation, and the period from day 91 to 2 years after initiation, using an individual-level, interrupted time-series approach. Roughly three quarters of participants had at least one weight measurement and about a quarter had at least one A1c measurement.

Before starting antipsychotic therapy, A1c increased at a rate of 0.01 mmol/mol per week. During the first 90 days of treatment, the rate accelerated to 0.12 mmol/mol per week — about 14 times faster than the pre-treatment increase, with an estimated average increase of 1.53 mmol/mol over 90 days.

Similarly, weight gain accelerated from 0.02 kg per week before treatment to 0.21 kg per week during the first 90 days. That corresponds to an estimated gain of 2.66 kg (about 5.9 lb), about nine times higher than the weight gain rate before treatment initiation.

After 90 days, the rates of increase in both A1c and weight slowed substantially, returning to near-pretreatment levels. However, neither measure returned to baseline, and both continued to rise more gradually during follow-up.

Asked why the metabolic changes slowed after 90 days, Bazo-Alvarez said the early rise is consistent with an acute metabolic response, but changes in clinical management may also play a role.

“In routine clinical care, rising weight or A1c may prompt lifestyle advice, closer monitoring, medication switching or adjustment, or other interventions, which could attenuate later trajectories,” he said.

The study could not distinguish biological adaptation from changes in clinical management, he added.

Changes Vary by Drug and Sex

Metabolic changes varied by antipsychotic and sex. Olanzapine was associated with the steepest early weight gain, at 0.28 kg per week, and a substantial increase in A1c of 0.18 mmol/mol per week during the first 90 days. Aripiprazole was also associated with a relatively steep early A1c increase of 0.18 mmol/mol per week, although weight gain was lower than with olanzapine, at 0.16 kg per week.

In contrast, quetiapine was associated with substantial weight gain (0.19 kg per week) but minimal A1c change (0.02 mmol/mol per week), underscoring why weight gain alone may not reliably reflect glycemic risk.

The differences may partly reflect “weight-independent effects of antipsychotics on glucose regulation, including effects on insulin secretion and sensitivity,” Bazo-Alvarez said. Weight gain with quetiapine may also reflect increased appetite, sedation, and reduced activity, he said.

However, the study could not establish the underlying mechanisms, and differences in dose or prescribing patterns may have contributed.

Women generally experienced greater early metabolic changes than men. During the first 90 days, A1c increased at a rate of 0.14 mmol/mol per week in women compared with 0.10 mmol/mol per week in men. Corresponding rates of weight gain were 0.22 kg and 0.20 kg per week, respectively.

Women starting olanzapine appeared particularly vulnerable, with an additional weight increase of 4.16 kg (approximately 9.2 lb) and an additional A1c increase of 3.27 mmol/mol during the first 90 days relative to expected pre-treatment trends.

Baseline glycemic status strongly predicted subsequent diabetes risk. Among 918 patients with prediabetes at the start of therapy, the estimated 2-year cumulative incidence of type 2 diabetes was 19% compared with 3% among 9171 patients with normal baseline A1c.

Implications for Monitoring

The findings underscore the need for early, risk-stratified metabolic monitoring and intervention, particularly during the first 3 months after antipsychotic initiation, the investigators wrote.

Bazo-Alvarez cautioned against using the findings alone to guide antipsychotic selection. “Choice of treatment has to balance psychiatric effectiveness, previous response, patient preference, and the known adverse-effect profile of each drug,” he said.

The investigators also suggested that patients at increased metabolic risk may benefit from early lifestyle interventions, review of antipsychotic selection, and consideration of metformin when clinically appropriate.

Deanna L. Kelly, PharmD, who wasn’t involved in the study, said clinicians may not fully appreciate the differences in metabolic effects among individual antipsychotics.

“I don’t think a lot of practitioners have knowledge of nuanced differences in lipids, A1c, and weight gain liability,” Kelly, professor of psychiatry at the University of Maryland School of Medicine, Baltimore, told Medscape Medical News.

The finding that metabolic effects can occur independently of weight gain has been reported previously but is not necessarily well known, she noted.

Commenting on the findings for Medscape Medical News, Leslie Citrome, MD, MPH, clinical professor of psychiatry and behavioral sciences at New York Medical College, Valhalla, emphasized the importance of routine metabolic assessment.

“Metabolic monitoring is necessary. Testing for A1c is pragmatically simpler than attempting to collect a fasting blood sample to measure plasma glucose,” said Citrome, who also wasn’t part of the study. “In addition, it is advisable to consider starting metformin when initiating treatment with olanzapine or clozapine,” he added.

The authors of an accompanying editorial published in Lancet Psychiatry went a step further, raising the question of whether metformin “should be recommended, unless contraindicated, for all people with [severe mental illness] starting a second-generation antipsychotic medicine,” rather than only for those taking higher-risk medications or already experiencing weight gain.

“Such a shift would target the early, often asymptomatic, metabolic changes documented in this study,” rather than waiting for patients to develop more advanced metabolic disease or cardiovascular complications, the authors wrote.

The study was supported by the UK’s National Institute for Health and Care Research and other public research funding sources. Disclosures for authors of the study and accompanying editorials are available with the original publication. Citrome has served as a consultant for AbbVie, Acadia, Alkermes, Allergan, Astellas, Avanir, Axsome, BioXcel, Boehringer Ingelheim, Cadent Therapeutics, Eisai, Impel, Intra-Cellular Therapies, Janssen, Karuna, Lundbeck, Luye, Lyndra, Medavante-ProPhase, Merck, Neurocrine, Noven, Osmotica, Otsuka, Relmada, Sage, Shire, Sunovion, Takeda, and Teva. Kelly has served on advisory boards for Alkermes, Karuna, and Teva.