Blood Glucose Surges Rapidly Within 90 Days of Antipsychotic Therapy
Adults with severe mental illness experience a sharp acceleration in blood glucose and body weight during the first three months of starting second-generation antipsychotic therapy, according to electronic health record data published in The Lancet Psychiatry. Researchers found that HbA1c levels surge rapidly through both weight-dependent and weight-independent pathways, prompting calls from clinicians for earlier metabolic monitoring rather than waiting for visible weight gain.
Evaluation of 96,849 Adults in England Demonstrates Metabolic Acceleration
Using England’s Clinical Practice Research Datalink Aurum database from 2000 to 2023, investigators evaluated 96,849 adults aged 18 to 59 with severe mental illness, including schizophrenia, schizoaffective disorder, and bipolar disorder, who initiated oral second-generation antipsychotics, MedPage Today reported. Median baseline weight across the cohort stood at 167.6 lb, while HbA1c measured 35 mmol/mol or 5.4%. Before treatment, participants experienced a weekly HbA1c rise of 0.01 mmol/mol and a weekly weight gain of 0.04 lb. During the initial 90 days post-initiation, the weekly rate of HbA1c increase jumped roughly 14 times to 0.12 mmol/mol, yielding an excess increase of 1.42 mmol/mol compared with pre-treatment trends. Beyond day 90, the rate returned to baseline levels, though the early increase remained unreversed. Weight followed a parallel trajectory as patients gained an average of 0.46 lb weekly during the first 90 days—representing an excess gain of 5.22 lb—before slowing to 0.07 lb weekly from day 91 onward. Testing rates showed a distinct skew, with 76.6% of patients having a recorded follow-up weight, but only 24.9% having a recorded HbA1c measurement.
Medication Differences and Patient Subgroups Reveal Divergent Trajectories
Early weight and glycemic changes varied across individual medications at day 90. Olanzapine produced a 7.26 lb excess weight gain alongside a 2.33 mmol/mol excess HbA1c increase, marking the steepest combined increases in the study. Aripiprazole showed a 3.84 lb excess weight gain and a 2.27 mmol/mol excess HbA1c increase. Quetiapine demonstrated a 4.98 lb excess weight gain paired with a minor 0.15 mmol/mol excess HbA1c change, while risperidone resulted in a 4.92 lb excess weight gain and a 0.54 mmol/mol excess HbA1c increase. Commenting on the uncoupling of metrics, study author Juan Carlos Bazo-Alvarez of University College London noted that weight and HbA1c do not always move together, pointing out that quetiapine drove substantial weight gain with relatively little glycemic change. Subgroup disparities also emerged, as women experienced steeper initial surges than men, recording an excess 90-day HbA1c of 1.68 mmol/mol compared with 1.18 mmol/mol, and an excess weight gain of 5.73 lb versus 5.18 lb. These peaks concentrated in women starting olanzapine, who experienced an excess weight gain of 9.17 lb and an excess HbA1c increase of 3.27 mmol/mol. Furthermore, baseline prediabetes substantially amplified long-term risk, as 13.7% of those patients developed type 2 diabetes during follow-up, reaching an estimated 2-year cumulative incidence of 19.0% compared with 3.0% of normoglycemic patients.
Commentators and Researchers Call for Earlier Prophylaxis
In an accompanying commentary published in the same journal, Caroline Hynes-Ryan of St. John of God University Hospital in Dublin and her colleagues emphasized that rapid HbA1c shifts frequently go unnoticed compared to visible weight gain. Because visible weight changes command immediate clinical and personal attention, asymptomatic cardiometabolic risk factors like dysglycemia often evade detection until routine screening occurs. Current clinical guidelines generally restrict preventive metformin to higher-risk agents like olanzapine or clozapine, or to patients who have already gained substantial weight. In response to these findings, Hynes-Ryan’s group suggested that clinicians consider prescribing metformin, unless contraindicated, for all patients with severe mental illness who start a second-generation antipsychotic.
Clinical Implications and Treatment Decisions
Bazo-Alvarez stressed that clinicians should assess both weight and HbA1c at baseline and at 12 weeks post-initiation rather than relying on weight change as a single proxy for metabolic risk. Patients starting agents with greater metabolic liability, particularly olanzapine, along with women and individuals with prediabetes, require closer follow-up and earlier preventive support. However, Bazo-Alvarez cautioned against using observational findings to avoid specific therapies, noting that treatment selection must balance psychiatric effectiveness, previous patient response, personal preference, and adverse-effect profiles.
Frequently Asked Questions About Antipsychotic Metabolic Risks
Why did researchers focus specifically on the first 90 days of antipsychotic therapy?
Investigators observed that metabolic acceleration spikes dramatically during the initial 3 months, with weekly HbA1c increases jumping roughly 14 times higher than pre-treatment trends before returning to baseline levels after day 90.
How did researchers gather the data for this evaluation?
The study evaluated 96,849 adults aged 18 to 59 in England using the Clinical Practice Research Datalink Aurum database covering the years 2000 to 2023.
Which medication was associated with the steepest combined increases in weight and HbA1c?
Olanzapine produced the steepest combined increases, showing a 7.26 lb excess weight gain and a 2.33 mmol/mol excess HbA1c increase at day 90.
What proportion of patients had their blood glucose monitored during follow-up?
While 76.6% of patients had a recorded weight during follow-up, only 24.9% had an HbA1c measurement recorded in their electronic health records.