Does Clozapine Raise Blood Sugars?
Yes, clozapine significantly raises blood glucose levels and increases the risk of hyperglycemia, impaired fasting glucose, and new-onset diabetes mellitus. 1
Magnitude of Risk
Clozapine is classified among second-generation antipsychotics with more metabolic effects (along with haloperidol, quetiapine, and risperidone), in contrast to aripiprazole and ziprasidone which have fewer metabolic effects. 2
The FDA drug label explicitly warns that hyperglycemia—in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death—has been reported in patients treated with clozapine. 1
Specific Data on Glucose Elevation:
Mean fasting glucose increase: Clozapine causes a mean increase of +11 mg/dL in fasting glucose concentrations 1
Categorical glucose changes in patients without diabetes:
Undiagnosed hyperglycemia: In one study of clozapine-treated patients without prior diabetes diagnosis, 23% had elevated fasting plasma glucose, including 17% with impaired fasting glucose and 6% meeting criteria for diabetes 3
New-onset diabetes: A surveillance study identified 242 definitive cases of new-onset diabetes in clozapine-treated patients, with 25 deaths during hyperglycemic episodes 4
Clinical Mechanism
Research demonstrates that clozapine increases blood glucose through increased insulin resistance, evidenced by elevated insulin and C-peptide levels alongside hyperglycemia. 5 Animal studies suggest clozapine-induced acute hyperglycemia is mediated by elevated adrenaline and glucagon concentrations. 6
Mandatory Screening and Monitoring Protocol
The American Diabetes Association (2024) requires specific screening protocols for all patients on second-generation antipsychotics including clozapine: 2
Baseline Assessment (Before Starting Clozapine):
- Fasting blood glucose or HbA1c 2
- Body mass index and waist circumference 2
- Blood pressure 2
- Fasting lipid panel 2
Follow-up Monitoring Schedule:
- 12-16 weeks after medication initiation: Repeat glucose screening 2
- Annually thereafter: Continue screening for prediabetes or diabetes 2
- If fasting sample unavailable: Obtain random glucose as initial screening; if abnormal, prioritize fasting measurement 2
Additional Monitoring for Established Diabetes:
Patients with pre-existing diabetes started on clozapine require regular monitoring for worsening glucose control. 1
Clinical Pitfalls and Management Considerations
Common Pitfall #1: Delayed Recognition
Most cases of clozapine-associated diabetes appear within 6 months of initiating therapy, with one reported case occurring after a single 500-mg dose. 4 Early vigilance is critical.
Common Pitfall #2: Assuming Reversibility
While some cases of hyperglycemia resolved after clozapine discontinuation, some patients required continuation of antidiabetic treatment despite stopping the drug. 1 Do not assume glucose abnormalities will automatically reverse.
Risk Factors for Clozapine-Associated Hyperglycemia:
Symptom Monitoring:
Educate patients to report symptoms of hyperglycemia: polydipsia, polyuria, polyphagia, and weakness. 1 Obtain fasting blood glucose testing immediately if these symptoms develop.
Comparative Metabolic Risk
While both clozapine and olanzapine cause significant metabolic disturbances, long-term olanzapine treatment appears to more frequently lead to manifest diabetes mellitus than clozapine. 7 However, clozapine still carries substantial hyperglycemic risk requiring aggressive monitoring.
Seizure Risk Consideration:
Beyond hyperglycemia, clozapine has a 5% incidence of seizures at high dosages, which is notably higher than other antipsychotics. 2
When Clozapine Must Be Used Despite Metabolic Risk
If clozapine is clinically necessary despite diabetes risk, consider adjunctive metformin (500 mg once daily, titrating to 1 g twice daily as tolerated) to mitigate metabolic side effects. 2 Monitor weight, glycemic control, and cholesterol levels regularly. 2