Should metformin be started prophylactically in a healthy adult with normal fasting glucose and HbA1c who is beginning a second‑generation (atypical) antipsychotic?

Prophylactic Metformin with Second-Generation Antipsychotics

Metformin should be offered prophylactically when starting olanzapine or clozapine in healthy adults with normal glucose metabolism, but is not routinely recommended for other second-generation antipsychotics with lower metabolic risk. 1

Agent-Specific Recommendations

High Metabolic Risk Antipsychotics (Olanzapine and Clozapine)

Adjunctive metformin may be offered when initiating antipsychotics with a poor cardiometabolic profile (olanzapine and clozapine), even in patients without prediabetes. 1 This represents the most recent (2025) international guideline consensus from The Lancet Psychiatry.

• The rationale is that these agents carry substantial risk for rapid weight gain and metabolic derangement, particularly in young adults newly exposed to antipsychotic drugs. 2, 3, 4
• Metformin appears most beneficial when started early in the course of treatment, before significant metabolic complications develop. 2, 3, 4

Lower Metabolic Risk Antipsychotics

For second-generation antipsychotics with more benign metabolic profiles (aripiprazole, lurasidone, ziprasidone, brexpiprazole, cariprazine), prophylactic metformin is not routinely indicated in patients with normal baseline glucose metabolism. 1

• The risk-benefit calculation shifts when metabolic liability is lower.
• Close monitoring remains essential, but pharmacologic prophylaxis is not warranted. 1

Pre-Treatment Requirements

Before commencing metformin prophylactically:

• Assess renal function and avoid metformin in those with renal failure (eGFR <30 mL/min/1.73 m²). 1
• Obtain baseline metabolic parameters: BMI, waist circumference, blood pressure, HbA1c, glucose, and lipids. 1

Dosing Protocol

Start metformin at 500 mg once daily, then increase in 500 mg increments every 2 weeks up to 1 g twice daily, dependent on tolerability. 1

• Use modified-release preparation if available to minimize gastrointestinal side effects. 1
• This is the same dosing regimen used for diabetes treatment. 1

Ongoing Monitoring

Annual monitoring should include:

• Liver function tests 1
• HbA1c 1
• Renal function 1
• Vitamin B12 levels (critical pitfall: metformin-induced B12 deficiency is commonly overlooked) 1

Metabolic Surveillance Schedule

Regardless of whether metformin is initiated:

• Fasting glucose should be rechecked 4 weeks following antipsychotic initiation. 1
• BMI, waist circumference, and blood pressure should be checked weekly for 6 weeks. 1
• All metabolic parameters should be repeated at 3 months and annually thereafter. 1

Evidence Strength and Nuances

The 2025 Lancet Psychiatry INTEGRATE guidelines represent the highest quality and most recent evidence, explicitly stating that metformin "might be offered" prophylactically for olanzapine and clozapine. 1 This is a conditional recommendation reflecting:

• Strong evidence that metformin is beneficial when started early in treatment 2, 3, 4
• Recognition that not all patients will develop metabolic complications
• The need for shared decision-making based on individual risk factors

The 2019 American Diabetes Association guidelines recommend annual screening for prediabetes/diabetes in all patients on atypical antipsychotics, but do not explicitly endorse prophylactic metformin in non-diabetic patients. 1 However, this predates the 2025 international consensus.

Critical Pitfalls to Avoid

• Do not delay metformin initiation until after weight gain or glucose dysregulation occurs with high-risk agents—the evidence suggests early intervention is most effective. 2, 3, 4
• Do not use metformin as a substitute for lifestyle interventions—healthy diet, physical activity promotion, and tobacco cessation should be offered to all patients. 1
• Do not forget to monitor vitamin B12 annually—deficiency can develop insidiously and worsen psychiatric and neurologic symptoms. 1
• Do not initiate metformin during acute illness or when renal function may be compromised. 1

Alternative Strategy

If prophylactic metformin is declined or contraindicated, consider selecting an antipsychotic with a more benign metabolic profile (aripiprazole, cariprazine, lurasidone) if clinically appropriate for the psychiatric indication. 1