What medications can be used for prediabetes and weight loss in a patient who does not tolerate metformin (biguanide)?

Medications for Prediabetes and Weight Loss When Metformin is Not Tolerated

For patients with prediabetes and weight loss goals who cannot tolerate metformin, GLP-1 receptor agonists are the preferred alternative medication option due to their proven efficacy for both glycemic control and weight reduction. 1

First-Line Alternatives to Metformin

• GLP-1 receptor agonists (GLP-1 RAs) should be considered the primary alternative for patients with prediabetes who cannot tolerate metformin, as they provide robust glycemic control and significant weight loss benefits 1
• Liraglutide (3.0 mg daily) is FDA-approved for chronic weight management and has demonstrated greater weight loss than placebo or orlistat in patients without diabetes 2
• GLP-1 RAs reduce waist circumference, systolic and diastolic blood pressure, and improve lipid profiles in overweight and obese patients 2
• Semaglutide is another effective GLP-1 RA option with once-weekly dosing that provides substantial weight loss benefits 1

SGLT2 Inhibitors as Alternative Options

• SGLT2 inhibitors can be considered for patients who cannot tolerate metformin, particularly if they have cardiovascular risk factors 1
• These medications reduce glycemia, weight, and blood pressure through increased urinary glucose excretion 1
• SGLT2 inhibitors have demonstrated cardiorenal benefits independent of glucose lowering 1
• Common side effects include increased risk of genital mycotic infections and small increases in LDL-C 1

Considerations for GLP-1 RA Selection

• For patients prioritizing substantial weight loss, once-weekly dosing, or those with eGFR <45 ml/min/1.73 m², GLP-1 RAs are particularly advantageous 1
• Common side effects include nausea, vomiting, and diarrhea, which are usually transient during dose escalation 3
• Slow titration of GLP-1 RAs can mitigate gastrointestinal side effects 1
• Contraindications include history of medullary thyroid carcinoma, multiple endocrine neoplasia syndrome type 2, or acute pancreatitis 1, 3

Weight Loss Medication Options

• For patients with BMI ≥30 kg/m² or ≥27 kg/m² with weight-related comorbidities, FDA-approved weight loss medications should be considered 1
• Liraglutide 3.0 mg daily (higher dose than for diabetes management) is approved for chronic weight management 1, 2
• Phentermine can be considered for short-term use (12 weeks) as an affordable alternative but should be avoided in patients with coronary artery disease, uncontrolled hypertension, glaucoma, or history of substance use disorder 1
• Orlistat is associated with modest weight loss but has significant gastrointestinal side effects 1

Special Considerations for Prediabetes

• In the Diabetes Prevention Program, metformin was shown to delay progression to type 2 diabetes in patients with prediabetes 1
• For patients who cannot tolerate metformin, lifestyle modifications remain crucial and should be emphasized alongside pharmacotherapy 1
• GLP-1 RAs have demonstrated efficacy in preventing progression from prediabetes to diabetes, making them suitable alternatives to metformin 1
• Screening for and treatment of modifiable cardiovascular risk factors is essential in patients with prediabetes 1

Monitoring and Follow-up

• Assess efficacy and safety at least monthly for the first 3 months and then every 3 months thereafter 1
• If there is less than 5% weight loss at 12 weeks, consider discontinuing the medication and trying an alternative option 1
• Monitor for vitamin B12 deficiency, especially in patients with anemia or peripheral neuropathy, even with non-metformin therapies 1
• For GLP-1 RAs, be vigilant about potential gastrointestinal side effects, especially during the initial titration period 3

Pitfalls and Caveats

• Avoid using sympathomimetic agents like phentermine in patients with cardiovascular disease 1
• Be aware that semaglutide has been associated with diabetic retinopathy complications, particularly with rapid and marked glucose reductions 1
• Medicare currently excludes coverage of FDA-approved anti-obesity medications for a diagnosis of obesity alone, which may create access barriers 1
• When using SGLT2 inhibitors, be cautious in patients with history of genital candidiasis, diabetic ketoacidosis, or severe peripheral arterial disease 1