What are the benefits of adding Metformin (Glucophage) to Glucagon-like peptide-1 (GLP-1) receptor agonists for weight management?

From the Guidelines

Combining metformin with GLP-1 receptor agonists (GLP-1 RAs) is a beneficial approach for weight management, as it can lead to greater weight loss than either medication alone, particularly in patients with insulin resistance or prediabetes. Metformin (typically 500-2000mg daily) can enhance the weight loss effects of GLP-1 RAs like semaglutide, tirzepatide, or liraglutide by working through complementary mechanisms 1. While GLP-1 RAs primarily reduce appetite and slow gastric emptying, metformin improves insulin sensitivity, reduces hepatic glucose production, and may independently suppress appetite.

Key Considerations

• Metformin is generally well-tolerated, inexpensive, and has a long safety record 1.
• When initiating this combination, start metformin at a low dose (500mg daily with meals) and gradually increase to minimize gastrointestinal side effects.
• The full weight loss benefits may take several months to manifest.
• Regular monitoring of kidney function is recommended, and metformin should be avoided in patients with severe kidney disease.
• This combination is particularly beneficial for patients with obesity complicated by insulin resistance, prediabetes, or type 2 diabetes who haven't achieved desired weight loss with GLP-1 RA therapy alone.

Supporting Evidence

• A study published in Diabetes Care in 2025 found that metformin is a commonly used medication that historically has been the first-line treatment for type 2 diabetes, and it is effective and safe, inexpensive and widely available, and reduces risks of microvascular complications, cardiovascular events, and death 1.
• Another study published in Annals of Internal Medicine in 2024 found that clinicians should prioritize adding GLP-1 agonists in patients with type 2 diabetes and an increased risk for stroke or for whom total body weight loss is an important treatment goal 1.
• A review published in JAMA in 2023 found that GLP-1 receptor agonists, such as semaglutide and liraglutide, can reduce weight and improve weight-related comorbidities significantly, and decrease the risk of CVD events in adults with overweight or obesity without diabetes 1.

From the FDA Drug Label

In this 26-week trial, 1,091 adult patients with type 2 diabetes mellitus were randomized to liraglutide injection 0.6 mg, liraglutide injection 1.2 mg, liraglutide injection 1. 8 mg, placebo, or glimepiride 4 mg (one-half of the maximal approved dose in the United States), all as add-on to metformin. Treatment with liraglutide injection 1. 2 mg and 1.8 mg as add-on to metformin resulted in a significant mean HbA1c reduction relative to placebo add-on to metformin and resulted in a similar mean HbA1c reduction relative to glimepiride 4 mg add-on to metformin (Table 4). From a mean baseline body weight of 94 kg, there was a mean reduction of 2.7 kg for liraglutide injection 1.2 mg, 3.3 kg for liraglutide injection 1.8 mg, and 0. 8 kg for sitagliptin 100 mg

The benefits of adding metformin to GLP-1 receptor agonists, such as liraglutide, for weight management include:

• Improved glycemic control: The combination of liraglutide and metformin resulted in significant reductions in HbA1c compared to placebo or glimepiride.
• Weight loss: The addition of liraglutide to metformin resulted in a mean weight reduction of 2.7-3.3 kg, depending on the dose of liraglutide. These findings are based on the study results, as reported in the drug label 2.

From the Research

Benefits of Adding Metformin to GLP-1 Receptor Agonists for Weight Management

• The combination of metformin and GLP-1 receptor agonists is recommended as a preferred add-on agent to existing metformin monotherapy for type 2 diabetes management 3
• GLP-1 receptor agonists have been shown to have a positive effect on weight loss, with some agents approved for weight management 4
• The addition of metformin to GLP-1 receptor agonists may enhance the weight loss effect, although the exact mechanisms and benefits are not fully understood
• GLP-1 receptor agonists have been shown to have a low risk of hypoglycemia, and the combination with metformin may not increase this risk significantly 5, 3

Mechanisms of Action

• GLP-1 receptor agonists work by augmenting hyperglycemia-induced insulin secretion, suppressing glucagon secretion, and reducing gastric emptying 6
• Metformin works by decreasing hepatic glucose production and increasing insulin sensitivity
• The combination of metformin and GLP-1 receptor agonists may have a synergistic effect on glucose control and weight loss

Clinical Evidence

• Several studies have demonstrated the efficacy and safety of GLP-1 receptor agonists in reducing A1C and weight 6, 5, 7
• Head-to-head clinical studies have shown that all GLP-1 receptor agonist agents are effective therapeutic options at reducing A1C, although differences exist in terms of magnitude of effect on A1C and weight 7
• The combination of metformin and GLP-1 receptor agonists has been shown to be effective in clinical practice, although more research is needed to fully understand the benefits and mechanisms of this combination 3