Metformin sustains a >20% increase in total GLP-1 levels for 18 months in people without diabetes
Background
The incretin hormone glucagon-like peptide-1 (GLP-1) plays a crucial role in glucose metabolism, but its precise interaction with metformin, a first-line therapy for type 2 diabetes (T2DM), remains unclear. While metformin is known to affect the GLP-1 axis, it is not well understood if this influence is sustained over the long term or if it is merely a secondary consequence of metformin's effects on body weight and glycemic control. Understanding whether metformin directly and durably modulates GLP-1 levels is critical for optimizing T2DM treatment strategies and could reveal additional mechanisms behind metformin's metabolic benefits beyond its primary actions.
Study Design
This research involved two studies. First, the CAMERA trial (NCT00723307), a double-blind, randomized, placebo-controlled study, enrolled 173 participants without diabetes. They received either metformin or a placebo for 18 months. Fasted total GLP-1 levels were measured every 6 months, and the sustained effect was evaluated using repeated-measures analysis. Second, the cross-sectional DIRECT study examined 775 people recently diagnosed with T2DM, comparing fasting and post-meal GLP-1 levels between those treated with metformin versus diet alone using Student's t-tests and linear regression.
Results
In the CAMERA trial (non-diabetic participants), metformin therapy significantly increased total GLP-1 levels compared to placebo. The increases were sustained over the entire study period: +20.7% at 6 months, +26.7% at 12 months, and +18.7% at 18 months.
The overall increase across the 18-month period was 23.4% (95% CI 11.2-36.9; P < .0001). Crucially, adjusting for changes in glycaemia or adiposity did not diminish this effect. In the DIRECT study (T2DM patients), metformin was associated with significantly higher fasting active
GLP-1(+39.1%) and fasting totalGLP-1(+14.1%). However, it was not associated with changes in post-meal incrementalGLP-1. These associations were independent of confounders like age, sex, adiposity, and glycated haemoglobin.
Key Findings
- In people without diabetes, metformin increased total GLP-1 by 23.4% over 18 months vs placebo (P < .0001).
- The GLP-1 increase from metformin was sustained at 6 (+20.7%), 12 (+26.7%), and 18 months (+18.7%).
- Metformin's effect on GLP-1 was independent of changes in weight or glycaemia in non-diabetics.
- In T2DM patients, metformin use was associated with 39.1% higher fasting active GLP-1.
- Metformin use was also associated with 14.1% higher fasting total GLP-1 in T2DM patients.
Why It Matters
The findings confirm that metformin's effect on raising GLP-1 is not a transient phenomenon but a durable, long-term physiological change. This effect is a direct action of the drug, not a secondary result of weight loss or improved glucose control. This suggests that part of metformin's therapeutic benefit comes from chronically elevating endogenous GLP-1 levels, which has implications for both treatment and prevention of metabolic disease. For individuals using metformin, this provides a clearer picture of its multi-faceted mechanism. Clinically, this reinforces the rationale for metformin as a foundational therapy in T2DM, as its benefits extend to modulating the key incretin system independently of its other known metabolic effects.
metformin
glp-1
type 2 diabetes
insulin resistance
clinical trial
longitudinal study
