From the Guidelines
Metformin lowers blood glucose by improving insulin sensitivity, reducing glucose absorption, and promoting glucose excretion, making it a commonly used and effective medication for type 2 diabetes management, as supported by the most recent evidence from 2025 1.
Mechanism of Action
The exact mechanism of how metformin lowers blood glucose is complex and involves multiple pathways. However, it is known to:
- Improve insulin sensitivity, allowing glucose to enter cells more effectively
- Reduce glucose absorption from the gut
- Promote glucose excretion through the kidneys
- Decrease glucose production in the liver
Clinical Evidence
The 2025 study published in Diabetes Care 1 highlights metformin as a first-line treatment for type 2 diabetes, citing its effectiveness, safety, and ability to reduce risks of microvascular complications, cardiovascular events, and death. This study also notes that metformin is available in immediate-release and extended-release forms, with the latter potentially mitigating gastrointestinal side effects.
Comparison with Other Treatments
When compared to other glucose-lowering agents, metformin has been shown to have beneficial effects on A1C, is weight neutral, does not cause hypoglycemia, and reduces cardiovascular mortality, making it a preferred initial pharmacological agent for type 2 diabetes, as stated in the 2014 standards of medical care in diabetes 1 and the 2012 position statement by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) 1.
Important Considerations
While metformin is generally well-tolerated, it can cause gastrointestinal side effects, and its use may be associated with an increased risk of vitamin B12 deficiency and worsening of neuropathy symptoms. Therefore, periodic testing of vitamin B12 levels is recommended, especially in patients with risk factors for deficiency 1. Additionally, metformin should be used with caution in patients with renal impairment, as it may increase the risk of lactic acidosis in those with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² 1.
From the FDA Drug Label
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization Metformin hydrochloride tablets help control your blood sugar in a number of ways. These include helping your body respond better to the insulin it makes naturally, decreasing the amount of sugar your liver makes, and decreasing the amount of sugar your intestines absorb.
Metformin lowers blood glucose by:
- Decreasing hepatic glucose production
- Decreasing intestinal absorption of glucose
- Improving insulin sensitivity by increasing peripheral glucose uptake and utilization 2 2
From the Research
Mechanism of Action
- Metformin lowers blood glucose concentration by mechanisms different from those of insulin secretagogues, such as sulphonylureas, or exogenous insulin therapy 3.
- It acts by enhancing insulin sensitivity, inducing greater peripheral uptake of glucose, and decreasing hepatic glucose output 3, 4.
- Metformin sensitizes the liver to the effect of insulin, suppressing hepatic glucose output 5.
Effects on Blood Glucose and Insulin Levels
- Metformin lowers fasting plasma insulin concentrations and blood glucose levels with minimal risk of hypoglycaemia 3.
- It can lower HbA1c by around 1.5% when used as monotherapy 3.
- Metformin has been shown to significantly improve blood glucose levels while lowering total daily insulin dose and body weight when used in combination with insulin 5.
Comparison with Other Therapies
- Metformin is recommended as a first-line oral agent for the treatment of type 2 diabetes by the American Diabetes Association and the European Association for the Study of Diabetes 3, 4.
- Newer agents, such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, are favored as the first-line therapy in individuals with type 2 diabetes who would benefit from cardio-renal protection 4.
- Combination therapy using metformin or thiazolidinediones and insulin can be effective in lowering blood glucose levels and total daily insulin dose 5, 6.