From the Guidelines
Metformin works by decreasing hepatic glucose production, increasing peripheral insulin sensitivity, and reducing hyperglycemia in adults with type 2 diabetes mellitus (T2DM) 1.
Mechanism of Action
Metformin's primary mechanism of action is through the activation of AMP-activated protein kinase (AMPK), which leads to decreased gluconeogenesis in the liver, thereby lowering blood sugar levels without causing hypoglycemia when used alone 1.
- It enhances glucose uptake in peripheral tissues by making cells more responsive to insulin, effectively addressing insulin resistance.
- It slows carbohydrate absorption from the intestines and may positively affect gut microbiota.
Dosage and Administration
Typical dosing starts at 500 mg once or twice daily with meals, potentially increasing to a maximum of 2000-2550 mg daily divided into 2-3 doses.
- Side effects commonly include gastrointestinal issues like diarrhea and nausea, which can be minimized by starting with a low dose and taking it with food.
Benefits and Considerations
Unlike some diabetes medications, metformin doesn't cause weight gain and may even support modest weight loss, making it particularly valuable for overweight patients with type 2 diabetes 1.
- Metformin is effective and safe, is inexpensive and widely available, and reduces risks of microvascular complications, cardiovascular events, and death 1.
- However, metformin carries a small risk of lactic acidosis and must be used with caution in patients with chronic kidney disease (CKD) 1.
Clinical Guidelines
The 2025 standards of care in diabetes recommend metformin as the first-line treatment for type 2 diabetes due to its beneficial effects on A1C, weight, and improved ASCVD outcomes, as well as its acceptable safety profile and low cost 1.
- For individuals with an estimated glomerular filtration rate (eGFR) of 30–45 mL/min/1.73 m², there is an increased risk for periodic decreases of eGFR to ≤30 mL/min/1.73 m², which heightens the risk of lactic acidosis 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 With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.
Metformin works by:
- Decreasing hepatic glucose production
- Decreasing intestinal absorption of glucose
- Improving insulin sensitivity by increasing peripheral glucose uptake and utilization 2
From the Research
Mechanism of Action of Metformin
- Metformin enhances insulin sensitivity and is used to prevent and treat diabetes, although its mechanism of action remains elusive 3.
- The drug reduces post-prandial plasma glucose, suggesting that it facilitates glucose storage as hepatic glycogen after meals, which in turn attenuates the accelerated rate of gluconeogenesis and reduces both glycogen cycling and hepatic glucose output 3.
- Metformin also reduces fasting hyperglycemia due to declining hepatic glucose production and decreases the amount of insulin required for metabolic control in patients with diabetes, reflecting improvement of insulin activity 3, 4.
Effects on Glucose Metabolism
- Metformin reduces glucose production in the liver, decreases insulin resistance, and increases insulin sensitivity 4, 5.
- The drug has been shown to lower blood glucose levels without increasing the risk of hypoglycemia 4.
- Metformin's effects on glucose metabolism are complex and not fully understood, with evidence suggesting a key role for the gut and multiple modes of action, including AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms 5.
Molecular Targets of Metformin
- One of the best understood molecular targets of metformin is the mitochondrial complex I 6.
- Metformin may also act on multiple targets, including endosomal Na+ /H+ exchangers and the V-ATPase, and may directly act on endosome/lysosome regulation to regulate metabolism and alleviate type 2 diabetes 6.