From the Guidelines
Metformin works primarily by reducing glucose production in the liver, improving insulin sensitivity in peripheral tissues, and decreasing intestinal glucose absorption, as evidenced by the most recent and highest quality study 1.
Mechanism of Action
The mechanism of action of metformin involves the activation of AMP-activated protein kinase (AMPK), an enzyme that plays a key role in cellular energy homeostasis. This activation leads to decreased hepatic gluconeogenesis, which is the process by which the liver produces glucose. Additionally, metformin enhances glucose uptake in skeletal muscle by increasing insulin receptor activity and glucose transporter (GLUT4) translocation to cell membranes. In the intestines, metformin delays glucose absorption, which helps reduce post-meal blood glucose spikes.
Key Points
- Metformin is effective and safe, and may reduce the risk of microvascular complications, cardiovascular events, and death 1.
- The principal side effects of metformin are gastrointestinal intolerance due to bloating, abdominal discomfort, and diarrhea, which can be mitigated by gradual dose titration and/or using extended-release formulation 1.
- Metformin may be safely used in patients with reduced estimated glomerular filtration rates (eGFR); the FDA has revised the label for metformin to reflect its safety in patients with eGFR ≥30 mL/min/1.73 m² 1.
- Long-term use of metformin may be associated with biochemical vitamin B12 deficiency, and periodic measurement of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy 1.
Clinical Use
The typical starting dose of metformin is 500 mg once or twice daily with meals, which can be gradually increased to a maximum of 2000-2550 mg daily, divided into two or three doses to minimize gastrointestinal side effects. Metformin is available in an immediate-release form for twice-daily dosing or as an extended-release form that can be given once daily.
Benefits
- Metformin does not cause hypoglycemia when used alone and may assist with modest weight loss, making it particularly valuable for overweight or obese patients with type 2 diabetes 1.
- Metformin has beneficial effects on A1C, weight, and cardiovascular mortality compared to sulfonylureas as first-line therapy 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.
The mechanism of action of Metformin is to:
- Decrease hepatic glucose production
- Decrease intestinal absorption of glucose
- Improve insulin sensitivity by increasing peripheral glucose uptake and utilization This is based on information from 2 and 2.
From the Research
Metformin Mechanism of Action
The mechanism of action of Metformin, a biguanide, is multifaceted and involves several key processes:
- Reducing glucose production in the liver 3
- Decreasing insulin resistance 3
- Increasing insulin sensitivity 3
Effects of Metformin
The effects of Metformin include:
- Lowering blood glucose levels without increasing the risk of hypoglycemia 3
- Treatment of obesity, gestational diabetes, and polycystic ovary syndrome 3
Clinical Use of Metformin
Metformin can be used as the first-line agent in the management of diabetes, although newer agents may be favored in certain cases, such as: