Metformin is one of the most prescribed and extensively studied medications for the treatment of type 2 diabetes mellitus (T2DM). It plays a central role in glycemic management, prevention of diabetes-related complications, and even in conditions beyond diabetes such as polycystic ovary syndrome (PCOS) and metabolic syndrome. With decades of clinical use, metformin remains a first-line pharmacologic agent due to its effectiveness, safety profile, and cost-efficiency.
What is Metformin?
Metformin is an oral antihyperglycemic agent classified as a biguanide. It is used primarily to reduce blood sugar levels in patients with type 2 diabetes. Unlike insulin or sulfonylureas, metformin does not increase insulin secretion. Instead, it improves insulin sensitivity, reduces hepatic glucose production, and enhances peripheral glucose uptake.
Mechanism of Action: How Metformin Works
The primary effect of metformin is the suppression of hepatic gluconeogenesis — the liver’s production of glucose. It acts by:
Activating AMP-activated protein kinase (AMPK), a cellular energy sensor that reduces liver glucose output
Increasing insulin sensitivity in muscle tissues
Improving glucose uptake and utilization
Reducing intestinal absorption of glucose
These actions contribute to lower fasting plasma glucose (FPG) and HbA1c levels, thereby improving overall glycemic control without causing hypoglycemia in most patients.
Clinical Uses of Metformin
Type 2 Diabetes Mellitus
Metformin is the first-line pharmacological treatment recommended by major guidelines (ADA, EASD, WHO) for patients with T2DM, especially in overweight or obese individuals.
Prediabetes
In individuals with impaired glucose tolerance, metformin can reduce the progression to full-blown diabetes by up to 31%, particularly in younger, heavier individuals or women with a history of gestational diabetes.
Polycystic Ovary Syndrome (PCOS)
Metformin improves insulin resistance, restores ovulatory cycles, and reduces androgen levels in women with PCOS. It may enhance fertility and is often used adjunctively in reproductive treatment plans.
Gestational Diabetes Mellitus (GDM)
Although insulin remains the gold standard, metformin is increasingly used for GDM due to its oral administration and favorable side effect profile.
Weight Management and Metabolic Syndrome
Some studies support modest weight loss in obese or overweight patients, making it useful in metabolic syndrome.
Dosage and Administration
Metformin is available in several formulations:
Immediate-release (IR) tablets: 500 mg, 850 mg, 1000 mg
Extended-release (ER or XR) tablets: 500 mg, 750 mg, 1000 mg
Liquid (metformin oral solution): suitable for pediatric or dysphagic patients
Starting Dose
Initial: 500 mg once or twice daily with meals
Titration: Increase by 500 mg every week or biweekly as tolerated
Maximum dose: 2000–2550 mg/day, divided doses
Gradual dose escalation helps minimize gastrointestinal side effects.
Side Effects and Tolerability
Common Side Effects
Gastrointestinal upset: nausea, diarrhea, abdominal discomfort
Metallic taste in the mouth
Flatulence or bloating
Taking metformin with food, switching to extended-release formulations, or reducing the dose can mitigate these issues.
Rare but Serious Risks
Lactic acidosis: A rare but potentially fatal condition, especially in patients with renal impairment or severe heart/lung disease.
Vitamin B12 deficiency: Long-term use may impair B12 absorption; annual monitoring is recommended.
Contraindications and Cautions
Metformin should not be used in the following conditions:
Severe renal impairment (eGFR <30 mL/min/1.73 m²)
Acute or chronic metabolic acidosis, including diabetic ketoacidosis
Severe hepatic insufficiency
Alcohol abuse
Dehydration or shock
Use with caution in:
Patients undergoing radiologic studies with iodinated contrast media
Older adults with reduced renal reserve
Monitoring and Follow-Up
Routine monitoring ensures safe and effective use:
Renal function: Baseline and at least annually (more frequently in elderly or those with risk of renal decline)
HbA1c: Every 3–6 months to assess glycemic control
Vitamin B12 levels: Periodically, especially in patients with anemia or neuropathy
Drug Interactions
While metformin has relatively few interactions, some noteworthy ones include:
Iodinated contrast agents: Risk of lactic acidosis—pause metformin before and after contrast imaging.
Cimetidine: Can increase metformin plasma concentration by reducing renal clearance.
Loop diuretics, NSAIDs, and ACE inhibitors: May affect renal function.
Always review concurrent medications in patients starting metformin therapy.
Metformin in Special Populations
Elderly
Start with a lower dose and monitor renal function closely due to increased risk of renal decline.
Children
Approved for use in children aged 10 years and older for type 2 diabetes. Pediatric dosing follows similar principles to adult initiation.
Pregnancy and Breastfeeding
While metformin crosses the placenta, it is considered relatively safe during pregnancy and is sometimes used in gestational diabetes. It is also excreted in breast milk, but levels are typically low and not considered harmful in most cases.
Metformin and Cardiovascular Health
Recent studies (e.g., UKPDS) have shown cardiovascular benefits of metformin in overweight type 2 diabetics. It reduces the risk of myocardial infarction and stroke, potentially through mechanisms related to insulin sensitivity and lipid profile improvement.
Extended Benefits: Anti-Aging, Cancer, and Longevity Research
Research is ongoing into metformin’s non-glycemic benefits, including:
Anti-aging effects due to AMPK activation and reduced oxidative stress
Cancer prevention, particularly in breast, colon, and pancreatic cancers
Potential roles in neurodegenerative disorders such as Alzheimer’s disease
While promising, these applications remain investigational and are not yet standard practice.
Metformin Alternatives and Adjuncts
When monotherapy is inadequate, metformin can be combined with:
Sulfonylureas (e.g., glipizide)
DPP-4 inhibitors (e.g., sitagliptin)
SGLT2 inhibitors (e.g., empagliflozin)
GLP-1 receptor agonists (e.g., liraglutide)
Insulin
It is also commonly found in fixed-dose combination tablets for ease of use and improved adherence.
Conclusion: The Enduring Value of Metformin
Metformin remains the cornerstone of type 2 diabetes management due to its efficacy, safety, and broad utility across metabolic conditions. As both a monotherapy and foundational component of combination regimens, it provides unparalleled benefits with minimal risk when used correctly. Ongoing research into its extended uses may further cement its place as one of the most valuable pharmaceuticals in modern medicine.
