Introduction to Metformin’s Mechanism of Action
Glucophage, the brand name for metformin hydrochloride, is a cornerstone in the management of Type 2 Diabetes Mellitus (T2DM). As a biguanide-class medication, its primary function is to improve glycemic control through three key mechanisms:
- Suppression of hepatic gluconeogenesis: Reduces excessive glucose production by the liver.
- Enhancement of peripheral insulin sensitivity: Facilitates glucose uptake in muscle and adipose tissues.
- Delayed intestinal glucose absorption: Modulates postprandial blood sugar spikes.
Unlike insulin secretagogues (e.g., sulfonylureas), metformin does not induce hypoglycemia, making it a safer first-line therapy.
1. FDA-Approved Indications
Type 2 Diabetes Mellitus (T2DM)
Metformin is the first-line pharmacotherapy for T2DM per the American Diabetes Association (ADA) guidelines. Clinical benefits include:
- Reduction of HbA1c by 1–2%.
- Potential weight neutrality or modest weight loss (versus weight gain with insulin/thiazolidinediones).
- Cardiovascular risk reduction in obese patients.
Pediatric Use (Ages 10+)
Approved for children with T2DM, though lifestyle modification remains paramount.
2. Off-Label Applications
Polycystic Ovary Syndrome (PCOS)
Metformin is widely used off-label for PCOS due to its ability to:
- Improve ovulatory function in anovulatory women.
- Reduce hyperandrogenism (hirsutism, acne).
- Mitigate insulin resistance present in 50–70% of PCOS cases.
Note: While not FDA-approved for PCOS, it is endorsed by the Endocrine Society as adjunctive therapy.
Gestational Diabetes Mellitus (GDM)
Emerging evidence supports metformin as an alternative to insulin in GDM, though insulin remains gold standard due to placental transfer concerns.
3. Investigational Uses
Anti-Aging and Longevity
Preliminary studies (e.g., Targeting Aging with Metformin [TAME] trial) suggest metformin may:
- Activate AMPK pathways, mimicking caloric restriction.
- Reduce oxidative stress and inflammation.
Current stance: Insufficient evidence for non-diabetic use; research is ongoing.
Cancer Risk Reduction
Observational data associate metformin with lower incidence of certain cancers (e.g., breast, colorectal), possibly due to mTOR inhibition.
Contraindications: When to Avoid Metformin
- Severe renal impairment (eGFR <30 mL/min): Risk of lactic acidosis.
- Acute/chronic metabolic acidosis: Including diabetic ketoacidosis.
- Hypersensitivity to metformin: Rare but documented.