Metformin (Glucophage®)
 |
|
| Metformin | |
|---|---|
| Brand Names | Glucophage®, Glucophage XR®, Riomet® |
| Drug Class | Biguanide |
| Primary Indication | Type 2 Diabetes Mellitus |
| A1c Reduction | ~1–1.5% |
| Hypoglycemia Risk | Low |
| Weight Effect | Neutral to ↓ |
| Elimination | Renal |
| Black Box Warning | Lactic Acidosis |
| Landmark Evidence | UKPDS |
| FDA Approval | 1994 |
Overview
Metformin is a biguanide and the first-line pharmacologic therapy for Type 2 Diabetes Mellitus.
It lowers plasma glucose primarily through suppression of hepatic gluconeogenesis and improvement of peripheral insulin sensitivity, without increasing pancreatic insulin secretion.
Clinically, metformin reduces A1c by approximately 1–1.5%, carries minimal risk of hypoglycemia, is weight-neutral or modestly weight-reducing, and remains the foundational agent in cardiometabolic disease management unless contraindicated.
Mechanism of Action
Primary Cellular Target
- Inhibition of mitochondrial complex I
- Increased AMP:ATP ratio
- Activation of AMP-activated protein kinase (AMPK)
Hepatic Effects
- ↓ Expression of gluconeogenic enzymes (PEPCK, G6Pase)
- ↓ Hepatic glucose production
Peripheral Effects
- ↑ Skeletal muscle glucose uptake
- ↑ Insulin sensitivity
Net Physiologic Outcome
- ↓ Fasting plasma glucose
- Improved glycemic control without hypoglycemia
Indications
- Prevention of progression in prediabetes (selected patients)
Common off-label:
- Polycystic ovarian syndrome (PCOS)
- Insulin resistance states
Black Box Warning
Metformin carries a boxed warning for lactic acidosis, a rare but potentially fatal complication.
Risk is increased in:
- Advanced renal impairment
- Severe hepatic disease
- Hypoxic states (CHF exacerbation, sepsis)
- Excess alcohol intake
Metformin should be withheld during acute illness, dehydration, or iodinated contrast exposure when renal function is unstable.
Contraindications
Absolute:
- eGFR < 30 mL/min/1.73 m²
- Acute metabolic acidosis
Relative / Caution:
- eGFR 30–45 (dose adjustment required)
- Advanced liver disease
- Acute heart failure exacerbation
Dosing
Initial:
- 500 mg once or twice daily with meals
Titration:
- Increase every 1–2 weeks as tolerated
Typical effective dose:
- 1500–2000 mg/day
Maximum dose:
- 2550 mg/day (IR)
- 2000 mg/day (XR)
Renal dosing:
- eGFR 30–45 → reduce dose
- Avoid if eGFR < 30
Pharmacokinetics
Absorption:
- Oral
Bioavailability:
- ~50–60%
Protein binding:
- Minimal
Metabolism:
- Not metabolized
Half-life:
- ~6 hours
Elimination:
- Renal (unchanged)
Adverse Effects
Common:
- Gastrointestinal upset
- Diarrhea
- Metallic taste
Long-term:
- Vitamin B12 deficiency
Serious:
- Lactic acidosis (rare)
Drug Interactions
Increased lactic acidosis risk:
- Alcohol
- Iodinated contrast
Renal clearance competition:
- Cimetidine
Monitoring
Labs:
- A1c
- Fasting glucose
- Renal function (baseline and periodically)
- Vitamin B12 (long-term therapy)
Clinical:
- GI tolerance
- Signs of acidosis in high-risk patients
Clinical Pearls
- First-line therapy in most patients with Type 2 DM
- Does not cause hypoglycemia as monotherapy
- May confer cardiovascular benefit
- Weight-neutral or modest weight loss
- Always assess renal function before initiation
Comparison Within Class
Metformin is the only widely used agent in the biguanide class.
Compared to other antihyperglycemics:
- Lower hypoglycemia risk than Sulfonylureas
- Less weight gain than TZDs
- Less potent A1c reduction than combination therapy