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Metformin
Brand Names	Glucophage®, Glucophage XR®, Riomet®
Drug Class	Biguanide
Primary Use	Type 2 Diabetes
A1c Reduction	~1–1.5%
Hypoglycemia Risk	Low
Weight Effect	Neutral to ↓
Elimination	Renal
Black Box	Lactic Acidosis
FDA Approval	1994

Metformin (Glucophage®)

Overview

Metformin is a biguanide and first-line pharmacologic therapy for Type 2 Diabetes Mellitus.

It lowers plasma glucose primarily by suppressing hepatic gluconeogenesis and improving peripheral insulin sensitivity without increasing insulin secretion.

Metformin reduces A1c by approximately 1–1.5%, carries minimal hypoglycemia risk, and is weight-neutral or modestly weight-reducing. It remains the foundational agent in cardiometabolic management unless contraindicated.

Mechanism of Action

Primary Target: AMP-activated protein kinase (AMPK)

Cellular Effects:

Inhibits mitochondrial complex I → ↓ ATP production
↑ AMP/ATP ratio → AMPK activation
Suppresses hepatic gluconeogenesis
↓ expression of gluconeogenic enzymes (PEPCK, G6Pase)
Improves insulin-mediated glucose uptake in skeletal muscle

Net Physiologic Effect:

↓ Hepatic glucose output
↓ Fasting plasma glucose
Improved insulin sensitivity

Key Concept: Metformin does not stimulate insulin secretion.

Indications

Type 2 Diabetes Mellitus
Prediabetes (risk reduction)
Polycystic Ovary Syndrome (off-label)

Black Box Warning – Lactic Acidosis

Rare but potentially fatal.

Risk increases in:

Advanced renal impairment
Severe hepatic dysfunction
Hypoxia / shock
Excess alcohol use

Avoid when eGFR <30 mL/min/1.73m².

Contraindications

Absolute:

eGFR <30 mL/min/1.73m²
Acute metabolic acidosis
Severe hypoxia states

Relative / Caution:

eGFR 30–45 (dose reduction)
Iodinated contrast exposure
Advanced liver disease

Dosing

Immediate Release:

Start: 500 mg once or twice daily
Titrate weekly
Max: 2000–2550 mg/day

Extended Release:

Start: 500 mg daily
Max: 2000 mg/day

Titrate slowly to minimize GI intolerance.

Pharmacokinetics

Absorption:

~50–60% bioavailability

Protein Binding:

Negligible

Metabolism:

None

Half-life:

~4–8 hours

Elimination:

Renal (unchanged)

Adverse Effects

Common:

GI upset (nausea, diarrhea)
Metallic taste

Long-Term:

Vitamin B12 deficiency

Serious (Rare):

Lactic acidosis

Drug Interactions

Cimetidine → ↓ renal clearance
Contrast dye → risk of acute kidney injury
Alcohol → ↑ lactic acidosis risk

Monitoring

A1c every 3–6 months
eGFR at baseline and annually
Vitamin B12 periodically (long-term use)

Clinical Pearls

First-line therapy in nearly all Type 2 DM unless contraindicated
Does not cause hypoglycemia when used alone
Cardiovascular benefit likely mediated through metabolic improvement
Hold during acute illness or contrast studies
GI effects improve with slow titration

Comparison Within Class

Metformin is the only widely used agent in the biguanide class.

Compared to:

Sulfonylureas → no hypoglycemia
TZDs → no weight gain, no edema
GLP-1 RAs → less weight loss but lower cost