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

It lowers blood glucose primarily by reducing hepatic glucose production and improving insulin sensitivity.

It does NOT increase insulin secretion and carries minimal hypoglycemia risk.

→ Diabetes Pharmacology

Metformin primarily reduces hepatic gluconeogenesis.

The dominant mechanism involves inhibition of mitochondrial oxidative phosphorylation in hepatocytes.

Specifically:

• Inhibits mitochondrial respiratory chain complex I
• Decreases ATP production
• Increases intracellular AMP and ADP
• Raises the AMP:ATP ratio

Elevated AMP leads to:

• Inhibition of key gluconeogenic enzymes
• Suppression of hepatic glucose production
• Reduced fasting glucose levels

AMP-activated protein kinase (AMPK) activation occurs secondarily and contributes to:

• Increased fatty acid oxidation
• Decreased lipogenesis
• Improved peripheral insulin sensitivity

Importantly:

• AMPK activation is not required for metformin’s glucose-lowering effect.
• The primary glucose effect is suppression of hepatic gluconeogenesis.

Additional mechanisms:

• Decreased intestinal glucose absorption
• Increased endogenous GLP-1 levels
• Alteration of gut microbiome

Net Result:

• Reduced hepatic glucose output
• Improved insulin sensitivity
• Lower fasting glucose

• Moderate HbA1c reduction
• Weight neutral or mild weight loss
• Low hypoglycemia risk
• Mild triglyceride reduction

Metformin is first-line therapy in most patients with Type 2 Diabetes unless contraindicated.

Metformin:

• Improves insulin resistance
• Modestly reduces cardiovascular risk (UKPDS data)
• Does NOT cause weight gain
• Does NOT cause edema

However, it does NOT provide the same heart failure or ASCVD benefit as:

• GLP-1 Receptor Agonists
• SGLT2 Inhibitors

→ Cardiovascular Pharmacology

• Type 2 Diabetes Mellitus
• Prediabetes (select patients)
• Polycystic Ovary Syndrome (off-label)

• Start low and titrate gradually
• Extended-release formulations improve GI tolerance
• Take with meals to reduce GI side effects

Common:

• Nausea
• Diarrhea
• Abdominal discomfort

Serious (rare):

• Lactic acidosis
• Vitamin B12 deficiency (long-term use)

Lactic acidosis risk is extremely low but increases in:

• Severe renal failure
• Hypoxia
• Sepsis
• Shock

Monitor:

• Renal function
• Vitamin B12 levels in long-term therapy

• Severe renal impairment
• Acute metabolic acidosis
• Unstable hemodynamic states

Temporarily hold:

• During acute illness
• Prior to iodinated contrast (depending on renal function)

Compared to:

• Sulfonylureas → no hypoglycemia
• Thiazolidinediones → no edema
• Insulin Therapy → no weight gain
• GLP-1 Receptor Agonists → less weight loss
• SGLT2 Inhibitors → no heart failure benefit

Metformin remains foundational therapy but is often combined with cardioprotective agents.

• Inhibits mitochondrial complex I
• Raises AMP → suppresses gluconeogenesis
• AMPK activation is secondary
• First-line in Type 2 Diabetes
• Weight neutral
• Monitor B12 long-term
• Rare lactic acidosis risk

• Diabetes Pharmacology
• Thiazolidinediones
• GLP-1 Receptor Agonists
• SGLT2 Inhibitors
• Heart Failure Module