====== Metformin (Glucophage®) ======

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<WRAP infobox>
| | {{ :endocrine:biguanides:metformin.svg |}} |
^ Metformin |
| Brand Names | Glucophage®, Glucophage XR®, Riomet® |
| Drug Class | [[endocrine:biguanides:start|Biguanide]] |
| Primary Indication | [[endocrine:diabetes:start|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 |
</WRAP>
</WRAP>

===== Overview =====

Metformin is a [[endocrine:biguanides:start|biguanide]] and the first-line pharmacologic therapy for [[endocrine:diabetes:start|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.

<WRAP clear></WRAP>

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===== 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  

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===== Indications =====

  * [[endocrine:diabetes:start|Type 2 Diabetes Mellitus]]  
  * Prevention of progression in prediabetes (selected patients)

Common off-label:
  * Polycystic ovarian syndrome (PCOS)  
  * Insulin resistance states  

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<WRAP blackbox>
===== 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.
</WRAP>

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<WRAP contra>
===== 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  
</WRAP>

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<WRAP details>
===== 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  

</WRAP>

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<WRAP details>
===== Pharmacokinetics =====

Absorption:
  * Oral  

Bioavailability:
  * ~50–60%  

Protein binding:
  * Minimal  

Metabolism:
  * Not metabolized  

Half-life:
  * ~6 hours  

Elimination:
  * Renal (unchanged)  
</WRAP>

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<WRAP details>
===== Adverse Effects =====

Common:
  * Gastrointestinal upset  
  * Diarrhea  
  * Metallic taste  

Long-term:
  * Vitamin B12 deficiency  

Serious:
  * Lactic acidosis (rare)  
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<WRAP details>
===== Drug Interactions =====

Increased lactic acidosis risk:
  * Alcohol  
  * Iodinated contrast  

Renal clearance competition:
  * Cimetidine  

</WRAP>

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<WRAP monitoring>
===== 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  
</WRAP>

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<WRAP pearls>
===== 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  
</WRAP>

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===== Comparison Within Class =====

Metformin is the only widely used agent in the [[endocrine:biguanides:start|biguanide]] class.

Compared to other antihyperglycemics:
  * Lower hypoglycemia risk than [[endocrine:sulfonylureas:start|Sulfonylureas]]  
  * Less weight gain than [[endocrine:tzds:start|TZDs]]  
  * Less potent A1c reduction than combination therapy  

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===== Related =====

  * [[endocrine:biguanides:start|Biguanides]]
  * [[endocrine:diabetes:start|Diabetes Pharmacology]]
  * [[cardio:intro:start|Cardiovascular Pharmacology]]