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--- endocrine:biguanides:metformin [2026/02/13 15:57] – andrew2393cns
+++ endocrine:biguanides:metformin [2026/02/13 16:12] (current) – andrew2393cns
@@ Line 1: / Line 1: @@
-<WRAP right 280px>
+====== Metformin (Glucophage®) ======
-<WRAP infobox>
-{{ :endocrine:biguanides:metformin.svg |}}
+<WRAP right 340px>
+<WRAP infobox>
+| | {{ :endocrine:biguanides:metformin.svg |}} |
 ^ Metformin |
 | Brand Names | Glucophage®, Glucophage XR®, Riomet® |
 | Drug Class | [[endocrine:biguanides:start|Biguanide]] |
-| Primary Use | [[endocrine:diabetes:start|Type 2 Diabetes]] |
+| Primary Indication | [[endocrine:diabetes:start|Type 2 Diabetes Mellitus]] |
 | A1c Reduction | ~1–1.5% |
 | Hypoglycemia Risk | Low |
-| Weight Effect | Neutral / ↓ |
+| Weight Effect | Neutral to ↓ |
 | Elimination | Renal |
-| Black Box | Lactic Acidosis |
+| Black Box Warning | Lactic Acidosis |
+| Landmark Evidence | UKPDS |
 | FDA Approval | 1994 |
 </WRAP>
 </WRAP>
-====== Metformin (Glucophage®) ======
 ===== Overview =====
-Metformin is a [[endocrine:biguanides:start|biguanide]] and first-line pharmacologic therapy for [[endocrine:diabetes:start|Type 2 Diabetes]].
-It lowers plasma glucose primarily by reducing hepatic glucose production and improving insulin sensitivity without stimulating insulin secretion.
------
+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>
+----
 ===== Mechanism of Action =====
-Metformin activates **AMP-activated protein kinase (AMPK)**.
-This results in:
+**Primary Cellular Target**
-  * Decreased hepatic gluconeogenesis
+  * Inhibition of mitochondrial complex I
-  * Improved peripheral glucose uptake
+  * Increased AMP:ATP ratio
-  * Reduced fasting plasma glucose
+  * Activation of AMP-activated protein kinase (AMPK)
-Because it does not increase insulin secretion, hypoglycemia is uncommon when used as monotherapy.
+**Hepatic Effects**
+  * ↓ Expression of gluconeogenic enzymes (PEPCK, G6Pase)
+  * ↓ Hepatic glucose production
------
+**Peripheral Effects**
+  * ↑ Skeletal muscle glucose uptake
+  * ↑ Insulin sensitivity
-===== Clinical Use =====
+**Net Physiologic Outcome**
-  * First-line therapy in most patients with Type 2 Diabetes
+  * ↓ Fasting plasma glucose
-  * Combination therapy with:
+  * Improved glycemic control without hypoglycemia
-    * [[endocrine:glp1:start|GLP-1 receptor agonists]]
-    * [[endocrine:sglt2:start|SGLT2 inhibitors]]
-    * [[endocrine:sulfonylureas:start|Sulfonylureas]]
-Preferred in overweight patients and in early disease.
+----
------
+===== Indications =====
-===== Safety =====
+  * [[endocrine:diabetes:start|Type 2 Diabetes Mellitus]]
+  * Prevention of progression in prediabetes (selected patients)
-==== Black Box Warning ====
+Common off-label:
-Risk of lactic acidosis.
+  * Polycystic ovarian syndrome (PCOS)
+  * Insulin resistance states
-Increased risk in:
+----
-  * eGFR < 30 mL/min/1.73m²
-  * Severe hepatic impairment
-  * Hypoxic states
-  * Acute illness or dehydration
-==== Contraindications ====
+<WRAP blackbox>
-  * eGFR < 30
+===== Black Box Warning =====
-  * Acute metabolic acidosis
------
+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>
+----
+<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>
+----
 <WRAP details>
 ===== Dosing =====
-Initial: 500 mg daily
-Titrate weekly
+Initial:
-Typical: 1500–2000 mg/day
+  * 500 mg once or twice daily with meals
-Reduce dose if eGFR 30–45
-Avoid if eGFR < 30
+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>
+----
 <WRAP details>
 ===== Pharmacokinetics =====
-Absorption: ~50–60%
-Metabolism: None
+Absorption:
-Half-life: ~6 hours
+  * Oral
-Elimination: Renal (unchanged)
+Bioavailability:
+  * ~50–60%
+Protein binding:
+  * Minimal
+Metabolism:
+  * Not metabolized
+Half-life:
+  * ~6 hours
+Elimination:
+  * Renal (unchanged)
 </WRAP>
+----
 <WRAP details>
 ===== Adverse Effects =====
 Common:
   * Gastrointestinal upset
   * Diarrhea
   * Metallic taste
 Long-term:
   * Vitamin B12 deficiency
 Serious:
   * Lactic acidosis (rare)
 </WRAP>
------
+----
+<WRAP details>
+===== Drug Interactions =====
+Increased lactic acidosis risk:
+  * Alcohol
+  * Iodinated contrast
+Renal clearance competition:
+  * Cimetidine
+</WRAP>
+----
+<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>
+----
+<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>
+----
 ===== Comparison Within Class =====
-Metformin is the only clinically used biguanide.
-Compared with:
+Metformin is the only widely used agent in the [[endocrine:biguanides:start|biguanide]] class.
-  * [[endocrine:sulfonylureas:start|Sulfonylureas]] → no hypoglycemia
-  * [[endocrine:glp1:start|GLP-1 receptor agonists]] → less weight loss
+Compared to other antihyperglycemics:
-  * [[endocrine:sglt2:start|SGLT2 inhibitors]] → no heart failure or CKD benefit
+  * Lower hypoglycemia risk than [[endocrine:sulfonylureas:start|Sulfonylureas]]
+  * Less weight gain than [[endocrine:tzds:start|TZDs]]
+  * Less potent A1c reduction than combination therapy
+----
+===== Related =====
+  * [[endocrine:biguanides:start|Biguanides]]
+  * [[endocrine:diabetes:start|Diabetes Pharmacology]]
+  * [[cardio:intro:start|Cardiovascular Pharmacology]]