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--- endocrine:biguanides:metformin [2026/02/13 15:53] – andrew2393cns
+++ endocrine:biguanides:metformin [2026/02/13 16:12] (current) – andrew2393cns
@@ Line 1: / Line 1: @@
-<WRAP right 280px>
+====== Metformin (Glucophage®) ======
-<WRAP infobox>
-{{:images:drugs:metformin_structure.png?220|Metformin (chemical structure)}}
+<WRAP right 340px>
+<WRAP infobox>
+| | {{ :endocrine:biguanides:metformin.svg |}} |
 ^ Metformin |
 | Brand Names | Glucophage®, Glucophage XR®, Riomet® |
 | Drug Class | [[endocrine:biguanides:start|Biguanide]] |
-| Primary Indications | [[endocrine:diabetes:start|Type 2 Diabetes]] |
+| Primary Indication | [[endocrine:diabetes:start|Type 2 Diabetes Mellitus]] |
-| Route(s) | Oral |
+| A1c Reduction | ~1–1.5% |
-| Onset | Days |
+| Hypoglycemia Risk | Low |
-| Duration | 12–24 hours |
+| Weight Effect | Neutral to ↓ |
-| Metabolism | None |
-| Half-life | ~6 hours |
 | Elimination | Renal |
-| Pregnancy | Generally safe |
+| Black Box Warning | Lactic Acidosis |
-| Renal Adjustment | Yes |
+| Landmark Evidence | UKPDS |
-| Hepatic Adjustment | Caution |
-| Black Box Warning | Yes |
-| Controlled | No |
 | FDA Approval | 1994 |
 </WRAP>
 </WRAP>
-====== Metformin (Glucophage®) ======
+===== Overview =====
-<span class="badge badge-endo">Endocrine</span>
+Metformin is a [[endocrine:biguanides:start|biguanide]] and the first-line pharmacologic therapy for [[endocrine:diabetes:start|Type 2 Diabetes Mellitus]].
-<span class="badge badge-common">Common</span>
-<span class="badge badge-firstline">First-line</span>
-<span class="badge badge-bbw">Black Box</span>
-===== Overview =====
+It lowers plasma glucose primarily through **suppression of hepatic gluconeogenesis** and **improvement of peripheral insulin sensitivity**, without increasing pancreatic insulin secretion.
-Metformin is a [[endocrine:biguanides:start|biguanide]] and first-line pharmacologic therapy for [[endocrine:diabetes:start|Type 2 Diabetes]].
-It lowers glucose primarily by reducing hepatic glucose production and improving insulin sensitivity without increasing insulin secretion.
-It carries minimal hypoglycemia risk and is weight-neutral to modestly weight-reducing.
+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 =====
-  * Activates **AMP-activated protein kinase (AMPK)**
-  * Decreases hepatic gluconeogenesis
-  * Improves peripheral insulin sensitivity
-  * Decreases intestinal glucose absorption (minor effect)
-Net effect:
+**Primary Cellular Target**
-  * ↓ Fasting plasma glucose
+  * Inhibition of mitochondrial complex I
-  * ↓ A1c (~1–1.5%)
+  * Increased AMP:ATP ratio
-  * No stimulation of insulin secretion
+  * 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 =====
-  * [[endocrine:diabetes:start|Type 2 Diabetes]]
-  * [[endocrine:reproductive:pcos|Polycystic Ovary Syndrome]] (off-label)
-  * Prediabetes (high-risk patients)
------
+  * [[endocrine:diabetes:start|Type 2 Diabetes Mellitus]]
+  * Prevention of progression in prediabetes (selected patients)
+Common off-label:
+  * Polycystic ovarian syndrome (PCOS)
+  * Insulin resistance states
+----
 <WRAP blackbox>
 ===== Black Box Warning =====
-**Risk of Lactic Acidosis**
-  * Rare but potentially fatal
+Metformin carries a boxed warning for **lactic acidosis**, a rare but potentially fatal complication.
-  * Increased risk in:
-    * Severe renal impairment
+Risk is increased in:
-    * Advanced liver disease
+  * Advanced renal impairment
-    * Hypoxia
+  * Severe hepatic disease
-    * Acute illness / dehydration
+  * 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/1.73m²
+  * eGFR < 30 mL/min/1.73 m²
   * Acute metabolic acidosis
-Relative:
+Relative / Caution:
-  * eGFR 30–45 (dose reduction)
+  * eGFR 30–45 (dose adjustment required)
-  * Advanced hepatic failure
+  * Advanced liver disease
-  * Severe dehydration
+  * Acute heart failure exacerbation
 </WRAP>
------
+----
 <WRAP details>
 ===== Dosing =====
 Initial:
-  * 500 mg once or twice daily
+  * 500 mg once or twice daily with meals
 Titration:
-  * Increase by 500 mg weekly as tolerated
+  * Increase every 1–2 weeks as tolerated
-Typical:
+Typical effective dose:
   * 1500–2000 mg/day
-Max:
+Maximum dose:
   * 2550 mg/day (IR)
   * 2000 mg/day (XR)
 Renal dosing:
   * eGFR 30–45 → reduce dose
-  * eGFR <30 → contraindicated
+  * Avoid if eGFR < 30
 </WRAP>
------
+----
 <WRAP details>
 ===== Pharmacokinetics =====
 Absorption:
-  * ~50–60%
+  * Oral
+Bioavailability:
+  * ~50–60%
 Protein binding:
   * Minimal
 Metabolism:
-  * None
+  * Not metabolized
 Half-life:
-  * ~6 hours (IR)
+  * ~6 hours
 Elimination:
   * Renal (unchanged)
-Extended-release formulations:
-  * Reduced GI side effects
 </WRAP>
------
+----
 <WRAP details>
 ===== Adverse Effects =====
 Common:
-  * GI upset
+  * Gastrointestinal upset
   * Diarrhea
   * Metallic taste
 Long-term:
   * Vitamin B12 deficiency
 Serious:
   * Lactic acidosis (rare)
 </WRAP>
------
+----
 <WRAP details>
 ===== Drug Interactions =====
-  * Contrast media (temporary hold recommended)
-  * Cimetidine (reduced renal clearance)
+Increased lactic acidosis risk:
-  * Other nephrotoxic agents
+  * Alcohol
+  * Iodinated contrast
+Renal clearance competition:
+  * Cimetidine
 </WRAP>
------
+----
 <WRAP monitoring>
 ===== Monitoring =====
-  * A1c every 3–6 months
-  * Renal function (eGFR)
+Labs:
-  * Vitamin B12 (long-term use)
+  * 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 for most patients with Type 2 Diabetes
-  * Does NOT cause hypoglycemia alone
+  * First-line therapy in most patients with Type 2 DM
-  * Weight neutral to mild weight loss
+  * Does not cause hypoglycemia as monotherapy
-  * Hold during acute illness or before iodinated contrast
+  * May confer cardiovascular benefit
+  * Weight-neutral or modest weight loss
+  * Always assess renal function before initiation
 </WRAP>
------
+----
 ===== Comparison Within Class =====
-Metformin is the only widely used [[endocrine:biguanides:start|biguanide]] in clinical practice.
-Compared to:
+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
-  * [[endocrine:sglt2:start|SGLT2 Inhibitors]] → no HF/CKD benefit
------
+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
+----
 ===== Related =====
   * [[endocrine:biguanides:start|Biguanides]]
   * [[endocrine:diabetes:start|Diabetes Pharmacology]]
-  * [[endocrine:start|Endocrine Pharmacology]]
+  * [[cardio:intro:start|Cardiovascular Pharmacology]]