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--- endocrine:biguanides:metformin [2026/02/13 16:02] – andrew2393cns
+++ endocrine:biguanides:metformin [2026/02/13 16:12] (current) – andrew2393cns
@@ Line 1: / Line 1: @@
-<WRAP right 300px>
+====== 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 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 to ↓ |
 | Elimination | Renal |
-| Black Box | Lactic Acidosis |
+| Black Box Warning | Lactic Acidosis |
+| Landmark Evidence | UKPDS |
 | FDA Approval | 1994 |
 </WRAP>
 </WRAP>
-====== Metformin (Glucophage®) ======
-<WRAP overview>
 ===== Overview =====
-Metformin is a [[endocrine:biguanides:start|biguanide]] and first-line pharmacologic therapy for [[endocrine:diabetes:start|Type 2 Diabetes Mellitus]].
+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 by suppressing hepatic gluconeogenesis and improving peripheral insulin sensitivity without increasing insulin secretion.
+It lowers plasma glucose primarily through **suppression of hepatic gluconeogenesis** and **improvement of peripheral insulin sensitivity**, without increasing pancreatic 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.
+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>
-<WRAP clearfix></WRAP>
+<WRAP clear></WRAP>
---------------------------------------------------------------------
+----
 ===== Mechanism of Action =====
-**Primary Target:**
+**Primary Cellular Target**
-AMP-activated protein kinase (AMPK)
+  * Inhibition of mitochondrial complex I
+  * Increased AMP:ATP ratio
+  * Activation of AMP-activated protein kinase (AMPK)
-**Cellular Effects:**
+**Hepatic Effects**
-  * Inhibits mitochondrial complex I → ↓ ATP production
+  * ↓ Expression of gluconeogenic enzymes (PEPCK, G6Pase)
-  * ↑ AMP/ATP ratio → AMPK activation
+  * ↓ Hepatic glucose production
-  * Suppresses hepatic gluconeogenesis
-  * ↓ expression of gluconeogenic enzymes (PEPCK, G6Pase)
-  * Improves insulin-mediated glucose uptake in skeletal muscle
-**Net Physiologic Effect:**
+**Peripheral Effects**
-  * ↓ Hepatic glucose output
+  * ↑ Skeletal muscle glucose uptake
-  * ↓ Fasting plasma glucose
+  * ↑ Insulin sensitivity
-  * Improved insulin sensitivity
-**Key Concept:**
+**Net Physiologic Outcome**
-Metformin does **not** stimulate insulin secretion.
+  * ↓ Fasting plasma glucose
+  * Improved glycemic control without hypoglycemia
---------------------------------------------------------------------
+----
 ===== Indications =====
   * [[endocrine:diabetes:start|Type 2 Diabetes Mellitus]]
-  * Prediabetes (risk reduction)
+  * Prevention of progression in prediabetes (selected patients)
-  * Polycystic Ovary Syndrome (off-label)
---------------------------------------------------------------------
+Common off-label:
+  * Polycystic ovarian syndrome (PCOS)
+  * Insulin resistance states
+----
 <WRAP blackbox>
-===== Black Box Warning – Lactic Acidosis =====
+===== Black Box Warning =====
-Rare but potentially fatal.
+Metformin carries a boxed warning for **lactic acidosis**, a rare but potentially fatal complication.
-Risk increases in:
+Risk is increased in:
   * Advanced renal impairment
-  * Severe hepatic dysfunction
+  * Severe hepatic disease
-  * Hypoxia / shock
+  * Hypoxic states (CHF exacerbation, sepsis)
-  * Excess alcohol use
+  * Excess alcohol intake
-Avoid when eGFR <30 mL/min/1.73m².
+Metformin should be withheld during acute illness, dehydration, or iodinated contrast exposure when renal function is unstable.
 </WRAP>
---------------------------------------------------------------------
+----
+<WRAP contra>
 ===== Contraindications =====
-**Absolute:**
+Absolute:
-  * eGFR <30 mL/min/1.73m²
+  * eGFR < 30 mL/min/1.73 m²
   * Acute metabolic acidosis
-  * Severe hypoxia states
-**Relative / Caution:**
+Relative / Caution:
-  * eGFR 30–45 (dose reduction)
+  * eGFR 30–45 (dose adjustment required)
-  * Iodinated contrast exposure
+  * Advanced liver disease
-  * Advanced liver disease
+  * Acute heart failure exacerbation
+</WRAP>
---------------------------------------------------------------------
+----
+<WRAP details>
 ===== Dosing =====
-**Immediate Release:**
+Initial:
-  * Start: 500 mg once or twice daily
+  * 500 mg once or twice daily with meals
-  * Titrate weekly
-  * Max: 2000–2550 mg/day
-**Extended Release:**
+Titration:
-  * Start: 500 mg daily
+  * Increase every 1–2 weeks as tolerated
-  * Max: 2000 mg/day
-Titrate slowly to minimize GI intolerance.
+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% bioavailability
+  * Oral
+Bioavailability:
+  * ~50–60%
-Protein Binding:
+Protein binding:
-  * Negligible
+  * Minimal
 Metabolism:
-  * None
+  * Not metabolized
 Half-life:
-  * ~4–8 hours
+  * ~6 hours
 Elimination:
   * Renal (unchanged)
+</WRAP>
---------------------------------------------------------------------
+----
+<WRAP details>
 ===== Adverse Effects =====
-**Common:**
+Common:
-  * GI upset (nausea, diarrhea)
+  * Gastrointestinal upset
-  * Metallic taste
+  * Diarrhea
+  * Metallic taste
-**Long-Term:**
+Long-term:
   * Vitamin B12 deficiency
-**Serious (Rare):**
+Serious:
-  * Lactic acidosis
+  * Lactic acidosis (rare)
+</WRAP>
---------------------------------------------------------------------
+----
+<WRAP details>
 ===== Drug Interactions =====
-  * Cimetidine → ↓ renal clearance
+Increased lactic acidosis risk:
-  * Contrast dye → risk of acute kidney injury
+  * Alcohol
-  * Alcohol → ↑ lactic acidosis risk
+  * Iodinated contrast
---------------------------------------------------------------------
+Renal clearance competition:
+  * Cimetidine
+</WRAP>
+----
+<WRAP monitoring>
 ===== Monitoring =====
-  * A1c every 3–6 months
+Labs:
-  * eGFR at baseline and annually
+  * A1c
-  * Vitamin B12 periodically (long-term use)
+  * 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 nearly all Type 2 DM unless contraindicated
+  * First-line therapy in most patients with Type 2 DM
-  * Does not cause hypoglycemia when used alone
+  * Does not cause hypoglycemia as monotherapy
-  * Cardiovascular benefit likely mediated through metabolic improvement
+  * May confer cardiovascular benefit
-  * Hold during acute illness or contrast studies
+  * Weight-neutral or modest weight loss
-  * GI effects improve with slow titration
+  * Always assess renal function before initiation
+</WRAP>
---------------------------------------------------------------------
+----
 ===== Comparison Within Class =====
@@ Line 170: / Line 204: @@
 Metformin is the only widely used agent in the [[endocrine:biguanides:start|biguanide]] class.
-Compared to:
+Compared to other antihyperglycemics:
-  * [[endocrine:sulfonylureas:start|Sulfonylureas]] → no hypoglycemia
+  * Lower hypoglycemia risk than [[endocrine:sulfonylureas:start|Sulfonylureas]]
-  * [[endocrine:tzds:start|TZDs]] → no weight gain, no edema
+  * Less weight gain than [[endocrine:tzds:start|TZDs]]
-  * [[endocrine:glp1:start|GLP-1 RAs]] → less weight loss but lower cost
+  * Less potent A1c reduction than combination therapy
---------------------------------------------------------------------
+----
 ===== Related =====