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--- endocrine:biguanides:metformin [2026/02/13 14:53] – andrew2393cns
+++ endocrine:biguanides:metformin [2026/02/13 16:12] (current) – andrew2393cns
@@ Line 1: / Line 1: @@
-  {{:images:drugs:metformin_structure.png?220|Metformin Chemical Structure}}
+====== Metformin (Glucophage®) ======
+<WRAP right 340px>
+<WRAP infobox>
+| | {{ :endocrine:biguanides:metformin.svg |}} |
 ^ Metformin |
-| Brand Names | Glucophage®, Glucophage XR® |
+| Brand Names | Glucophage®, Glucophage XR®, Riomet® |
-| Drug Class | [[endocrine:biguanides:metformin|Biguanide]] |
+| Drug Class | [[endocrine:biguanides:start|Biguanide]] |
-| Primary Use | Type 2 Diabetes |
+| Primary Indication | [[endocrine:diabetes:start|Type 2 Diabetes Mellitus]] |
-| Mechanism | AMPK activation |
+| A1c Reduction | ~1–1.5% |
 | Hypoglycemia Risk | Low |
-| Weight Effect | Neutral / ↓ |
+| Weight Effect | Neutral to ↓ |
-| CV Benefit | Possible ASCVD benefit |
+| Elimination | Renal |
+| Black Box Warning | Lactic Acidosis |
+| Landmark Evidence | UKPDS |
 | FDA Approval | 1994 |
+</WRAP>
+</WRAP>
-====== Metformin ======
+===== Overview =====
-Metformin is a biguanide and first-line therapy for Type 2 Diabetes.
+Metformin is a [[endocrine:biguanides:start|biguanide]] and the first-line pharmacologic therapy for [[endocrine:diabetes:start|Type 2 Diabetes Mellitus]].
-It lowers blood glucose primarily by reducing hepatic glucose production and improving insulin sensitivity.
+It lowers plasma glucose primarily through **suppression of hepatic gluconeogenesis** and **improvement of peripheral insulin sensitivity**, without increasing pancreatic insulin secretion.
-It does NOT increase insulin secretion and carries minimal hypoglycemia risk.
+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.
-→ [[endocrine:diabetes:start|Diabetes Pharmacology]]
+<WRAP clear></WRAP>
---------------------------------------------------------------------
+----
 ===== Mechanism of Action =====
-Metformin primarily reduces hepatic gluconeogenesis.
+**Primary Cellular Target**
+  * Inhibition of mitochondrial complex I
+  * Increased AMP:ATP ratio
+  * Activation of AMP-activated protein kinase (AMPK)
-The dominant mechanism involves inhibition of mitochondrial oxidative phosphorylation in hepatocytes.
+**Hepatic Effects**
+  * ↓ Expression of gluconeogenic enzymes (PEPCK, G6Pase)
+  * ↓ Hepatic glucose production
-Specifically:
+**Peripheral Effects**
+  * ↑ Skeletal muscle glucose uptake
+  * ↑ Insulin sensitivity
-  * Inhibits mitochondrial respiratory chain complex I
+**Net Physiologic Outcome**
-  * Decreases ATP production
+  * ↓ Fasting plasma glucose
-  * Increases intracellular AMP and ADP
+  * Improved glycemic control without hypoglycemia
-  * Raises the AMP:ATP ratio
-Elevated AMP leads to:
+----
-  * Inhibition of key gluconeogenic enzymes
+===== Indications =====
-  * Suppression of hepatic glucose production
-  * Reduced fasting glucose levels
-AMP-activated protein kinase (AMPK) activation occurs secondarily and contributes to:
+  * [[endocrine:diabetes:start|Type 2 Diabetes Mellitus]]
+  * Prevention of progression in prediabetes (selected patients)
-  * Increased fatty acid oxidation
+Common off-label:
-  * Decreased lipogenesis
+  * Polycystic ovarian syndrome (PCOS)
-  * Improved peripheral insulin sensitivity
+  * Insulin resistance states
-Importantly:
+----
-  * AMPK activation is not required for metformin’s glucose-lowering effect.
+<WRAP blackbox>
-  * The primary glucose effect is suppression of hepatic gluconeogenesis.
+===== Black Box Warning =====
-Additional mechanisms:
+Metformin carries a boxed warning for **lactic acidosis**, a rare but potentially fatal complication.
-  * Decreased intestinal glucose absorption
+Risk is increased in:
-  * Increased endogenous GLP-1 levels
+  * Advanced renal impairment
-  * Alteration of gut microbiome
+  * Severe hepatic disease
+  * Hypoxic states (CHF exacerbation, sepsis)
+  * Excess alcohol intake
-Net Result:
+Metformin should be withheld during acute illness, dehydration, or iodinated contrast exposure when renal function is unstable.
+</WRAP>
-  * Reduced hepatic glucose output
+----
-  * Improved insulin sensitivity
-  * Lower fasting glucose
---------------------------------------------------------------------
+<WRAP contra>
+===== Contraindications =====
-===== Clinical Effects =====
+Absolute:
+  * eGFR < 30 mL/min/1.73 m²
+  * Acute metabolic acidosis
-  * Moderate HbA1c reduction
+Relative / Caution:
-  * Weight neutral or mild weight loss
+  * eGFR 30–45 (dose adjustment required)
-  * Low hypoglycemia risk
+  * Advanced liver disease
-  * Mild triglyceride reduction
+  * Acute heart failure exacerbation
+</WRAP>
-Metformin is first-line therapy in most patients with Type 2 Diabetes unless contraindicated.
+----
---------------------------------------------------------------------
+<WRAP details>
+===== Dosing =====
-===== Cardiometabolic Impact =====
+Initial:
+  * 500 mg once or twice daily with meals
-Metformin:
+Titration:
+  * Increase every 1–2 weeks as tolerated
-  * Improves insulin resistance
+Typical effective dose:
-  * Modestly reduces cardiovascular risk (UKPDS data)
+  * 1500–2000 mg/day
-  * Does NOT cause weight gain
-  * Does NOT cause edema
-However, it does NOT provide the same heart failure or ASCVD benefit as:
+Maximum dose:
+  * 2550 mg/day (IR)
+  * 2000 mg/day (XR)
-  * [[endocrine:glp1:start|GLP-1 Receptor Agonists]]
+Renal dosing:
-  * [[endocrine:sglt2:start|SGLT2 Inhibitors]]
+  * eGFR 30–45 → reduce dose
+  * Avoid if eGFR < 30
-→ [[cardio:intro:start|Cardiovascular Pharmacology]]
+</WRAP>
---------------------------------------------------------------------
+----
-===== Indications =====
+<WRAP details>
+===== Pharmacokinetics =====
-  * Type 2 Diabetes Mellitus
+Absorption:
-  * Prediabetes (select patients)
+  * Oral
-  * Polycystic Ovary Syndrome (off-label)
---------------------------------------------------------------------
+Bioavailability:
+  * ~50–60%
-===== Dosing Considerations =====
+Protein binding:
+  * Minimal
-  * Start low and titrate gradually
+Metabolism:
-  * Extended-release formulations improve GI tolerance
+  * Not metabolized
-  * Take with meals to reduce GI side effects
---------------------------------------------------------------------
+Half-life:
+  * ~6 hours
+Elimination:
+  * Renal (unchanged)
+</WRAP>
+----
+<WRAP details>
 ===== Adverse Effects =====
 Common:
+  * Gastrointestinal upset
+  * Diarrhea
+  * Metallic taste
-  * Nausea
+Long-term:
-  * Diarrhea
+  * Vitamin B12 deficiency
-  * Abdominal discomfort
-Serious (rare):
+Serious:
+  * Lactic acidosis (rare)
+</WRAP>
-  * Lactic acidosis
+----
-  * Vitamin B12 deficiency (long-term use)
-Lactic acidosis risk is extremely low but increases in:
+<WRAP details>
+===== Drug Interactions =====
-  * Severe renal failure
+Increased lactic acidosis risk:
-  * Hypoxia
+  * Alcohol
-  * Sepsis
+  * Iodinated contrast
-  * Shock
-Monitor:
+Renal clearance competition:
+  * Cimetidine
-  * Renal function
+</WRAP>
-  * Vitamin B12 levels in long-term therapy
---------------------------------------------------------------------
+----
-===== Contraindications =====
+<WRAP monitoring>
+===== Monitoring =====
-  * Severe renal impairment
+Labs:
-  * Acute metabolic acidosis
+  * A1c
-  * Unstable hemodynamic states
+  * Fasting glucose
+  * Renal function (baseline and periodically)
+  * Vitamin B12 (long-term therapy)
-Temporarily hold:
+Clinical:
+  * GI tolerance
+  * Signs of acidosis in high-risk patients
+</WRAP>
-  * During acute illness
+----
-  * Prior to iodinated contrast (depending on renal function)
---------------------------------------------------------------------
+<WRAP pearls>
+===== Clinical Pearls =====
-===== Metformin vs Other Antihyperglycemics =====
+  * 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>
-Compared to:
+----
-  * [[endocrine:sulfonylureas:start|Sulfonylureas]] → no hypoglycemia
+===== Comparison Within Class =====
-  * [[endocrine:tzds:start|Thiazolidinediones]] → no edema
-  * [[endocrine:insulin:start|Insulin Therapy]] → no weight gain
-  * [[endocrine:glp1:start|GLP-1 Receptor Agonists]] → less weight loss
-  * [[endocrine:sglt2:start|SGLT2 Inhibitors]] → no heart failure benefit
-Metformin remains foundational therapy but is often combined with cardioprotective agents.
+Metformin is the only widely used agent in the [[endocrine:biguanides:start|biguanide]] class.
---------------------------------------------------------------------
-===== Clinical Pearls =====
-  * Inhibits mitochondrial complex I
+Compared to other antihyperglycemics:
-  * Raises AMP → suppresses gluconeogenesis
+  * Lower hypoglycemia risk than [[endocrine:sulfonylureas:start|Sulfonylureas]]
-  * AMPK activation is secondary
+  * Less weight gain than [[endocrine:tzds:start|TZDs]]
-  * First-line in Type 2 Diabetes
+  * Less potent A1c reduction than combination therapy
-  * Weight neutral
-  * Monitor B12 long-term
-  * Rare lactic acidosis risk
---------------------------------------------------------------------
+----
 ===== Related =====
+  * [[endocrine:biguanides:start|Biguanides]]
   * [[endocrine:diabetes:start|Diabetes Pharmacology]]
-  * [[endocrine:tzds:start|Thiazolidinediones]]
+  * [[cardio:intro:start|Cardiovascular Pharmacology]]
-  * [[endocrine:glp1:start|GLP-1 Receptor Agonists]]
-  * [[endocrine:sglt2:start|SGLT2 Inhibitors]]
-  * [[cardio:heart_failure:start|Heart Failure Module]]