Understanding Metformin

Metformin is a safe and widely recommended add-on for managing weight gain and metabolic issues caused by psychotropic medications. Its mechanism is surprisingly intriguing—and even bears a biochemical resemblance to cyanide.

This content is from the forthcoming book: Cafer's Psychopharmacology 2nd Edition Series: Prescribing Lithium

Pronunciation: met-FOR-min (GLOO-ko-fahj)

Mnemonic phrase: “Met formin’ Glucose fudge”

Classification: Biguanide anti-hyperglycemic

FDA Approved for: Diabetes mellitus, type 2

Available strengths:

❖ ER: 500 & 750 mg

❖ IR: 500, 850, &1000 mg

Metformin song (10 versions): YouTube Music

Used Off-Label for:

❖ Polycystic ovary syndrome (PCOS)

❖ Antipsychotic-induced weight gain

❖ Weight loss

❖ Prevention of type 2 diabetes (prediabetes)

❖ Nonalcoholic fatty liver disease (NAFLD)

❖ Gestational diabetes

❖ Type 1 diabetes (to ↓ insulin requirements)

❖ Longevity (investigational)

Metformin Basics

❖ First-line type 2 diabetes medication 

❖ Low risk of hypoglycemia, even in non-diabetics

❖ Plasma half-life: ~ 5 hours

❖ Elimination half-life (from tissues): ~20 hours 

Weight Management

❖ First-line for antipsychotic-induced weight gain

    ➤ may mitigate prolactin elevation

❖ Metformin found slightly more effective than topiramate (Maayan et al, 2010)

❖ GLP-1 agonists are the most effective

Longevity

❖ In animal models

    ➤ slows biologic aging process

    ➤ decreases incidence of cancer

❖ Appears to prevent cognitive decline with aging (Ng et al, 2014)

❖ Targeting Aging with Metformin (TAME) controlled trial is in progress

    ➤ longevity benefit in humans unproven

Side Effects

❖ Diarrhea – 50% IR, 10% ER formulation

❖ Nausea – 25%

❖ Flatulence – 10%

❖ Vitamin B12 (cobalamin) deficiency – 3–30%

❖ May blunt muscle growth in response to strength training

    ➤ metformin’s activation of AMPK antagonizes mTOR signaling, which is essential for muscle protein synthesis and hypertrophy

BLACK BOX WARNING: Lactic Acidosis

❖ Potentially fatal

    ➤ FDA has relaxed the warning for patients with stable renal function

❖ ~33% risk with large overdose

❖ Extremely rare in healthy individuals

    ➤ near-zero risk with eGFR > 30 mL/min (Lipska et al, 2011)

❖ Heavy alcohol consumption increases the risk of lactic acidosis

⭐ Avoid in patients with serious medical illness

Principal Mechanism – Sequence of Events

❖ Metformin inhibits mitochondrial Complex I → slows the electron transport chain →  decreases ATP production → cell senses energy depletion → activates AMPK (AMP-activated protein kinase) = master regulator of cellular energy → shifts metabolism toward energy conservation:

    ➤ ↓ glucose production by the liver

    ➤ ↑ insulin sensitivity of body tissues

    ➤ ↓ fat accumulation

    ➤ ↑ mitochondrial biogenesis

❖ Metformin creates mild energy stress inside cells (especially liver, gut) → reprograms the body’s metabolism to:

    ➤ use energy more wisely

❖ Example of hormesis

    ➤ low doses of a stressor stimulate beneficial adaptive responses, while higher doses are  harmful

Mechanistically-Related Drugs

❖ Berberine (nutritional supplement) has the same basic mechanism: mild inhibition of mitochondrial Complex I → AMPK activation

❖ Cyanide (poison) completely inhibits mitochondrial Complex IV → cellular hypoxia → severe lactic acidosis → multi-organ failure and death

Additional Mechanisms

❖ Reduces intestinal glucose absorption

    ➤ modulation of gut microbiota

    ➤ enhanced GLP-1 secretion

Overdose

❖ Mitochondrial Complex I inhibition → energy crisis (low ATP) → lactic acidosis (~33%)

❖ Hypoglycemia in ~10% of cases 

❖ Survival is common with aggressive support (IV fluids, hemodialysis)

Potential Benefits as Lithium Adjunct

❖ Weight management

    ➤ while lithium is less likely to cause weight gain than most alternatives (valproate, quetiapine), weight gain is a commonly cited reason for lithium discontinuation 

❖ Reversal of insulin resistance

    ➤ brain insulin resistance may contribute to bipolar mood destabilization (TRIO-BD study)

❖ Protection against lithium-induced vasopressin resistance (animal models) 

✅Monitoring

❖ Baseline: eGFR, LFTs, B12, HbA1c, weight

❖ Routine: eGFR (annual, q3–6m if <60), B12 (q2–3y), HbA1c (q3–6m if diabetic)

❖ Situational: lactate if acidosis suspected, electrolytes if severe illness

❖ Acidosis on metabolic panel is evidenced by low bicarbonate (listed as CO₂)

❖ Signs of acidosis are nonspecific with subtle onset, including malaise, myalgias, abdominal pain, respiratory distress, or somnolence

❖ Signs of B12 deficiency

    ➤ macrocytic anemia, neuropathy, glossitis

❖ Hemoglobin A1c

    ➤ normal 4.0–5.6% 

        ◇ average glucose of 100 → A1c 5.1%

    ➤ prediabetes 5.7–6.4% 

    ➤ diabetes ≥ 6.5% 

        ◇ average glucose of 200 → A1c 8.6%

        ◇ average glucose of 300 → A1c 12.1%

Dosing

🟥 Not recommended if eGFR < 45 mL/min

🟥 Supplement Vit B12 (500–1000 mcg) and calcium (1200–1500 mg) if B12 low or borderline

▶️ For type 2 diabetes (FDA dosing) – IR

    ➤ Start 850 mg QD or 500 mg BID with meals

    ➤ Increase by 500 mg/day q week or 850 mg/day q 2 wk as tolerated

    ➤ Target of 850–1000 mg BID

    ➤ Max of 2550 mg/day (3 x 850 mg)

   🔴 Change to ER form if diarrhea or GI distress

▶️ For type 2 diabetes (FDA dosing) – ER

    ➤ Start 500 mg ER or 750 ER q PM

    ➤ Increase by 500 mg/day q week as tolerated

    ➤ Target of 1000–2000 mg ER q PM

    ➤ Max of 2000 mg ER / day 

    ➤ May add 500 mg IR if inadequate

▶️ For weight management (off label)

    ➤ Same as DM2 dosing 

▶️ For longevity (investigational)

    ➤ The TAME longevity study is using 1500 mg of metformin ER

    ➤ Some taking metformin for longevity skip it on weight training days because it may blunt muscle growth

🟥 Hold treatment for surgery 

🟥 Hold if restricting food/fluid

🟥 Hold for iodinated contrast study, restart after 48 hr if stable renal function

🟥 Discontinue metformin if eGFR falls below 30

Dynamic Interactions

❖ Risk of lactic acidosis, which is increased by carbonic anhydrase inhibitors (CAIs) such as  dichlorphenamide > acetazolamide > methazolamide > topiramate > zonisamide

    ➤ risk remains theoretical and not consistently observed in clinical practice

Kinetic interactions

❖ Excreted unmetabolized in urine via active tubular secretion, primarily by OCT2 and MATE-1 transporters

    ➤ Dual OCT2/MATE-1 inhibitors increase metformin serum levels ~35–50%

        ◇ cimetidine (Tagamet)

        ◇ pyrimethamine  (Daraprim) 

        ◇ trimethoprim (in Bactrim with SMX)

        ◇ vandetanib (Caprelsa) > crizotinib (Xalkori)

        ◇ dolutegravir (in HIV combos)

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