Metformin is the first-line medicine for type 2 diabetes. It helps lower blood sugar, often together with diet and exercise. It is generally well tolerated; the most common effects are gastrointestinal at the start of treatment.
Also known as: Glucophage
Additive hypoglycaemic effect — higher risk of hypoglycaemia in diabetic patients.
Hydroxychloroquine can cause severe and potentially fatal hypoglycaemia, "in the presence or absence of antidiabetic agents" (the label explicitly states that it "may enhance the effects of insulin and antidiabetic drugs and, consequently, increase the hypoglycaemic risk — a decrease in the dosage of insulin and other antidiabetic drugs may be necessary", and recommends monitoring blood glucose in diabetic patients). The combination with metformin adds up the hypoglycaemic effects. Note: the hydroxychloroquine label indicates it does not inhibit OCT2 in vitro, so the mechanism is essentially pharmacodynamic. Monitor glycaemia at the start of the combination and whenever the hydroxychloroquine dose changes, warn the patient about hypoglycaemia signs (sweating, tremor, palpitations, confusion) and consider reducing the metformin or other antidiabetic dose.
Hydroxychloroquine + metformin: additive hypoglycaemia. Monitor glycaemia and consider reducing the antidiabetic dose.
Hydroxychloroquine improves insulin sensitivity, enhancing the Metformin effect.
Capillary glucose, HbA1c and hypoglycaemia symptoms.
Sweating, tremor, confusion, fainting.
Monitor glycaemia and adjust the antidiabetic dose if needed.
DailyMed/FDA (NIH/NLM) — approved Hydroxychloroquine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=34496b43-05a2-45fb-a769-52b12e099341 ; approved Metformin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=13b1e35f-d047-8ddc-e063-6394a90a24dd
Hypoglycaemia. Combining two oral antidiabetics requires dose adjustment and surveillance; not contraindicated.
Glibenclamide (sulphonylurea) stimulates insulin secretion and metformin reduces hepatic glucose production and improves insulin sensitivity — complementary and synergistic mechanisms, making the combination a usual option in type 2 diabetes. The main risk is hypoglycaemia, potentiated by the sulphonylurea, especially in the elderly, prolonged fasting, renal impairment or reduced food intake. Start with low doses, titrate slowly, educate the patient about hypoglycaemia signs and adjust glibenclamide with any deterioration of renal function.
Hypoglycaemia. Combining two oral antidiabetics requires dose adjustment and surveillance; not contraindicated.
Additive glucose-lowering effect: the sulfonylurea stimulates insulin and metformin reduces hepatic glucose output.
Capillary glucose and hypoglycaemia signs.
Tremor, sweating, confusion, pallor — signs of hypoglycaemia.
Start the sulfonylurea at a low dose and titrate on glucose readings.
DailyMed/FDA (NIH/NLM) — approved Glibenclamide label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=524eec41-37ee-419a-b7a1-d23e888ae6ab ; approved Metformin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=13b1e35f-d047-8ddc-e063-6394a90a24dd
Corticosteroids (such as prednisolone) can raise blood sugar and reduce the effect of metformin. Monitor blood glucose during treatment.
Systemic corticosteroids increase insulin resistance and hepatic glucose production, antagonising the effect of antidiabetics — the Prontuário states explicitly that antidiabetics antagonise the hyperglycaemic effects of corticosteroids and that in diabetics these should only be used when strictly necessary. During prolonged or high-dose corticosteroid therapy, blood glucose must be monitored and antidiabetic therapy adjusted (often the metformin dose must be increased or insulin added).
Glucocorticoids have a hyperglycaemic effect and antagonise antidiabetics; the metformin dose may need adjustment (or insulin added) during corticosteroid therapy, with blood glucose monitoring.
Hyperglycaemic effect of glucocorticoids (increased insulin resistance and gluconeogenesis).
Capillary glucose; symptoms of hyperglycaemia.
Thirst, polyuria, fatigue, blurred vision — decompensated hyperglycaemia.
Monitor blood glucose (and HbA1c on prolonged use) during corticosteroid therapy; adjust the metformin dose as needed and reduce it when the steroid is stopped.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — section 8.2.2 ; DailyMed/FDA (NIH/NLM) — approved Prednisolone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=757b41c4-a0fe-4a09-8816-a4cdb7558f41 ; approved Metformin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=13b1e35f-d047-8ddc-e063-6394a90a24dd
Increased risk of lactic acidosis: the trimethoprim component reduces renal clearance of Metformin, raising its levels.
Metformin is eliminated renally through the organic cation transporter OCT2, and trimethoprim (a co-trimoxazole component) is an OCT2 inhibitor, which can raise metformin concentrations and the risk of lactic acidosis, especially in patients with reduced renal function, the elderly or with other causes of acidosis; the co-trimoxazole label recommends avoiding co-administration with OCT2 substrates (metformin is explicitly mentioned) and monitoring glycaemia. During the combination, monitor renal function, signs of lactic acidosis (malaise, myalgia, abdominal pain, dyspnoea, drowsiness) and consider temporarily stopping metformin in at-risk patients.
Co-trimoxazole + metformin: trimethoprim inhibits OCT2 and raises metformin levels, with a risk of lactic acidosis. Monitor renal function and glycaemia.
Trimethoprim competes with Metformin for renal tubular secretion (OCT2 transporter), reducing its elimination.
Renal function before and during; signs of acidosis (Kussmaul breathing, drowsiness, hypotension).
Weakness, myalgia, abdominal pain, hyperventilation, drowsiness — stop and seek medical help.
Monitor for lactic acidosis in patients with reduced renal function; consider low Metformin doses during antibiotic therapy.
DailyMed/FDA (NIH/NLM) — approved Metformin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=13b1e35f-d047-8ddc-e063-6394a90a24dd ; approved Co-trimoxazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08500fcb-dbec-4ac2-91c3-189d27907ec0
Acute alcohol intoxication increases the risk of lactic acidosis, especially during fasting, malnutrition or hepatic impairment; alcoholism is a contraindication.
Avoid excessive alcohol intake and any acute alcohol intoxication during metformin treatment.
EMC-UK (MHRA) — approved Metformin SmPC: https://www.medicines.org.uk/emc/product/987/smpc
Metformin is contraindicated when eGFR < 30 mL/min; drug accumulation increases the risk of lactic acidosis.
Do not prescribe when eGFR < 30 mL/min; adjust the dose between 30 and 89 mL/min and stop temporarily in acute conditions altering renal function.
EMC-UK (MHRA) — approved Metformin SmPC: https://www.medicines.org.uk/emc/product/987/smpc
Acute metabolic acidosis (lactic, diabetic ketoacidosis) and diabetic pre-coma are absolute contraindications.
Do not use in patients with acidosis; if lactic acidosis is suspected, stop and seek urgent medical evaluation.
EMC-UK (MHRA) — approved Metformin SmPC: https://www.medicines.org.uk/emc/product/987/smpc
Hepatic insufficiency reduces lactate clearance and predisposes to lactic acidosis.
Avoid metformin in patients with hepatic insufficiency or alcoholism.
EMC-UK (MHRA) — approved Metformin SmPC: https://www.medicines.org.uk/emc/product/987/smpc
Decompensated heart failure, respiratory failure, recent myocardial infarction and shock increase the risk of lactic acidosis.
Do not start during acute hypoxic states; stop during such episodes and reassess after stabilisation.
EMC-UK (MHRA) — approved Metformin SmPC: https://www.medicines.org.uk/emc/product/987/smpc
In patients with MELAS or MIDD, metformin is not recommended due to the risk of worsening lactic acidosis and neurological complications.
Avoid metformin in these patients; stop and evaluate promptly if suggestive signs appear.
EMC-UK (MHRA) — approved Metformin SmPC: https://www.medicines.org.uk/emc/product/987/smpc
Iodinated contrast can cause contrast-induced nephropathy, with metformin accumulation and lactic acidosis risk.
Stop metformin at the time of the scan and resume only 48 hours later if renal function remains stable.
EMC-UK (MHRA) — approved Metformin SmPC: https://www.medicines.org.uk/emc/product/987/smpc
Extensive data (over 1000 pregnancies) indicate no increased risk of congenital malformations or feto-neonatal toxicity with metformin.
Use can be considered during pregnancy and in the periconceptional phase as an alternative or addition to insulin, if clinically needed.
Metformin is excreted into breast milk; no adverse effects observed but data are limited — breastfeeding is not recommended during treatment.
EMC-UK (MHRA) — approved Metformin SmPC: https://www.medicines.org.uk/emc/product/987/smpc
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Antihyperglycaemic agent of the biguanide class that improves glucose tolerance in type 2 diabetes, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion, so it does not cause hypoglycaemia when used alone; insulin secretion remains unchanged, while fasting insulin levels may decrease.
Decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilisation.
With extended-release tablets, peak plasma concentrations are reached at a median of 7 hours (4 to 8 hours); with immediate-release tablets, in 2 to 3 hours. Food decreases the extent and delays the absorption (Cmax about 40% lower). Plasma protein binding is negligible.
Metformin is excreted unchanged in urine and undergoes no hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance is about 3.5 times greater than creatinine clearance, indicating that tubular secretion is the major route of elimination; about 90% of the absorbed drug is eliminated renally within the first 24 hours.
The plasma elimination half-life is approximately 6.2 hours; in blood, the half-life is approximately 17.6 hours, suggesting that the erythrocyte mass is a compartment of distribution.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
