Drug Summary – Metformin

(Refer to: Drug review: Metformin for full text and references)

Mechanism of Action	Metformin targets the liver, skeletal muscle and the gut to reduce hepatic glucose output, increase skeletal muscle glucose uptake, increase GLP-1 levels and reduce glucose absorption
Glycaemic efficacy and indications	Mean HbA1C reductions As monotherapy vs. placebo: -1.1% As add-on therapy to other non-insulin agents: -0.9% As add-on to insulin: -0.6%
Cardiovascular outcome trials	Proven superiority vs. diet alone in obese patients - reduced all-cause mortality, diabetes related mortality and myocardial infarction, but not peripheral vascular disease or microvascular disease Proven superiority vs. SU and insulin in obese patients: reduced all cause mortality and stroke, but not myocardial infarction, diabetes-related deaths peripheral vascular disease or microvascular disease Safety when added to SU’s (glibenclamide and chlorpropamide) is unclear
Hypoglycaemia	No severe hypoglycaemia as monotherapy Some patients may have symptoms of hypoglycaemia  Can potentiate the hypoglycaemic effect of insulin or insulin secretagogues
Weight	Weight neutral or causes modest weight loss (-1.2kg) No weight loss in non-diabetic individuals
Non-glycaemic benefits	Improves lipid profile Reduces cancer rates in population studies May improve outcomes in mild to moderate heart failure; Improves laboratory measures of inflammation, coagulation, oxidative stress, endothelial function and tumour suppression; cancer rates are lower
Side Effects and Precautions	Gastrointestinal (GI) side-effects are common, are not dose-dependent, and occur in 20-30% of patients (diarrhoea, nausea, vomiting, cramping, bloating and flatulence). Up to 10% will discontinue therapy due to GI side effects. Switching to an extended release formulation improves GI tolerability and adherence Lactic Acidosis is rare with current usage (0.04 cases per 1000 patient years) and not different to non-metformin users Metformin should be discontinued at the time of, or before an iodinated contrast imaging procedure or general anaesthesia in the following categories of patients: those with an eGFR < 60 mL/minute/1.73 m2; those with a history of liver disease, alcoholism, or heart failure; those who will receive intra-arterial iodinated contrast Re-evaluate eGFR 48 hours after the procedure and restart metformin if renal function is stable and the patient is eating normally   Can cause low levels of serum vitamin B12 in 7-30% of long-term users, but is rarely associated with the clinical features of vitamin B12 deficiency The exact mechanism and significance is unknown There is no recommendation to screen for vitamin B12 deficiency routinely Investigate and manage vitamin B12 deficiency according to standard clinical practice, with a high index of suspicion in patients who are vegetarian or anaemic, or have peripheral neuropathy
Dosing and prescribing	Metformin (standard release): Dose range is 500 mg/day to 3 000 mg/day in two or three divided doses with meals. Optimum glycaemic efficacy is achieved with 2 000 mg/day; few patients have additional glycaemic benefit with higher doses. The optimum dose for cardiovascular benefit in obese patients is 2 550mg/day Metformin extended-release: Dose range is 500 mg/day to 2 000 mg/day as a single dose with the evening meal. The 2 000mg dose can be split to 1000mg twice daily without losing efficacy Start with 500 mg/day of standard metformin tablets, and increase the dose by 500 mg every one to two weeks to minimise side effects. If GI side effects occur reduce the dose and re-titrate slowly If GI disturbances persist try switching to the extended-release formulation
Renal dosing	eGFR ≥60 ml/min	45-60 ml/min	30-45 ml/min	< 30 ml/min
	Standard dosing Monitor eGFR annually	Standard dosing Monitor eGFR 3 to 6 monthly	Maximum dose: 1000 mg/day Monitor eGFR 3 to 6 monthly	Metformin is contraindicated

 

(See Strength of Recommendations Taxonomy (SORT) for explanation of Grade A-C)

SEMDSA 2017 Recommendations for metformin
Initiate standard-release metformin therapy in all newly diagnosed obese patients with type 2 diabetes	A
Initiate standard-release metformin therapy in all newly diagnosed non-obese patients with type 2 diabetes	C
Dosing: Start with 500 mg once daily and up-titrate the dose slowly every 10 to 14 days until glycaemic targets are met or side effects occur Few patients will achieve and maintain glycaemic targets with 500 mg once daily Most patients will require 1000 – 2550 mg per day in two or three divided doses The optimum dose for cardiovascular benefit in obese patients is 2550 mg/day (850 mg TDS)	B
If gastrointestinal (GI) adverse events are limiting, try temporarily reducing or discontinuing the drug, and retitrate when the GI disturbances resolve. The GI side-effects with metformin extended-release is not different to the standard release when used as initial therapy; however patients who switch due to the extended release may have improved tolerability If GI disturbances remain intolerable with standard metformin tablets, try switching to a metformin extended release (XR) formulation and titrate the dose every 10-14 days again	B
The extended release formulation should be dosed once daily with the evening meal at a dose not exceeding 2000 mg/day The 2000 mg dose can be taken as 1000 mg twice a day without disadvantages if the patient so prefers Patients not achieving their glycaemic target with 2000 mg of the extended release may benefit from switching to a higher dose of the standard release metformin	B
Monitor renal function (eGFR) in all patients at least annually Do not exceed 1000 mg/day if the eGFR is 30-45 ml/min/1.73m2 Stop metformin therapy if the eGFR is < 30 ml/min/1.73m2	B
The significance of low serum vitamin B12 levels associated with long-term metformin use is not known Measure and treat whenever clinically appropriate	B
Profile of the patient in whom metformin may not be a preferred option: Patients with irritable bowel syndrome or other chronic gastrointestinal disorders Normal weight individuals who do not wish to lose weight Patients at high risk for lactic acidosis (severe heart, lung, liver, renal or peripheral vascular disease) There is a history of metformin intolerance	C

Caution:

Do not persist with any chosen treatment if the HbA_1C has not decreased by > 0.5% after six months

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