Dr. Anant Patil answers ten common questions on metformin and its use in type 2 diabetes mellitus. He also reminds  healthcare professionals to refer to updated prescribing information of metformin for approved indications and use.

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When and how is metformin used in the treatment of type 2 diabetes mellitus?

Metformin is a potent anti-hyperglycaemic drug. [1] It is considered as the preferred initial drug for the treatment of type 2 diabetes. Metformin is recommended for use at the time of diagnosis of type 2 diabetes, unless there are any contraindications for its use. [2]

In many patients, metformin plus lifestyle modifications work well for the control of hyperglycaemia. Some patients may need to be started on combination at treatment initiation for faster achievement of glycaemic target. Such treatment is considered when patient has HbA1c 1.5-2% above the target level. [2]

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How long can treatment with metformin be continued in a patient with type 2 diabetes mellitus?

Once initiated, metformin can be continued for as long as the patient can tolerate it and there are no contraindications. Other agents, including insulin can be added to metformin in patients with inadequate control of type 2 diabetes mellitus. Other medications are added in stepwise manner to maintain the level of glycosylated haemoglobin (HbA1c) at target. [2]

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How long should we wait to add another medication to metformin?

If the target of HbA1C is not achieved after approximately three months of metformin therapy, an anti-diabetic drug from another class may be added. [2] Compliance with metformin should also be checked.

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Why is metformin so commonly used in patients with type 2 diabetes mellitus?

Metformin works by several mechanisms including reduction in intestinal absorption of glucose, improved uptake of glucose by peripheral tissues and increase in insulin sensitivity. [3] Occurrence of hypoglycaemic episodes is less common with use of metformin as compared to sulfonylurea. [4] Use of metformin is associated with weight loss or less weight gain. [3] It may also reduce the risk of cardiovascular events and mortality. As compared to sulfonylurea, first-line therapy with metformin offers better effects on body weight and deaths due to cardiovascular causes. [2]

The results of a recently published study [5] with a follow-up of six years, showed less occurrence of new onset symptomatic heart failure with preserved ejection fraction and left ventricular diastolic dysfunction in patients with type 2 diabetes mellitus and hypertension without clinical signs or symptoms of heart failure. All these advantages make metformin a preferred drug for initial therapy in type 2 diabetes mellitus. [2]

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Which are the different formulations of metformin?

Metformin is available in an immediate-release formulation as well as extended release formulation. Metformin in immediate-release formulation is given twice daily whereas extended-release form can be given once a day. [2]

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What are the adverse events associated with metformin?

The common side effects associated with use of metformin are related to the gastrointestinal tract. Some patients may not tolerate metformin and report abdominal discomfort and/or diarrhoea. In order to reduce the risk of developing such adverse effects, dose of metformin should be gradually increased. [2]

Long term use of metformin is associated with reduction in serum levels of vitamin B12 as well as increase in rise of serum methylmalonic acid, a biomarker for tissue deficiency of vitamin B12. [6] Data published in 2018, suggests that B12 deficiency associated with use of metformin is clinically relevant and hence monitoring of B12 should be considered in patients using metformin. Another report from the Diabetes Prevention Program Outcomes Study (DPPOS) published in 2016 also reported B12 deficiency with long term use of metformin and suggested routine testing of vitamin B12 levels in patients treated with metformin. [7]

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What are the contraindications for use of metformin?

Metformin should be avoided in patients having hypersensitivity to it and those with metabolic acidosis (including diabetic ketoacidosis ± coma). Metformin is eliminated through the kidneys. Very high levels of metformin in patients with renal failure have been associated with lactic acidosis, but the chances of this are very low. [2] Use of metformin is also contraindicated in patients with severe renal impairment (eGFR below 30 mL/min/1.73 m²). [8]

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What if patient cannot tolerate metformin or have contraindications for its use?

If a patient has contraindication for the use of metformin or cannot tolerate it because of adverse events, a drug from another category should be selected considering other factors such as risk of hypoglycaemia, body weight, financial capacity of the patient to afford an alternate drug, and the safety profile of the drug. [2]

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What are the important interactions and precautions for use of metformin?

The following drugs can interact with metformin:

• Carbonic anhydrase inhibitors: Concurrent use of these agents with metformin may increase risk of lactic acidosis. [9]
• Drugs like cimetidine [9,10] ranolazine, [9] vandetanib, [9] and dolutegravir [9] can increase levels of metformin due to decrease in its clearance

Excessive use of alcohol can increase the effect of metformin on metabolism of lactate. [9] Patients with hepatic impairment may develop metformin-associated lactic acidosis due to impaired lactate clearance. [9]

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Is there any evidence to support metformin in the prevention of diabetes?

In a study by Diabetes Prevention Program Research Group [11] during the 15 years of follow up after randomisation, metformin showed reduction in the incidence of diabetes as compared to placebo. The reduction in incidence was 17% based on glucose level and 36% based on the HbA1c level. The subgroups which showed most benefit were people with higher level of baseline fasting glucose, higher level of HbA1c and females with history of gestational diabetes mellitus.

The findings from a Cochrane meta-analysis of randomised controlled trials also suggested that as compared to placebo or diet and exercise, metformin reduces or delays the risk of type 2 diabetes mellitus in those with higher risk of type 2 diabetes. However, as compared to intensive diet and exercise it did not decrease the risk of type 2 diabetes. [12]

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Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

The information is only for educational purpose. Healthcare professionals are requested to refer the updated prescribing information of metformin for approved indications and its use.

The author, Dr. Anant Patil is Assistant Professor of Pharmacology.