Chinese Expert Consensus Statement on Metformin in Clinical Practice

Metformin, one of the most widely used oral hypoglycemic agents globally, has been a cornerstone in the treatment of type 2 diabetes mellitus (T2DM) for decades. Its efficacy, safety, and health economic benefits have led to its recommendation as a first-line drug in diabetes guidelines worldwide. Despite its long-standing use, misconceptions about metformin persist among clinicians and patients in China, leading to missed treatment opportunities for some patients who could benefit from it. To address these issues, the Chinese Expert Consensus Statement on Metformin in Clinical Practice was developed by a panel of endocrinologists and pharmaceutical experts. This consensus aims to guide clinicians and patients in correctly understanding and rationally using metformin.

Clinical Status and Initial Treatment Opportunity

Metformin is the first-choice and full-course drug for the treatment of T2DM, provided there are no contraindications or intolerances. It should always be retained in the treatment regimen of diabetes mellitus. This recommendation is supported by a Class of Recommendation (COR) I and Level of Evidence (LOE) A.

Metformin is not only the first-choice drug for T2DM patients who are overweight or obese but is also applicable for those with normal weight. The efficacy and adverse reactions of metformin are not related to the body mass index (BMI) of patients. This recommendation is also classified as COR I and LOE A.

For the pre-diabetic population, metformin can effectively reduce the risk of developing T2DM. However, it has not yet been approved for the prevention of diabetes mellitus in China. This recommendation is classified as COR IIb and LOE C-Expert Opinion (C-EO).

Mechanism of Action

Metformin primarily reduces blood glucose by decreasing hepatic glucose output, improving insulin resistance, reducing small intestinal glucose uptake, and activating AMP-activated protein kinase (AMPK). These mechanisms contribute to its efficacy in managing blood glucose levels in patients with T2DM.

Drug Dose and Clinical Efficacy

The minimum effective dose of metformin is 500 mg/day, with the optimal effective dose being 2000 mg/day. The maximum recommended dose for adults is 2550 mg/day. The efficacy of metformin is dose-dependent, and it is recommended to gradually increase the dose to the optimal effective dose (2000 mg/day) to achieve and maintain good glycemic control. This recommendation is classified as COR I and LOE C-EO.

Metformin has a reliable hypoglycemic effect, with monotherapy reducing hemoglobin A1c (HbA1c) by 1.0%–2.0% (after removing the placebo effect). This recommendation is classified as COR I and LOE A.

Metformin can be used in combination therapy with any other non-insulin hypoglycemic agents. For patients with poor glycemic control, adding other hypoglycemic agents after three months of full-dose metformin monotherapy can significantly improve blood glucose levels. This recommendation is classified as COR I and LOE A.

Combination therapy with metformin and insulin can further improve glycemic control, reduce insulin dose, and mitigate the risks of weight gain and hypoglycemia associated with insulin therapy. This recommendation is classified as COR IIa and LOE B-Randomized (B-R).

For type 1 diabetes mellitus (T1DM) patients requiring glycemic control, metformin can be added to insulin therapy. This recommendation is classified as COR IIa and LOE C-EO.

Drug Use in Special Diabetic Populations

Metformin is applicable in children aged 10 years or older. There is no age limit for the use of metformin in elderly patients. However, due to the potential for renal hypofunction in elderly patients, the dose of metformin should be adjusted according to renal function before and during medication. This recommendation is classified as COR IIa and LOE C-EO.

Metformin should be avoided in patients whose serum transaminase levels are more than three times the upper limit of the normal value. This recommendation is classified as COR IIa and LOE C-EO.

For patients with renal insufficiency, the dose of metformin should be adjusted based on the estimated glomerular filtration rate (eGFR). No dose adjustment is needed if eGFR is ≥60 mL/min per 1.73 m². Dose adjustment is required if eGFR is between 45–59 mL/min per 1.73 m², and metformin should be avoided if eGFR is <45 mL/min per 1.73 m². This recommendation is classified as COR IIa and LOE C-EO.

For patients with eGFR >60 mL/min per 1.73 m², metformin should be discontinued before or at the time of angiography and can be resumed at least 48 hours after the examination, provided renal function has not deteriorated. For patients with moderate renal insufficiency (eGFR: 45–59 mL/min per 1.73 m²), metformin should be temporarily discontinued 48 hours before using contrast agents and general anesthesia, and should remain discontinued for 48–72 hours, resuming only if renal function has not deteriorated. This recommendation is classified as COR I and LOE C-EO.

Safety

The primary adverse reaction of metformin is gastrointestinal discomfort, which mostly occurs within 10 weeks of treatment. Most patients gradually tolerate these symptoms, or they disappear over time. Starting with a small dose and gradually increasing it, along with taking non-extended-release preparations three times a day with meals or extended-release preparations once a day, can reduce the incidence of gastrointestinal reactions. This recommendation is classified as COR I and LOE B-R.

Metformin itself has no hepatotoxicity or nephrotoxicity. This recommendation is classified as COR IIa and LOE C-EO.

There is no definitive evidence that metformin is associated with lactic acidosis. When contraindications are properly managed, long-term use of metformin does not increase the risk of lactic acidosis. This recommendation is classified as COR IIb and LOE B-R.

Effects on the Cardiovascular System

Metformin has a definite cardiovascular protective effect. It can reduce the occurrence of cardiovascular events in newly diagnosed T2DM patients and those with pre-existing cardiovascular disease. This recommendation is classified as COR IIa and LOE B-Non-randomized (B-NR).

Conclusion

The Chinese Expert Consensus Statement on Metformin in Clinical Practice provides comprehensive guidelines for the use of metformin in various clinical scenarios. It emphasizes the drug’s efficacy, safety, and cardiovascular benefits, while also addressing its use in special populations and potential adverse reactions. By following these recommendations, clinicians can optimize the use of metformin to improve outcomes for patients with diabetes mellitus.

doi.org/10.1097/CM9.0000000000000883

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