Metformin was first officially used in clinical treatment of diabetes in 1957, and China has more than 30 years of clinical application experience. Metformin has good efficacy, safety, health economic evidence, and evidence related to cardiovascular protection. It also has various effects beyond blood glucose reduction, and has been recommended as the first-line drug for controlling hyperglycemia in type 2 diabetes mellitus (T2DM) by multiple guidelines both domestically and internationally.
In recent years, both basic and clinical research related to metformin have made several new advances, and clinical evidence for the combined use of new hypoglycemic drugs with metformin has become increasingly abundant. Therefore, the expert group has updated the “Expert Consensus on Clinical Application of Metformin (2018 Edition)”. The main recommendations are shown in Table 1.
Table 1 Main Recommendations for Clinical Application of Metformin
|
Item and Recommendation |
Recommendation Level |
Evidence Level |
|
Clinical Position and Timing of Use |
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1.Metformin is the basic treatment drug for controlling hyperglycemia. In the absence of strong indications for renal protection with GLP-1RA or SGLT2i, it is recommended that metformin be used as the first-line hypoglycemic drug for T2DM and should always be included in the treatment plan. |
I |
A |
|
2.If GLP-1RA or (and) SGLT2i treatment is prioritized for improving renal clinical outcomes, metformin can be used as the preferred hypoglycemic drug in combination therapy. |
I |
B |
|
3.Metformin is suitable for T2DM patients with normal weight, overweight, or obesity, and its efficacy and adverse reactions are independent of body mass index. |
I |
A |
|
Mechanism of Action |
||
|
The hypoglycemic mechanism of metformin mainly includes reducing hepatic glucose output, improving insulin resistance, reducing intestinal glucose absorption, and promoting glucose excretion into the intestine. |
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|
Dosing and Efficacy |
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|
1.The minimum effective dose of metformin is 500 mg/d, with the optimal effective dose being 2,000 mg/d and the maximum recommended dose for adults being 2,550 mg/d. The efficacy of metformin is dose-dependent. If the patient can tolerate it, it is recommended to gradually increase the dose to the optimal effective dose. |
I |
A |
|
2.Monotherapy with metformin can reduce HbA1c by 1.0%~1.5%, and it can be combined with any other hypoglycemic drugs to further improve blood glucose control. |
I |
A |
|
3.Early combination therapy with DPP-4i based on the maximum tolerated dose of metformin can more effectively improve long-term blood glucose control. |
I |
A |
|
4.Combining metformin with insulin can reduce insulin dosage and lower the risk of weight gain and hypoglycemia associated with insulin treatment. |
IIa |
B |
|
Special Population Medications |
||
|
1.Metformin can be used in children and adolescents aged 10 years and older with T2DM. |
IIa |
B |
|
2.Older adults and T2DM patients with renal insufficiency should have their renal function regularly checked before and during medication, and the dose of metformin should be adjusted according to the eGFR level. |
IIa |
B |
|
3.Metformin should be used with caution or reduced in patients with eGFR<45 ml‧min-1‧1.73 m-2, and is contraindicated in patients with eGFR<30 ml‧min-1‧1.73 m-2. |
IIb |
B |
|
4.Metformin should be avoided in patients with serum transaminases exceeding three times the upper limit of normal. |
III |
B |
|
5.Metformin should be avoided in patients with acute and decompensated heart failure. |
III |
B |
|
6.Metformin is not approved for the treatment of type 1 diabetes in China, but it may be used at the discretion of the physician in overweight or obese patients aged 10 years and older with informed consent. |
IIb |
B |
|
7.Patients should stop taking metformin before and during imaging examinations, anesthesia/surgery, and should resume treatment at least 48 h after the examination and only after renal function is confirmed to be stable. |
III |
B |
|
Safety |
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|
1.The most common adverse reactions to metformin are gastrointestinal reactions. Starting with a low dose and gradually increasing the dose, taking non-sustained release formulations with meals, or switching to sustained release formulations can reduce gastrointestinal adverse reactions. |
IIa |
B |
|
2.Metformin itself does not significantly increase the risk of liver or kidney damage. |
IIa |
B |
|
3.The relationship between metformin and the risk of lactic acidosis is still uncertain. Under the premise of understanding contraindications, long-term use of metformin does not increase the risk of lactic acidosis. |
IIa |
B |
|
4.Long-term use of metformin is associated with a decrease in vitamin B12 levels. For patients with insufficient intake or absorption of vitamin B12, it is beneficial to monitor serum vitamin B12 levels once a year. |
IIa |
B |
|
Effects on the Cardiovascular System |
||
|
1.Metformin has cardiovascular protective effects. It can reduce the risk of cardiovascular disease in newly diagnosed overweight or obese T2DM patients, and can also reduce the risk of recurrence of cardiovascular disease in T2DM patients with existing cardiovascular disease. |
IIa |
B |
|
2.In T2DM patients with atherosclerotic cardiovascular disease or high cardiovascular risk factors, heart failure, or chronic kidney disease, combining metformin with GLP-1RA or SGLT2i that have evidence of cardiovascular or renal benefits can help achieve blood glucose control and reduce the risk of cardiovascular disease. |
IIa |
C |
|
Preventive Effects on Diabetes |
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|
Metformin can effectively reduce the risk of developing T2DM in populations with prediabetes. |
IIb |
A |
Note:GLP-1RA refers to glucagon-like peptide-1 receptor agonists; SGLT2i refers to sodium-glucose cotransporter 2 inhibitors; HbA1c refers to glycated hemoglobin; DPP-4i refers to dipeptidyl peptidase-4 inhibitors; eGFR refers to estimated glomerular filtration rate; recommendation levels: I indicates recommended use, IIa indicates should be considered, IIb indicates can be considered, and III indicates not recommended; evidence levels: A indicates high-quality evidence, B indicates moderate-quality evidence, and C indicates limited data or expert opinion.
1. Clinical Position and Timing of Use
1. Metformin is the basic treatment drug for controlling hyperglycemia: Metformin has good hypoglycemic efficacy and can mildly reduce weight. Under similar baseline values of glycated hemoglobin (hemoglobin A1c, HbA1c), the hypoglycemic efficacy of the optimal effective dose (2,000 mg/d) of metformin is superior to that of other oral hypoglycemic drugs. Compared to other oral hypoglycemic drugs as first-line treatment, patients treated with metformin as first-line treatment require the latest combination of a second oral hypoglycemic drug or insulin treatment, and the probability of needing to adjust the treatment plan is also the lowest. Metformin can be combined with any other hypoglycemic drugs to further improve blood glucose control; when combined with insulin treatment, it can also reduce insulin dosage, thereby lowering the risk of weight gain and hypoglycemia associated with insulin treatment. Metformin also has many effects beyond blood glucose reduction.
Metformin has good safety and tolerance, and does not increase the risk of hypoglycemia when used alone; its gastrointestinal adverse reactions are mostly transient; under the premise of understanding contraindications, long-term use of metformin does not increase the risk of lactic acidosis; compared to other hypoglycemic drugs, metformin has good cost-effectiveness. Therefore, multiple guidelines recommend metformin as the basic medication for controlling hyperglycemia in T2DM.
In the absence of strong indications for renal protection with glucagon-like peptide-1 receptor agonists (GLP-1RA) or sodium-glucose cotransporter 2 inhibitors (SGLT2i), it is recommended that metformin be used as the first-line hypoglycemic drug for T2DM and should always be included in the diabetes treatment plan. When GLP-1RA or/and SGLT2i treatment is prioritized for improving renal clinical outcomes, metformin can be used as the preferred hypoglycemic drug in combination therapy.
2. The efficacy of metformin is not limited by weight: Retrospective and prospective clinical study results show that metformin has comparable hypoglycemic efficacy in T2DM patients of normal weight, overweight, and obesity, with similar adverse reactions, and better weight loss effects in overweight and obese patients. Therefore, regardless of whether T2DM patients are of normal weight, overweight, or obese, metformin is recommended as the basic medication for controlling hyperglycemia.
2. Mechanism of Action
The main mechanism by which metformin improves hyperglycemia is through its action on the liver, inhibiting gluconeogenesis and reducing hepatic glucose output; acting on peripheral tissues (muscle, fat), improving insulin sensitivity, increasing glucose uptake and utilization, promoting muscle glycogen synthesis, and lowering free fatty acids; acting on the intestine, inhibiting glucose uptake by intestinal epithelial cells, promoting glucose excretion into the intestine, and increasing GLP-1 levels. The molecular mechanism of action of metformin may be related to its action on PEN2 (a subunit of γ-secretase), activating AMP-activated protein kinase (AMPK), and improving energy metabolism in muscle, fat, and liver.
3. Dosing and Efficacy
1. Minimum, maximum, and optimal doses of metformin: Within the dose range of 500~2,000 mg/d, the hypoglycemic effect of metformin is positively correlated with the dose. Excluding the placebo effect, 500 mg/d of metformin can reduce HbA1c by 0.6%, while 2,000 mg/d can reduce HbA1c by 2.0%, and gastrointestinal adverse reactions are not significantly different from those at 1,000 mg/d or 1,500 mg/d. The minimum recommended effective dose of metformin is 500 mg/d, and the optimal effective dose is 2,000 mg/d. The maximum available dose for ordinary tablets in adults is 2,550 mg/d, while the recommended maximum dose for sustained-release formulations is 2,000 mg/d.
2. Adjustment of metformin dosage: Metformin can be taken with meals or immediately after meals, and the principle of dosage adjustment is “start with a low dose and gradually increase the dose”, usually with a daily dose of 1,500~2,000 mg, divided into 2~3 doses. Considering the efficacy of the drug and patient compliance, simplified dosage adjustment schemes can be adopted, such as starting with 500 mg, twice daily, and if there are no significant gastrointestinal adverse reactions, gradually increasing to 500 mg, three times daily, or 1,000 mg, twice daily (or the maximum tolerated dose). When switching from ordinary metformin tablets to sustained-release tablets, the same dose is recommended.
3. Forms of metformin: Currently, the main forms available in China and abroad are single-component metformin ordinary tablets, metformin sustained-release tablets or capsules, and metformin enteric-coated tablets or capsules. In addition, there are also compound preparations of metformin combined with other oral hypoglycemic drugs.
4. Differences in efficacy between different forms of metformin: The main difference between different forms of metformin lies in the dissolution and release methods after administration. There is no difference in hypoglycemic efficacy between formulations of the same dose. Ordinary tablets dissolve and release in the stomach, while enteric-coated tablets and capsules dissolve and release in the intestine, and sustained-release tablets and capsules dissolve and release slowly in the gastrointestinal tract. Compared to ordinary tablets, sustained-release formulations have fewer adverse reactions such as bloating and diarrhea, leading to higher patient compliance.
5. Monotherapy with metformin: Systematic review results show that metformin can reduce HbA1c in T2DM patients by 1.0%~1.5% (excluding the placebo effect). Foreign studies show that in newly diagnosed T2DM patients, monotherapy with metformin (maximum dose up to 2,500 mg/d) for 29 weeks can reduce fasting blood glucose by 3.2 mmol/L, postprandial blood glucose by 4.0 mmol/L, and HbA1c by 1.8% (excluding the placebo effect). Studies in China show that compared to baseline, monotherapy with metformin (2,000 mg/d) for 16 weeks can reduce HbA1c in newly diagnosed T2DM patients by 1.8%, regardless of body mass index. In the study of initial treatment plans for newly diagnosed T2DM patients in China (MARCH), patients receiving metformin (1,500 mg/d) or acarbose (300 mg/d) treatment for 48 weeks had HbA1c reductions of 1.12% and 1.11%, respectively; and the hypoglycemic effects were similar among patients with different pancreatic β-cell functions.
6. Combining metformin with other oral hypoglycemic drugs: Combining metformin with insulin secretagogues (sulfonylureas or meglitinides) has a synergistic effect, but care should be taken regarding weight gain and hypoglycemia risks. In newly diagnosed T2DM patients with high baseline HbA1c levels, the combination of repaglinide and metformin is more effective at reducing HbA1c than metformin alone, with no significant increase in the risk of hypoglycemia.
When combined with thiazolidinediones, the hypoglycemic efficacy and improvement of insulin resistance are superior to those of either drug alone, but caution should be taken regarding weight gain and water retention risks.
Combining metformin with α-glucosidase inhibitors can address both fasting and postprandial blood glucose. In overweight T2DM patients where metformin alone is insufficient, adding acarbose can better control blood glucose and weight. However, this combination may increase the occurrence of gastrointestinal adverse reactions.
In T2DM patients with poor control on metformin monotherapy, combining with dipeptidyl peptidase-4 inhibitors (DPP-4i) can effectively improve blood glucose levels with good tolerance. Existing studies show that gradually increasing the dose of metformin (2,000 mg/d) has similar efficacy and safety to low-dose metformin (1,000 mg/d) combined with DPP-4i. The study on early combination therapy of vildagliptin with metformin in newly diagnosed T2DM (VERIFY) shows that early combination therapy with DPP-4i and metformin (2,000 mg/d) significantly reduces the relative risk of treatment failure by 49% compared to metformin monotherapy. Therefore, if patients have no contraindications or intolerance, adjusting metformin to the optimal effective dose and combining with DPP-4i can more effectively improve long-term blood glucose control.
In T2DM patients with poor control on metformin monotherapy, combining with SGLT2i can further lower blood glucose, significantly reduce weight, and improve blood pressure control. Currently available SGLT2i in China include dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, and the compound preparation of metformin/empagliflozin. SGLT2i can significantly reduce the risk of major adverse cardiovascular events and mortality, as well as the risk of hospitalization for heart failure and adverse renal outcomes in T2DM patients.
7. Combining metformin with GLP-1RA: Combining GLP-1RA with metformin can further lower HbA1c, improve the rate of achieving blood glucose control, enhance pancreatic β-cell function and insulin resistance, reduce weight and systolic blood pressure, and not increase the occurrence of hypoglycemic events. Studies in China show that compared to glimepiride combined with metformin, liraglutide combined with metformin has comparable hypoglycemic efficacy, but significantly reduces patients’ weight and blood pressure, with a lower risk of hypoglycemia and increased gastrointestinal adverse reactions. GLP-1RA can significantly reduce the risk of major adverse cardiovascular events in T2DM patients and decrease the risk of new-onset macroalbuminuria.
8. Combining metformin with insulin: Metformin can enhance insulin sensitivity in the liver and peripheral tissues, and when combined with insulin treatment, it can reduce the amount of insulin needed. Therefore, it is recommended to retain metformin when initiating insulin treatment in T2DM patients with poor blood glucose control on oral hypoglycemic agents. Compared to insulin monotherapy, combining metformin with insulin significantly improves hypoglycemic efficacy, reduces insulin dosage, and lowers the risk of weight gain and hypoglycemia. Inpatients with T2DM receiving multiple daily insulin injections or insulin pump therapy, combining with metformin can significantly reduce blood glucose fluctuations and the occurrence of nocturnal hypoglycemia.
9. After short-term intensive insulin therapy, T2DM patients with good pancreatic function can be switched to oral hypoglycemic therapy based on metformin: Studies in China show that newly diagnosed T2DM patients with high baseline HbA1c levels undergoing short-term intensive insulin therapy (IIT) can be switched to oral hypoglycemic therapy based on metformin with efficacy comparable to switching to glargine insulin therapy, and the former scheme is simpler and more cost-effective. In another study, newly diagnosed T2DM patients receiving three weeks of IIT treatment were switched to metformin maintenance therapy or received IIT every three months for two years, and the results showed that periodic IIT treatment did not further enhance the effect of metformin maintenance therapy on β-cell function. Therefore, for newly diagnosed T2DM patients with significant improvement in hyperglycemic symptoms after IIT treatment and good pancreatic function, it is recommended to switch to a single or combined hypoglycemic treatment plan based on metformin.
10. Metformin should be used early and at sufficient doses to maintain longer periods of achieving target levels: The Diabetes Outcome Progression Trial (ADOPT) shows that newly diagnosed T2DM patients using metformin (2,000 mg/d) monotherapy can maintain an average HbA1c<7% for up to four years. In a 104-week study, metformin (2,000 mg/d) monotherapy can increase the duration of HbA1c<7% by approximately 24 weeks compared to DPP-4i monotherapy. Therefore, when selecting oral hypoglycemic agents for monotherapy, the optimal effective dose of metformin helps maintain long-term good blood glucose control.
11. The weight loss effect of metformin: Metformin has a mild weight loss effect. Newly diagnosed T2DM patients in China receiving metformin monotherapy for 16 weeks saw weight reductions of 1.47, 2.81, and 2.92 kg for normal weight, overweight, and obese patients, respectively; the heavier and larger the waist circumference of the patients, the more weight loss after metformin treatment. Other hypoglycemic agents such as sulfonylureas, thiazolidinediones, and insulin can increase weight, and combining with metformin can mitigate the weight gain effects of these drugs.
4. Special Population Medications
1. Patients with hyperglycemia during pregnancy: There are currently no indications for the use of metformin in pregnant women in China. For patients planning to become pregnant or already pregnant, insulin is the first choice for hypoglycemic drugs. For pregnant women with severe insulin resistance, where increasing insulin dosage is difficult to effectively control blood glucose, metformin may be added with informed consent. Although systematic reviews have shown that the use of metformin during pregnancy does not increase adverse pregnancy outcomes compared to insulin, long-term follow-up studies indicate that metformin can cross the placenta and may impact fetal growth and long-term weight. Therefore, metformin should only be considered as an alternative option when pregnant women cannot use insulin treatment or when the physician deems insulin treatment inappropriate. Metformin is contraindicated in pregnant women with type 1 diabetes, gestational hypertension, preeclampsia, and intrauterine growth restriction.
2. Nursing mothers: Metformin can be excreted in breast milk, and its use is not recommended during breastfeeding. It may be resumed after breastfeeding. Studies have shown that metformin can be detected in the breast milk of nursing mothers, with a milk/plasma drug concentration ratio between 0.13~1. This may lead to an indirect dose ingested by infants of approximately 0.11%~1% of the maternal weight-adjusted dose. Due to the small sample size of the studies and limited data on adverse events collected in infants, these studies have not clarified the impact of metformin on infant development and health during breastfeeding. Therefore, in light of the current lack of data on the effects of metformin on the development and health of infants and young children, this expert consensus does not recommend the use of metformin by nursing mothers.
3. T2DM patients in children and adolescents: Metformin is currently the only oral hypoglycemic drug approved for use in children and adolescents aged 10 years and older with T2DM, with a maximum daily dose not exceeding 2,000 mg, and it is not recommended for children under 10 years old. The 2023 edition of the American Diabetes Association (ADA) guidelines recommends that metformin be used as the initial treatment for children and adolescents with T2DM when HbA1c<8.5%. If HbA1c≥8.5% or random blood glucose ≥13.9 mmol/L with significant hyperglycemic symptoms and no ketoacidosis, it is recommended to start with basal insulin therapy while initiating metformin, gradually increasing from a low dose to the therapeutic dose.
4. Patients aged 65 and older: For older T2DM patients with normal renal function, in the absence of strong indications for renal protection with GLP-1RA or SGLT2i, metformin remains the first choice for hypoglycemic drugs, and there are no specific age restrictions. If older patients have renal insufficiency, it is recommended to check renal function every 3-6 months and adjust the dose of metformin according to the estimated glomerular filtration rate (eGFR).
5. Patients with renal insufficiency: Metformin itself does not have adverse effects on renal function, but since it is excreted unchanged by the kidneys, the risk of accumulation and lactic acidosis increases in patients with renal insufficiency. Renal function should be checked at least annually before starting treatment and during treatment. It is recommended to adjust the dose of metformin based on the patient’s eGFR level. The domestic instructions for metformin recommend that it be contraindicated when eGFR<45 ml‧min-1‧1.73 m-2. The 2022 KDIGO guidelines for improving global kidney disease outcomes and the 2023 ADA guidelines recommend that metformin be reduced when eGFR<45 ml‧min-1‧1.73 m-2 and contraindicated when eGFR<30 ml‧min-1‧1.73 m-2.
Observational study evidence supports that metformin can be used in patients with stage 3b chronic kidney disease, and its use is even associated with a reduced risk of all-cause mortality without increasing the risk of lactic acidosis, but this still needs to be verified by high-quality randomized controlled clinical trials. The 2023 ADA guidelines recommend that metformin be contraindicated in patients with eGFR<30 ml‧min-1‧1.73 m-2; eGFR should be monitored while on metformin; when eGFR declines to <45 ml‧min-1‧1.73 m-2, the benefits and risks of continuing treatment should be reassessed, and if metformin treatment is continued, the dose may be reduced; for patients with eGFR 30~60 ml‧min-1‧1.73 m-2, metformin should be paused before the use of iodinated contrast agents.
6. Patients with liver insufficiency: Metformin is not metabolized by the liver and does not significantly increase the risk of liver damage. Systematic reviews show that metformin is beneficial for liver disease treatment, especially in cases of insulin resistance and inflammatory response. Meta-analysis shows that metformin can significantly improve alkaline phosphatase levels compared to thiazolidinediones. Severe liver impairment can significantly limit the ability to clear lactate, and it is recommended to avoid using metformin in patients with serum transaminases exceeding three times the upper limit of normal or with severe liver insufficiency.
7. Patients with heart failure: Metformin is contraindicated in patients with acute and decompensated heart failure. Metformin itself does not cause heart failure and is not contraindicated in chronic heart failure. Retrospective cohort studies and systematic review results suggest that metformin treatment in T2DM patients with heart failure may also reduce the risk of hospitalization or death due to heart failure. For T2DM patients with chronic heart failure, treatment plans can be selected based on the patient’s HbA1c level; if the HbA1c level exceeds the target value by 1.5% and is ≤10%, combined treatment with SGLT2i and metformin can be used.
8. Patients with T1DM: T1DM patients must use insulin treatment. Metformin is not yet approved for T1DM treatment in China, but it may be used at the discretion of the physician in overweight or obese T1DM patients aged 10 years and older with informed consent. Existing studies show that in T1DM patients receiving insulin treatment, combining with metformin can slightly reduce HbA1c, reduce weight, and lower low-density lipoprotein cholesterol levels without increasing the risk of hypoglycemia or diabetic ketoacidosis, but it does not improve long-term blood glucose control. Domestic small sample studies show that metformin can improve heart rate variability in children and adolescents with T1DM, and may improve cardiovascular autonomic function.
9. Patients should stop taking metformin before imaging or anesthesia/surgery and the time to resume: Intravenous injection of iodinated contrast agents may lead to contrast-induced nephropathy, which may cause metformin accumulation and increase the risk of lactic acidosis. Therefore, it is recommended that patients stop taking metformin before and during imaging examinations, and may resume treatment at least 48 hours after the examination and only after renal function is confirmed to be stable. It is also recommended to stop taking metformin during surgeries involving routine, spinal, or epidural anesthesia, and to resume treatment at least 48 hours after the surgery or when food intake is restored and renal function is assessed as stable.
5. Safety
1. Contraindications for metformin: Contraindications for metformin include: (1) severe renal insufficiency; (2) acute conditions that may affect renal function, such as dehydration, severe infections, shock, etc.; (3) diseases that can cause tissue hypoxia (especially acute diseases or chronic disease exacerbation), such as decompensated heart failure, respiratory failure, recent myocardial infarction, and shock; (4) severe infections and trauma, major surgical procedures, with clinical low blood pressure and hypoxia; (5) allergy to any component of the drug; (6) any acute metabolic acidosis, including ketoacidosis and lactic acidosis; (7) liver dysfunction, acute alcohol intoxication, and alcoholism; (8) uncorrected vitamin B12 and folate deficiencies.
2. Common adverse reactions of metformin: The most common adverse reactions to metformin are nausea, vomiting, diarrhea, abdominal pain, and loss of appetite, which mostly occur in the early stages of treatment. With prolonged treatment time, most patients can usually relieve themselves. Starting with a low dose, gradually increasing the dose, or switching to sustained-release formulations can improve gastrointestinal tolerance.
3. The effect of metformin on vitamin B12 absorption: Long-term use of metformin can lead to vitamin B12 deficiency. It is recommended that patients with insufficient intake or absorption of vitamin B12 monitor their vitamin B12 levels once a year before starting and after starting metformin treatment, and if deficient, appropriate supplementation is necessary, especially for patients with anemia and peripheral neuropathy.
4. Metformin and lactic acidosis: There is currently no definitive evidence that proper use of metformin is related to lactic acidosis; long-term use of metformin in patients with normal liver and kidney function does not increase the risk of lactic acidosis. The incidence of lactic acidosis with proper use of metformin is not significantly different from other hypoglycemic treatments.
5. Interactions between metformin and non-hypoglycemic drugs: The following situations suggest close monitoring of blood glucose levels and adjustment of metformin and/or interacting drug doses: (1) Use of cationic drugs excreted by renal tubules, such as amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, phenazopyridine, methotrexate, vancomycin, etc.; (2) Taking certain drugs that can raise blood glucose, such as thiazide or other diuretics, glucocorticoids, phenothiazines, thyroid preparations, estrogens, oral contraceptives, phenytoin, niacin, sympathomimetics, calcium channel blockers, isoniazid, etc.; (3) Due to the long action duration of chlorpropamide in the body (24~48 hours), hypoglycemia is easy to occur. Patients taking chlorpropamide should closely monitor blood glucose levels during the first two weeks of switching to metformin; (4) Metformin has an increased tendency to anticoagulate with warfarin; (5) Combining with resin drugs (such as suhexiang, xuejie, and ruxiang) can reduce the absorption of metformin.
6. Metformin and alcohol: Patients taking metformin should avoid drinking alcohol. Alcohol can inhibit hepatic glycogenolysis and endogenous gluconeogenesis. These two reactions are key to maintaining blood glucose homeostasis by releasing glucose from glycogen stores or breaking down fats during fasting. Diabetic patients taking metformin who consume large amounts of alcohol, especially on an empty stomach, will worsen the inhibition of gluconeogenesis and glycogenolysis, leading to more severe hypoglycemia. In cases of liver and kidney dysfunction or diseases that can lead to hypoxia, drinking alcohol while taking metformin significantly increases the risk of lactic acidosis.
6. Effects on the Cardiovascular System
The mechanisms of cardiovascular protective effects of metformin include improving blood glucose, reducing weight, regulating gut microbiota, regulating coagulation function, reducing inflammation and oxidative stress, improving endothelial function, and other metabolic indicators.
Multiple randomized controlled clinical trials, prospective observational studies, and large meta-analyses have shown that long-term use of metformin is associated with reduced risk of cardiovascular disease and cardiovascular mortality. The UK Prospective Diabetes Study (UKPDS) explored the effects of different treatment strategies for T2DM on diabetes complications, with follow-up lasting up to 44 years since the study began. The results of the UKPDS 34 study show that in newly diagnosed overweight or obese T2DM patients, early use of metformin in the intensive blood glucose control group reduced the risk of myocardial infarction by 39%, all-cause mortality risk by 36%, and any diabetes-related endpoint risk by 32% compared to the conventional treatment group. Long-term follow-up results of the UKPDS show that the metabolic memory effect of early blood glucose control with metformin persists, and it has good cost-effectiveness. The results of the Reduce Atherosclerotic Cardiovascular Events (REACH) study showed that compared to other hypoglycemic drugs, metformin reduced the all-cause mortality risk in T2DM patients with atherosclerotic cardiovascular disease by 24%. The results of the High Insulin Levels-Metabolic Effects (HOME) study showed that metformin combined with insulin significantly reduced the risk of major vascular events in T2DM patients by 39% compared to insulin monotherapy. A study based on the Chinese population on the effects of metformin and glipizide on cardiovascular outcomes in T2DM patients with coronary artery disease (SPREAD-DIMCAD) showed that in T2DM patients with a history of coronary heart disease, the risk of composite cardiovascular events was reduced by 46% in the metformin treatment group compared to glipizide. Large meta-analysis results also support that metformin can reduce the risk of cardiovascular events and cardiovascular mortality in T2DM patients with coronary heart disease. A recent cohort study comparing cardiovascular outcomes of using SGLT2i or metformin as first-line treatment in T2DM patients showed similar risks of myocardial infarction, stroke, and death.
The above clinical evidence indicates that metformin can reduce the risk of cardiovascular disease in newly diagnosed overweight or obese T2DM patients, and can also reduce the risk of recurrence of cardiovascular disease in T2DM patients with existing cardiovascular disease. Based on the good hypoglycemic effect of metformin and its improvement of cardiovascular metabolic risk factors, combining metformin with GLP-1RA or SGLT2i that have evidence of cardiovascular or renal benefits in T2DM patients with atherosclerotic cardiovascular disease or high cardiovascular risk factors, heart failure, or chronic kidney disease will help achieve blood glucose control and reduce the risk of cardiovascular disease.
7. Preventive Effects on Diabetes
Multiple diabetes prevention studies have shown that metformin can significantly reduce the risk of developing diabetes in populations with prediabetes, demonstrating long-term effectiveness and good cost-effectiveness. Meta-analysis shows that, regardless of Eastern or Western populations, metformin can reduce the risk of new-onset diabetes compared to placebo or conventional lifestyle management, with better effects in Asian populations. The 2023 ADA guidelines recommend that adults with prediabetes should consider using metformin to prevent T2DM, especially those aged 25-59 years, with a body mass index ≥35 kg/m2, fasting blood glucose ≥6.1 mmol/L, HbA1c ≥6.0%, and women with a history of gestational diabetes.
Currently, metformin is not approved for diabetes prevention in China. There is sufficient evidence for the effectiveness and safety of long-term use of metformin in populations with prediabetes. Adults at high risk for diabetes or with health needs, and who have economic and medical conditions, can consider using metformin in conjunction with lifestyle interventions to prevent diabetes.
8. Other Effects
1. Effects on blood lipids: Metformin can improve fat synthesis and metabolism, lowering total cholesterol and low-density lipoprotein cholesterol levels while maintaining or slightly increasing high-density lipoprotein cholesterol levels.
2. Effects on non-alcoholic fatty liver: Although metformin does not improve the pathological changes of non-alcoholic steatohepatitis, it can improve insulin resistance, lower blood glucose, and reduce weight. Therefore, metformin can be used for blood glucose treatment in overweight or obese T2DM patients with non-alcoholic fatty liver. A review summarized 14 clinical studies evaluating the improvement of liver histology, serum enzymes, and insulin resistance indicators in patients with non-alcoholic fatty liver, all studies showed significant improvement in insulin resistance index, 13 studies showed significant reductions in serum enzymes (alanine aminotransferase, aspartate aminotransferase), and 5 studies showed significant improvements in liver inflammation, steatosis, and fibrosis with metformin.
3. Effects on polycystic ovary syndrome: Metformin is not yet approved for the treatment of polycystic ovary syndrome (PCOS) in China. The 2018 edition of the “Chinese Diagnosis and Treatment Guidelines for Polycystic Ovary Syndrome” recommends that metformin can be used in the following situations: (1) PCOS patients with insulin resistance; (2) PCOS patients who are infertile and resistant to clomiphene, as a pre-treatment for gonadotropin ovulation induction. Studies show that metformin can improve insulin resistance and metabolic abnormalities in PCOS patients, induce ovulation, restore menstruation, and stopping metformin in early pregnancy does not increase miscarriage rates. However, the use of metformin is associated with an increased risk of obesity in offspring, so caution should be exercised in pregnant PCOS patients.
4. Metformin and tumors: Existing studies show that T2DM is associated with an increased risk of colorectal cancer, hepatocellular carcinoma, gallbladder cancer, breast cancer, endometrial cancer, and pancreatic cancer. Meta-analysis shows that metformin treatment is associated with a reduced risk of various malignancies, including lung cancer, prostate cancer, colorectal cancer, and breast cancer.
5. Metformin and cognitive function: The effects of metformin on cognitive function are currently unclear. Basic research shows that metformin may activate the atypical PKC-CBP pathway in neural stem cells through the AMPK signaling pathway, promoting the growth of new neurons or having a repair effect on nerve system injuries. Prospective observational studies show that the use of metformin is associated with a reduced risk of cognitive decline in elderly T2DM patients. Retrospective cohort studies show that the use of metformin is associated with a reduced risk of Parkinson’s disease in T2DM patients.
6. Metformin and novel coronavirus infection: Existing research evidence indicates that diabetic patients taking metformin may have potential benefits after being infected with the novel coronavirus. Multiple observational studies or retrospective cohort studies have shown that pre-admission treatment with metformin is associated with a reduced risk of severe outcomes and mortality in diabetic patients with novel coronavirus infection. A network meta-analysis shows that diabetic patients with novel coronavirus infection using metformin have a significantly reduced risk of mortality by 26% compared to those not using metformin. The secondary endpoint results of the randomized, double-blind, placebo-controlled study (COVID-OUT) show that early use of metformin can significantly reduce the risk of emergency visits, hospitalization, or death in patients with novel coronavirus infection by 42%. In confirmed cases of novel coronavirus infection in diabetic patients, if there is suspected or confirmed hypoxemia and severe infection, consideration should be given to stopping metformin based on concerns about the potential risk of lactic acidosis.
9. Summary
Metformin has good hypoglycemic effects and potential cardiovascular protective effects, with good long-term safety. In the absence of contraindications and intolerance, and without strong indications for GLP-1RA or SGLT2i renal protection, metformin should still be used as the first-line drug for controlling hyperglycemia in newly diagnosed T2DM patients and as the basic drug in combination therapy throughout the course of diabetes treatment.
Written by: Hong Tianpei; Zhou Xianghai; Lv Zhaohui
Consensus Update Expert Group Members (in alphabetical order by surname): Chen Limin (Endocrinology Department, Tianjin Medical University Zhu Xianyi Memorial Hospital); Guo Lixin (Endocrinology Department, Beijing Hospital, National Center for Geriatrics); Guo Shuqin (Endocrinology Department, Baoding First Central Hospital); Hong Tianpei (Endocrinology Department, Peking University Third Hospital); Ji Qiuhe (Endocrinology Department, Xi’an International Medical Center, Northwest University); Ji Linong (Endocrinology Department, Peking University People’s Hospital); Ji Liwei (Pharmacy Department, Beijing Hospital, National Center for Geriatrics); Li Quanmin (Endocrinology Department, Rocket Army Characteristic Medical Center); Li Xiaoying (Endocrinology Department, Fudan University Zhongshan Hospital); Li Yanbing (Endocrinology Department, First Affiliated Hospital of Sun Yat-sen University); Li Yiming (Endocrinology Department, Fudan University Huashan Hospital); Li Yong (Cardiology Department, Fudan University Huashan Hospital); Liu Jing (Cardiology Department, Peking University People’s Hospital); Lv Zhaohui (Endocrinology Department, PLA General Hospital First Medical Center); Ma Jianhua (Endocrinology Department, Nanjing First Hospital); Mu Yiming (Endocrinology Department, PLA General Hospital First Medical Center); Peng Yongde (Endocrinology Department, Shanghai First People’s Hospital); Shan Zhongyan (Endocrinology Department, China Medical University First Affiliated Hospital); Shi Lixin (Guizhou International General Hospital Endocrinology Department); Wu Jiuhong (Pharmacy Department, Strategic Support Force General Hospital); Xiao Xinhua (Endocrinology Department, Beijing Union Medical College Hospital); Xue Yaoming (Endocrinology Department, Southern Medical University Southern Hospital); Yu Xuefeng (Endocrinology Department, Tongji Medical College, Huazhong University of Science and Technology); Zhang Junqing (Endocrinology Department, Peking University First Hospital); Zhang Qiu (Endocrinology Department, First Affiliated Hospital of Anhui Medical University); Zhou Xianghai (Endocrinology Department, Peking University People’s Hospital); Zhu Dalong (Endocrinology Department, Nanjing Medical University Affiliated Gulou Hospital)
This article is sourced from: Chinese Journal of Internal Medicine, 2023, 62(6): 619-630.
This article was edited by: Zhao Jinghui
