Most patients should receive it, with exceptions as noted below. Metformin is the cornerstone of diabetes therapy and should be considered in all patients with type 2 diabetes. Both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE)1,2 recommend it as first-line treatment for type 2 diabetes. It lowers blood glucose levels by inhibiting hepatic glucose production, and it does not tend to cause hypoglycemia.
However, metformin is underused. A 2012 study showed that only 50% to 70% of patients with type 2 diabetes treated with a sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor, thiazolidinedione, or glucagon-like peptide-1 analogue also received metformin.3 This occurred despite guidelines recommending continuing metformin when starting other diabetes drugs.4
EVIDENCE METFORMIN IS EFFECTIVE
The United Kingdom Prospective Diabetes Study (UKPDS)5 found that metformin significantly reduced the incidence of:
- Any diabetes-related end point (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.53–0.87)
- Myocardial infarction (HR 0.61, 95% CI 0.41–0.89)
- Diabetes-related death (HR 0.58, 95% CI 0.37–0.91)
- All-cause mortality (HR 0.64; 95% CI 0.45–0.91).
The Hyperinsulinemia: Outcomes of Its Metabolic Effects (HOME) trial,6 a multicenter trial conducted in the Netherlands, evaluated the effect of adding metformin (vs placebo) to existing insulin regimens. Metformin recipients had a significantly lower rate of macrovascular mortality (HR 0.61, 95% CI 0.40–0.94, P = .02), but not of the primary end point, an aggregate of microvascular and macrovascular morbidity and mortality.
The Study on the Prognosis and Effect of Antidiabetic Drugs on Type 2 Diabetes Mellitus With Coronary Artery Disease trial,7 a multicenter trial conducted in China, compared the effects of metformin vs glipizide on cardiovascular outcomes. At about 3 years of treatment, the metformin group had a significantly lower rate of the composite primary end point of recurrent cardiovascular events (HR 0.54, 95% CI 0.30–0.90). This end point included nonfatal myocardial infarction, nonfatal stroke, arterial revascularization by percutaneous transluminal coronary angioplasty or by coronary artery bypass graft, death from a cardiovascular cause, and death from any cause.
These studies prompted the ADA to emphasize that metformin can reduce the risk of cardiovascular events or death. Metformin also has been shown to be weight-neutral or to induce slight weight loss. Furthermore, it is inexpensive.
WHAT ABOUT THE RENAL EFFECTS?
Because metformin is renally cleared, it has caused some concern about nephrotoxicity, especially lactic acidosis, in patients with impaired renal function. But the most recent guidelines have relaxed the criteria for metformin use in this patient population.
Metformin’s labeling,8 revised in 2016, states the following:
- If the estimated glomerular filtration rate (eGFR) is below 30 mL/min/1.73 m2, metformin is contraindicated
- If the eGFR is between 30 and 45 mL/min/1.73 m2, metformin is not recommended
- If the eGFR is below 45 mL/min/1.73 m2 in a patient taking metformin, the risks and benefits of continuing treatment should be assessed, the dosage may need to be adjusted, and renal function should be monitored more frequently.8
These labeling revisions were based on a systematic review by Inzucchi et al9 that found metformin is not associated with increased rates of lactic acidosis in patients with mild to moderate kidney disease. Subsequently, an observational study published in 2018 by Lazarus et al10 showed that metformin increases the risk of acidosis only at eGFR levels below 30 mL/min/1.73 m2. Also, a Cochrane review published in 2003 did not find a single case of lactic acidosis in 347 trials with 70,490 patient-years of metformin treatment.11
Previous guidelines used serum creatinine levels, with metformin contraindicated at levels of 1.5 mg/dL or above for men and 1.4 mg/dL for women, or with abnormal creatinine clearance. The ADA and the AACE now use the eGFR1,2 instead of the serum creatinine level to measure kidney function because it better accounts for factors such as the patient’s age, sex, race, and weight.
Despite the evidence, the common patient perception is that metformin is nephrotoxic, and it is important for practitioners to dispel this myth during clinic visits.
What about metformin use with contrast agents?
Labeling has a precautionary note stating that metformin should be held at the time of, or prior to, any imaging procedure involving iodinated contrast agents in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. The eGFR should be reevaluated 48 hours after the imaging procedure.8
Additionally, if the iodinated contrast agent causes acute kidney injury, metformin could accumulate, with resultant lactate accumulation.
The American College of Radiology (ACR) has proposed less stringent guidelines for metformin during radiocontrast imaging studies. This change is based on evidence that lactic acidosis is rare—about 10 cases per 100,000 patient-years—and that there are no reports of lactic acidosis after intravenously administered iodinated contrast in properly selected patients.12,13
The ACR divides patients taking metformin into 2 categories:
- No evidence of acute kidney injury and eGFR greater than 30 mL/min/1.73 m2
- Either acute kidney injury or chronic kidney disease with eGFR below 30 mL/min/1.73 m2 or undergoing arterial catheter studies with a high chance of embolization to the renal arteries.14
For the first group, they recommend against discontinuing metformin before or after giving iodinated contrast or checking kidney function after the procedure.
For the second group, they recommend holding metformin before and 48 hours after the procedure. It should not be restarted until renal function is confirmed to be normal.