Spotlight on metformin

In the past month, a new meta-analysis compared metformin to other diabetes drugs, and the FDA expanded metformin's indications in patients with reduced kidney function.

The systematic review and meta-analysis included 179 trials and 25 observational studies that offered head-to-head comparisons of monotherapy with metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, or glucagon-like peptide-1 (GLP-1) receptor agonists, as well as selected metformin-based combination therapies. Results were published by Annals of Internal Medicine on April 19.

Metformin was associated with lower cardiovascular mortality than sulfonylureas, the analysis found. All of the drugs provided similar reductions in HbA1c, except for DPP-4 inhibitors, which showed smaller effects. Body weight was reduced or maintained on metformin, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors and increased on the other options. Looking at adverse events, researchers found hypoglycemia with sulfonylureas, gastrointestinal effects with metformin and GLP-1 receptor agonists, heart failure with thiazolidinediones, and genital mycotic infections with SGLT-2 inhibitors, but notably, no increase in lactic acidosis with metformin. The results support guideline recommendations for metformin as first-line therapy, the authors concluded. However, without more definitive evidence on the risks and benefits of second-line or alternative medications, selection of other drugs should be driven by patient factors, such as comorbidities, and patient preferences regarding the known comparative effects (HbA1c, weight, hypoglycemia, and gastrointestinal effects), uncertainty of risk, and cost, the authors said.

The FDA announced in April that metformin can be used safely in most patients with mild kidney impairment and in some with moderate impairment, contrary to previous restrictions. The drug is still contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m² and initiation is not recommended in those with an eGFR between 30 and 45 mL/min/1.73 m², but metformin can be used in patients with renal function above those cutoffs. The agency is also changing the drug's labeling to recommend that the decision to use metformin be based on eGFR rather than creatinine, according to a safety communication.

Physicians should obtain an eGFR at least annually in all patients taking metformin and more frequently in those with risk factors for renal impairment, the FDA said. If a patient's eGFR falls below 45 mL/min/1.73 m² while on metformin, benefits and risks of continuing treatment should be assessed. Below 30 mL/min/1.73 m², the drug should be discontinued. It should also be discontinued at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/minute/1.73 m²; those with a history of liver disease, alcoholism, or heart failure; or those receiving intra-arterial iodinated contrast. Clinicians should reevaluate eGFR 48 hours after the imaging procedure and restart metformin if renal function is stable.