Spotlight on COVID-19 and diabetes medications

Several recent studies have found evidence that outcomes from COVID-19 differ by the diabetes medications patients were taking before they got sick, including metformin being associated with better outcomes, but confounding by indication is likely, researchers noted.

Common glucose-lowering drugs were associated with differing risks of death from COVID-19, but none so dramatic as to support changing prescribing, according to a retrospective study published by The Lancet Diabetes & Endocrinology on March 30. The cohort study included more than 2 million English patients with type 2 diabetes, 13,479 of whom died of COVID-19. Compared to patients without prescriptions for the following drugs, adjusted hazard ratios for death from COVID-19 were 0.77 (95% CI, 0.73 to 0.81) for metformin users, 0.94 (95% CI, 0.89 to 0.99) for sulfonylureas, 1.07 (95% CI, 1.01 to 1.13) for dipeptidyl peptidase-4 (DPP-4) inhibitors, and 1.42 (95% CI, 1.35 to 1.49) for insulin; differences were not significant for meglitinides, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, thiazolidinediones, glucagon-like peptide-1 receptor agonists, and alpha-glucosidase inhibitors. The study is thought to be the largest to examine associations between these drug classes and COVID-19 mortality, but the findings are likely at least in part confounded by indication given use of different drug classes at different stages of type 2 diabetes progression, and the overall differences were small, the authors said. “We interpret these findings to suggest that there is, as yet, no clear indication to jeopardise a modifiable risk factor—glucose control—or other potential glucose-independent benefits of specific drugs by stopping or changing diabetes medications in people with type 2 diabetes in daily practice,” they wrote.

An accompanying editorial noted that some experts have previously recommended caution in the use of SGLT-2 inhibitors in patients with COVID-19 and discontinuation of metformin in severe cases. Based on this study's results, “recommendations on the use of glucose-lowering drugs by people with type 2 diabetes during the COVID-19 pandemic might now become more liberal, allowing use of all glucose-lowering drugs in stable situations,” the authors said. They called for randomized trials to more definitively determine the benefits and harms of these drugs in COVID-19 patients.

A systematic review, published by Diabetes & Metabolic Syndrome: Clinical Research & Reviews on April 1, found that patients taking DPP-4 inhibitors had lower risk of death from COVID-19. It included nine studies and 4,477 COVID-19 patients, 31% who were taking a DPP-4 inhibitor before hospitalization. The mortality rate was 23% overall and was significantly lower in patients taking DPP-4 inhibitors than in those not on the drugs (risk ratio, 0.76 [95% CI, 0.60 to 0.97]; P=0.030). A meta-regression analysis showed that the association between DPP-4 inhibitors and mortality was weaker in patients also taking metformin or an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. “As the evidence stands, it is recommended to continue the medication in patients using it routinely,” the authors said. Similarly, a meta-analysis of 14 publications about COVID-19 patients taking metformin, published by Frontiers in Endocrinology on March 19, found overall evidence for the drug being associated with less severe outcomes but mixed results that were less than definitive.

In other news on COVID-19 and diabetes, on March 29 the CDC added type 1 diabetes to its list of underlying medical conditions associated with high risk for severe COVID-19. A page for clinicians reports some of the data underlying this decision. A study published March 10 by JAMA Network Open found that 210 patients who had diabetic ketoacidosis (DKA) with COVID-19 had higher insulin requirements, longer time to resolution of DKA, and higher mortality (30% vs. 5%) compared to 4,819 DKA patients without COVID-19.