Observational studies on the association of outpatient antidiabetic medication use and COVID-19 outcomes: are the findings more relevant to diabetes management than to COVID-19 pathology? A mini-review

At the start of the COVID-19 pandemic, there were concerns that some antidiabetic medications might worsen outcomes, though anti-inflammatory properties suggested possible benefits. Many observational studies examined antidiabetic medications use and COVID-19 outcomes. Meta-analyses showed that insulin was linked to worse outcomes, while metformin, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, and glucagon-like peptide-1 (GLP-1) agonists were associated with better outcomes. Findings on dipeptidyl peptidase-4 (DPP-4) inhibitors, pioglitazone, and sulfonylureas were mixed-showing neutral, beneficial, or negative effects. However, randomized controlled trials (RCTs) testing these medications after SARS-CoV-2 infection found no effect on COVID-19 outcomes, implying that their anti-inflammatory effects do not translate into meaningful clinical benefits during acute infection. This discrepancy prompts questioning what observational studies actually measured. Given that many studies applied robust statistical methods, their results are unlikely solely due to confounding or indication bias. We hypothesize that these studies reveal broader cardiovascular effects and illuminate diabetes management more than they inform COVID-19 pathology. Their findings align with current 2022 American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) consensus guidelines for the management of type 2 diabetes mellitus endorsing metformin, SGLT-2 inhibitors, and GLP-1 agonists as first-line therapies, recommending cautious early insulin use, and reserving DPP-4 inhibitors, sulfonylureas, and pioglitazone for selective cases. This is applicable regardless of COVID-19 status. Further research should determine whether infection-related clinical endpoints, such as mortality or hospitalization from COVID-19 or other infections, might serve as valid surrogate markers for cardiovascular outcomes.