Metformin or Sulfonylurea Use Significantly Lowered Risk of Mortality for COVID-19 Patients with T2D

Insulin is not recommended for COVID-19 patients with T2D due to increased mortality risk, but metformin or sulfonylurea treatment showed benefits.

Despite recent COVID-19 treatment developments, individuals with a concurrent chronic disease have a much higher rate of severe complications than individuals without a chronic disease. Mortality among hospitalized patients with diabetes or hyperglycemia was higher (29%) than individuals without diabetes or hyperglycemia (6%). Studies found that mortality continued to be higher in these patients despite adjustment for age, ethnicity, obesity, and hypertension. Antidiabetic medications play an essential role in controlling elevated blood glucose for patients with T2D. Several studies have examined mortality alongside antidiabetic treatment in patients with T2D who have COVID-19. The researchers of this study wanted to streamline the current research due to variation in experimental design. Therefore, they conducted a systemic review to examine the associations of antidiabetic agents with mortality in patients with T2DM who have COVID-19.

This Meta-Analysis looked at eighteen studies of individuals with T2D alongside COVID-19. The intervention included any antidiabetic agent. This was compared to no diabetic medication usage. The outcome looked at study type and mortality. The study excluded review articles, case reports, case series, summaries discussions, or letters to the editor. In addition, data containing incomplete patient information, duplications, and the absence of mortality outcomes were omitted. Relationships between antidiabetic agents and mortality were calculated using odds ratios (OR) and 95% confidence intervals (CI). Heterogeneity was assessed using the random-effects model (P<0.1 or I2 >50%) and a fixed-effects model (P>0.1 and I2<50%). Egger’s and Begg’s tests were used to evaluate publication bias if >5 studies were used. Publication bias was absent if P >0.05. Article quality was appraised using the Newcastle-Ottawa Scale tool.

676 studies were found in the PubMed, Web of Science, Embase, and the Cochrane Library databases. Duplicates were removed, leaving 318 articles for the title and abstract screening. The final analysis included information on eighteen studies totaling 17,338 patients. Seven of the studies were conducted in China; two were from the United States, one was from South Korea, two were from the United Kingdom, three were from Italy, and three were from France. All Newcastle-Ottawa Scale scores were >/=7.

Researchers found a significant association between antidiabetic agent use (i.e., metformin, sulfonylurea, and insulin) and mortality (P<0.05). There was no significant association between DPP-4 inhibitor use and mortality (P>0.05). Pooled OR analysis found significantly lower mortality with metformin users than with non-users (pooled OR= 0.69, CI =0.55–0.86, P=0.001). Five studies found lower mortality in sulfonylurea users compared to sulfonylurea non-users (pooled OR=0.80, CI=0.66–0.96, P=0.016). Seven studies found more significant mortality in insulin users than non-users (pooled OR= 2.20; CI=1.34–3.60, P=0.002).

Patients with T2D and COVID-19 had the lowest mortality risk while on metformin or a sulfonylurea. This was the first study that examined the mortality risk associated with using different antidiabetic agents among T2DM patients with COVID-1. This research coincides with several earlier meta-analyses that found metformin was associated with lower mortality (OR, 0.62; 95% CI, 0.43–0.89). The researchers of this study propose anti-inflammatory properties in metformin as the mechanism of action for this beneficial effect. The beneficial mechanism for sulfonylureas is unknown. The use of a DPP-4 inhibitor was not associated with mortality. Individuals taking insulin were found to have an increased mortality risk. Previous studies found a higher mortality rate among those receiving insulin treatment for diabetes and sepsis than those receiving oral antidiabetic agents. Despite these findings on insulin, many experts have recommended it for patients with T2D experiencing SARS-CoV-2 infection. Limitations of the study include limitations of the included studies. Future studies need to compare varying antidiabetic agents alongside COVID-19 to confirm these results.

Practice Pearls:

• Metformin and sulfonylurea users had a significantly lower mortality risk in patients with T2D and COVID-19 than non-users.
• Insulin users had a significantly higher risk of mortality in patients with T2D and COVID-19 than non-users.
• There was no associated mortality risk found in patients with T2D and COVID-19 on a DPP-4 inhibitor.

Kan C, Zhang Y, Han F, Xu Q, Ye T, Hou N, Sun X. Mortality Risk of Antidiabetic Agents for Type 2 Diabetes With COVID-19: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne). 2021 Sep 16;12:708494. doi: 10.3389/fendo.2021.708494. PMID: 34603199; PMCID: PMC8481667. https://doi.org/10.3389/fendo.2021.708494

Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA (2020) 323:2052–9. doi: 10.1001/jama.2020.6775. https://jamanetwork.com/journals/jama/fullarticle/2765184

Author: Kornelia Ilias, Pharm.D. Candidate, Creighton University School of Pharmacy and Health Professions