Association Between Anti-diabetic Agents and Clinical Outcomes of COVID-19 in Patients with Diabetes: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: During the current Coronavirus Disease 2019 (COVID-19) pandemic, patients with diabetes face disproportionately more. This study was performed to clarify anti-inflammatory effects of anti-diabetic agents on COVID-19 in patients with diabetes. METHODS AND RESULTS: Relevant literature was searched on 15 databases up to November 14, 2020 and was updated on April 13, 2021. The pooled ORs along with 95% CIs were calculated to evaluate combined effects. 31 studies with 66,914 patients were included in qualitative and quantitative synthesis. Meta-analysis showed that metformin was associated with a statistically significant lower mortality (pooled OR = 0.62, 95% CI, 0.50-0.76, p = 0.000) and poor composite outcomes (pooled OR = 0.83, 95% CI, 0.71-0.97, p = 0.022) in diabetic patients with COVID-19. Significance of slight lower mortality remained in sulfonylurea/glinides (pooled OR = 0.93, 95% CI, 0.89-0.98, p = 0.004), but of poor composite outcomes was not (pooled OR = 1.48, 95% CI, 0.61-3.60, p = 0.384). Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) were associated with statistically non-significant lower mortality (pooled OR = 0.95, 95% CI, 0.72-1.26, p = 0.739) or poor composite outcomes (pooled OR = 1.27, 95% CI, 0.91-1.77, p = 0.162) of COVID-19 in diabetic patients. CONCLUSION: Metformin might be beneficial in decreasing mortality and poor composite outcomes in diabetic patients infected with SARS-CoV-2. DPP-4 inhibitors, sulfonylurea/glinides, SGLT-2 inhibitors, and GLP-1RA would not seem to be adverse. There was insufficient evidence to conclude effects of other anti-diabetic agents. Limited by retrospective characteristics, with relative weak capability to verify causality, more prospective studies, especially RCTs are needed. REGISTRATION NUMBER: PROSPERO-CRD42020221951.

Is DPP-4 Use Associated With a Decreased Mortality for COVID-19 Diabetic Patients? A Meta-Analysis

Introduction: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Dipeptidyl peptidase-4 (DPP-4) is a multi-expressed glycoprotein that is speculated to be a functional SARS-CoV-2 receptor. Previous studies remain controversial regarding whether DPP-4 use is associated with reduced risk for COVID-19 diabetic patients. Thus, this meta-analysis is performed. Method: A comprehensive literature search on PubMed was conducted to identify all relevant studies published prior to October 2020. This meta-analysis was reported in conformity to the Preferred Reporting Project declared by the Systematic Review and Meta-Analysis (PRISMA). The quality assessment was performed by the Newcastle-Ottawa Scale (NOS). The pooled odds ratio (OR) and 95% confidence intervals (CI) were calculated. Random-effect model or fixed-effect model was used based on heterogeneity. Subgroup analyses were performed based on types of diabetes, geographic locations, study designs, and different sample sizes. Sensitivity analysis and publication bias detection were also performed. All statistical analyses were performed using RevMan and STATA 12.0 statistical software, and all P values were two-tailed, the test level was 0.05. Result: 69 articles were obtained. 5 articles involving 49,989 participants were included. All included studies were considered moderate to high quality. No decreased mortality of COVID-19 diabetic patients was found among DPP-4 users (OR 0.86, 95%CI: 0.22,3.41, P=0.083, I2=81%). In the subgroup analysis, studies in Asia (OR 3.11, 95%CI: 0.78, 12.34, P=0.001, I2=70%) did not found reduced mortality, whereas studies in Europe (OR 0.36, 95%CI: 0.23, 0.56, P<0.00001, I2=0%) were associated with reduced mortality. Based on study designs, the four case-control studies (OR 1.27, 95%CI: 0.27, 5.93, P=0.76, I2=89%) did not find reduced mortality, but one cohort study (OR 0.13, 95%CI: 0.02, 0.84, P=0.03) showed a reduced mortality. The four studies investigating Type 2 Diabetes Mellitus (T2DM) did found reduced mortality (OR 0.74, 95%CI: 0.13, 4.24, P=0.73, I2=90%). For sample size >200, reduced risk of mortality (OR 0.28, 95%CI: 0.07, 1.15, P=0.08, I2=32%) was found, however, for sample ≤200, no statistically significant association (OR 1.44, 95%CI: 0.23, 8.89, P=0.70, I2=93%) was found. Sensitivity analysis by changing models and omitting each study at a time confirm the stability of the result. Begg’s test (z=-0.24, P=1.000) and Egger’s test (t=0.56, P=0.618) did not detect a significant risk of publication bias. Conclusion: The current meta-analysis did not find reduced mortality for COVID-19 diabetic patients who take DPP-4. However, subgroup-analyses found reduced mortality in Europe. More high-quality original studies are needed to further explore the association between DPP-4 use and the mortality risk of COVID-19.