The Association between Hypoglycemic Agents and Clinical Outcomes of COVID-19 in Patients with Diabetes: A Systematic Review and Meta-Analysis (preprint)

Background: During the current Coronavirus Disease 2019 (COVID-19) pandemic, diabetic patients face disproportionately more. Anti-inflammatory effects of hypoglycemic agents have been reported, and their effects in patients with diabetes and COVID-19 remain controversial. This study was performed to clarify this association.Methods: Relevant literature was searched on China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform, Chinese periodical service platform VIP Database, Sinomed (China Biology Medicine, CBM), MedRxiv, PubMed, ScienceDirect, Web of Science, Ovid Databases (LWW), Springer Link, Wiley Online Library, Oxford Academic, Nature Press Group, Cochrane Library, and BMJ Evidence-Based Medicine up to November 14, 2020. Only observational studies of hypoglycemic agents vs. other drugs or therapy in adult diabetic patients with COVID-19 were included. Data of death and poor composite outcomes were extracted. The pooled effects of hypoglycemic agents on mortality and poor composite outcomes of COVID-19 in diabetic patients, pooled ORs along with 95% CIs, were calculated using the fixed-effects or random-effects models based on heterogeneity assessment. Registration number of PROSPERO is CRD42020221951.Findings: 16 studies were included in the qualitative analysis and 14 studies with 13,371 patients were included in quantitative synthesis. Meta-analysis showed that metformin was associated with a statistically significant lower mortality in diabetic patients with COVID-19 (pooled OR=0·56, 95% CI, 0·39-0·81, p=0·002), especially home use of metformin (pooled OR=0·60, 95%CI, 0·40-0·88, p=0·01). but in-hospital use of metformin was associated with statistically non-significant lower mortality (pooled OR=0·44, 95%CI, 0·15-1·33, p=0·14) or poor composite outcomes (pooled OR=0·93, 95% CI, 0·79-1·11, p=0·44). Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) were associated with statistically non-significant lower mortality (pooled OR=0·63, 95% CI, 0·26-1·56, p=0·32) or poor composite outcomes of COVID-19 in diabetic patients (pooled OR=0·96, 95% CI, 0·74-1·26, p=0·78).Interpretation: Home use of metformin might be beneficial in decreasing mortality in diabetic patients infected with SARS-CoV-2. There is insufficient evidence to conclude that metformin and other hypoglycemic agents are associated with poor composite outcomes. Limited by retrospective characteristics, with relative weak capability to verify causality, more prospective studies, especially RCTs are needed.Funding Statement: This study is financially supported by Hunan Provincial Key Laboratory of Clinical Epidemiology (grant number: 2020ZNDXLCL002).Declaration of Interests: We declare no competing interests.

The Association Between Hypoglycemic Agents and Clinical Outcomes of COVID-19 in Patients with Diabetes: A Systematic Review and Meta-Analysis (preprint)

Background During the current Coronavirus Disease 2019 (COVID-19) pandemic, diabetic patients face disproportionately more. Anti-inflammatory effects of hypoglycemic agents have been reported, and their beneficial or harmful effects in patients with diabetes and COVID-19 remain controversial. Purpose This study was performed to clarify this association. Data Sources Relevant literature was searched on China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform, Chinese periodical service platform VIP Database, Sinomed (China Biology Medicine, CBM), MedRxiv, PubMed, ScienceDirect, Web of Science, Ovid Databases (LWW), Springer Link, Wiley Online Library, Oxford Academic, Nature Press Group, Cochrane Library and BMJ Evidence-Based Medicine up to November 14, 2020. Study Selection Only observational studies of hypoglycemic agents vs. drugs or therapy without hypoglycemic agents in adult diabetic patients with COVID-19 were included. Data Extraction Data of death and poor composite outcomes were extracted. Data Synthesis The pooled effects were calculated using the fixed-effects or random-effects models based on heterogeneity assessment. Limitation Most studies were retrospective cohort studies with relative weak capability to verify causality. Conclusion Home use of metformin might be beneficial in decreasing mortality in diabetic patients infected with SARS-CoV-2. There is insufficient evidence to conclude that metformin and other hypoglycemic agents are associated with poor composite outcomes. More prospective studies, especially RCTs are needed. Registration-PROSPERO CRD42020221951.

Will Proton Pump Inhibitors Lead to a Higher Risk of COVID-19 Infection and Progression to Severe Disease? A Meta-analysis (preprint)

BackgroundPrevious researches on the association between proton pump inhibitors (PPIs) use and the treatment and prevention of COVID-19 have generated inconsistent findings. Therefore, this Meta-analysis was conducted to clarify the outcome in patients who take PPIs. MethodsWe carried out a systematic search to identify potential studies until November 2020. Heterogeneity was assessed using the I-squared statistic. Odds ratios (ORs) with its 95% confidence intervals (CIs) were calculated by fixed-effects or random-effects models according to the heterogeneity. Sensitivity analyses and tests for publication bias were also performed. ResultsEight articles with more than 268,683 subjects were included. PPI use was not associated with increased or decreased risk of COVID-19 infection (OR:3.16, 95%CI = 0.74-13.43, P=0.12) or mortality risk of COVID-19 patients (OR=1.91, 95% CI=0.86-4.24, P=0.11). While it can add risk of severe disease (OR=1.54, 95% CI=1.20-1.99, P<0.001;) and secondary infection (OR=4.33, 95% CI=2.57-7.29). No publication bias was detected. ConclusionsPPI use is not associated with increased risk infection and may not change the mortality risk of COVID-19, but appeared to be associated with increased risk of progression to severe disease and secondary infection. However, more original studies to further clarify the relationship between PPI and COVID-19 are still urgently needed.

Association between angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers use and the risk of infection and clinical outcome of COVID-19: a comprehensive systematic review and meta-analysis. (preprint)

Background The effect of using Angiotensin-converting enzyme inhibitors (ACEIs) and Angiotensin-receptor blockers (ARBs) on the risk of coronavirus disease 2019 (COVID-19) is a topic of recent debate. Although studies have examined the potential association between them, the results remain controversial. This study aims to determine the true effect of ACEI/ARBs use on the risk of infection and clinical outcome of COVID-19. Methods Five electronic databases (PubMed, Web of science, Cochrane library, China National Knowledge Infrastructure database, medRxiv preprint server) were retrieved to find eligible studies. Meta-analysis was performed to examine the association between ACEI/ARBs use and the risk of infection and clinical outcome of COVID-19. Results 22 articles containing 157,328 patients were included. Use of ACEI/ARBs was not associated with increased risk of infection (Adjusted OR: 0.96, 95% CI: 0.91-1.01, I2=5.8%) or increased severity (Adjusted OR: 0.90, 95% CI: 0.77-1.05, I2=27.6%) of COVID-19. The use of ACEI/ARBs was associated with lower risk of death from COVID-19 (Adjusted OR: 0.66, 95% CI: 0.44-0.99, I2=57.9%). Similar results of reduced risk of death were also found for ACEI/ARB use in COVID-19 patients with hypertension (Adjusted OR: 0.36, 95% CI: 0.17-0.77, I2=0). Conclusion This study provides evidence that ACEI/ARBs use for COVID-19 patients does not lead to harmful outcomes and may even provide a beneficial role and decrease mortality from COVID-19. Clinicians should not discontinue ACEI/ARBs for patients diagnosed with COVID-19 if they are already on these agents. Keywords: COVID-19; Angiotensin-converting enzyme inhibitor; Angiotensin-receptor blockers; risk; systematic review; meta-analysis