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Commentary: Mortality Risk of Antidiabetic Agents for Type 2 Diabetes With COVID-19: A Systematic Review and Meta-Analysis

In a recent article (1), Kan and colleagues assessed the association between use of four kinds of hypoglycemic agents (i.e., metformin, sulfonylurea, dipeptidyl peptidase-4 inhibitors [DPP4i], and insulin) and risk of COVID-19 mortality in patients with type 2 diabetes mellitus (T2DM), by performing meta-analysis based on eligible studies. However, the authors did not address the association of two novel classes of hypoglycemic agents (i.e., sodium-glucose cotransporter-2 inhibitors [SGLT2i] and glucagon-like peptide-1 receptor agonists [GLP1RA]) with COVID-19 mortality, due to the limited number of included studies regarding SGLT2i and GLP1RA. Nowadays, more and more studies have been published, mainly targeting the relationship between SGLT2i or GLP1RA use and COVID-19 mortality risk (2–10). Therefore, we intended to include these recent studies regarding SGLT2i and GLP1RA to conduct an updated meta-analysis to address their association with COVID-19 mortality in T2DM patients. Moreover, several new cohort studies (2–4, 8, 11–14) targeting the relationship of DPP4i use with COVID-19 death risk


INTRODUCTION
In a recent article (1), Kan and colleagues assessed the association between use of four kinds of hypoglycemic agents (i.e., metformin, sulfonylurea, dipeptidyl peptidase-4 inhibitors [DPP4i], and insulin) and risk of COVID-19 mortality in patients with type 2 diabetes mellitus (T2DM), by performing meta-analysis based on eligible studies. However, the authors did not address the association of two novel classes of hypoglycemic agents (i.e., sodium-glucose cotransporter-2 inhibitors [SGLT2i] and glucagon-like peptide-1 receptor agonists [GLP1RA]) with COVID-19 mortality, due to the limited number of included studies regarding SGLT2i and GLP1RA. Nowadays, more and more studies have been published, mainly targeting the relationship between SGLT2i or GLP1RA use and COVID-19 mortality risk (2)(3)(4)(5)(6)(7)(8)(9)(10). Therefore, we intended to include these recent studies regarding SGLT2i and GLP1RA to conduct an updated meta-analysis to address their association with COVID-19 mortality in T2DM patients. Moreover, several new cohort studies (2-4, 8, 11-14) targeting the relationship of DPP4i use with COVID-19 death risk have been published after Kan et al.'s meta-analysis (1). Thus, in this updated meta-analysis we would also include these new DPP4i studies to reassess the association between use of DPP4i and risk of COVID-19 death in T2DM patients.

METHODS
Eligible studies for inclusion in this updated meta-analysis were cohort studies that enrolled T2DM patients with COVID-19 and estimated the COVID-19 mortality risk of use of DPP4i, SGLT2i, or GLP1RA, compared to no use of DPP4i, SGLT2i, or GLP1RA, respectively. The comparison of SGLT2i/GLP1RA use versus no SGLT2i/GLP1RA use included that of SGLT2i/GLP1RA use versus DPP4i use, whereas the comparison of DPP4i use versus no DPP4i use did not include that of DPP4i use versus SGLT2i/ GLP1RA use. Outcome of interest was COVID-19 death, and we preferred to use the most long-term outcome data. For example, if 7-day death (i.e., death within 7 days following hospital admission due to COVID-19) and 30-day death were both reported in included studies, we would use 30-day death. We searched PubMed, Cochrane Library, and Embase from the inception date of databases to November 21, 2021, using the main search terms: "COVID-19", "SARS-CoV-2", "type 2 diabetes mellitus", "DPP4i", "SGLT2i", "GLP1RA", "death", and "mortality". Two authors independently performed study selection, quality assessment, and data extraction; and a third author addressed their divergences when necessary. The quality of included studies was assessed using the Newcastle-Ottawa Scale (15), according to which a quality score for included studies ranged from 0 to 9, with a score of ≥7 being regarded as "high quality".
We extracted the estimators of relative risk (RR) and 95% confidence interval (CI) from included studies to perform metaanalysis. We preferentially extracted hazard ratio as RR, followed by risk ratio and odds ratio. Meta-analysis was conducted based on the comparisons of DPP4i versus Non-DPP4i, SGLT2i versus Non-SGLT2i, and GLP1RA versus Non-GLP1RA, respectively. Meta-analysis was done using a random-effects model when I 2 ≥50%, or using a fixed-effects model when I 2 <50%. We drew funnel plots and performed Egger's test to judge publication bias. Sensitivity analysis was conducted via the leave-one-out method (omitting one study each time), to evaluate the robustness of meta-analysis results. All statistical analyses were completed in Stata/MP 16.0.

3).
Publication bias was observed in the meta-analysis of DPP4i (P Egger =0.012; Figure S1), and was not observed in the metaanalyses of SGLT2i (P Egger =0.885; Figure S2) and GLP1RA (P Egger =0.092; Figure S3). The results of sensitivity analysis for DPP4i ( Figure S4), SGLT2i ( Figure S5), and GLP1RA ( Figure  S6) were similar with primary analysis results, which suggested the robustness of meta-analysis results.
One strength of this study is that sensitivity analyses suggested the robustness of meta-analysis results although possible publication bias was observed in DPP4i's metaanalysis. Oppositely, this study has two main weaknesses. First, we did meta-analyses based on cohort studies. Although we extracted the adjusted RRs and 95% CIs from included studies to perform meta-analyses, there must be certain confounding factors unadjusted. Thus, relevant randomized trials are needed to verify our findings. Second, we failed to compare various hypoglycemic agents in COVID-19 death risk, and future studies comparing them are clinically meaningful. Three new classes of hypoglycemic agents (i.e., SGLT2i, GLP1RA, and DPP4i) were significantly associated with reduced risk of COVID-19 death in T2DM patients with COVID-19, which highlights the potential of these new drugs used to prevent COVID-19 death in T2DM patients with COVID-19. Further studies are needed to assess whether there are significant differences in the risk of COVID-19 death among various kinds of hypoglycemic agents.