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Pre-admission use of sodium glucose transporter-2 inhibitor (SGLT-2i) may significantly improves Covid-19 outcomes in patients with diabetes: A systematic review, meta-analysis, and meta-regression

Published:December 08, 2022DOI:https://doi.org/10.1016/j.diabres.2022.110205

      Highlights

      • Evidence regarding the benefit of SGLT-2i towards Covid-19 remains unclear..
      • Pre-admission use of SGLT-2i may significantly lower the Covid-19 mortality.
      • Pre-admission use of SGLT-2i may also reduce the severity from Covid-19.

      Abstract

      Aims

      This study aims to examine the effectiveness of using sodium glucose transporter-2 inhibitor (SGLT-2i) before hospital admission on Covid-19 outcomes in diabetic patients.

      Methods

      A literature search was conducted using specific keywords until October 24th, 2022 on 4 databases: Medline, Scopus, Cochrane Library, and ClinicalTrials.gov. All articles regarding SGLT-2i in diabetic patients with Covid-19 were included in the study. Outcomes in this study were calculated using random-effect models to generate pooled odds ratio (OR) with 95% confidence intervals (CI).

      Results

      A total of 17 studies were included in the analysis. Our meta-analysis showed that pre-admission use of SGLT-2i was associated with reduced mortality (OR 0.69; 95 %CI: 0.56 – 0.87, p = 0.001, I2 = 91 %) and severity of Covid-19 (OR 0.88; 95 %CI: 0.80 – 0.97, p = 0.008, I2 = 13 %). This benefit of SGLT-2i on Covid-19 mortality was not significantly affected by patient's factors such as age (p = 0.2335), sex (p = 0.2742), hypertension (p = 0.2165), heart failure (p = 0.1616), HbA1c levels (p = 0.4924), metformin use (p = 0.6617), duration of diabetes (p = 0.7233), and BMI (p = 0.1797).

      Conclusions

      This study suggests that SGLT-2i as glucose lowering treatment in patients with diabetes has a positive effect on Covid-19 outcomes, therefore can be considered as an antidiabetic drug of choice, especially during the Covid-19 pandemic.
      Short Title: SGLT-2i in diabetes and Covid-19.
      Registration details: CRD42022369784.

      Keywords

      1. Introduction

      Coronavirus disease 2019 (Covid-19) is a respiratory tract infection caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) which was firstly reported on December 2019 in Wuhan, China.[
      • Wiersinga W.J.
      • Rhodes A.
      • Cheng A.C.
      • Peacock S.J.
      • Prescott H.C.
      Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review.
      ] This disease has spread quickly across the countries and caused a global pandemic with total reported cases of more than 621 million and 6,5 million deaths until October 19th, 2022.[

      World Health Organization. Coronavirus disease (COVID-19): situation report. Accessed October 24, 2022. https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---19-october-2022.

      ] The manifestation of Covid-19 is widely varied, starting from asymptomatic or mild symptoms such as fever and cough to more serious conditions such as sepsis, altered consciousness, and shock.[

      Hariyanto TI, Putri C, Hananto JE, Arisa J, Fransisca V Situmeang R, Kurniawan A. Delirium is a good predictor for poor outcomes from coronavirus disease 2019 (COVID-19) pneumonia: A systematic review, meta-analysis, and meta-regression. J Psychiatr Res. 2021 Oct;142:361-368. https://doi.org/10.1016/j.jpsychires.2021.08.031.

      ,
      • Kwenandar F.
      • Japar K.V.
      • Damay V.
      • Hariyanto T.I.
      • Tanaka M.
      • Lugito N.P.H.
      • et al.
      Coronavirus disease 2019 and cardiovascular system: a narrative review.
      ] These differences in the clinical manifestations of Covid-19 is significantly influenced by patients’ comorbid factors. Patients with hypertension, diabetes, cardiovascular disease, obesity and neurological diseases are more commonly develop severe-critical conditions which often lead to deaths.[
      • Bailly L.
      • Fabre R.
      • Courjon J.
      • Carles M.
      • Dellamonica J.
      • Pradier C.
      Obesity, diabetes, hypertension and severe outcomes among inpatients with coronavirus disease 2019: a nationwide study.
      ,
      • Hariyanto T.I.
      • Kurniawan A.
      Obstructive sleep apnea (OSA) and outcomes from coronavirus disease 2019 (COVID-19) pneumonia: a systematic review and meta-analysis.
      ,
      • Putri C.
      • Hariyanto T.I.
      • Hananto J.E.
      • Christian K.
      • Situmeang R.F.V.
      • Kurniawan A.
      Parkinson's disease may worsen outcomes from coronavirus disease 2019 (COVID-19) pneumonia in hospitalized patients: a systematic review, meta-analysis, and meta-regression.
      ].
      Before Covid-19 pandemic, individuals with diabetes mellitus around the world reach 422 million people in 2014 and have increased to a total of 463 million people in 2019.[
      • Zhou B.
      • Lu Y.
      • Hajifathalian K.
      • Bentham J.
      • Di Cesare M.
      • Danaei G.
      • et al.
      Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4·4 million participants.
      ,
      • Saeedi P.
      • Petersohn I.
      • Salpea P.
      • Malanda B.
      • Karuranga S.
      • Unwin N.
      • et al.
      Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition.
      ] These numbers can give us a picture that during Covid-19 pandemic, there will be more diabetes patients who need extra care because diabetes itself is closely related to severity and mortality from Covid-19.[
      • Rajpal A.
      • Rahimi L.
      • Ismail-Beigi F.
      Factors leading to high morbidity and mortality of COVID-19 in patients with type 2 diabetes.
      ] A meta-analysis from Pinedo-Torres et al.[

      I, Pinedo-Torres, M, Flores-Fernández, M, Yovera-Aldana, M, Gutierrez-Ortiz C, Zegarra-Lizana P, Intimayta-Escalante C, et al. Prevalence of Diabetes Mellitus and Its Associated Unfavorable Outcomes in Patients With Acute Respiratory Syndromes Due to Coronaviruses Infection: A Systematic Review and Meta-Analysis. Clin Med Insights Endocrinol Diabetes. 2020 Oct 19;13:1179551420962495. https://doi.org/10.1177/1179551420962495.

      ] has stated that the prevalence of diabetes mellitus is about 42 cases per 1,000 patients infected with SARS-CoV-2 with 10 % mortality rate. Another meta-analysis from 158 observational studies has also showed that patients with diabetes were at a higher risk of ICU admission and Covid-19-related mortality.[
      • Kastora S.
      • Patel M.
      • Carter B.
      • Delibegovic M.
      • Myint P.K.
      Impact of diabetes on COVID-19 mortality and hospital outcomes from a global perspective: an umbrella systematic review and meta-analysis.
      ] Therefore, the use of glucose lowering treatment has still become one of the most important aspects in the management of diabetes because hyperglycemia, either measured from fasting plasma glucose (FPG) or hemoglobin A1c (HbA1c) is closely related to higher severity from Covid-19.[
      • Khunti K.
      • Del Prato S.
      • Mathieu C.
      • Kahn S.E.
      • Gabbay R.A.
      • Buse J.B.
      COVID-19, Hyperglycemia, and New-Onset Diabetes.
      ] Previous studies have showed that among antidiabetic agents, metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon like peptide-1 receptor agonist (GLP-1RA) may significantly reduce mortality from Covid-19, while insulin treatment was associated with poor Covid-19 outcomes, instead.[
      • Hariyanto T.I.
      • Kurniawan A.
      Metformin use is associated with reduced mortality rate from coronavirus disease 2019 (COVID-19) infection.
      ,
      • Yang Y.
      • Cai Z.
      • Zhang J.
      • Ashraf G.M.
      DPP-4 inhibitors may improve the mortality of coronavirus disease 2019: A meta-analysis.
      ,
      • Hariyanto T.I.
      • Intan D.
      • Hananto J.E.
      • Putri C.
      • Kurniawan A.
      Pre-admission glucagon-like peptide-1 receptor agonist (GLP-1RA) and mortality from coronavirus disease 2019 (Covid-19): A systematic review, meta-analysis, and meta-regression.
      ,
      • Hariyanto T.I.
      • Lugito N.P.H.
      • Yanto T.A.
      • Siregar J.I.
      • Kurniawan A.
      Insulin Therapy and Outcome of Coronavirus Disease 2019 (COVID-19): a systematic review, meta-analysis, and meta-regression.
      ] Another commonly used glucose lowering treatment, especially in the diabetes patients who concurrently have chronic kidney disease or heart failure is sodium glucose transporter-2 inhibitors (SGLT-2i).[
      • van der Aart-van der Beek A.B.
      • de Boer R.A.
      • Heerspink H.J.L.
      Kidney and heart failure outcomes associated with SGLT2 inhibitor use.
      ] However, the evidence regarding benefit of SGLT-2i in diabetes patients with Covid-19 is still unclear. This study aimed to analyze the Covid-19 outcomes in diabetes patients using SGLT-2i as pre-admission glucose lowering treatment.

      2. Materials and methods

      2.1 Eligibility criteria

      We conducted a systematic review and meta-analysis study from clinical trials and observational studies based on the meta-analysis of Observational Studies in Epidemiology (MOOSE)[
      • Stroup D.F.
      • Berlin J.A.
      • Morton S.C.
      • Olkin I.
      • Williamson G.D.
      • Rennie D.
      • et al.
      Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
      ] and Preferred Reporting Items for Systematic Reviews and meta-Analyses (PRISMA) guidelines.[

      MJ, Page, JE, McKenzie, PM, Bossuyt, I, Boutron, TC, Hoffmann, CD, Mulrow et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021 Mar 29;372:n71. https://doi.org/10.1136/bmj.n71.

      ] The protocol of this study has been retrospectively registered in PROSPERO (CRD42022369784). Inclusion criteria were established according to PECOS formulation and were as follows: (1) Type of populations: diabetes patients with documented SARS-CoV-2 infection through RT-PCR methods; (2) Type of exposure: pre-admission use of sodium glucose transporter-2 inhibitors (SGLT-2i) as glucose lowering treatment; (3) Type of controls: did not use any SGLT-2i before hospital admission or using other antidiabetic drugs besides SGLT-2i; (4) Type of outcome: contain the data for primary outcome (mortality from Covid-19) and/or secondary outcomes (severe Covid-19 and diabetic ketoacidosis); (5) Type of study design: randomized or randomized clinical trials, observational studies (cohort or case-control), and case-series; and (6) presentation as a full-text article (which included preprints). Meanwhile, the exclusion criteria were formulated as follows: (1) studies that were done on non-diabetic Covid-19 patients; (2) studies focusing on the use of SGLT-2i after hospital admission; (3) unpublished study or abstract; (4) and nonprimary research.

      2.2 Search strategy and study selection

      We searched the following databases for articles published in English up to October 24th, 2022: Medline, Scopus, Cochrane Library, and ClinicalTrials.gov. Keywords such as “(sodium glucose transporter-2 inhibitors OR SGLT-2 inhibitors OR SGLT-2i OR glucose lowering treatment OR antidiabetic drugs OR antidiabetic agents) AND (diabetes OR diabetes mellitus OR DM OR type 1 diabetes OR T1D OR type 2 diabetes OR T2D) AND (coronavirus OR coronavirus disease 2019 OR Covid-19 OR n-CoV2019 OR severe acute respiratory syndrome coronavirus 2 OR SARS-CoV-2)” were used to filter the intended studies. Details regarding search strategy used for each database can be seen in Table 1. We used a two-stage screening process, performed independently by two reviewers to identify articles that would be eligible for inclusion: title and abstract, followed by full-text review. Any original manuscripts referenced by systematic reviews or meta-analyses but not identified by the initial search were also included if they were eligible. All articles were then screened for duplicates. Any disagreements during the screening process were resolved by a third, independent reviewer.
      Table 1Literature search strategy.
      1A. Medline Search String:
      “(sodium glucose transporter-2 inhibitors OR SGLT-2 inhibitors OR SGLT-2i OR glucose lowering treatment OR antidiabetic drugs OR antidiabetic agents) AND (diabetes OR diabetes mellitus OR DM OR type 1 diabetes OR T1D OR type 2 diabetes OR T2D) AND (coronavirus OR coronavirus disease 2019 OR Covid-19 OR n-CoV2019 OR severe acute respiratory syndrome coronavirus 2 OR SARS-CoV-2)”
      1B. Example Scopus, Cochrane Library, and ClinicalTrials.gov Search Strategy:
      1. sodium glucose transporter-2 inhibitors
      2. SGLT-2 inhibitors
      3. SGLT-2i
      4. glucose lowering treatment
      5. antidiabetic drugs
      6. antidiabetic agents
      7. diabetes
      8. diabetes mellitus
      9. DM
      10. type 1 diabetes
      11. T1D
      12. type 2 diabetes
      13. T2D
      14. coronavirus
      15. coronavirus disease 2019
      16. Covid-19
      17. n-CoV2019
      18. severe acute respiratory syndrome coronavirus 2
      19. SARS-CoV-2
      20. 1 or 2 or 3 or 4 or 5 or 6
      21. 7 or 8 or 9 or 10 or 11 or 12 or 13
      22. 14 or 15 or 16 or 17 or 18 or 19
      23. 20 and 21 and 22

      2.3 Data extraction

      Data extraction was performed independently and cross-checked by two researchers. The extracted data included: the authors' name, year of study, study design, characteristics of study participants (age, sex, comorbidities, Covid-19 category, diabetes duration, baseline HbA1c levels, background metformin therapy, BMI), number of participants in the exposed group, the control group in included studies, as well as the participants with outcome per group.
      We have divided the outcome of interest in this study into primary and secondary outcomes. The primary outcome of this study was mortality from Covid-19. The mortality from Covid-19 was defined as the number of patients in each study group who were died with a positive Covid-19 RT-PCR test results during the follow-up period. The secondary outcomes were severe Covid-19 and diabetic ketoacidosis (DKA). Severe Covid-19 was defined according to the Guidelines for the Diagnosis and Treatment of New Coronavirus Pneumonia (fifth edition).[

      National Health Commission of the People’s Republic of China. Diagnosis and treatment of new coronavirus pneumonitis. (trial version 5). http://www.nhc.gov.cn/yzygj/s7653p/202002/3b09b894ac9b4204a79db5b8912d4440.shtml.

      ] The guidelines state that patients with severe COVID-19 outcomes are those who during disease progression (whether it was at the time of, during, or after admission) developed any of the following symptoms or features: (1) respiratory distress (defined as a respiratory rate ≥ 30 breaths per min); (2) resting oxygen saturation ≤ 93 %; (3) ratio of partial pressure of arterial oxygen to fraction of inspired oxygen ≤ 300 mmHg; or (4) critical complications (respiratory failure, septic shock, or multiple organ dysfunction/failure); or (5) admission to the intensive care unit (ICU).

      2.4 Risk of bias assessment

      Systematic appraisal of bias in the included clinical trial studies was performed by two researchers using the Risk of Bias version 2 (RoB v2) from Cochrane Collaborations[

      JAC, Sterne, J, Savović, MJ, Page, RG, Elbers, NS, Blencowe, I, Boutron et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019 Aug 28;366:l4898. https://doi.org/10.1136/bmj.l4898.

      ], which consists of five domains for methodological evaluation: (a) randomization process; (b) deviations from intended interventions; (c) missing outcome data; (d) measurement of the outcome; and (e) selection of the reported result. The RCT was classified as low risk of bias (low risk of bias for all domains), high risk (high risk of bias for one or more domains), or some-concern risk (some-concern risk of bias for one or more key domains). Two researchers also independently assessed the quality of each observational study involved in this study by using the Newcastle–Ottawa Scale (NOS). The assessment process included reviewing the comparability, selection, and outcome of each study, then each research was assigned a total score beginning with zero until nine. Research is graded good if it scores ≥ 7.[
      • Margulis A.V.
      • Pladevall M.
      • Riera-Guardia N.
      • Varas-Lorenzo C.
      • Hazell L.
      • Berkman N.D.
      • et al.
      Quality assessment of observational studies in a drug-safety systematic review, comparison of two tools: the Newcastle-Ottawa Scale and the RTI item bank.
      ].

      2.5 Statistical analysis

      The dichotomous variable outcomes were reported as odds ratio (OR) along with its 95 % confidence interval (95 % CI) by using the Generic Inverse-Variance formula. Random-effect models were used if the heterogeneity of the analysis was found to be high or significant, besides that fixed effect models were used instead. Heterogeneity between studies was assessed using the I-squared (I2; Inconsistency) statistics. The I2 with a value of less than 25 % is considered as a low degree of heterogeneity, 26–50 % moderate degree of heterogeneity, and greater than 50 % considered a high degree of heterogeneity. I2 of at least 50 % is considered substantial heterogeneity; it means that at least half of the total variability among effect sizes is due to true heterogeneity between studies.[

      P, Sedgwick, Meta-analyses: what is heterogeneity? BMJ. 2015 Mar 16;350:h1435. https://doi.org/10.1136/bmj.h1435.

      ] meta-regression with a random-effects model was performed using a restricted-maximum likelihood for pre-specified variables including age, sex, hypertension, heart failure, diabetes duration, HbA1c levels, metformin use, and body mass index (BMI) to see the interaction effect between pre-admission SGLT-2i use and these variables in influencing the primary outcome. Assessment of publication bias through a funnel plot was considered if more than 10 studies were pooled in the meta-analysis. All analyses in this study were conducted using the Review Manager 5.4 software from Cochrane Collaboration and Comprehensive meta-Analysis 3 software.

      3. Results

      3.1 Study selection and characteristics

      Database searches identified 1,308 studies. After removing duplicates, reviewing the secondary reference lists from include papers and screening the tile/abstract, we assessed a total of 39 full-text articles based on the eligibility criteria. Of these 39 full-text articles, 22 articles were further excluded because they did not match our inclusion and exclusion criteria. Twelve articles were review articles, six articles did not have the specified outcome of interest, three articles did not have control group, and the remaining one article started SGLT-2i only at the time of Covid-19 diagnosis, thus resulting in the final number of 17 studies [
      • Elibol A.
      • Eren D.
      • Erdoğan M.D.
      • Elmaağaç M.
      • Dizdar O.S.
      • Çelik İ.
      • et al.
      Factors influencing on development of COVID-19 pneumonia and association with oral anti-diabetic drugs in hospitalized patients with diabetes mellitus.
      ,
      • Israelsen S.B.
      • Pottegård A.
      • Sandholdt H.
      • Madsbad S.
      • Thomsen R.W.
      • Benfield T.
      Comparable COVID-19 outcomes with current use of GLP-1 receptor agonists, DPP-4 inhibitors or SGLT-2 inhibitors among patients with diabetes who tested positive for SARS-CoV-2.
      ,
      • Kahkoska A.R.
      • Abrahamsen T.J.
      • Alexander G.C.
      • Bennett T.D.
      • Chute C.G.
      • Haendel M.A.
      • et al.
      N3C Consortium. Association Between Glucagon-Like Peptide 1 Receptor Agonist and Sodium-Glucose Cotransporter 2 Inhibitor Use and COVID-19 Outcomes.
      ,

      K, Khunti, P, Knighton, F, Zaccardi, C, Bakhai, E, Barron, N, Holman et al. Prescription of glucose-lowering therapies and risk of COVID-19 mortality in people with type 2 diabetes: a nationwide observational study in England. Lancet Diabetes Endocrinol. 2021 May;9(5):293-303. https://doi.org/10.1016/S2213-8587(21)00050-4.

      ,

      K, Khunti, Y, Ruan, J, Davies, Field BCT, Harris S, Kosiborod M, et al; ABCD COVID-19 Diabetes National Audit Investigators. Association Between SGLT2 Inhibitor Treatment and Diabetic Ketoacidosis and Mortality in People With Type 2 Diabetes Admitted to Hospital With COVID-19. Diabetes Care. 2022 Sep 8:dc220357. https://doi.org/10.2337/dc22-0357.

      ,
      • Kim M.K.
      • Jeon J.-H.
      • Kim S.-W.
      • Moon J.S.
      • Cho N.H.
      • Han E.
      • et al.
      The Clinical Characteristics and Outcomes of Patients with Moderate-to-Severe Coronavirus Disease 2019 Infection and Diabetes in Daegu.
      ,
      • Kosiborod M.N.
      • Esterline R.
      • Furtado R.H.M.
      • Oscarsson J.
      • Gasparyan S.B.
      • Koch G.G.
      • et al.
      Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trial.
      ,
      • Min J.
      • Simmons W.
      • Banerjee S.
      • Wang F.
      • Williams N.
      • Zhang Y.
      • et al.
      Association between antidiabetic drug use and the risk of COVID-19 hospitalization in the INSIGHT Clinical Research Network in New York City.
      ,
      • Nyland J.E.
      • Raja-Khan N.T.
      • Bettermann K.
      • Haouzi P.A.
      • Leslie D.L.
      • Kraschnewski J.L.
      • et al.
      Diabetes, Drug Treatment, and Mortality in COVID-19: a multinational retrospective cohort study.
      ,
      • Orioli L.
      • Servais T.
      • Belkhir L.
      • Laterre P.-F.
      • Thissen J.-P.
      • Vandeleene B.
      • et al.
      Clinical characteristics and short-term prognosis of in-patients with diabetes and COVID-19: a retrospective study from an academic center in Belgium.
      ,
      • Pérez-Belmonte L.M.
      • Torres-Peña J.D.
      • López-Carmona M.D.
      • Ayala-Gutiérrez M.M.
      • Fuentes-Jiménez F.
      • Huerta L.J.
      • et al.
      Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: a nationwide cohort study.
      ,

      JM, Ramos-Rincón, LM, Pérez-Belmonte, FJ, Carrasco-Sánchez, S, Jansen-Chaparro, M, De-Sousa-Baena, J, Bueno-Fonseca et al; SEMI-COVID-19 Network. Cardiometabolic Therapy and Mortality in Very Old Patients With Diabetes Hospitalized due to COVID-19. J Gerontol A Biol Sci Med Sci. 2021 Jul 13;76(8):e102-e109. https://doi.org/10.1093/gerona/glab124.

      ,
      • Shestakova M.V.
      • Vikulova O.K.
      • Elfimova A.R.
      • Deviatkin A.A.
      • Dedov I.I.
      • Mokrysheva N.G.
      Risk factors for COVID-19 case fatality rate in people with type 1 and type 2 diabetes mellitus: a nationwide retrospective cohort study of 235,248 patients in the Russian Federation.
      ,
      • Silverii G.A.
      • Monami M.
      • Cernigliaro A.
      • Vigneri E.
      • Guarnotta V.
      • Scondotto S.
      • et al.
      Are diabetes and its medications risk factors for the development of COVID-19? Data from a population-based study in Sicily.
      ,
      • Sourij H.
      • Aziz F.
      • Bräuer A.
      • Ciardi C.
      • Clodi M.
      • Fasching P.
      • et al.
      COVID-19 in diabetes in Austria study group. COVID-19 fatality prediction in people with diabetes and prediabetes using a simple score upon hospital admission.
      ,
      • Wander P.L.
      • Lowy E.
      • Beste L.A.
      • Tulloch-Palomino L.
      • Korpak A.
      • Peterson A.C.
      • et al.
      Prior Glucose-Lowering Medication Use and 30-Day Outcomes Among 64,892 Veterans With Diabetes and COVID-19.
      ,
      • Yeh H.-C.
      • Kraschnewski J.L.
      • Kong L.
      • Lehman E.B.
      • Heilbrunn E.S.
      • Williams P.
      • et al.
      Hospitalization and mortality in patients with COVID-19 with or at risk of type 2 diabetes: data from five health systems in Pennsylvania and Maryland.
      ] which included a total of 3,228,038 diabetes patients with Covid-19 for the analysis (Fig. 1). Sixteen out of seventeen included studies were retrospective cohorts, while the remaining one study was a double-blind RCT. Five studies came from the United States of America (USA), two studies came from England, two studies came from Spain, and one study each came from Denmark, Austria, Italy, Russia, Turkey, South Korea, Belgium, and multi-countries (USA, Canada, Brazil, Argentina, Mexico, UK, India), respectively. More than half of the included studies (9 out of 17) involved only participants with type 2 diabetes, while the rest did not specify which type of diabetes’ populations they include or include mixed diabetes types (type 1, type 2, prediabetes, or secondary diabetes). Mean diabetes duration in the included studies varied from 6.2 to 11.3 years. Almost all of the included studies involved patients with mild to severe Covid-19. A detailed overview of the study can be found in Table 2.
      Figure thumbnail gr1
      Fig. 1PRISMA diagram of the detailed process of selection of studies for inclusion in the systematic review and meta-analysis.
      Table 2Characteristics of included studies.
      StudyCountryDesignStudy’s time pointsSample sizeType of diabetesDM duration (years)Age

      (years)
      Male

      (%)
      HTN

      (%)
      HF

      (%)
      HbA1c

      (%)
      Metformin (%)BMI

      (kg/m2)
      Elibol A et al.
      • Elibol A.
      • Eren D.
      • Erdoğan M.D.
      • Elmaağaç M.
      • Dizdar O.S.
      • Çelik İ.
      • et al.
      Factors influencing on development of COVID-19 pneumonia and association with oral anti-diabetic drugs in hospitalized patients with diabetes mellitus.
      2021
      TurkeyCross-sectional1 March 2020 – 15 September 2020432Type 2 DM: 100 %6.2 ± 2.963.345.6 %74.1 %N/AN/A89.6 %N/A
      Israelsen SB et al.
      • Israelsen S.B.
      • Pottegård A.
      • Sandholdt H.
      • Madsbad S.
      • Thomsen R.W.
      • Benfield T.
      Comparable COVID-19 outcomes with current use of GLP-1 receptor agonists, DPP-4 inhibitors or SGLT-2 inhibitors among patients with diabetes who tested positive for SARS-CoV-2.
      2021
      DenmarkRetrospective cohortUp to 1 November 2020928Not specified10 ± 7.461.957.5 %N/A6.2 %N/A69.2 %N/A
      Kahkoska AR et al.
      • Kahkoska A.R.
      • Abrahamsen T.J.
      • Alexander G.C.
      • Bennett T.D.
      • Chute C.G.
      • Haendel M.A.
      • et al.
      N3C Consortium. Association Between Glucagon-Like Peptide 1 Receptor Agonist and Sodium-Glucose Cotransporter 2 Inhibitor Use and COVID-19 Outcomes.
      2021
      USARetrospective cohort1 January 2020 – February 202112,446Not specifiedN/A58.646.7 %75.9 %16.9 %8 %61.6 %35.4
      Khunti K et al.

      K, Khunti, P, Knighton, F, Zaccardi, C, Bakhai, E, Barron, N, Holman et al. Prescription of glucose-lowering therapies and risk of COVID-19 mortality in people with type 2 diabetes: a nationwide observational study in England. Lancet Diabetes Endocrinol. 2021 May;9(5):293-303. https://doi.org/10.1016/S2213-8587(21)00050-4.

      2021
      EnglandRetrospective cohort16 February 2020 – 31 August 20202,851,465Type 2 DM: 100 %11.3 ± 9.762.555.9 %76.7 %N/AN/A63.1 %N/A
      Khunti K et al.

      K, Khunti, Y, Ruan, J, Davies, Field BCT, Harris S, Kosiborod M, et al; ABCD COVID-19 Diabetes National Audit Investigators. Association Between SGLT2 Inhibitor Treatment and Diabetic Ketoacidosis and Mortality in People With Type 2 Diabetes Admitted to Hospital With COVID-19. Diabetes Care. 2022 Sep 8:dc220357. https://doi.org/10.2337/dc22-0357.

      2022
      EnglandRetrospective cohortMarch 2020 – 8 December 20203,067Type 2 DM: 100 %N/A72.762.2 %65.9 %N/A7.5 %N/A29.4
      Kim MK et al.
      • Kim M.K.
      • Jeon J.-H.
      • Kim S.-W.
      • Moon J.S.
      • Cho N.H.
      • Han E.
      • et al.
      The Clinical Characteristics and Outcomes of Patients with Moderate-to-Severe Coronavirus Disease 2019 Infection and Diabetes in Daegu.
      2020
      South KoreaRetrospective cohort18 February 2020 – 31 March 2020235Not specifiedN/A68.345.1 %62.6 %N/A7.7 %48.1 %23.6
      Kosiborod MN et al.
      • Kosiborod M.N.
      • Esterline R.
      • Furtado R.H.M.
      • Oscarsson J.
      • Gasparyan S.B.
      • Koch G.G.
      • et al.
      Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trial.
      2021
      Multiple countriesDouble-blind RCT22 April 2020 – 1 January 20211,250Type 2 DM: 50.9 %N/A61.457.4 %84.8 %7.2 %N/A12.6 %30.7
      Min JY et al.
      • Min J.
      • Simmons W.
      • Banerjee S.
      • Wang F.
      • Williams N.
      • Zhang Y.
      • et al.
      Association between antidiabetic drug use and the risk of COVID-19 hospitalization in the INSIGHT Clinical Research Network in New York City.
      2022
      USARetrospective cohort15 March 2020 – 15 June 202030,747Type 2 DM: 100 %N/A63.250 %68.8 %5 %7.8 %100 %31.3
      Nyland JE et al.
      • Nyland J.E.
      • Raja-Khan N.T.
      • Bettermann K.
      • Haouzi P.A.
      • Leslie D.L.
      • Kraschnewski J.L.
      • et al.
      Diabetes, Drug Treatment, and Mortality in COVID-19: a multinational retrospective cohort study.
      2021
      USARetrospective cohort1 January 2020 – 1 September 202029,516Type 2 DM: 100 %N/A60.948.2 %47.7 %11.9 %7.7 %N/A32.8
      Orioli L et al.
      • Orioli L.
      • Servais T.
      • Belkhir L.
      • Laterre P.-F.
      • Thissen J.-P.
      • Vandeleene B.
      • et al.
      Clinical characteristics and short-term prognosis of in-patients with diabetes and COVID-19: a retrospective study from an academic center in Belgium.
      2021
      BelgiumRetrospective cohort1 March 2020 – 6 May 202073Type 2 DM: 89 %

      Secondary: 4.1 %

      New: 6.9 %
      11.3 ± 9.66948 %80.8 %N/A7.3 %66.2 %30.5
      Perez-Belmonte LM et al.
      • Pérez-Belmonte L.M.
      • Torres-Peña J.D.
      • López-Carmona M.D.
      • Ayala-Gutiérrez M.M.
      • Fuentes-Jiménez F.
      • Huerta L.J.
      • et al.
      Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: a nationwide cohort study.
      2020
      SpainRetrospective cohort1 March 2020 – 19 July 20202,666Type 2 DM: 100 %N/A74.961.9 %76.2 %16.7 %N/A60.8 %N/A
      Ramos-Rincon JM et al.

      JM, Ramos-Rincón, LM, Pérez-Belmonte, FJ, Carrasco-Sánchez, S, Jansen-Chaparro, M, De-Sousa-Baena, J, Bueno-Fonseca et al; SEMI-COVID-19 Network. Cardiometabolic Therapy and Mortality in Very Old Patients With Diabetes Hospitalized due to COVID-19. J Gerontol A Biol Sci Med Sci. 2021 Jul 13;76(8):e102-e109. https://doi.org/10.1093/gerona/glab124.

      2021
      SpainRetrospective cohort1 March 2020 – 29 May 2020790Type 2 DM: 100 %N/A85.847.5 %93.9 %22.2 %N/A59.2 %N/A
      Shestakova MV et al.
      • Shestakova M.V.
      • Vikulova O.K.
      • Elfimova A.R.
      • Deviatkin A.A.
      • Dedov I.I.
      • Mokrysheva N.G.
      Risk factors for COVID-19 case fatality rate in people with type 1 and type 2 diabetes mellitus: a nationwide retrospective cohort study of 235,248 patients in the Russian Federation.
      2022
      RussiaRetrospective cohort20 March 2020 – 25 November 2021224,190Type 2 DM: 100 %7.4 ± 7.265.931.4 %N/AN/A7.3 %71.8 %32.1
      Silverii GA et al.
      • Silverii G.A.
      • Monami M.
      • Cernigliaro A.
      • Vigneri E.
      • Guarnotta V.
      • Scondotto S.
      • et al.
      Are diabetes and its medications risk factors for the development of COVID-19? Data from a population-based study in Sicily.
      2021
      ItalyRetrospective cohortUp to 14 May 2020159Not specifiedN/A73.354.1 %N/AN/AN/A47.8 %N/A
      Sourij H et al.
      • Sourij H.
      • Aziz F.
      • Bräuer A.
      • Ciardi C.
      • Clodi M.
      • Fasching P.
      • et al.
      COVID-19 in diabetes in Austria study group. COVID-19 fatality prediction in people with diabetes and prediabetes using a simple score upon hospital admission.
      2020
      AustriaRetrospective cohort15 April 2020 – 30 June 2020238Type 1 DM: 4.6 %

      Type 2 DM: 75.6 %

      Prediabetes: 19.8 %
      N/A71.163.9 %71 %12.6 %6.4 %32.3 %29.1
      Wander PL et al.
      • Wander P.L.
      • Lowy E.
      • Beste L.A.
      • Tulloch-Palomino L.
      • Korpak A.
      • Peterson A.C.
      • et al.
      Prior Glucose-Lowering Medication Use and 30-Day Outcomes Among 64,892 Veterans With Diabetes and COVID-19.
      2021
      USARetrospective cohort1 March 2020 – 10 March 202164,892Not specifiedN/A67.794 %89 %19 %7.8 %46 %32.8
      Yeh HC et al.
      • Yeh H.-C.
      • Kraschnewski J.L.
      • Kong L.
      • Lehman E.B.
      • Heilbrunn E.S.
      • Williams P.
      • et al.
      Hospitalization and mortality in patients with COVID-19 with or at risk of type 2 diabetes: data from five health systems in Pennsylvania and Maryland.
      2022
      USARetrospective cohort1 March 2020 – 28 February 20214,944Type 2 DM: 100 %N/A62.346.2 %N/A24.3 %7.6 %42.3 %34.2
      Covid-19 = coronavirus disease 2019; DM = diabetes mellitus; HbA1c = hemoglobin A1c; HF = heart failure; HTN = hypertension; N/A = not available; RCT = randomized clinical trial; USA = United States of America.

      3.2 Quality of study assessment

      Based on the assessment using RoB v2 tool, the only one included clinical trial study was graded as having low risk of bias in all five domains of assessment (randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported results). Meanwhile, all of the cohort studies included in this review were all having good quality according to NOS assessment scale (Table 3). All studies were deemed fit to be included in the meta-analysis.
      Table 3Newcastle-Ottawa quality assessment of observational studies.
      First author, yearStudy designSelection
      (1) representativeness of the exposed cohort; (2) selection of the non-exposed cohort; (3) ascertainment of exposure; (4) demonstration that outcome of interest was not present at start of study.
      Comparability
      (1) comparability of cohorts on the basis of design or analysis, (maximum two stars).
      Outcome
      (1) assessment of outcome; (2) was follow-up long enough for outcomes to occur; (3) adequacy of follow up of cohorts.
      Total scoreResult
      Elibol A et al.
      • Elibol A.
      • Eren D.
      • Erdoğan M.D.
      • Elmaağaç M.
      • Dizdar O.S.
      • Çelik İ.
      • et al.
      Factors influencing on development of COVID-19 pneumonia and association with oral anti-diabetic drugs in hospitalized patients with diabetes mellitus.
      2021
      Cross-sectional*******7Good
      Israelsen SB et al.
      • Israelsen S.B.
      • Pottegård A.
      • Sandholdt H.
      • Madsbad S.
      • Thomsen R.W.
      • Benfield T.
      Comparable COVID-19 outcomes with current use of GLP-1 receptor agonists, DPP-4 inhibitors or SGLT-2 inhibitors among patients with diabetes who tested positive for SARS-CoV-2.
      2021
      Cohort********8Good
      Kahkoska AR et al.
      • Kahkoska A.R.
      • Abrahamsen T.J.
      • Alexander G.C.
      • Bennett T.D.
      • Chute C.G.
      • Haendel M.A.
      • et al.
      N3C Consortium. Association Between Glucagon-Like Peptide 1 Receptor Agonist and Sodium-Glucose Cotransporter 2 Inhibitor Use and COVID-19 Outcomes.
      2021
      Cohort********8Good
      Khunti K et al.

      K, Khunti, P, Knighton, F, Zaccardi, C, Bakhai, E, Barron, N, Holman et al. Prescription of glucose-lowering therapies and risk of COVID-19 mortality in people with type 2 diabetes: a nationwide observational study in England. Lancet Diabetes Endocrinol. 2021 May;9(5):293-303. https://doi.org/10.1016/S2213-8587(21)00050-4.

      2021
      Cohort********8Good
      Khunti K et al.

      K, Khunti, Y, Ruan, J, Davies, Field BCT, Harris S, Kosiborod M, et al; ABCD COVID-19 Diabetes National Audit Investigators. Association Between SGLT2 Inhibitor Treatment and Diabetic Ketoacidosis and Mortality in People With Type 2 Diabetes Admitted to Hospital With COVID-19. Diabetes Care. 2022 Sep 8:dc220357. https://doi.org/10.2337/dc22-0357.

      2022
      Cohort********8Good
      Kim MK et al.
      • Kim M.K.
      • Jeon J.-H.
      • Kim S.-W.
      • Moon J.S.
      • Cho N.H.
      • Han E.
      • et al.
      The Clinical Characteristics and Outcomes of Patients with Moderate-to-Severe Coronavirus Disease 2019 Infection and Diabetes in Daegu.
      2020
      Cohort********8Good
      Min JY et al.
      • Min J.
      • Simmons W.
      • Banerjee S.
      • Wang F.
      • Williams N.
      • Zhang Y.
      • et al.
      Association between antidiabetic drug use and the risk of COVID-19 hospitalization in the INSIGHT Clinical Research Network in New York City.
      2022
      Cohort********8Good
      Nyland JE et al.
      • Nyland J.E.
      • Raja-Khan N.T.
      • Bettermann K.
      • Haouzi P.A.
      • Leslie D.L.
      • Kraschnewski J.L.
      • et al.
      Diabetes, Drug Treatment, and Mortality in COVID-19: a multinational retrospective cohort study.
      2021
      Cohort********8Good
      Orioli L et al.
      • Orioli L.
      • Servais T.
      • Belkhir L.
      • Laterre P.-F.
      • Thissen J.-P.
      • Vandeleene B.
      • et al.
      Clinical characteristics and short-term prognosis of in-patients with diabetes and COVID-19: a retrospective study from an academic center in Belgium.
      2021
      Cohort*******7Good
      Perez-Belmonte LM et al.
      • Pérez-Belmonte L.M.
      • Torres-Peña J.D.
      • López-Carmona M.D.
      • Ayala-Gutiérrez M.M.
      • Fuentes-Jiménez F.
      • Huerta L.J.
      • et al.
      Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: a nationwide cohort study.
      2020
      Cohort********8Good
      Ramos-Rincon JM et al.

      JM, Ramos-Rincón, LM, Pérez-Belmonte, FJ, Carrasco-Sánchez, S, Jansen-Chaparro, M, De-Sousa-Baena, J, Bueno-Fonseca et al; SEMI-COVID-19 Network. Cardiometabolic Therapy and Mortality in Very Old Patients With Diabetes Hospitalized due to COVID-19. J Gerontol A Biol Sci Med Sci. 2021 Jul 13;76(8):e102-e109. https://doi.org/10.1093/gerona/glab124.

      2021
      Cohort********8Good
      Shestakova MV et al.
      • Shestakova M.V.
      • Vikulova O.K.
      • Elfimova A.R.
      • Deviatkin A.A.
      • Dedov I.I.
      • Mokrysheva N.G.
      Risk factors for COVID-19 case fatality rate in people with type 1 and type 2 diabetes mellitus: a nationwide retrospective cohort study of 235,248 patients in the Russian Federation.
      2022
      Cohort********8Good
      Silverii GA et al.
      • Silverii G.A.
      • Monami M.
      • Cernigliaro A.
      • Vigneri E.
      • Guarnotta V.
      • Scondotto S.
      • et al.
      Are diabetes and its medications risk factors for the development of COVID-19? Data from a population-based study in Sicily.
      2021
      Cohort*******7Good
      Sourij H et al.
      • Sourij H.
      • Aziz F.
      • Bräuer A.
      • Ciardi C.
      • Clodi M.
      • Fasching P.
      • et al.
      COVID-19 in diabetes in Austria study group. COVID-19 fatality prediction in people with diabetes and prediabetes using a simple score upon hospital admission.
      2020
      Cohort********8Good
      Wander PL et al.
      • Wander P.L.
      • Lowy E.
      • Beste L.A.
      • Tulloch-Palomino L.
      • Korpak A.
      • Peterson A.C.
      • et al.
      Prior Glucose-Lowering Medication Use and 30-Day Outcomes Among 64,892 Veterans With Diabetes and COVID-19.
      2021
      Cohort*******7Good
      Yeh HC et al.
      • Yeh H.-C.
      • Kraschnewski J.L.
      • Kong L.
      • Lehman E.B.
      • Heilbrunn E.S.
      • Williams P.
      • et al.
      Hospitalization and mortality in patients with COVID-19 with or at risk of type 2 diabetes: data from five health systems in Pennsylvania and Maryland.
      2022
      Cohort********8Good
      a (1) representativeness of the exposed cohort; (2) selection of the non-exposed cohort; (3) ascertainment of exposure; (4) demonstration that outcome of interest was not present at start of study.
      b (1) comparability of cohorts on the basis of design or analysis, (maximum two stars).
      c (1) assessment of outcome; (2) was follow-up long enough for outcomes to occur; (3) adequacy of follow up of cohorts.

      3.3 Mortality from Covid-19

      All included studies reported the mortality from Covid-19 outcome. Our pooled analysis revealed that pre-admission use of SGLT-2i in patients with diabetes was associated with lower mortality from Covid-19 when compared to those who did not use SGLT-2i as their glucose lowering treatment (OR 0.69; 95 %CI: 0.56 – 0.87, p = 0.001, I2 = 91 %, random-effect model) (Fig. 2A).
      Figure thumbnail gr2
      Fig. 2Forest plot that demonstrates the association between pre-admission use of SGLT-2i with Covid-19 mortality (A), Covid-19 severity (B), and diabetic ketoacidosis risk (C) in patients with diabetes.

      3.4 Severe Covid-19

      Six studies reported the severe Covid-19 outcome. From our meta-analysis, it was revealed that among those who have diabetes and Covid-19 diagnosis, the risk of severe Covid-19 was lowered in the SGLT-2i group compared with no SGLT-2i group (OR 0.88; 95 %CI: 0.80 – 0.97, p = 0.008, I2 = 13 %, fixed-effect model) (Fig. 2B).

      3.5 Diabetic ketoacidosis (DKA)

      Three studies reported the diabetic ketoacidosis (DKA) outcome. From our meta-analysis, it was revealed that among those who have diabetes and Covid-19 diagnosis, the risk of developing diabetic ketoacidosis (DKA) did not differ significantly between SGLT-2i group with no SGLT-2i group (OR 1.08; 95 %CI: 0.60 – 1.97, p = 0.79, I2 = 0 %, fixed-effect model) (Fig. 2C).

      3.6 meta-Regression

      Identification of risk factors that influence the relationship between pre-admission SGLT-2i use and primary outcome (mortality from Covid-19) was done with meta-regression. Our meta-regression revealed that variability in that outcome in diabetes patients with Covid-19 using SGLT-2i cannot be explained by known patient’s factors associated with predictors of treatment outcomes (Table 4). From our meta-regression analysis, it was revealed that mortality from Covid-19 in diabetes patients was not significantly influenced by age (p = 0.2335) (Supplementary Fig. 1A), sex (p = 0.2742) (Supplementary Fig. 1B), hypertension (p = 0.2165) (Supplementary Fig. 1C), heart failure (p = 0.1616) (Supplementary Fig. 1D), HbA1c levels (p = 0.4924) (Supplementary Fig. 1E), metformin use (p = 0.6617) (Supplementary Fig. 1F), diabetes duration (p = 0.7233) (Supplementary Fig. 1G), nor BMI (p = 0.1797) (Supplementary Fig. 1H).
      Table 4Results for the meta-regression models for mortality from Covid-19 outcome.
      Mortality from Covid-19
      CovariateCoefficient95 % CI (min)95 % CI (max)S.E.p-value
      Age0.0181−0.01170.04790.01520.2335
      Sex0.0060−0.00480.01680.00550.2742
      Hypertension0.0098−0.00570.02520.00790.2165
      Heart Failure0.0208−0.00830.04980.01480.1616
      HbA1c0.2678−0.49681.03250.39010.4924
      Metformin use−0.0021−0.01150.00730.00480.6617
      Diabetes duration−0.0517−0.33770.23440.14600.7233
      BMI−0.0719−0.17690.03310.05360.1797

      3.7 Publication bias

      We used Funnel plot analysis for the publication bias assessment. This analysis showed a relatively symmetrical inverted plot for mortality from Covid-19 (Fig. 3), indicating no publication bias. Quantitative assessment of publication bias using both Begg’s rank correlation test (p = 0.4338) and Egger’s regression method (p = 0.1374) did not show any significant results, confirming the result from funnel plot analysis that no indication of publication bias was found. Meanwhile, the assessment of publication bias for severe Covid-19 and diabetic ketoacidosis (DKA) outcomes were not performed because there were fewer than 10 studies included in this outcome where publication bias detection is not much reliable.[
      • Thornton A.
      • Lee P.
      Publication bias in meta-analysis: its causes and consequences.
      ,
      • Terrin N.
      • Schmid C.H.
      • Lau J.
      • Olkin I.
      Adjusting for publication bias in the presence of heterogeneity.
      ].
      Figure thumbnail gr3
      Fig. 3Relatively symmetrical inverted plot for the association between SGLT-2i use and Covid-19 mortality which indicates no publication bias.

      4. Discussion

      Our meta-analysis which is based on 17 studies has showed that SGLT-2i utilization as pre-admission glucose lowering treatment in diabetes patients with Covid-19 may significantly reduce the mortality and severity from Covid-19. SGLT-2i is also relatively safe to be used during Covid-19 because it does not increase the risk of developing diabetic ketoacidosis (DKA). Further regression analysis has also showed that the beneficial effect of SGLT-2i towards Covid-19 mortality is produced independently, not significantly affected by age, sex, hypertension, heart failure, HbA1c levels, metformin use, diabetes duration, and BMI.
      There are several possible mechanisms which underlie beneficial effects from SGLT-2i in Covid-19. Covid-19 infection caused by SARS-CoV-2 can make anaerobic environment by impairing tissue oxygenation and increasing the production of lactate by anaerobic glycolysis.[
      • Das L.
      • Dutta P.
      SGLT2 inhibition and COVID-19: The road not taken.
      ,
      • Cure E.
      • Cumhur Cure M.
      Can dapagliflozin have a protective effect against COVID-19 infection? a hypothesis.
      ] These lactates are then entered the cells together with H+ through lactate/H+ symporter.[
      • Das L.
      • Dutta P.
      SGLT2 inhibition and COVID-19: The road not taken.
      ,
      • Cure E.
      • Cumhur Cure M.
      Can dapagliflozin have a protective effect against COVID-19 infection? a hypothesis.
      ] The increase in H+ concentration within the cells will activate natrium/hydrogen (Na+/H+) exchanger (NHE) where H+ will be pumped out of the cells while Na+ will enter the cells.[
      • Das L.
      • Dutta P.
      SGLT2 inhibition and COVID-19: The road not taken.
      ,
      • Cure E.
      • Cumhur Cure M.
      Can dapagliflozin have a protective effect against COVID-19 infection? a hypothesis.
      ] The intracellular accumulation of natrium will cause cellular edema and necrosis which subsequently increase the oxidative stress and pro-inflammatory cytokines.[
      • Das L.
      • Dutta P.
      SGLT2 inhibition and COVID-19: The road not taken.
      ,
      • Cure E.
      • Cumhur Cure M.
      Can dapagliflozin have a protective effect against COVID-19 infection? a hypothesis.
      ] Dapagliflozin, one of the drugs which belong to SGLT-2i may reduce lactate concentration through several mechanisms. Dapagliflozin can reduce the oxygen consumption in adipose tissue and increase glucose utility in aerobic pathway, thus the lactate release from epicardial adipose tissue will be decreased.[
      • Das L.
      • Dutta P.
      SGLT2 inhibition and COVID-19: The road not taken.
      ,
      • Cure E.
      • Cumhur Cure M.
      Can dapagliflozin have a protective effect against COVID-19 infection? a hypothesis.
      ,
      • Scheen A.J.
      SGLT2 inhibition during the COVID-19 epidemic: Friend or foe?.
      ] Dapagliflozin can also increase the urinary excretion of lactate.[
      • Das L.
      • Dutta P.
      SGLT2 inhibition and COVID-19: The road not taken.
      ,
      • Cure E.
      • Cumhur Cure M.
      Can dapagliflozin have a protective effect against COVID-19 infection? a hypothesis.
      ,
      • Scheen A.J.
      SGLT2 inhibition during the COVID-19 epidemic: Friend or foe?.
      ] Reduction in lactate concentration will cause decreased activity of lactate/H+ symporter and intracellular pH can be maintained.[
      • Das L.
      • Dutta P.
      SGLT2 inhibition and COVID-19: The road not taken.
      ,
      • Cure E.
      • Cumhur Cure M.
      Can dapagliflozin have a protective effect against COVID-19 infection? a hypothesis.
      ,
      • Scheen A.J.
      SGLT2 inhibition during the COVID-19 epidemic: Friend or foe?.
      ] Not only that, dapagliflozin may also inhibit Na+/H+ exchanger (NHE) directly, so that natrium accumulation and cell deaths can be prevented.[
      • Das L.
      • Dutta P.
      SGLT2 inhibition and COVID-19: The road not taken.
      ,
      • Cure E.
      • Cumhur Cure M.
      Can dapagliflozin have a protective effect against COVID-19 infection? a hypothesis.
      ,
      • Scheen A.J.
      SGLT2 inhibition during the COVID-19 epidemic: Friend or foe?.
      ].
      SGLT-2i can also exert anti-inflammatory effects, both on systemic and peripheral tissue. One of these anti-inflammatory properties is achieved through reduction in adipose-tissue inflammation which is characterized by weight loss.[
      • Couselo-Seijas M.
      • Agra-Bermejo R.M.
      • Fernández A.L.
      • Martínez-Cereijo J.M.
      • Sierra J.
      • Soto-Pérez M.
      • et al.
      High released lactate by epicardial fat from coronary artery disease patients is reduced by dapagliflozin treatment.
      ] SGLT-2i will promote increased fat utilization, reduce obesity-induced inflammation, and reduce insulin resistance through activation of M2 macrophages.[
      • Cure E.
      • Cumhur Cure M.
      Can dapagliflozin have a protective effect against COVID-19 infection? a hypothesis.
      ,
      • Lytvyn Y.
      • Bjornstad P.
      • Udell J.A.
      • Lovshin J.A.
      • Cherney D.Z.I.
      Sodium Glucose Cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials.
      ] Adipose tissue itself plays an important role in the pathogenesis of cytokine storm in Covid-19. meta-analysis studies have shown that adipose tissue and obesity are closely related to mortality rates from Covid-19.[

      L, Yu, X, Zhang, S, Ye, H, Lian, H, Wang, J, Ye Obesity and COVID-19: Mechanistic Insights From Adipose Tissue. J Clin Endocrinol Metab. 2022 Jun 16;107(7):1799-1811. https://doi.org/10.1210/clinem/dgac137.

      ,
      • Cai Z.
      • Yang Y.
      • Zhang J.
      Obesity is associated with severe disease and mortality in patients with coronavirus disease 2019 (COVID-19): a meta-analysis.
      ,
      • Siahaan Y.M.T.
      • Hartoyo V.
      • Hariyanto T.I.
      • Kurniawan A.
      Coronavirus disease 2019 (Covid-19) outcomes in patients with sarcopenia: a meta-analysis and meta-regression.
      ] Therefore, inhibition of inflammation in adipose tissue via SGLT-2i can reduce the risk of cytokine storm and reduce the mortality from Covid-19.[
      • Cure E.
      • Cumhur Cure M.
      Can dapagliflozin have a protective effect against COVID-19 infection? a hypothesis.
      ,
      • Lytvyn Y.
      • Bjornstad P.
      • Udell J.A.
      • Lovshin J.A.
      • Cherney D.Z.I.
      Sodium Glucose Cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials.
      ] In addition, SGLT-2i is able to reduce the inflammatory response directly by inhibiting several pro-inflammatory cytokines such as IL-6 and TNF-alpha.[
      • Theofilis P.
      • Sagris M.
      • Oikonomou E.
      • Antonopoulos A.S.
      • Siasos G.
      • Tsioufis K.
      • et al.
      The impact of SGLT2 inhibitors on inflammation: A systematic review and meta-analysis of studies in rodents.
      ] These cytokines are closely related to high mortality from Covid-19, so reduction in the number of pro-inflammatory cytokines by SGLT-2i will be able to prevent their deleterious effects.[
      • Cure E.
      • Cumhur Cure M.
      Can dapagliflozin have a protective effect against COVID-19 infection? a hypothesis.
      ,
      • Lytvyn Y.
      • Bjornstad P.
      • Udell J.A.
      • Lovshin J.A.
      • Cherney D.Z.I.
      Sodium Glucose Cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials.
      ,
      • Del Valle D.M.
      • Kim-Schulze S.
      • Huang H.-H.
      • Beckmann N.D.
      • Nirenberg S.
      • Wang B.o.
      • et al.
      An inflammatory cytokine signature predicts COVID-19 severity and survival.
      ].
      Finally, literatures have showed that angiotensin converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 can be found in most organs, including the heart and kidneys.[
      • Hariyanto T.I.
      • Japar K.V.
      • Damay V.
      • Kwenandar F.
      • Sieto N.L.
      • Kurniawan A.
      The use of ACE inhibitor/ARB in SARS-CoV-2 patients: a comprehensive narrative review.
      ] This virus can cause damage to endothelial blood vessels and cardiomyocytes which is characterized by manifestations of myocardial infarction (increased cardiac troponin), myocarditis, and heart failure that will increase patient’s mortality.[
      • Hariyanto T.I.
      • Japar K.V.
      • Damay V.
      • Kwenandar F.
      • Sieto N.L.
      • Kurniawan A.
      The use of ACE inhibitor/ARB in SARS-CoV-2 patients: a comprehensive narrative review.
      ,
      • Kwenandar F.
      • Japar K.V.
      • Damay V.
      • Hariyanto T.I.
      • Tanaka M.
      • Lugito N.P.H.
      • et al.
      Coronavirus disease 2019 and cardiovascular system: a narrative review.
      ] In addition, this virus is also capable of causing AKI manifestations due to damage to the endothelium and tubulointerstitial which often lead to death.[
      • Legrand M.
      • Bell S.
      • Forni L.
      • Joannidis M.
      • Koyner J.L.
      • Liu K.
      • et al.
      Pathophysiology of COVID-19-associated acute kidney injury.
      ] SGLT-2i has protective effects on organs, especially the heart and kidneys.[
      • Fernandez-Fernandez B.
      • D’Marco L.
      • Górriz J.L.
      • Jacobs-Cachá C.
      • Kanbay M.
      • Luis-Lima S.
      • et al.
      Exploring Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors for Organ Protection in COVID-19.
      ] In the cardiovascular system, SGLT-2i is able to reduce preload and afterload through loss of interstitial volume, improve bioenergetic cardiomyocytes by increasing lipolysis so that more ketone bodies can be used as efficient energy substrates, increase hematocrit through increased erythropoietin, and decrease blood pressure and body weights.[
      • Das L.
      • Dutta P.
      SGLT2 inhibition and COVID-19: The road not taken.
      ,
      • Fernandez-Fernandez B.
      • D’Marco L.
      • Górriz J.L.
      • Jacobs-Cachá C.
      • Kanbay M.
      • Luis-Lima S.
      • et al.
      Exploring Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors for Organ Protection in COVID-19.
      ] Within the kidney, SGLT-2i is able to restore tubuloglomerular feedback by increasing sodium delivery to the macula densa, resulting in afferent arteriolar vasoconstriction and reduction in albuminuria.[
      • Das L.
      • Dutta P.
      SGLT2 inhibition and COVID-19: The road not taken.
      ,
      • Fernandez-Fernandez B.
      • D’Marco L.
      • Górriz J.L.
      • Jacobs-Cachá C.
      • Kanbay M.
      • Luis-Lima S.
      • et al.
      Exploring Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors for Organ Protection in COVID-19.
      ] All of these good effects on the organs from SGLT-2i will be able to reduce the risk of death from Covid-19.
      In our knowledge, this is the first systematic review and meta-analysis study which analyze comprehensively about SGLT-2i use in diabetes patients with Covid-19. Previous meta-analysis study was not done specifically to assess SGLT-2i in diabetes patients with Covid-19, but analyze the role of anti-diabetic agents in general.[
      • Han T.
      • Ma S.
      • Sun C.
      • Zhang H.
      • Qu G.
      • Chen Y.
      • et al.
      Association between anti-diabetic agents and clinical outcomes of COVID-19 in patients with diabetes: a systematic review and meta-analysis.
      ] This previous meta-analysis only include 3 studies on SGLT-2i and showed that SGLT-2i use cannot improve mortality from Covid-19 in patients with diabetes.[
      • Han T.
      • Ma S.
      • Sun C.
      • Zhang H.
      • Qu G.
      • Chen Y.
      • et al.
      Association between anti-diabetic agents and clinical outcomes of COVID-19 in patients with diabetes: a systematic review and meta-analysis.
      ] In contrast, our meta-analysis based on 17 studies shows that pre-admission use of SGLT-2i can significantly reduce mortality and severity of Covid-19 in patients with diabetes. Furthermore, our study is also equipped with a meta-regression analysis to see whether the relationship between SGLT-2i and Covid-19 outcomes is influenced by confounding factors such as age, sex, comorbid, and glycemic status.
      Our study is not without any limitations. The results of our study are mostly based on observational studies which can be influenced by selection bias and information bias, due to the limitations of the available clinical trials. The outcome of interest in our study also had a relatively high heterogeneity which may be caused by differences in the duration of follow-up, differences in duration of diabetes, and differences in glycemic status of the patients. Information regarding the dose of SGLT-2i, patients’ financial and social status, and patients’ access to medical care in each study is limited so that no further analysis is possible. Data regarding ethnicities were also too varied within the included studies which prevent further analysis on this matter. Finally, all of the included studies in this review were performed during the year of 2020 where the original SARS-CoV-2 (Wuhan variant) has still dominated and become variant of concern (VOC), therefore our analysis results should be interpreted cautiously and may not be applied to other SARS-CoV-2 variants (such as Delta variant which has higher severity or Omicron variant which has lower severity than Wuhan variant). Further studies during predominantly Delta variant or Omicron variant are still needed to confirm the benefit of preadmission SGLT-2i use for SARS-CoV-2 other than Wuhan variant. Nevertheless, we still believe that the results from our systematic review and meta-analysis can give further insight into the management of diabetes during Covid-19.

      5. Conclusion

      Our systematic review and meta-analysis showed that preadmission use of SGLT-2i as glucose lowering treatment in diabetic patients may reduce mortality and severity of Covid-19, but without increased risk of developing diabetic ketoacidosis (DKA). The advantages of SGLT-2i are also not influenced by patient's factors such as age, sex, and comorbid conditions. However, other confounding factors which cannot be addressed in our current study such as patients’ financial status, social status, and access to health care should still be considered when interpreting the results of our study regarding the benefit of SGLT-2i for Covid-19. More randomized clinical trials are still needed to confirm the results of our study.

      CRediT authorship contribution statement

      Hikmat Permana: Conceptualization, Methodology, Data curation, Writing – original draft, Project administration. Theo Audi Yanto: Conceptualization, Methodology, Writing – review & editing. Timotius Ivan Hariyanto: Investigation, Methodology, Writing – review & editing, Supervision.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgments

      None.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Appendix A. Supplementary material

      The following are the Supplementary data to this article:

      References

        • Wiersinga W.J.
        • Rhodes A.
        • Cheng A.C.
        • Peacock S.J.
        • Prescott H.C.
        Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review.
        JAMA. 2020 Aug 25; 324: 782-793https://doi.org/10.1001/jama.2020.12839
      1. World Health Organization. Coronavirus disease (COVID-19): situation report. Accessed October 24, 2022. https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---19-october-2022.

      2. Hariyanto TI, Putri C, Hananto JE, Arisa J, Fransisca V Situmeang R, Kurniawan A. Delirium is a good predictor for poor outcomes from coronavirus disease 2019 (COVID-19) pneumonia: A systematic review, meta-analysis, and meta-regression. J Psychiatr Res. 2021 Oct;142:361-368. https://doi.org/10.1016/j.jpsychires.2021.08.031.

        • Kwenandar F.
        • Japar K.V.
        • Damay V.
        • Hariyanto T.I.
        • Tanaka M.
        • Lugito N.P.H.
        • et al.
        Coronavirus disease 2019 and cardiovascular system: a narrative review.
        Int J Cardiol Heart Vasc. 2020; 29: 100557
        • Bailly L.
        • Fabre R.
        • Courjon J.
        • Carles M.
        • Dellamonica J.
        • Pradier C.
        Obesity, diabetes, hypertension and severe outcomes among inpatients with coronavirus disease 2019: a nationwide study.
        Clin Microbiol Infect. 2022 Jan; 28: 114-123https://doi.org/10.1016/j.cmi.2021.09.010
        • Hariyanto T.I.
        • Kurniawan A.
        Obstructive sleep apnea (OSA) and outcomes from coronavirus disease 2019 (COVID-19) pneumonia: a systematic review and meta-analysis.
        Sleep Med. 2021 Jun; 82: 47-53https://doi.org/10.1016/j.sleep.2021.03.029
        • Putri C.
        • Hariyanto T.I.
        • Hananto J.E.
        • Christian K.
        • Situmeang R.F.V.
        • Kurniawan A.
        Parkinson's disease may worsen outcomes from coronavirus disease 2019 (COVID-19) pneumonia in hospitalized patients: a systematic review, meta-analysis, and meta-regression.
        Parkinsonism Relat Disord. 2021 Jun; 87: 155-161https://doi.org/10.1016/j.parkreldis.2021.04.019
        • Zhou B.
        • Lu Y.
        • Hajifathalian K.
        • Bentham J.
        • Di Cesare M.
        • Danaei G.
        • et al.
        Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4·4 million participants.
        Lancet. 2016; 387: 1513-1530
        • Saeedi P.
        • Petersohn I.
        • Salpea P.
        • Malanda B.
        • Karuranga S.
        • Unwin N.
        • et al.
        Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition.
        Diabetes Res Clin Pract. 2019; 157: 107843s
        • Rajpal A.
        • Rahimi L.
        • Ismail-Beigi F.
        Factors leading to high morbidity and mortality of COVID-19 in patients with type 2 diabetes.
        J Diabetes. 2020 Dec; 12: 895-908https://doi.org/10.1111/1753-0407.13085
      3. I, Pinedo-Torres, M, Flores-Fernández, M, Yovera-Aldana, M, Gutierrez-Ortiz C, Zegarra-Lizana P, Intimayta-Escalante C, et al. Prevalence of Diabetes Mellitus and Its Associated Unfavorable Outcomes in Patients With Acute Respiratory Syndromes Due to Coronaviruses Infection: A Systematic Review and Meta-Analysis. Clin Med Insights Endocrinol Diabetes. 2020 Oct 19;13:1179551420962495. https://doi.org/10.1177/1179551420962495.

        • Kastora S.
        • Patel M.
        • Carter B.
        • Delibegovic M.
        • Myint P.K.
        Impact of diabetes on COVID-19 mortality and hospital outcomes from a global perspective: an umbrella systematic review and meta-analysis.
        Endocrinol Diabetes Metab. 2022 May; 5: e00338
        • Khunti K.
        • Del Prato S.
        • Mathieu C.
        • Kahn S.E.
        • Gabbay R.A.
        • Buse J.B.
        COVID-19, Hyperglycemia, and New-Onset Diabetes.
        Diabetes Care. 2021 Dec; 44: 2645-2655https://doi.org/10.2337/dc21-1318
        • Hariyanto T.I.
        • Kurniawan A.
        Metformin use is associated with reduced mortality rate from coronavirus disease 2019 (COVID-19) infection.
        Obes Med. 2020 Sep; 19100290https://doi.org/10.1016/j.obmed.2020.100290
        • Yang Y.
        • Cai Z.
        • Zhang J.
        • Ashraf G.M.
        DPP-4 inhibitors may improve the mortality of coronavirus disease 2019: A meta-analysis.
        PLoS One. 2021 May 20; 16: e0251916
        • Hariyanto T.I.
        • Intan D.
        • Hananto J.E.
        • Putri C.
        • Kurniawan A.
        Pre-admission glucagon-like peptide-1 receptor agonist (GLP-1RA) and mortality from coronavirus disease 2019 (Covid-19): A systematic review, meta-analysis, and meta-regression.
        Diabetes Res Clin Pract. 2021 Sep; 179109031https://doi.org/10.1016/j.diabres.2021.109031
        • Hariyanto T.I.
        • Lugito N.P.H.
        • Yanto T.A.
        • Siregar J.I.
        • Kurniawan A.
        Insulin Therapy and Outcome of Coronavirus Disease 2019 (COVID-19): a systematic review, meta-analysis, and meta-regression.
        Endocr Metab Immune Disord Drug Targets. 2022; 22: 481-489https://doi.org/10.2174/1871530321666210709164925
        • van der Aart-van der Beek A.B.
        • de Boer R.A.
        • Heerspink H.J.L.
        Kidney and heart failure outcomes associated with SGLT2 inhibitor use.
        Nat Rev Nephrol. 2022; 18: 294-306
        • Stroup D.F.
        • Berlin J.A.
        • Morton S.C.
        • Olkin I.
        • Williamson G.D.
        • Rennie D.
        • et al.
        Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
        JAMA. 2000 Apr 19; 283: 2008-2012https://doi.org/10.1001/jama.283.15.2008
      4. MJ, Page, JE, McKenzie, PM, Bossuyt, I, Boutron, TC, Hoffmann, CD, Mulrow et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021 Mar 29;372:n71. https://doi.org/10.1136/bmj.n71.

      5. National Health Commission of the People’s Republic of China. Diagnosis and treatment of new coronavirus pneumonitis. (trial version 5). http://www.nhc.gov.cn/yzygj/s7653p/202002/3b09b894ac9b4204a79db5b8912d4440.shtml.

      6. JAC, Sterne, J, Savović, MJ, Page, RG, Elbers, NS, Blencowe, I, Boutron et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019 Aug 28;366:l4898. https://doi.org/10.1136/bmj.l4898.

        • Margulis A.V.
        • Pladevall M.
        • Riera-Guardia N.
        • Varas-Lorenzo C.
        • Hazell L.
        • Berkman N.D.
        • et al.
        Quality assessment of observational studies in a drug-safety systematic review, comparison of two tools: the Newcastle-Ottawa Scale and the RTI item bank.
        Clin Epidemiol. 2014 Oct; 10: 359-368https://doi.org/10.2147/CLEP.S66677
      7. P, Sedgwick, Meta-analyses: what is heterogeneity? BMJ. 2015 Mar 16;350:h1435. https://doi.org/10.1136/bmj.h1435.

        • Elibol A.
        • Eren D.
        • Erdoğan M.D.
        • Elmaağaç M.
        • Dizdar O.S.
        • Çelik İ.
        • et al.
        Factors influencing on development of COVID-19 pneumonia and association with oral anti-diabetic drugs in hospitalized patients with diabetes mellitus.
        Prim Care Diabetes. 2021; 15: 806-812
        • Israelsen S.B.
        • Pottegård A.
        • Sandholdt H.
        • Madsbad S.
        • Thomsen R.W.
        • Benfield T.
        Comparable COVID-19 outcomes with current use of GLP-1 receptor agonists, DPP-4 inhibitors or SGLT-2 inhibitors among patients with diabetes who tested positive for SARS-CoV-2.
        Diabetes Obes Metab. 2021 Jun; 23: 1397-1401https://doi.org/10.1111/dom.14329
        • Kahkoska A.R.
        • Abrahamsen T.J.
        • Alexander G.C.
        • Bennett T.D.
        • Chute C.G.
        • Haendel M.A.
        • et al.
        N3C Consortium. Association Between Glucagon-Like Peptide 1 Receptor Agonist and Sodium-Glucose Cotransporter 2 Inhibitor Use and COVID-19 Outcomes.
        Diabetes Care. 2021; 44: 1564-1572
      8. K, Khunti, P, Knighton, F, Zaccardi, C, Bakhai, E, Barron, N, Holman et al. Prescription of glucose-lowering therapies and risk of COVID-19 mortality in people with type 2 diabetes: a nationwide observational study in England. Lancet Diabetes Endocrinol. 2021 May;9(5):293-303. https://doi.org/10.1016/S2213-8587(21)00050-4.

      9. K, Khunti, Y, Ruan, J, Davies, Field BCT, Harris S, Kosiborod M, et al; ABCD COVID-19 Diabetes National Audit Investigators. Association Between SGLT2 Inhibitor Treatment and Diabetic Ketoacidosis and Mortality in People With Type 2 Diabetes Admitted to Hospital With COVID-19. Diabetes Care. 2022 Sep 8:dc220357. https://doi.org/10.2337/dc22-0357.

        • Kim M.K.
        • Jeon J.-H.
        • Kim S.-W.
        • Moon J.S.
        • Cho N.H.
        • Han E.
        • et al.
        The Clinical Characteristics and Outcomes of Patients with Moderate-to-Severe Coronavirus Disease 2019 Infection and Diabetes in Daegu.
        South Korea Diabetes Metab J. 2020; 44: 602
        • Kosiborod M.N.
        • Esterline R.
        • Furtado R.H.M.
        • Oscarsson J.
        • Gasparyan S.B.
        • Koch G.G.
        • et al.
        Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trial.
        Lancet Diabetes Endocrinol. 2021; 9: 586-594
        • Min J.
        • Simmons W.
        • Banerjee S.
        • Wang F.
        • Williams N.
        • Zhang Y.
        • et al.
        Association between antidiabetic drug use and the risk of COVID-19 hospitalization in the INSIGHT Clinical Research Network in New York City.
        Diabetes Obes Metab. 2022 Jul; 24: 1402-1405https://doi.org/10.1111/dom.14704
        • Nyland J.E.
        • Raja-Khan N.T.
        • Bettermann K.
        • Haouzi P.A.
        • Leslie D.L.
        • Kraschnewski J.L.
        • et al.
        Diabetes, Drug Treatment, and Mortality in COVID-19: a multinational retrospective cohort study.
        Diabetes. 2021; 70: 2903-2916
        • Orioli L.
        • Servais T.
        • Belkhir L.
        • Laterre P.-F.
        • Thissen J.-P.
        • Vandeleene B.
        • et al.
        Clinical characteristics and short-term prognosis of in-patients with diabetes and COVID-19: a retrospective study from an academic center in Belgium.
        Diabetes Metab Syndr. 2021; 15: 149-157
        • Pérez-Belmonte L.M.
        • Torres-Peña J.D.
        • López-Carmona M.D.
        • Ayala-Gutiérrez M.M.
        • Fuentes-Jiménez F.
        • Huerta L.J.
        • et al.
        Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: a nationwide cohort study.
        BMC Med. 2020; 18
      10. JM, Ramos-Rincón, LM, Pérez-Belmonte, FJ, Carrasco-Sánchez, S, Jansen-Chaparro, M, De-Sousa-Baena, J, Bueno-Fonseca et al; SEMI-COVID-19 Network. Cardiometabolic Therapy and Mortality in Very Old Patients With Diabetes Hospitalized due to COVID-19. J Gerontol A Biol Sci Med Sci. 2021 Jul 13;76(8):e102-e109. https://doi.org/10.1093/gerona/glab124.

        • Shestakova M.V.
        • Vikulova O.K.
        • Elfimova A.R.
        • Deviatkin A.A.
        • Dedov I.I.
        • Mokrysheva N.G.
        Risk factors for COVID-19 case fatality rate in people with type 1 and type 2 diabetes mellitus: a nationwide retrospective cohort study of 235,248 patients in the Russian Federation.
        Front Endocrinol (Lausanne). 2022 Aug; 9909874https://doi.org/10.3389/fendo.2022.909874
        • Silverii G.A.
        • Monami M.
        • Cernigliaro A.
        • Vigneri E.
        • Guarnotta V.
        • Scondotto S.
        • et al.
        Are diabetes and its medications risk factors for the development of COVID-19? Data from a population-based study in Sicily.
        Nutr Metab Cardiovasc Dis. 2021; 31: 396-398
        • Sourij H.
        • Aziz F.
        • Bräuer A.
        • Ciardi C.
        • Clodi M.
        • Fasching P.
        • et al.
        COVID-19 in diabetes in Austria study group. COVID-19 fatality prediction in people with diabetes and prediabetes using a simple score upon hospital admission.
        Diabetes Obes Metab. 2021; 23: 589-598
        • Wander P.L.
        • Lowy E.
        • Beste L.A.
        • Tulloch-Palomino L.
        • Korpak A.
        • Peterson A.C.
        • et al.
        Prior Glucose-Lowering Medication Use and 30-Day Outcomes Among 64,892 Veterans With Diabetes and COVID-19.
        Diabetes Care. 2021; 44: 2708-2713
        • Yeh H.-C.
        • Kraschnewski J.L.
        • Kong L.
        • Lehman E.B.
        • Heilbrunn E.S.
        • Williams P.
        • et al.
        Hospitalization and mortality in patients with COVID-19 with or at risk of type 2 diabetes: data from five health systems in Pennsylvania and Maryland.
        BMJ Open Diabetes Res Care. 2022; 10: e002774
        • Thornton A.
        • Lee P.
        Publication bias in meta-analysis: its causes and consequences.
        J Clin Epidemiol. 2000 Feb; 53: 207-216https://doi.org/10.1016/s0895-4356(99)00161-4
        • Terrin N.
        • Schmid C.H.
        • Lau J.
        • Olkin I.
        Adjusting for publication bias in the presence of heterogeneity.
        Stat Med. 2003 Jul 15; 22: 2113-2126https://doi.org/10.1002/sim.1461
        • Das L.
        • Dutta P.
        SGLT2 inhibition and COVID-19: The road not taken.
        Eur J Clin Invest. 2020 Dec; 50: e13339
        • Cure E.
        • Cumhur Cure M.
        Can dapagliflozin have a protective effect against COVID-19 infection? a hypothesis.
        Diabetes Metab Syndr. 2020; 14: 405-406
        • Scheen A.J.
        SGLT2 inhibition during the COVID-19 epidemic: Friend or foe?.
        Diabetes Metab. 2020 Oct; 46: 343-344https://doi.org/10.1016/j.diabet.2020.06.003
        • Couselo-Seijas M.
        • Agra-Bermejo R.M.
        • Fernández A.L.
        • Martínez-Cereijo J.M.
        • Sierra J.
        • Soto-Pérez M.
        • et al.
        High released lactate by epicardial fat from coronary artery disease patients is reduced by dapagliflozin treatment.
        Atherosclerosis. 2020; 292: 60-69
        • Lytvyn Y.
        • Bjornstad P.
        • Udell J.A.
        • Lovshin J.A.
        • Cherney D.Z.I.
        Sodium Glucose Cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials.
        Circulation. 2017 Oct 24; 136: 1643-1658https://doi.org/10.1161/CIRCULATIONAHA.117.030012
      11. L, Yu, X, Zhang, S, Ye, H, Lian, H, Wang, J, Ye Obesity and COVID-19: Mechanistic Insights From Adipose Tissue. J Clin Endocrinol Metab. 2022 Jun 16;107(7):1799-1811. https://doi.org/10.1210/clinem/dgac137.

        • Cai Z.
        • Yang Y.
        • Zhang J.
        Obesity is associated with severe disease and mortality in patients with coronavirus disease 2019 (COVID-19): a meta-analysis.
        BMC Public Health. 2021 Aug 4; 21: 1505https://doi.org/10.1186/s12889-021-11546-6
        • Siahaan Y.M.T.
        • Hartoyo V.
        • Hariyanto T.I.
        • Kurniawan A.
        Coronavirus disease 2019 (Covid-19) outcomes in patients with sarcopenia: a meta-analysis and meta-regression.
        Clin Nutr ESPEN. 2022 Apr; 48: 158-166https://doi.org/10.1016/j.clnesp.2022.01.016
        • Theofilis P.
        • Sagris M.
        • Oikonomou E.
        • Antonopoulos A.S.
        • Siasos G.
        • Tsioufis K.
        • et al.
        The impact of SGLT2 inhibitors on inflammation: A systematic review and meta-analysis of studies in rodents.
        Int Immunopharmacol. 2022; 111: 109080
        • Del Valle D.M.
        • Kim-Schulze S.
        • Huang H.-H.
        • Beckmann N.D.
        • Nirenberg S.
        • Wang B.o.
        • et al.
        An inflammatory cytokine signature predicts COVID-19 severity and survival.
        Nat Med. 2020; 26: 1636-1643
        • Hariyanto T.I.
        • Japar K.V.
        • Damay V.
        • Kwenandar F.
        • Sieto N.L.
        • Kurniawan A.
        The use of ACE inhibitor/ARB in SARS-CoV-2 patients: a comprehensive narrative review.
        Asian J Med Sci. 2020; 11: 113-120https://doi.org/10.3126/ajms.v11i6.29911
        • Legrand M.
        • Bell S.
        • Forni L.
        • Joannidis M.
        • Koyner J.L.
        • Liu K.
        • et al.
        Pathophysiology of COVID-19-associated acute kidney injury.
        Nat Rev Nephrol. 2021; 17: 751-764
        • Fernandez-Fernandez B.
        • D’Marco L.
        • Górriz J.L.
        • Jacobs-Cachá C.
        • Kanbay M.
        • Luis-Lima S.
        • et al.
        Exploring Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors for Organ Protection in COVID-19.
        J Clin Med. 2020 Jun 28; 9: 2030
        • Han T.
        • Ma S.
        • Sun C.
        • Zhang H.
        • Qu G.
        • Chen Y.
        • et al.
        Association between anti-diabetic agents and clinical outcomes of COVID-19 in patients with diabetes: a systematic review and meta-analysis.
        Arch Med Res. 2022; 53: 186-195