If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
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
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.
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.[
] 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.[
] 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.
] 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.[
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.[
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.[
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.[
] 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.[
] 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.[
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.
] 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).[
] 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)[
Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
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, andClinicalTrials.govSearch 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
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).[
] 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.[
Quality assessment of observational studies in a drug-safety systematic review, comparison of two tools: the Newcastle-Ottawa Scale and the RTI item bank.
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.[
] 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 [
Factors influencing on development of COVID-19 pneumonia and association with oral anti-diabetic drugs in hospitalized patients with diabetes mellitus.
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.
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.
Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trial.
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.
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.
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.
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.
Fig. 1PRISMA diagram of the detailed process of selection of studies for inclusion in the systematic review and meta-analysis.
Factors influencing on development of COVID-19 pneumonia and association with oral anti-diabetic drugs in hospitalized patients with diabetes mellitus.
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.
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.
Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trial.
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.
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.
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.
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.
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.
(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.
Factors influencing on development of COVID-19 pneumonia and association with oral anti-diabetic drugs in hospitalized patients with diabetes mellitus.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.[
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.[
] 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.[
] The intracellular accumulation of natrium will cause cellular edema and necrosis which subsequently increase the oxidative stress and pro-inflammatory cytokines.[
] 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.[
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.[
] SGLT-2i will promote increased fat utilization, reduce obesity-induced inflammation, and reduce insulin resistance through activation of M2 macrophages.[
] 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.[
] 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.[
] 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.[
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.[
] 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.[
] In addition, this virus is also capable of causing AKI manifestations due to damage to the endothelium and tubulointerstitial which often lead to death.[
] 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.[
] 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.[
] 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.[
] 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.[
] 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:
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.
Parkinson's disease may worsen outcomes from coronavirus disease 2019 (COVID-19) pneumonia in hospitalized patients: a systematic review, meta-analysis, and meta-regression.
Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition.
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.
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.
Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
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.
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.
Quality assessment of observational studies in a drug-safety systematic review, comparison of two tools: the Newcastle-Ottawa Scale and the RTI item bank.
Factors influencing on development of COVID-19 pneumonia and association with oral anti-diabetic drugs in hospitalized patients with diabetes mellitus.
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.
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.
Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trial.
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.
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.
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.
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.
01019-1&id=gr1.jpg){kind=link}
01019-1&id=gr2.jpg){kind=link}
01019-1&id=gr3.jpg){kind=link}