No study has yet systematically evaluated the effect of antidiabetic therapy on clinical outcomes of COVID-19 patients with type 2 diabetes (T2D).
Objective:
We aimed to evaluate the effect of different antidiabetic therapy on clinical outcomes of COVID-19 patients with T2D.
Methods:
We comprehensively retrieved the published research which examined the effect of antidiabetic therapy on clinical outcomes of COVID-19 patients with T2D. The odds ratio (OR) and its 95% confidence interval (95% CI) for clinical outcomes were calculated using the random-effects model, and meta-regression was adopted to evaluate the potential sources of heterogeneity between studies.
Results:
A total of 54 studies were included in this study. We found that the use of metformin (OR = 0.66, 95% CI: 0.58-0.75), SGLT-2i (OR = 0.80, 95% CI: 0.73-0.88), and GLP-1ra (OR = 0.83, 95% CI: 0.70-0.98) were significantly associated with lower mortality risk in COVID-19 patients with T2D, while insulin use might unexpectedly increase the ICU admission rate (OR = 2.32, 95% CI: 1.34-4.01) and risk of death (OR = 1.52, 95% CI: 1.32-1.75). No statistically significant associations were identified for DPP-4i, SUs, AGIs, and TZDs.
Conclusion and Relevance:
We demonstrated that the usage of metformin, SGLT-2i, and GLP-1ra could significantly decrease mortality in COVID-19 patients with T2D. The heterogeneity across the studies, baseline characteristics of the included patients, shortage of dosage and the duration of antidiabetic drugs and autonomy of drug selection might limit the objectivity and accuracy of results. Further adequately powered and high-quality randomized controlled trials are warranted for conclusive findings.
HuangCWangYLiX, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. doi:10.1016/S0140-6736(20)30183-5.
3.
WangDHuBHuC, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-1069. doi:10.1001/jama.2020.1585.
4.
ChenNZhouMDongX, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-513. doi:10.1016/S0140-6736(20)30211-7.
5.
ZhangXWangFShenY, et al. Symptoms and health outcomes among survivors of COVID-19 infection 1 year after discharge from hospitals in Wuhan, China. JAMA Netw Open. 2021;4(9):e2127403. doi:10.1001/jamanetworkopen.2021.27403.
6.
FangXMingCCenY, et al. Post-sequelae one year after hospital discharge among older COVID-19 patients: a multi-center prospective cohort study. J Infect. 2022;84(2):179-186. doi:10.1016/j.jinf.2021.12.005.
7.
YangXYuYXuJ, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475-481. doi:10.1016/S2213-2600(20)30079-5.
8.
LiLFangXChengL, et al. Development and validation of a prognostic nomogram for predicting in-hospital mortality of COVID-19: a multicenter retrospective cohort study of 4086 cases in China. Aging. 2021;13(3):3176-3189. doi:10.18632/aging.202605.
9.
FangXLiSYuH, et al. Epidemiological, comorbidity factors with severity and prognosis of COVID-19: a systematic review and meta-analysis. Aging. 2020;12(13):12493-12503. doi:10.18632/aging.103579.
10.
BarronEBakhaiCKarP, et al. Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study. Lancet Diabetes Endocrinol. 2020;8(10):813-822. doi:10.1016/S2213-8587(20)30272-2.
11.
ZhanKZhangXWangB, et al. Short and long-term prognosis of glycemic control in COVID-19 patients with type 2 diabetes [published online ahead of print January 31, 2022]. QJM. doi:10.1093/qjmed/hcac020.
12.
ZhuLSheZGChengX, et al. Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes. Cell Metab. 2020;31(6):1068-1077.e3. doi:10.1016/j.cmet.2020.04.021.
13.
ZhanKZhangXWangB, et al. Response to letter to editor by Dr. Pranav Ish entitled “COVID-19 and diabetes-double whammy” [published online ahead of print February 19, 2022]. QJM. doi:10.1093/qjmed/hcac048.
14.
ZhanKZhangXWangB, et al. Response to letter to editor by Dr. Rohan Magoon entitled “Glycemic control and COVID-19 outcomes: the missing metabolic players” [published online ahead of print February 16, 2022]. QJM. doi:10.1093/qjmed/hcac044.
15.
NylandJERaja-KhanNTBettermannK, et al. Diabetes, drug treatment and mortality in COVID-19: a multinational retrospective cohort study. Diabetes. 2021;70(12):2903-2916. doi:10.2337/db21-0385.
16.
LiuZBaiXHanX, et al. The association of diabetes and the prognosis of COVID-19 patients: a retrospective study. Diabetes Res Clin Pract. 2020;169:108386. doi:10.1016/j.diabres.2020.108386.
17.
SilveriiGAMonamiMCernigliaroA, 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(2):396-398. doi:10.1016/j.numecd.2020.09.028.
18.
Pérez-BelmonteLMTorres-PeñaJDLópez-CarmonaMD, 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(1):359. doi:10.1186/s12916-020-01832-2.
19.
BossiACForloniFColombelliPL. Lack of efficacy of SGLT2-i in severe pneumonia related to novel coronavirus (nCoV) infection: no little help from our friends. Diabetes Ther. 2020;11(7):1605-1606. doi:10.1007/s13300-020-00844-8.
20.
HanTMaSSunC, et al. The association between anti-diabetic agents and clinical outcomes of COVID-19 in patients with diabetes: a systematic review and meta-analysis. Arch Med Res. 2021;53(2):186-195. doi:10.1016/j.arcmed.2021.08.002.
21.
GuptaRHussainAMisraA. Diabetes and COVID-19: evidence, current status and unanswered research questions. Eur J Clin Nutr. 2020;74(6):864-870. doi:10.1038/s41430-020-0652-1.
22.
PalRBanerjeeMMukherjeeSBhogalRSKaurABhadadaSK. Dipeptidyl peptidase-4 inhibitor use and mortality in COVID-19 patients with diabetes mellitus: an updated systematic review and meta-analysis. Ther Adv Endocrinol Metab. 2021;12:2042018821996482. doi:10.1177/2042018821996482.
23.
MeijerRIHoekstraTvan den OeverNCG, et al. Treatment with a DPP-4 inhibitor at time of hospital admission for COVID-19 is not associated with improved clinical outcomes: data from the COVID-PREDICT cohort study in The Netherlands. J Diabetes Metab Disord. 2021;20(2):1155-1160. doi:10.1007/s40200-021-00833-z.
24.
PolyTNIslamMMLiYJLinM-CHsuM-HWangY-C. Metformin use is associated with decreased mortality in COVID-19 patients with diabetes: evidence from retrospective studies and biological mechanism. J Clin Med. 2021;10(16):3507. doi:10.3390/jcm10163507.
25.
VargheseESamuelSMLiskovaAKubatkaPBüsselbergD. Diabetes and coronavirus (SARS-CoV-2): molecular mechanism of Metformin intervention and the scientific basis of drug repurposing. PLoS Pathog. 2021;17(6):e1009634. doi:10.1371/journal.ppat.1009634.
26.
YangWSunXZhangJZhangK. The effect of metformin on mortality and severity in COVID-19 patients with diabetes mellitus. Diabetes Res Clin Pract. 2021;178:108977. doi:10.1016/j.diabres.2021.108977.
27.
GaneshARandallMD. Does metformin affect outcomes in COVID-19 patients with new or pre-existing diabetes mellitus? A systematic review and meta-analysis. Br J Clin Pharmacol. 2022;88(6):2642-2656. doi:10.1111/bcp.15258.
28.
ChengXLiuYMLiH, et al. Metformin is associated with higher incidence of acidosis, but not mortality, in individuals with COVID-19 and pre-existing type 2 diabetes. Cell Metab. 2020;32(4):537-547.e3. doi:10.1016/j.cmet.2020.08.013.
29.
Al-SalamehABennisYCariouBLalauJ-D. The association between metformin treatment and COVID-19 outcomes according to metformin continuation during hospitalisation. Diabetes Metab. 2021;47(6):101297. doi:10.1016/j.diabet.2021.101297.
30.
WangJCooperJMGokhaleK, et al. Association of metformin with susceptibility to COVID-19 in people with type 2 diabetes. J Clin Endocrinol Metab. 2021;106(5):1255-1268. doi:10.1210/clinem/dgab067.
31.
StroupDFBerlinJAMortonSC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting: meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA2000;283(15):2008-2012. doi:10.1001/jama.283.15.2008.
32.
PageMJMcKenzieJEBossuytPM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ2021;372:n71. doi:10.1136/bmj.n71.
33.
BramanteCTIngrahamNEMurrayTA, et al. Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis. Lancet Healthy Longev. 2021;2(1):e34-e41. doi:10.1016/S2666-7568(20)30033-7.
34.
CrouseABGrimesTLiPMightMOvalleFShalevA. Metformin use is associated with reduced mortality in a diverse population with COVID-19 and diabetes. Front Endocrinol. 2020;11:600439. doi:10.3389/fendo.2020.600439.
35.
SamuelSMVargheseEBusselbergD. Therapeutic potential of metformin in COVID-19: reasoning for its protective role. Trends Microbiol. 2021;29(10):894-907. doi:10.1016/j.tim.2021.03.004.
36.
GianchandaniREsfandiariNHAngL, et al. Managing hyperglycemia in the COVID-19 inflammatory storm. Diabetes2020;69(10):2048-2053. doi:10.2337/dbi20-0022.
37.
RiahiSLoKBAnastasopoulouC, et al. Insulin use and poor COVID-19 outcomes among diabetes patients: association not necessarily causation. Endocr Res. 2021;46(2):53-54. doi:10.1080/07435800.2021.1894821.
38.
ShangJWangQZhangH, et al. The relationship between diabetes mellitus and COVID-19 prognosis: a retrospective cohort study in Wuhan, China. Am J Med. 2021;134(1):e6-e14. doi:10.1016/j.amjmed.2020.05.033.
39.
DandonaPGhanimH. Diabetes, obesity, COVID-19, insulin, and other antidiabetes drugs. Diabetes Care2021;44(9):1929-1933. doi:10.2337/dci21-0003.
40.
AttriBGoyalAGuptaYTandonN. Basal-bolus insulin regimen for hospitalised patients with COVID-19 and diabetes mellitus: a practical approach. Diabetes Ther. 2020;11(9):2177-2194. doi:10.1007/s13300-020-00873-3.
41.
KalraSMukherjeeJJVenkataramanS, et al. Hypoglycemia: the neglected complication. Indian J Endocrinol Metab. 2013;17(5):819-834. doi:10.4103/2230-8210.117219.
42.
TanNCGohSYKhooEY, et al. Self-reported hypoglycaemia in insulin-treated patients with diabetes mellitus: results from the Singapore cohort of the International Operations Hypoglycaemia Assessment Tool study. Singapore Med J. 2020;61(3):129-136. doi:10.11622/smedj.2019081.
43.
MendesTBCâmara-de-SouzaABHalpernB. Hospital management of hyperglycemia in the context of COVID-19: evidence-based clinical considerations. Diabetol Metab Syndr. 2022;14(1):37. doi:10.1186/s13098-022-00808-x.
44.
AlessiJde OliveiraGBSchaanBDTeloGH. Dexamethasone in the era of COVID-19: friend or foe? An essay on the effects of dexamethasone and the potential risks of its inadvertent use in patients with diabetes. Diabetol Metab Syndr. 2020;12:80. doi:10.1186/s13098-020-00583-7.
45.
SuhSParkMK. Glucocorticoid-induced diabetes mellitus: an important but overlooked problem. Endocrinol Metab2017;32(2):180-189. doi:10.3803/EnM.2017.32.2.180.
46.
XuZWangZWangS, et al. The impact of type 2 diabetes and its management on the prognosis of patients with severe COVID-19. J Diabetes. 2020;12(12):909-918. doi:10.1111/1753-0407.13084.
47.
LiXXuSYuM, et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J Allergy Clin Immunol. 2020;146(1):110-118. doi:10.1016/j.jaci.2020.04.006.
48.
DasSRastogiAHarikumarKVS, et al. Diagnosis and management considerations in steroid-related hyperglycemia in COVID-19: a position statement from the endocrine society of India. Indian J Endocrinol Metab. 2021;25(1):4-11. doi:10.4103/ijem.ijem_227_21.
49.
ChenCFChienCHYangYP, et al. Role of dipeptidyl peptidase-4 inhibitors in patients with diabetes infected with coronavirus-19. J Chin Med Assoc. 2020;83(8):710-711. doi:10.1097/JCMA.0000000000000338.
50.
DalanR. Is DPP4 inhibition a comrade or adversary in COVID-19 infection. Diabetes Res Clin Pract. 2020;164:108216. doi:10.1016/j.diabres.2020.108216.
51.
WargnyMPotierLGourdyP, et al. Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study. Diabetologia. 2021;64(4):778-794. doi:10.1007/s00125-020-05351-w.
52.
WanderPLLowyEBesteLA, et al. Risk factors for adverse outcomes among 35 879 veterans with and without diabetes after diagnosis with COVID-19. BMJ Open Diabetes Res Care. 2021;9(1):e002252. doi:10.1136/bmjdrc-2021-002252.
MirabelliMChiefariEPuccioL, et al. Potential benefits and harms of novel antidiabetic drugs during COVID-19 crisis. Int J Environ Res Public Health. 2020;17(10):3664. doi:10.3390/ijerph17103664.
55.
SachinidisANikolicDStoianAP, et al. Cardiovascular outcomes trials with incretin-based medications: a critical review of data available on GLP-1 receptor agonists and DPP-4 inhibitors. Metabolism. 2020;111:154343. doi:10.1016/j.metabol.2020.154343.
56.
MarantaFCianfanelliLRizzoMCianfloneD. Filling the gap between Guidelines and Real World in the cardiovascular approach to the diabetic patients: the need for a call to action. Int J Cardiol. 2021;329:205-207. doi:10.1016/j.ijcard.2020.12.074.
57.
RadosDVViecceliCPintoLC, et al. Metabolic effects of antihyperglycemic agents and mortality: meta-analysis of randomized controlled trials. Sci Rep. 2020;10(1):12837. doi:10.1038/s41598-020-69738-w.
58.
PapadopoulosVPKoutroulosMVZikoudiDG, et al. Diabetes-related acute metabolic emergencies in COVID-19 patients: a systematic review and meta-analysis. Diabetol Int. 2021;12(4):445-459. doi:10.1007/s13340-021-00502-9.
59.
KoufakisTMetallidisSZebekakisPAjjanRAKotsaK. Sodium-glucose cotransporter 2 inhibitors in the era of COVID-19 pandemic: is the benefit to risk ratio still favorable. J Diabetes Sci Technol. 2020;14(4):745-747. doi:10.1177/1932296820932155.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
