Metformin use and its association with various outcomes in COVID-19 patients with diabetes mellitus: a retrospective cohort study in a tertiary care facility
Muhilvannan Somasundaram, Sanjay Kurian Mathew, Soumyajeet Paul, Shilia Jacob Kurian, Vijayanarayana Kunhikatta, Shubhada Karanth, Sahana Shetty, Chandrashekar Udyavara Kudru, Mohan K Manu, Kavitha Saravu, Mazhuvancherry Kesavan Unnikrishnan, Mahadev Rao, Sonal Sekhar Miraj
Annals of Medicine, doi:10.1080/07853890.2024.2425829
Background: evidence shows that diabetes raises the probability of contracting cOViD-19 and associated complications. We hypothesize that metformin, being pleiotropic, may improve cOViD-19 in diabetics. Methods: a retrospective cohort study was conducted with 421 cOViD-19 patients with diabetes, hospitalized between 1st april 2020 and 31st March 2022 in a tertiary-care hospital. Patients with metformin or its combination constituted the study cohort (sc; n = 221), while other antidiabetics constituted the reference cohort (Rc; n = 200). Results: sc and Rc were matched for mean age ± sD (sc: 53.3 ± 5.7 vs. Rc: 54.3 ± 8.2 years). the mean length of hospitalization (days) was significantly shorter in sc (9.0 ± 5.7) than in Rc (12.7 ± 6) (p < 0.02). Metformin use was associated with reduction in mortality risk (OR: 0.106, 95% ci = 0.039-0.287; p < 0.001). Moreover, sc also improved levels of lDh (OR: 0.243, 95% ci = 0.104-0.566; p < 0.001), cRP (OR: 0.281, 95% ci = 0.120-0.659; p < 0.004), and D-dimer (OR: 0.220, 95% ci = 0.089-0.539; p < 0.001) than Rc. the calculated number needed to treat for metformin was 3.1.
Conclusion: Metformin users have a decrease in hospital stay and mortality rates and improvement in lDh, cRP, and D-dimer levels. therefore, metformin might protect against mortality in cOViD-19 with diabetes.
KEY MESSAGES • the study observed that cOViD-19 patients with diabetes on metformin had lower cRP levels than those on other antidiabetics. • the incidence and mortality risk were significantly found to be reduced in metformin users than in non-metformin users. • improvement in D-dimer, lDh, and cRP levels were also associated with reduced mortality risk in metformin users. • the number needed to treat shows three patients would have to receive metformin to prevent one additional death in cOViD-19 with diabetes. • therefore, metformin could be beneficial in cOViD-19, in addition to its effect on diabetes.
Author contributions M.s., s.K.M., s.J.K., and s.s.M. conceptualized the study. M.s., and s.K.M. collected the data. s.P., s.J.K., s.s.M., and V.K. cured the data. s.P., and V.K. analyzed the data. M.s., s.K.M, and s.s.M., wrote the manuscript. V.K., s.K., s.s., c.U.K., M.K.M., M.K.U., K.s., M.R., and s.s.M. critically evaluated the manuscript. all the authors participated in the manuscript review and approved the final draft of the manuscript.
Disclosure statement No potential conflict of interest was reported by the authors.
References
Al-Kuraishy Hm, Ai, El Kholy Aa, the potential therapeutic effect of metformin in type 2 diabetic patients with severe cOViD-19, eur Rev Med Pharmacol sci,
doi:10.26355/eurrev_202312_34583Bramante, Ne, Ta, Metformin and risk of mortality in patients hospitalised with cOViD-19: a retrospective cohort analysis, lancet healthy longev,
doi:10.1016/S2666-7568(20)30033-7Chen, Guo H, Qiu, immunomodulatory and antiviral activity of metformin and its potential implications in treating coronavirus disease 2019 and lung injury, Front immunol,
doi:10.3389/fimmu.2020.02056Chen, Yang, Cheng, clinical characteristics and outcomes of patients with diabetes and cOViD-19 in association with glucose-lowering medication, Diabetes care,
doi:10.2337/dc20-0660Giri, Kumar A, Saini, living with the virus: infection and epidemiology of cOViD-19 in hotspot area of india, J Public aff,
doi:10.1002/pa.2651Grimes, Li, Metformin use is associated with reduced mortality in a diverse population with cOViD-19 and diabetes, front endocrinol,
doi:10.3389/fendo.2020.600439Gupta, Misra A, Diabetes and cOViD-19: evidence, current status and unanswered research questions, eur J clin Nutr,
doi:10.1038/s41430-020-0652-1Hong, Zhang, effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease, Diabetes care,
doi:10.2337/dc12-0719Jia, Dc, ace2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia, J Virol,
doi:10.1128/JVI.79.23.14614-14621.2005Jin, Zheng, Shi, correlation analysis between serum uric acid, prealbumin level, lactate dehydrogenase, and severity of cOViD-19, Front Mol Biosci,
doi:10.3389/fmolb.2021.615837Kamyshnyi, Matskevych, Metformin to decrease cOViD-19 severity and mortality: molecular mechanisms and therapeutic potential, Biomed Pharmacother,
doi:10.1016/j.biopha.2021.112230King, Peacock, Donnelly, the UK prospective diabetes study (UKPDs): clinical and therapeutic implications for type 2 diabetes, Br J clin Pharmacol,
doi:10.1046/j.1365-2125.1999.00092.xKoutsogiannaki, the use of volatile anesthetics as sedatives for acute respiratory distress syndrome, transl Perioper Pain Med,
doi:10.31480/2330-4871/084Luo, Qiu, Liu, Metformin treatment was associated with decreased mortality in cOViD-19 patients with diabetes in a retrospective analysis, am J trop Med hyg,
doi:10.4269/ajtmh.20-0375Ma, Patel, Vemparala, Metformin is associated with favorable outcomes in patients with cOViD-19 and type 2 diabetes mellitus, sci Rep,
doi:10.1038/s41598-022-09639-2Ml, tissue distribution of ace2 protein, the functional receptor for saRs coronavirus. a first step in understanding saRs pathogenesis, J Pathol,
doi:10.1002/path.1570Niu, Pulmonary pathology of early-phase 2019 novel coronavirus (cOViD-19) pneumonia in two patients with lung cancer, J thorac Oncol,
doi:10.1016/j.jtho.2020.02.010Olesen, Hansen, Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: a retrospective nationwide cohort study, Diabetologia,
doi:10.1007/s00125-010-1906-6Pan, Neutrophil extracellular traps are indirectly triggered by lipopolysaccharide and contribute to acute lung injury, sci Rep,
doi:10.1038/srep37252Pantalone, Kattan, Yu, increase in overall mortality risk in patients with type 2 diabetes receiving glipizide, glyburide or glimepiride monotherapy versus metformin: a retrospective analysis, Diabetes Obes Metab,
doi:10.1111/j.1463-1326.2012.01604.xPoudel, Poudel, D-dimer as a biomarker for assessment of cOViD-19 prognosis: d -dimer levels on admission and its role in predicting disease outcome in hospitalized patients with cOViD-19, Plos One,
doi:10.1371/journal.pone.0256744Re, Ky, Neutrophil elastase (Ne)-deficient mice demonstrate a nonredundant role for Ne in neutrophil migration, generation of proinflammatory mediators, and phagocytosis in response to zymosan particles in vivo, J immunol,
doi:10.4049/jimmunol.172.7.4493Samuel Sm, Varghese, Büsselberg, therapeutic potential of metformin in cOViD-19: reasoning for its protective role,
doi:10.1016/j.tim.2021.03.004Schramm Tk, Gh, Vaag, Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study, eur heart J,
doi:10.1093/eurheartj/ehr077Venmans Lm, Bont, Gorter, Prediction of complicated lower respiratory tract infections in older patients with diabetes, Br J Gen Pract,
doi:10.3399/bjgp08X319620Wargny, Phenotypic characteristics and prognosis of inpatients with cOViD-19 and diabetes: the cORONaDO study, Diabetologia,
doi:10.1007/s00125-020-05180-xYao, Wang, D-dimer as a biomarker for disease severity and mortality in cOViD-19 patients: a case control study, J intensive care,
doi:10.1186/s40560-020-00466-zZhang, Dong, Martin, aMP-activated protein kinase phosphorylation of angiotensin-converting enzyme 2 in endothelium mitigates pulmonary hypertension, am J Respir crit care Med,
doi:10.1164/rccm.201712-2570OCZhou, Fu, Zheng, Pathogenic t-cells and inflammatory monocytes incite inflammatory storms in severe cOViD-19 patients, Natl sci Rev,
doi:10.1093/nsr/nwaa041Zhou, Myers, Li, Role of aMP-activated protein kinase in mechanism of metformin action, J clin invest,
doi:10.1172/JCI13505{ 'indexed': { 'date-parts': [[2024, 11, 10]],
'date-time': '2024-11-10T05:05:54Z',
'timestamp': 1731215154350,
'version': '3.28.0'},
'reference-count': 39,
'publisher': 'Informa UK Limited',
'issue': '1',
'license': [ { 'start': { 'date-parts': [[2024, 11, 9]],
'date-time': '2024-11-09T00:00:00Z',
'timestamp': 1731110400000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'http://creativecommons.org/licenses/by-nc/4.0/'}],
'content-domain': {'domain': ['www.tandfonline.com'], 'crossmark-restriction': True},
'published-print': {'date-parts': [[2024, 12, 31]]},
'DOI': '10.1080/07853890.2024.2425829',
'type': 'journal-article',
'created': {'date-parts': [[2024, 11, 9]], 'date-time': '2024-11-09T09:13:01Z', 'timestamp': 1731143581000},
'update-policy': 'http://dx.doi.org/10.1080/tandf_crossmark_01',
'source': 'Crossref',
'is-referenced-by-count': 0,
'title': 'Metformin use and its association with various outcomes in COVID-19 patients with diabetes '
'mellitus: a retrospective cohort study in a tertiary care facility',
'prefix': '10.1080',
'volume': '56',
'author': [ { 'given': 'Muhilvannan',
'family': 'Somasundaram',
'sequence': 'first',
'affiliation': [ { 'name': 'Department of Pharmacy Practice, Manipal College of '
'Pharmaceutical Sciences, Manipal Academy of High Education, '
'Manipal, Karnataka, India'}]},
{ 'given': 'Sanjay Kurian',
'family': 'Mathew',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Pharmacy Practice, Manipal College of '
'Pharmaceutical Sciences, Manipal Academy of High Education, '
'Manipal, Karnataka, India'}]},
{ 'given': 'Soumyajeet',
'family': 'Paul',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Pharmacy Practice, Manipal College of '
'Pharmaceutical Sciences, Manipal Academy of High Education, '
'Manipal, Karnataka, India'}]},
{ 'given': 'Shilia Jacob',
'family': 'Kurian',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Pharmacy Practice, Manipal College of '
'Pharmaceutical Sciences, Manipal Academy of High Education, '
'Manipal, Karnataka, India'}]},
{ 'given': 'Vijayanarayana',
'family': 'Kunhikatta',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Pharmacy Practice, Manipal College of '
'Pharmaceutical Sciences, Manipal Academy of High Education, '
'Manipal, Karnataka, India'}]},
{ 'given': 'Shubhada',
'family': 'Karanth',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Medicine, Kasturba Medical College, Manipal, '
'Manipal Academy of High Education, Manipal, Karnataka, India'}]},
{ 'given': 'Sahana',
'family': 'Shetty',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Endocrinology, Kasturba Medical College, Manipal, '
'Manipal Academy of High Education, Manipal, Karnataka, India'}]},
{ 'given': 'Chandrashekar Udyavara',
'family': 'Kudru',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Medicine, Kasturba Medical College, Manipal, '
'Manipal Academy of High Education, Manipal, Karnataka, India'}]},
{ 'ORCID': 'http://orcid.org/0000-0002-9481-3189',
'authenticated-orcid': False,
'given': 'Mohan K.',
'family': 'Manu',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Respiratory Medicine, Kasturba Medical College, '
'Manipal, Manipal Academy of High Education, Manipal, Karnataka, '
'India'}]},
{ 'ORCID': 'http://orcid.org/0000-0001-6399-1129',
'authenticated-orcid': False,
'given': 'Kavitha',
'family': 'Saravu',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Infectious Diseases, Kasturba Medical College, '
'Manipal, Manipal Academy of High Education, Manipal, Karnataka, '
'India'},
{ 'name': 'Manipal Centre for Infectious Diseases, Prasanna School of '
'Public Health, Manipal Academy of Higher Education, Manipal, '
'India'}]},
{ 'given': 'Mazhuvancherry Kesavan',
'family': 'Unnikrishnan',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Pharmacy Practice, Amrita School of Pharmacy, '
'Amrita Vishwa Vidyapeetham, Kochi, India'}]},
{ 'given': 'Mahadev',
'family': 'Rao',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Pharmacy Practice, Manipal College of '
'Pharmaceutical Sciences, Manipal Academy of High Education, '
'Manipal, Karnataka, India'}]},
{ 'ORCID': 'http://orcid.org/0000-0003-3660-2022',
'authenticated-orcid': False,
'given': 'Sonal Sekhar',
'family': 'Miraj',
'sequence': 'additional',
'affiliation': [ { 'name': 'Department of Pharmacy Practice, Manipal College of '
'Pharmaceutical Sciences, Manipal Academy of High Education, '
'Manipal, Karnataka, India'},
{ 'name': 'Manipal Centre for Infectious Diseases, Prasanna School of '
'Public Health, Manipal Academy of Higher Education, Manipal, '
'India'}]}],
'member': '301',
'published-online': {'date-parts': [[2024, 11, 9]]},
'reference': [ {'key': 'e_1_3_5_3_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s12026-014-8534-z'},
{'key': 'e_1_3_5_4_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/pa.2651'},
{ 'key': 'e_1_3_5_5_1',
'unstructured': 'India: Coronavirus Cases. 2023 '
'https://www.worldometers.info/coronavirus/country/india/.'},
{ 'key': 'e_1_3_5_6_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/S0140-6736(20)30183-5'},
{'key': 'e_1_3_5_7_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/nsr/nwaa041'},
{ 'key': 'e_1_3_5_8_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/S2213-2600(20)30076-X'},
{'key': 'e_1_3_5_9_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jtho.2020.02.010'},
{ 'key': 'e_1_3_5_10_1',
'doi-asserted-by': 'publisher',
'DOI': '10.4049/jimmunol.172.7.4493'},
{'key': 'e_1_3_5_11_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/srep37252'},
{'key': 'e_1_3_5_12_1', 'doi-asserted-by': 'publisher', 'DOI': '10.31480/2330-4871/084'},
{'key': 'e_1_3_5_13_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41430-020-0652-1'},
{'key': 'e_1_3_5_14_1', 'doi-asserted-by': 'publisher', 'DOI': '10.3399/bjgp08X319620'},
{'key': 'e_1_3_5_15_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s40618-020-01236-2'},
{ 'key': 'e_1_3_5_16_1',
'unstructured': 'Istituto Superiore di Sanita. Report of characteristics of patients died '
'positive for COVID-19 in Italy; 2023. '
'https://www.epicentro.iss.it/coronavirus/bollettino/Report-COVID-2019_17_marzo-v2.pdf.'},
{'key': 'e_1_3_5_17_1', 'doi-asserted-by': 'publisher', 'DOI': '10.15585/mmwr.mm6913e2'},
{'key': 'e_1_3_5_18_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.tim.2021.03.004'},
{'key': 'e_1_3_6_2_1', 'doi-asserted-by': 'publisher', 'DOI': '10.3389/fimmu.2020.02056'},
{'key': 'e_1_3_7_2_1', 'doi-asserted-by': 'publisher', 'DOI': '10.2337/dc12-0719'},
{ 'key': 'e_1_3_7_3_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1111/j.1463-1326.2012.01604.x'},
{'key': 'e_1_3_7_4_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/eurheartj/ehr077'},
{'key': 'e_1_3_7_5_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s00125-010-1906-6'},
{'key': 'e_1_3_7_6_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1172/JCI13505'},
{'key': 'e_1_3_7_7_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/path.1570'},
{'key': 'e_1_3_7_8_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1164/rccm.201712-2570OC'},
{ 'key': 'e_1_3_7_9_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1128/JVI.79.23.14614-14621.2005'},
{'key': 'e_1_3_7_10_1', 'doi-asserted-by': 'publisher', 'DOI': '10.4269/ajtmh.20-0375'},
{ 'key': 'e_1_3_8_2_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.diabet.2020.101216'},
{'key': 'e_1_3_9_2_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s00125-020-05180-x'},
{'key': 'e_1_3_9_3_1', 'doi-asserted-by': 'publisher', 'DOI': '10.3389/fendo.2020.600439'},
{'key': 'e_1_3_10_2_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41598-022-09639-2'},
{ 'key': 'e_1_3_11_2_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1136/postgradmedj-2020-137935'},
{ 'key': 'e_1_3_11_3_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.biopha.2021.112230'},
{ 'key': 'e_1_3_11_4_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1371/journal.pone.0256744'},
{'key': 'e_1_3_11_5_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1186/s40560-020-00466-z'},
{'key': 'e_1_3_11_6_1', 'doi-asserted-by': 'publisher', 'DOI': '10.3389/fmolb.2021.615837'},
{ 'key': 'e_1_3_11_7_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1046/j.1365-2125.1999.00092.x'},
{'key': 'e_1_3_11_8_1', 'doi-asserted-by': 'publisher', 'DOI': '10.2337/dc20-0660'},
{ 'key': 'e_1_3_11_9_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/S2666-7568(20)30033-7'},
{ 'key': 'e_1_3_12_2_1',
'doi-asserted-by': 'publisher',
'DOI': '10.26355/eurrev_202312_34583'}],
'container-title': 'Annals of Medicine',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://www.tandfonline.com/doi/pdf/10.1080/07853890.2024.2425829',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2024, 11, 9]],
'date-time': '2024-11-09T09:13:05Z',
'timestamp': 1731143585000},
'score': 1,
'resource': {'primary': {'URL': 'https://www.tandfonline.com/doi/full/10.1080/07853890.2024.2425829'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2024, 11, 9]]},
'references-count': 39,
'journal-issue': {'issue': '1', 'published-print': {'date-parts': [[2024, 12, 31]]}},
'alternative-id': ['10.1080/07853890.2024.2425829'],
'URL': 'http://dx.doi.org/10.1080/07853890.2024.2425829',
'relation': {},
'ISSN': ['0785-3890', '1365-2060'],
'subject': [],
'container-title-short': 'Annals of Medicine',
'published': {'date-parts': [[2024, 11, 9]]},
'assertion': [ { 'value': 'The publishing and review policy for this title is described in its Aims & '
'Scope.',
'order': 1,
'name': 'peerreview_statement',
'label': 'Peer Review Statement'},
{ 'value': 'http://www.tandfonline.com/action/journalInformation?show=aimsScope&journalCode=iann20',
'URL': 'http://www.tandfonline.com/action/journalInformation?show=aimsScope&journalCode=iann20',
'order': 2,
'name': 'aims_and_scope_url',
'label': 'Aim & Scope'},
{ 'value': '2023-10-10',
'order': 0,
'name': 'received',
'label': 'Received',
'group': {'name': 'publication_history', 'label': 'Publication History'}},
{ 'value': '2024-10-21',
'order': 1,
'name': 'revised',
'label': 'Revised',
'group': {'name': 'publication_history', 'label': 'Publication History'}},
{ 'value': '2024-10-25',
'order': 2,
'name': 'accepted',
'label': 'Accepted',
'group': {'name': 'publication_history', 'label': 'Publication History'}},
{ 'value': '2024-11-09',
'order': 3,
'name': 'published',
'label': 'Published',
'group': {'name': 'publication_history', 'label': 'Publication History'}}]}
