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Metformin use in patients hospitalized with COVID-19: lower inflammation, oxidative stress, and thrombotic risk markers and better clinical outcomes

Usman et al., Journal of Thrombosis and Thrombolysis, doi:10.1007/s11239-022-02631-7
Jan 2022  
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0 0.5 1 1.5 2+ Mortality 60% Improvement Relative Risk Ventilation 76% Hospitalization time 34% Metformin for COVID-19  Usman et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 75 patients in the USA Lower mortality (p=0.21) and ventilation (p=0.054), not sig. c19early.org Usman et al., J. Thrombosis and Thromb.., Jan 2022 Favors metformin Favors control
Metformin for COVID-19
3rd treatment shown to reduce risk in July 2020
 
*, now known with p < 0.00000000001 from 91 studies.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,200+ studies for 70+ treatments. c19early.org
Retrospective 75 diabetes patients, 34 on metformin, showing improved clinical outcomes with treatment, without statistical significance.
risk of death, 59.8% lower, RR 0.40, p = 0.21, treatment 3 of 34 (8.8%), control 9 of 41 (22.0%), NNT 7.6.
risk of mechanical ventilation, 75.9% lower, RR 0.24, p = 0.05, treatment 2 of 34 (5.9%), control 10 of 41 (24.4%), NNT 5.4.
hospitalization time, 33.7% lower, relative time 0.66, p = 0.13, treatment 34, control 41.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Usman et al., 18 Jan 2022, retrospective, USA, peer-reviewed, 10 authors.
This PaperMetforminAll
Metformin use in patients hospitalized with COVID-19: lower inflammation, oxidative stress, and thrombotic risk markers and better clinical outcomes
Abira Usman, Kevin P Bliden, Alastair Cho, Naval Walia, Christophe Jerjian, Arvind Singh, Parshotam Kundan, Sanchit Duhan, Udaya S Tantry, Paul A Gurbel
Journal of Thrombosis and Thrombolysis, doi:10.1007/s11239-022-02631-7
Diabetes mellitus (DM) is associated with a greater risk of COVID-19 and an increased mortality when the disease is contracted. Metformin use in patients with DM is associated with less COVID-19-related mortality, but the underlying mechanism behind this association remains unclear. Our aim was to explore the effects of metformin on markers of inflammation, oxidative stress, and hypercoagulability, and on clinical outcomes. Patients with DM on metformin (n = 34) and metformin naïve (n = 41), and patients without DM (n = 73) were enrolled within 48 h of hospital admission for COVID-19. Patients on metformin compared to naïve patients had a lower white blood cell count (p = 0.02), d-dimer (p = 0.04), urinary 11-dehydro thromboxane B 2 (p = 0.01) and urinary liver-type fatty acid binding protein (p = 0.03) levels and had lower sequential organ failure assessment score (p = 0.002), and intubation rate (p = 0.03), fewer hospitalized days (p = 0.13), lower in-hospital mortality (p = 0.12) and lower mortality plus nonfatal thrombotic event occurrences (p = 0.10). Patients on metformin had similar clinical outcomes compared to patients without DM. In a multiple regression analysis, metformin use was associated with less days in hospital and lower intubation rate. In conclusion, metformin treatment in COVID-19 patients with DM was associated with lower markers of inflammation, renal ischemia, and thrombosis, and fewer hospitalized days and intubation requirement. Further focused studies are required to support these findings. Keywords COVID-19 • Diabetes • Metformin • Thromboelastography • Biomarker • Death • Intubation Highlights • Fasting blood glucose level in patients with has been shown to be associated with severity of the disease and poor outcomes, including mortality. • Metformin use in patients with DM is associated with less COVID-19-related mortality, but the underlying mechanism behind this association remains unclear. • In this single center study, metformin treatment in COVID-19 patients with DM was associated with lower markers of inflammation, renal ischemia, and thrombosis, and fewer hospitalized days and intubation requirement. • In a multiple regression analysis, metformin use was associated with less days in hospital and lower intubation rate.
Declarations Conflict of interest Dr. Gurbel reports grants and personal fees from Bayer HealthCare LLC, Otitopic Inc, Amgen, Janssen, and US World-Meds LLC; grants from Instrumentation Laboratory, Haemonetics, Medicure Inc, Idorsia Pharmaceuticals, and Hikari Dx; personal fees from UpToDate; Dr Gurbel is a relator and expert witness in litigation involving clopidogrel; in addition, Dr. Gurbel has two patents, Detection of restenosis risk in patients issued and Assessment of cardiac health and thrombotic risk in a patient. Dr. Tantry reports receiving honoraria from UptoDate and Aggredyne. Other authors report no disclosures. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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' 'Front Pharmacol 12:622262', 'journal-title': 'Front Pharmacol'}, { 'key': '2631_CR28', 'doi-asserted-by': 'crossref', 'first-page': '34', 'DOI': '10.1186/s12950-016-0142-3', 'volume': '13', 'author': 'W Chen', 'year': '2016', 'unstructured': 'Chen W, Liu X, Ye S (2016) Effects of metformin on blood and urine ' 'pro-inflammatory mediators in patients with type 2 diabetes. J Inflamm ' '(Lond) 13:34', 'journal-title': 'J Inflamm (Lond)'}, { 'key': '2631_CR29', 'doi-asserted-by': 'crossref', 'first-page': '1399', 'DOI': '10.2337/dc20-0660', 'volume': '43', 'author': 'Y Chen', 'year': '2020', 'unstructured': 'Chen Y, Yang D, Cheng B et al (2020) Clinical characteristics and ' 'outcomes of patients with diabetes and COVID-19 in association with ' 'glucose-lowering medication. Diabetes Care 43:1399–1407', 'journal-title': 'Diabetes Care'}, { 'key': '2631_CR30', 'first-page': 'e928236', 'volume': '26', 'author': 'K Torigoe', 'year': '2020', 'unstructured': 'Torigoe K, Muta K, Tsuji K et al (2020) Urinary liver-type fatty ' 'acid-binding protein predicts residual renal function decline in ' 'patients on peritoneal dialysis. Med Sci Monit 26:e928236', 'journal-title': 'Med Sci Monit'}, { 'issue': '1154–59', 'key': '2631_CR31', 'first-page': '25', 'volume': '174', 'author': 'K Negishi', 'year': '2009', 'unstructured': 'Negishi K, Noiri E, Doi K et al (2009) Monitoring of urinary L-type ' 'fatty acid-binding protein predicts histological severity of acute ' 'kidney injury. Am J Pathol 174(1154–59):25', 'journal-title': 'Am J Pathol'}, { 'key': '2631_CR32', 'doi-asserted-by': 'crossref', 'first-page': 'e0170', 'DOI': '10.1097/CCE.0000000000000170', 'volume': '2', 'author': 'D Katagiri', 'year': '2020', 'unstructured': 'Katagiri D, Ishikane M, Asai Y et al (2020) Evaluation of coronavirus ' 'disease 2019 severity using urine biomarkers. Crit Care Explor 2:e0170', 'journal-title': 'Crit Care Explor'}, { 'key': '2631_CR33', 'doi-asserted-by': 'crossref', 'first-page': '141', 'DOI': '10.1016/j.pcad.2009.05.001', 'volume': '52', 'author': 'US Tantry', 'year': '2009', 'unstructured': 'Tantry US, Mahla E, Gurbel PA (2009) Aspirin resistance. Prog Cardiovasc ' 'Dis 52:141–152', 'journal-title': 'Prog Cardiovasc Dis'}, { 'key': '2631_CR34', 'doi-asserted-by': 'crossref', 'first-page': '1650', 'DOI': '10.1161/01.CIR.0000013777.21160.07', 'volume': '105', 'author': 'JW Eikelboom', 'year': '2002', 'unstructured': 'Eikelboom JW, Hirsh J, Weitz JI et al (2002) Aspirin-resistant ' 'thromboxane biosynthesis and the risk of myocardial infarction, stroke, ' 'or cardiovascular death in patients at high risk for cardiovascular ' 'events. Circulation 105:1650–1655', 'journal-title': 'Circulation'}, { 'key': '2631_CR35', 'doi-asserted-by': 'crossref', 'first-page': '1705', 'DOI': '10.1161/CIRCULATIONAHA.108.768283', 'volume': '118', 'author': 'JW Eikelboom', 'year': '2008', 'unstructured': 'Eikelboom JW, Hankey GJ, Thom J et al (2008) Clopidogrel for High ' 'Atherothrombotic Risk and Ischemic Stabilization, Management and ' 'Avoidance (CHARISMA) Investigators. Incomplete inhibition of thromboxane ' 'biosynthesis by acetylsalicylic acid: determinants and effect on ' 'cardiovascular risk. Circulation 118:1705–1712', 'journal-title': 'Circulation'}, { 'issue': '2', 'key': '2631_CR36', 'first-page': 'ehaa946', 'volume': '41', 'author': 'B Rocca', 'year': '2020', 'unstructured': 'Rocca B, Buck G, Petrucci G et al (2020) Thromboxane metabolite ' 'excretion is associated with serious vascular events in diabetes ' 'mellitus: a sub-study of the ASCEND trial. Eur Heart J 41(2):ehaa946', 'journal-title': 'Eur Heart J'}, { 'key': '2631_CR37', 'doi-asserted-by': 'crossref', 'first-page': '3743', 'DOI': '10.3390/ijms21113743', 'volume': '21', 'author': 'M Graille', 'year': '2020', 'unstructured': 'Graille M, Wild P, Sauvain JJ et al (2020) Urinary 8-OHdG as a biomarker ' 'for oxidative stress: a systematic literature review and meta-analysis. ' 'Int J Mol Sci 21:3743', 'journal-title': 'Int J Mol Sci'}, { 'key': '2631_CR38', 'doi-asserted-by': 'crossref', 'first-page': '667', 'DOI': '10.1016/j.jacc.2013.03.089', 'volume': '62', 'author': 'D Tousoulis', 'year': '2013', 'unstructured': 'Tousoulis D, Papageorgiou N, Androulakis E, et al (2013) Diabetes ' 'mellitus-associated vascular impairment: novel circulating biomarkers ' 'and therapeutic approaches. J Am Coll Cardiol 62:667–676', 'journal-title': 'J Am Coll Cardiol'}, { 'key': '2631_CR39', 'doi-asserted-by': 'crossref', 'first-page': '548', 'DOI': '10.1089/ars.2015.6508', 'volume': '24', 'author': 'A Di Minno', 'year': '2016', 'unstructured': 'Di Minno A, Turnu L, Porro B et al (2016) 8-Hydroxy-2-deoxyguanosine ' 'levels and cardiovascular disease: a systematic review and meta-analysis ' 'of the literature. Antioxid Redox Signal 24:548–555', 'journal-title': 'Antioxid Redox Signal'}, { 'key': '2631_CR40', 'doi-asserted-by': 'crossref', 'first-page': '120', 'DOI': '10.1080/10590500902885684', 'volume': '27', 'author': 'A Valavanidis', 'year': '2009', 'unstructured': 'Valavanidis A, Vlachogianni T, Fiotakis C et al (2009) ' '“8-Hydroxy2’-deoxyguanosine (8-OHdG): a critical biomarker of oxidative ' 'stress and carcinogenesis. J Environ Sci Health C 27:120–139', 'journal-title': 'J Environ Sci Health C'}, { 'key': '2631_CR41', 'doi-asserted-by': 'crossref', 'first-page': '5953685', 'DOI': '10.1155/2019/5953685', 'volume': '2019', 'author': 'E Bigagli', 'year': '2019', 'unstructured': 'Bigagli E, Lodovici M (2019) Circulating oxidative stress biomarkers in ' 'clinical studies on type 2 diabetes and its complications. Oxid Med Cell ' 'Longev 2019:5953685', 'journal-title': 'Oxid Med Cell Longev'}, { 'key': '2631_CR42', 'doi-asserted-by': 'crossref', 'first-page': '423', 'DOI': '10.1016/j.diabet.2020.07.006', 'volume': '46', 'author': 'AJ Scheen', 'year': '2020', 'unstructured': 'Scheen AJ (2020) Metformin and COVID-19: from cellular mechanisms to ' 'reduced mortality. Diabetes Metab 46:423–426', 'journal-title': 'Diabetes Metab'}, { 'key': '2631_CR43', 'doi-asserted-by': 'crossref', 'first-page': '101216', 'DOI': '10.1016/j.diabet.2020.101216', 'volume': '47', 'author': 'JD Lalau', 'year': '2021', 'unstructured': 'Lalau JD, Al-Salameh A, Hadjadj S et al (2021) Metformin use is ' 'associated with a reduced risk of mortality in patients with diabetes ' 'hospitalised for COVID-19. Diabetes Metab 47:101216', 'journal-title': 'Diabetes Metab'}, { 'issue': '21', 'key': '2631_CR44', 'first-page': '00167', 'volume': 'S0188–4409', 'author': 'T Han', 'year': '2021', 'unstructured': 'Han T, Ma S, Sun C et al (2021) 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 ' 'S0188–4409(21):00167–00173', 'journal-title': 'Arch Med Res'}], 'container-title': ['Journal of Thrombosis and Thrombolysis'], 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://link.springer.com/content/pdf/10.1007/s11239-022-02631-7.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/article/10.1007/s11239-022-02631-7/fulltext.html', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/content/pdf/10.1007/s11239-022-02631-7.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2022, 1, 18]], 'date-time': '2022-01-18T10:11:27Z', 'timestamp': 1642500687000}, 'score': 1, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2022, 1, 18]]}, 'references-count': 44, 'alternative-id': ['2631'], 'URL': 'http://dx.doi.org/10.1007/s11239-022-02631-7', 'relation': {}, 'ISSN': ['0929-5305', '1573-742X'], 'issn-type': [{'value': '0929-5305', 'type': 'print'}, {'value': '1573-742X', 'type': 'electronic'}], 'subject': ['Cardiology and Cardiovascular Medicine', 'Hematology'], 'published': {'date-parts': [[2022, 1, 18]]}, 'assertion': [ { 'value': '30 December 2021', 'order': 1, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '18 January 2022', 'order': 2, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, {'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Declarations'}}, { 'value': 'Dr. Gurbel reports grants and personal fees from Bayer HealthCare LLC, Otitopic ' 'Inc, Amgen, Janssen, and US WorldMeds LLC; grants from Instrumentation ' 'Laboratory, Haemonetics, Medicure Inc, Idorsia Pharmaceuticals, and Hikari Dx; ' 'personal fees from UpToDate; Dr Gurbel is a relator and expert witness in ' 'litigation involving clopidogrel; in addition, Dr. Gurbel has two patents, ' 'Detection of restenosis risk in patients issued and Assessment of cardiac ' 'health and thrombotic risk in a patient. Dr. Tantry reports receiving honoraria ' 'from UptoDate and Aggredyne. Other authors report no disclosures.', 'order': 2, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Conflict of interest'}}, { 'value': 'This content has been made available to all.', 'name': 'free', 'label': 'Free to read'}]}
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