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0 0.5 1 1.5 2+ Mortality 22% Improvement Relative Risk Metformin for COVID-19  Shestakova et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 189,998 patients in Russia (March 2020 - November 2021) Lower mortality with metformin (p=0.0012) c19early.org Shestakova et al., Frontiers in Endocr.., Aug 2022 Favors metformin Favors control

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

Shestakova et al., Frontiers in Endocrinology, doi:10.3389/fendo.2022.909874
Aug 2022  
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Metformin for COVID-19
3rd treatment shown to reduce risk in July 2020
 
*, now known with p < 0.00000000001 from 89 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 224,190 type 2 diabetes patients in Russia, showing lower mortality with metformin use.
risk of death, 21.6% lower, RR 0.78, p = 0.001, treatment 21,471 of 139,637 (15.4%), control 12,721 of 50,361 (25.3%), adjusted per study, odds ratio converted to relative risk, Table S2, multivariable.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Shestakova et al., 9 Aug 2022, retrospective, Russia, peer-reviewed, 6 authors, study period 20 March, 2020 - 25 November, 2021. Contact: olga-vikulova-1973@yandex.ru.
This PaperMetforminAll
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
M V Shestakova, O K Vikulova, A R Elfimova, A A Deviatkin, I I Dedov, N G Mokrysheva
Frontiers in Endocrinology, doi:10.3389/fendo.2022.909874
The aim: To study the association of demographic, clinical, and laboratory factors and the use of glucose-lowering drugs and anti-coronavirus disease (COVID-19) vaccination with the COVID-19-related case fatality rate (CFR) in diabetes mellitus (DM) patients. Methods: This study is a nationwide observational cohort study based on the data from the National Diabetes Register (NDR) that is the database containing online clinical information about the population with DM. The outcomes (death or recovery) for COVID-19 were registered in 235,248 patients with DM [type 1 diabetes mellitus (T1DM), n = 11,058; type 2 diabetes mellitus (T2DM), n = 224,190] from March 20, 2020, until November 25, 2021. The unadjusted odds ratio (OR) and 95% confidence interval (CI) were used to estimate the risk factors for CFR. Then the ranging of significant factors was performed and the most vulnerable groups of factors for the lethal outcome were chosen. Results: The CFR due to COVID-19 was 8.1% in T1DM and 15.3% in T2DM. Increased CFR was associated with the male population [OR = 1.25 (95% CI: 1.09-1.44) in T1DM and 1.18 (95% CI: 1.15-1.21) in T2DM], age ≥65 years [OR = 4.44 (95% CI: 3.75-5.24) in T1DM and 3.18 (95% CI: 3.09-3.26) in T2DM], DM duration ≥10 years [OR = 2.46 (95% CI: 2.06-2.95) in T1DM and 2.11 (95% CI: 2.06-2.16) in T2DM], body mass index (BMI) ≥30 kg/m 2 [OR = 1.95 (95% CI: 1.52-2.50)] in T1DM, HbA1c ≥7% [OR = 1.35 (95% CI: 1.29-1.43)] in T2DM. The atherosclerotic cardiovascular disease (ASCVD) and chronic kidney disease (CKD) were associated with higher CFR in T1DM but not in T2DM. The pre-COVID-19 glucose-lowering therapy in T2DM was differently associated with CFR (OR): 0.61 (95% CI: 0.59-0.62) for metformin, 0.59 (95% CI: 0.57-0.61) for dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), 0.46 (95% CI: 0.44-0.49) for sodium-glucose co-transporter-2 (SGLT2) inhibitors, 0.38 (95% CI: 0.29-0.51) for glucagon-like peptide-1 receptor agonists (arGLP-1), 1.34 (95% CI: 1.31-1.37) for sulfonylurea (SU), and 1.47 (95% CI: 1.43-1.51) for insulin. Anti-Frontiers in Endocrinology frontiersin.org 01
Ethics statement The studies involving human participants (human data of register medical reports) were reviewed and approved by local ethics committee of Endocrinology Research Centre, Moscow, Russia. The patients/participants provided their written informed consent for use of medical data register records for the study. Author contributions MS, OV, ID and NM conceived and designed the study. AE, AD, and OV analyzed the data. OV, AD, AE, MS wrote the paper. ID and NM have done final revision of article. All authors, reviewed, edited, and approved the manuscript. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Supplementary material The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/ fendo.2022.909874/full#supplementary-material
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{ 'DOI': '10.3389/fendo.2022.909874', 'ISSN': ['1664-2392'], 'URL': 'http://dx.doi.org/10.3389/fendo.2022.909874', 'abstract': '<jats:sec><jats:title>The aim</jats:title><jats:p>To study the association of demographic, ' 'clinical, and laboratory factors and the use of glucose-lowering drugs and anti-coronavirus ' 'disease (COVID-19) vaccination with the COVID-19-related case fatality rate (CFR) in diabetes ' 'mellitus (DM) ' 'patients.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>This study is ' 'a nationwide observational cohort study based on the data from the National Diabetes Register ' '(NDR) that is the database containing online clinical information about the population with ' 'DM. The outcomes (death or recovery) for COVID-19 were registered in 235,248 patients with DM ' '[type 1 diabetes mellitus (T1DM), n = 11,058; type 2 diabetes mellitus (T2DM), n = 224,190] ' 'from March 20, 2020, until November 25, 2021. The unadjusted odds ratio (OR) and 95% ' 'confidence interval (CI) were used to estimate the risk factors for CFR. Then the ranging of ' 'significant factors was performed and the most vulnerable groups of factors for the lethal ' 'outcome were chosen.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The ' 'CFR due to COVID-19 was 8.1% in T1DM and 15.3% in T2DM. Increased CFR was associated with the ' 'male population [OR = 1.25 (95% CI: 1.09–1.44) in T1DM and 1.18 (95% CI: 1.15–1.21) in T2DM], ' 'age ≥65 years [OR = 4.44 (95% CI: 3.75–5.24) in T1DM and 3.18 (95% CI: 3.09–3.26) in T2DM], ' 'DM duration ≥10 years [OR = 2.46 (95% CI: 2.06–2.95) in T1DM and 2.11 (95% CI: 2.06–2.16) in ' 'T2DM], body mass index (BMI) ≥30 kg/m<jats:sup>2</jats:sup> [OR = 1.95 (95% CI: 1.52–2.50)] ' 'in T1DM, HbA1c ≥7% [OR = 1.35 (95% CI: 1.29–1.43)] in T2DM. The atherosclerotic ' 'cardiovascular disease (ASCVD) and chronic kidney disease (CKD) were associated with higher ' 'CFR in T1DM but not in T2DM. The pre-COVID-19 glucose-lowering therapy in T2DM was ' 'differently associated with CFR (OR): 0.61 (95% CI: 0.59–0.62) for metformin, 0.59 (95% CI: ' '0.57–0.61) for dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), 0.46 (95% CI: 0.44–0.49) ' 'for sodium-glucose co-transporter-2 (SGLT2) inhibitors, 0.38 (95% CI: 0.29–0.51) for ' 'glucagon-like peptide-1 receptor agonists (arGLP-1), 1.34 (95% CI: 1.31–1.37) for ' 'sulfonylurea (SU), and 1.47 (95% CI: 1.43–1.51) for insulin. Anti-COVID-19 vaccination was ' 'associated with a lower fatality risk in both DM types: OR = 0.07 (95% CI: 0.03–0.20) in T1DM ' 'and OR = 0.19 (95% CI: 0.17–0.22) in ' 'T2DM.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>The results of ' 'our study suggest that increased COVID-19-related fatality risk in both T1DM and T2DM ' 'patients associated with the male population, older age, longer DM duration, and absence of ' 'anti-COVID-19 vaccination. In T2DM, pre-COVID-19 glucose-lowering therapy with metformin, ' 'DPP-4 inhibitors, SGLT2 inhibitors, and arGLP-1 had a positive effect on the risk of death. ' 'The most vulnerable combination of risk factors for lethal outcome in both DM types was ' 'vaccine absence + age ≥65 years + DM duration ≥10 years.</jats:p></jats:sec>', 'alternative-id': ['10.3389/fendo.2022.909874'], 'author': [ {'affiliation': [], 'family': 'Shestakova', 'given': 'M. 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of SARS-CoV-2 infection and COVID-19 prognosis with the use of ' 'renin-angiotensin-aldosterone system (RAAS) inhibitors: A systematic ' 'review', 'author': 'Iheanacho', 'doi-asserted-by': 'publisher', 'first-page': '73', 'journal-title': 'Futur J Pharm Sci', 'key': 'B21', 'volume': '7', 'year': '2021'}, { 'DOI': '10.1136/heartjnl-2021-319552', 'article-title': 'Antiplatelet therapy and outcome in COVID-19: The health outcome ' 'predictive evaluation registry', 'author': 'Santoro', 'doi-asserted-by': 'publisher', 'journal-title': 'Heart', 'key': 'B22', 'volume': '108', 'year': '2021'}, { 'DOI': '10.1002/DMRR.3476/v2/response1', 'article-title': 'Elevated HbA1c levels in pre-Covid-19 infection increases the risk of ' 'mortality: A sistematic review and meta-analysis', 'author': 'Prattichizzo', 'doi-asserted-by': 'publisher', 'journal-title': 'Diabetes Metab Res Rev', 'key': 'B23', 'volume': '38', 'year': '2021'}, { 'DOI': '10.1016/j.orcp.2020.12.008', 'article-title': 'Retraction notice to obesity a nd mortality of COVID-19', 'author': 'Hussain', 'doi-asserted-by': 'publisher', 'first-page': '100', 'journal-title': 'Meta-analysis Obesity Res Clin Pract', 'key': 'B24', 'volume': '15', 'year': '2021'}, { 'DOI': '10.1038/s41598-021-86694-1', 'article-title': 'A systematic review and meta-analysis of obesity and COVID-19 outcomes', 'author': 'Zhang', 'doi-asserted-by': 'publisher', 'first-page': '7193', 'journal-title': 'Sci Rep', 'key': 'B25', 'volume': '11', 'year': '2021'}, { 'DOI': '10.1002/oby.23121', 'article-title': 'BMI and risk for severe COVID-19 among veterans health administration ' 'patients', 'author': 'Breland', 'doi-asserted-by': 'publisher', 'journal-title': 'Obesity', 'key': 'B26', 'volume': '29', 'year': '2021'}, { 'DOI': '10.1016/j.dsx.2020.11.006', 'article-title': 'The effect of metformin consumption on mortality in hospitalized ' 'COVID-19 patients: A systematic review and meta-analysis', 'author': 'Lukito', 'doi-asserted-by': 'publisher', 'journal-title': 'Diabetes Metab Syndr Clin Res Rev', 'key': 'B27', 'volume': '14', 'year': '2020'}, { 'DOI': '10.3389/fmed.2021.704666', 'article-title': 'Metformin in patients with COVID-19: A systematic review and ' 'meta-analysis', 'author': 'Li', 'doi-asserted-by': 'publisher', 'journal-title': 'Front Med', 'key': 'B28', 'volume': '8', 'year': '2021'}, { 'DOI': '10.3389/fendo.2021.708494/full', 'article-title': 'Mortality risk of antidiabetic agents for type 2 diabetes with ' 'COVID-19: A systematic review and meta-analysis', 'author': 'Kan', 'doi-asserted-by': 'publisher', 'journal-title': 'Front Endocrinol (Lausanne)', 'key': 'B29', 'volume': '12', 'year': '2021'}, { 'DOI': '10.1016/j.diabres.2020.108183', 'article-title': 'Metformin in COVID-19: A possible role beyond diabetes', 'author': 'Sharma', 'doi-asserted-by': 'publisher', 'first-page': '108183', 'journal-title': 'Diabetes Res Clin Pract', 'key': 'B30', 'volume': '164', 'year': '2020'}, { 'DOI': '10.1007/s00005-020-00602-5', 'article-title': 'DPP4 inhibitors and COVID-19-Holy grail or another dead end', 'author': 'Krejner-Bienias', 'doi-asserted-by': 'publisher', 'first-page': '1', 'journal-title': 'Arch Immunol Ther Exp (Warsz)', 'key': 'B31', 'volume': '69', 'year': '2021'}, { 'DOI': '10.1371/journal.pone.0251916', 'article-title': 'DPP-4 inhibitors may improve the mortality of coronavirus disease 2019: ' 'A meta-analysis', 'author': 'Yang', 'doi-asserted-by': 'publisher', 'first-page': 'e0251916', 'journal-title': 'PloS One', 'key': 'B32', 'volume': '16', 'year': '2021'}, { 'DOI': '10.1016/j.dsx.2021.03.027', 'article-title': 'Dipeptidyl peptidase-4 (DPP-4) inhibitor and mortality in coronavirus ' 'disease 2019 (COVID-19) - a systematic review, meta-analysis, and ' 'meta-regression', 'author': 'Rakhmat', 'doi-asserted-by': 'publisher', 'journal-title': 'Diabetes Metab Syndr', 'key': 'B33', 'volume': '15', 'year': '2021'}, { 'DOI': '10.1016/S2213-8587(21)00180-7', 'article-title': 'Dapagliflozin in patients with cardiometabolic risk factors ' 'hospitalised with COVID-19 (DARE-19): A randomised, double-blind, ' 'placebo-controlled, phase 3 trial', 'author': 'Kosiborod', 'doi-asserted-by': 'publisher', 'journal-title': 'Lancet Diabetes Endocrinol', 'key': 'B34', 'volume': '9', 'year': '2021'}, { 'DOI': '10.1007/s40200-021-00833-z', 'article-title': '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', 'author': 'Meijer', 'doi-asserted-by': 'publisher', 'first-page': '1', 'journal-title': 'J Diabetes Metab Disord', 'key': 'B35', 'volume': '20', 'year': '2021'}, { 'DOI': '10.1007/s13300-019-00686-z', 'article-title': 'The pleiotropic effects of sodium-glucose cotransporter-2 inhibitors: ' 'Beyond the glycemic benefit', 'author': 'Patel', 'doi-asserted-by': 'publisher', 'journal-title': 'Diabetes Ther Res Treat Educ Diabetes Relat Disord', 'key': 'B36', 'volume': '10', 'year': '2019'}, { 'DOI': '10.1093/eurjpc/zwab034', 'article-title': 'Protective effects of SGLT-2 inhibitors across the cardiorenal ' 'continuum: two faces of the same coin', 'author': 'Fontes-Carvalho', 'doi-asserted-by': 'publisher', 'journal-title': 'Eur J Prev Cardiol', 'key': 'B37', 'year': '2021'}, { 'DOI': '10.1016/j.diabres.2021.109031', 'article-title': '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', 'author': 'Hariyanto', 'doi-asserted-by': 'publisher', 'first-page': '109031', 'journal-title': 'Diabetes Res Clin Pract', 'key': 'B38', 'volume': '179', 'year': '2021'}, { 'DOI': '10.1016/j.molmet.2020.101102', 'article-title': 'GLP-1 receptor agonists in the treatment of type 2 diabetes - ' 'state-of-the-art', 'author': 'Nauck', 'doi-asserted-by': 'publisher', 'first-page': '101102', 'journal-title': 'Mol Metab', 'key': 'B39', 'volume': '46', 'year': '2021'}, { 'DOI': '10.2337/dc20-0660', 'article-title': 'Clinical characteristics and outcomes of patients with diabetes and ' 'COVID-19 in association with glucose-lowering medication', 'author': 'Chen', 'doi-asserted-by': 'publisher', 'journal-title': 'Diabetes Care', 'key': 'B40', 'volume': '43', 'year': '2020'}, { 'DOI': '10.3389/fendo.2021.696087/full', 'article-title': 'Insulin treatment may increase adverse outcomes in patients with ' 'COVID-19 and diabetes: A systematic review and meta-analysis', 'author': 'Yang', 'doi-asserted-by': 'publisher', 'journal-title': 'Front Endocrinol (Lausanne)', 'key': 'B41', 'volume': '12', 'year': '2021'}, { 'DOI': '10.1101/2021.01.26.21250506', 'article-title': 'The association between anti-diabetic agents and clinical outcomes of ' 'COVID-19 in patients with diabetes: A systematic review and ' 'meta-analysis', 'author': 'Han', 'doi-asserted-by': 'publisher', 'journal-title': 'Arch Med Res', 'key': 'B42', 'volume': '53', 'year': '2021'}, { 'DOI': '10.14341/DM12759', 'article-title': 'Epidemiological characteristics of diabetes mellitus in the Russian ' 'federation: Clinical and statistical analysis according to the federal ' 'diabetes register data of 01.01.2021', 'author': 'Dedov', 'doi-asserted-by': 'publisher', 'journal-title': 'Diabetes Mellit', 'key': 'B43', 'volume': '24', 'year': '2021'}, { 'DOI': '10.1111/dom.12280', 'article-title': 'Mortality risk with sulphonylureas compared to metformin', 'author': 'Holden', 'doi-asserted-by': 'publisher', 'journal-title': 'Diabetes Obes Metab', 'key': 'B44', 'volume': '16', 'year': '2014'}, { 'DOI': '10.1093/eurheartj/ehr077', 'article-title': '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', 'author': 'Schramm', 'doi-asserted-by': 'publisher', 'journal-title': 'Eur Heart J', 'key': 'B45', 'volume': '32', 'year': '2011'}, { 'DOI': '10.1136/bmj.k2693', 'article-title': 'Sulfonylureas as second line drugs in type 2 diabetes and the risk of ' 'cardiovascular and hypoglycaemic events: Population based cohort study', 'author': 'Douros', 'doi-asserted-by': 'publisher', 'first-page': 'k2693', 'journal-title': 'BMJ', 'key': 'B46', 'volume': '362', 'year': '2018'}, { 'DOI': '10.1016/S0140-6736(21)00234-8', 'article-title': 'Safety and efficacy of an rAd26 and rAd5 vector-based heterologous ' 'prime-boost COVID-19 vaccine: An interim analysis of a randomised ' 'controlled phase 3 trial in Russia', 'author': 'Logunov', 'doi-asserted-by': 'publisher', 'journal-title': 'Lancet', 'key': 'B47', 'volume': '397', 'year': '2021'}, { 'DOI': '10.1210/clinem/dgab055', 'article-title': 'Robust neutralizing antibodies to SARS-CoV-2 develop and persist in ' 'subjects with diabetes and COVID-19 pneumonia', 'author': 'Dispinseri', 'doi-asserted-by': 'publisher', 'journal-title': 'J Clin Endocrinol Metab', 'key': 'B48', 'volume': '106', 'year': '2021'}, { 'article-title': 'Deaths involving COVID-19 by vaccination status, England: deaths ' 'occurring between 2 January and 24 September 2021', 'author': 'Bermingham', 'key': 'B49', 'volume-title': 'Deaths involving COVID-19 by vaccination status, England: deaths ' 'occurring between 2 January and 24 September 2021', 'year': ''}], 'reference-count': 49, 'references-count': 49, 'relation': {}, 'resource': {'primary': {'URL': 'https://www.frontiersin.org/articles/10.3389/fendo.2022.909874/full'}}, 'score': 1, 'short-title': [], 'source': 'Crossref', 'subject': ['Endocrinology, Diabetes and Metabolism'], 'subtitle': [], 'title': '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', 'type': 'journal-article', 'update-policy': 'http://dx.doi.org/10.3389/crossmark-policy', 'volume': '13'}
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Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
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