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Risk phenotypes of diabetes and association with COVID-19 severity and death: an update of a living systematic review and meta-analysis

Schlesinger et al., Diabetologia, doi:10.1007/s00125-023-05928-1
May 2023  
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Metformin for COVID-19
3rd treatment shown to reduce risk in July 2020
*, now known with p < 0.00000000001 from 84 studies.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
3,800+ studies for 60+ treatments.
Systematic review and meta analysis showing significantly lower COVID-19 mortality and severity with metformin use. Authors analyze 169 studies of diabetes patients, with 23 reporting mortality results and 34 reporting severity results for metformin.
13 meta analyses show significant improvements with metformin for mortality Hariyanto, Kan, Kow, Li, Lukito, Ma, Oscanoa, Parveen, Petrelli, Poly, Schlesinger, Yang, hospitalization Li, progression Yang, and severity Petrelli, Schlesinger.
Currently there are 84 metformin for COVID-19 studies, showing 34% lower mortality [29‑39%], 31% lower ventilation [13‑45%], 17% lower ICU admission [7‑26%], 17% lower hospitalization [11‑23%], and 3% fewer cases [-6‑12%].
risk of death, 31.0% lower, RR 0.69, p < 0.001.
risk of severe case, 22.0% lower, RR 0.78, p < 0.001.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Schlesinger et al., 19 May 2023, peer-reviewed, 10 authors.
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Risk phenotypes of diabetes and association with COVID-19 severity and death: an update of a living systematic review and meta-analysis
Sabrina Schlesinger, Alexander Lang, Nikoletta Christodoulou, Philipp Linnerz, Kalliopi Pafili, Oliver Kuss, Christian Herder, Manuela Neuenschwander, Janett Barbaresko, Michael Roden
Diabetologia, doi:10.1007/s00125-023-05928-1
Aims/hypothesis To provide a systematic overview of the current body of evidence on high-risk phenotypes of diabetes associated with COVID-19 severity and death. Methods This is the first update of our recently published living systematic review and meta-analysis. Observational studies investigating phenotypes in individuals with diabetes and confirmed SARS-CoV-2 infection with regard to COVID-19-related death and severity were included. The literature search was conducted from inception up to 14 February 2022 in PubMed, Epistemonikos, Web of Science and the COVID-19 Research Database and updated using PubMed alert to 1 December 2022. A random-effects meta-analysis was used to calculate summary relative risks (SRRs) with 95% CIs. The risk of bias was evaluated using the Quality in Prognosis Studies (QUIPS) tool and the certainty of evidence using the GRADE approach. Results A total of 169 articles (147 new studies) based on approximately 900,000 individuals were included. We conducted 177 meta-analyses (83 on COVID-19-related death and 94 on COVID-19 severity). Certainty of evidence was strengthened for associations between male sex, older age, blood glucose level at admission, chronic insulin use, chronic metformin use (inversely) and pre-existing comorbidities (CVD, chronic kidney disease, chronic obstructive pulmonary disease) and COVID-19-related death. New evidence with moderate to high certainty emerged for the association between obesity (SRR [95% CI] 1.18 [1.04, 1.34], n=21 studies), HbA 1c (53-75 mmol/mol [7-9%]: 1.18 [1.06, 1.32], n=8), chronic glucagon-like peptide-1 receptor agonist use (0.83 [0.71, 0.97], n=9), pre-existing heart failure (1.33 [1.21, 1.47], n=14), pre-existing liver disease (1.40 [1.17, 1.67], n=6), the Charlson index (per 1 unit increase: 1.33 [1.13, 1.57], n=2), high levels of C-reactive protein (per 5 mg/l increase: 1.07 [1.02, 1.12], n=10), aspartate aminotransferase level (per 5 U/l increase: 1.28 [1.06, 1.54], n=5), eGFR (per 10 ml/min per 1.73 m 2 increase: 0.80 [0.71, 0.90], n=6), lactate dehydrogenase level (per 10 U/l increase: 1.03 [1.01, 1.04], n=7) and lymphocyte count (per 1×10 9 /l increase: 0.59 [0.40, 0.86], n=6) and COVID-19-related death. Similar associations were observed between risk phenotypes of diabetes and severity of COVID-19, with some new evidence on existing 0.38], n=3), pre-existing hypertension (1.23 [1.14, 1.33], n=49), neuropathy and cancer, and high IL-6 levels. A limitation of this study is that the included studies are observational in nature and residual or unmeasured confounding cannot be ruled out. Conclusions/interpretation Individuals with a more severe course of diabetes and pre-existing comorbidities had a poorer prognosis of COVID-19 than individuals with a milder course of the disease. Registration PROSPERO registration no. CRD42020193692. Previous version This is a living systematic review and meta-analysis. The previous version can be found at https:// link. sprin ger...
Supplementary Information The online version contains peer-reviewed but unedited supplementary material available at https:// doi. org/ 10. 1007/ s00125-023-05928-1. Authors' relationships and activities CH is a member of the editorial board of Diabetologia. MR received personal fees from Boehringer Ingelheim Pharma, Eli Lilly, Fishawack Group, Novo Nordisk, Sanofi US, Target NASH and Terra Firma, and investigator-initiated research support from Boehringer Ingelheim, Nutricia/Danone and Sanofi-Aventis. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement MR and SS designed the study and wrote the first draft of the manuscript. AL, NC, PL, MN, JB and SS performed the literature search and literature screening. CH assisted in the selection of eligible studies. AL, NC, PL and MN extracted data and KP assisted with extraction of data on treatment. AL, NC, PL, MN and SS assessed the risk of bias of the studies and JB, MN and SS assessed the certainty of evidence of the associations. SS performed the statistical analysis and OK assisted with the statistical analysis. All authors contributed to data acquisition, data interpretation and revision of manuscript drafts and read and approved the final manuscript. SS is the guarantor of this work. Authors and Affiliations Sabrina
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