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Diabetes, obesity, and glucose control affect COVID-19 and its outcomes

Presenter: Dror Dicker, MD, Sackler School of Medicine, Tel Aviv University, Israel

Evidence-Based Medicine and COVID-19: Global Health Lessons: A Joint ACP and EFIM Session. Presented April 28, 2023


Diabetes and obesity increase the risks for hospital admission and death in individuals infected with COVID-19. The interaction between obesity, diabetes, and COVID-19 and the effect of various glucose-lowering medications on COVD-19 outcomes were reviewed by Dror Dicker, MD, Sackler School of Medicine, Tel Aviv University, Israel.

Higher body mass index (BMI) has been identified as a major risk factor for COVID-19 death, with the greatest risk observed in persons with BMI higher than 40 kg/m2. Obesity is associated with many metabolic complications, he explained. Inflammation in adipose tissue is the main cause of these complications, and this inflammation is chronic in obese individuals. Hypertrophic adipocytes in obese individuals lead to macrophage activation and production of proinflammatory cytokines and chemokines.

The level of expression of angiotensin-converting enzyme 2 (ACE2) is elevated in adipose tissue, and SARS-CoV-2 invades cells through the ACE2 receptor. As vasodilating peptides with anti-inflammatory activity, higher levels of ACE1-7, formed in the endothelial layer of human blood vessels, are desirable. SARS-CoV-2 causes a disruption in the balance of ACE1-7 and ACE2 to favor ACE2 expression, which aids SARS-CoV-2 pathogenicity.

Invasion of SARS-CoV-2 into cells leads to impaired interferon gamma, and this reduced level of interferon gamma impairs the clearance of virus from the cells, whereas high expression of interferon gamma reduces the viral expression. “People with obesity have leptin resistance, shutting down activation of interferon gamma, reducing the effectiveness of removing SARS-CoV-2 from the body,” said Dr. Dicker.

SARS-CoV-2 also leads to hypercoagulability, he said. Lower levels of antithrombin are present in people with obesity, which also promotes a higher risk for thrombosis. This is another risk factor for morbidity and mortality.

People with obesity with viral infection are more contagious than lean people, as obesity alters within-host viral population dynamics. In studies in people infected with influenza H1N1, both the amount of viral RNA shed as well as the duration of positive samples for the virus are increased in obese adults, and BMI affects the clearance of this virus from the throat. In one study, it took 21 days for H1N1-infected obese individuals to become negative by polymerase chain reaction versus 7 to 10 days in lean individuals.

People with obesity are also less immune after vaccination compared with lean subjects, with lower levels of immunoglobulin. “In SARS-CoV-2, the higher the BMI, the lower the immunoglobulins that can be produced,” he said.

A higher prevalence of type 2 diabetes is observed in individuals with severe COVID-19 symptoms. The risk of COVID-19-related mortality is nearly triple in those with type 2 diabetes compared with those without type 2 diabetes, he noted. Apart from diabetes, a high glucose level itself is a risk factor for poor outcomes in persons with COVID-19. Patients with diabetes with adequate glucose control (< 126 mg/dL) have the same risk of mortality from COVID-19 as persons without diabetes.

“People with diabetes have the same disease that COVID-19 creates,” said Dr. Dicker, noting that induction of beta cell transdifferentiation produces an abundance of glucagon rather than insulin. Further, levels of interleukin-6 (IL-6) are higher in SARS-CoV-2-infected persons, and IL-6 overexpression can cause insulin resistance and increases in glucose level.

Treatment approaches

Treatment with metformin and sodium-glucose cotransporter 2 (SGLT2) inhibitors has been shown to reduce COVID-19-related mortality relative to other antidiabetes medications. “Not surprisingly, metformin reduces inflammation and blood glucose level,” he said.

SGLT2 inhibitors reduce levels of C-reactive protein, IL-6, and ferritin in human studies, thereby decreasing systemic inflammation to limit organ damage, which may explain the favorable effect of SGLT2 inhibitors on mortality in COVID-19 patients, said Dr. Dicker.

Initially, treatment with dipeptidyl peptidase 4 (DPP4) inhibitors (also called gliptins) was thought to worsen COVID-19-related outcomes but prospective studies have shown this not to be the case.

References

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McGonagle D, Sharif K, O'Regan A, Bridgewood C. The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev 2020; 19(6):102537. doi:10.1016/j.autrev.2020.102537

Beyerstedt S, Casaro EB, Rangel ÉB. COVID-19: angiotensin-converting enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 infection. Eur J Clin Microbiol Infect Dis 2021; 40(5):905–919. doi:10.1007/s10096-020-04138-6

Gazzaruso C, Paolozzi E, Valenti C, et al. Association between antithrombin and mortality in patients with COVID-19. A possible link with obesity. Nutr Metab Cardiovasc Dis 2020; 30(11):1914–1919. doi:10.1016/j.numecd.2020.07.040

Honce R, Schultz-Cherry S. Impact of obesity on influenza A virus pathogenesis, immune response, and evolution. Front Immunol 2019; 10:1071. doi:10.3389/fimmu.2019.01071

Gao M, Piernas C, Astbury NM, et al. Associations between body-mass index and COVID-19 severity in 6·9 million people in England: a prospective, community-based, cohort study. Lancet Diabetes Endocrinol 2021; 9(6):350–359. doi:10.1016/S2213-8587(21)00089-9

Cai Y, Shi S, Yang F, Yi B, Chen X, Li J, Wen Z. Fasting blood glucose level is a predictor of mortality in patients with COVID-19 independent of diabetes history. Diabetes Res Clin Pract 2020; 169:108437. doi: 10.1016/j.diabres.2020.108437

Reges O, Test T, Hoshen M, et al. Time-varying association of acute and post-acute COVID-19 with new-onset diabetes mellitus among hospitalized and non-hospitalized patients. BMJ Open Diabetes Res Care 2023; 11(1):e003052. doi:10.1136/bmjdrc-2022-003052

Caruso I, Giorgino F. The diabetic lung: an easy target for SARS-CoV-2? Diabetes Metab Res Rev 2020;36:e3346. doi: 10.1002/dmrr.3346

Tang X, Uhl S, Zhang T, et al. SARS-CoV-2 infection induces beta cell transdifferentiation. Cell Metab 2021; 33(8):1577–1591. doi: 10.1016/j.cmet.2021.05.015

Samuel SM, Varghese E, Büsselberg D. 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

Katsiki N, Ferrannini E. Anti-inflammatory properties of antidiabetic drugs: A "promised land" in the COVID-19 era? J Diabetes Complications. 2020; 34(12):107723. doi:10.1016/j.jdiacomp.2020.107723

Kosiborod MN, Esterline R, Furtado RHM, et al. Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol 2021; 9(9):586–594. doi:10.1016/S2213-8587(21)00180-7

Disclosures

Dror Dicker, MD, reports no relationships with entities whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

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