Erratum. The Incidence of Diabetes Among 2,777,768 Veterans With and Without Recent SARS-CoV-2 Infection. Diabetes Care 2022;45:782-788.

For the article cited above, an issue in the way the outcome (diabetes status) was coded was identified during a follow-up analysis. Participants with ICD-10 codes for diabetes at any time were excluded from the analysis, and incident diabetes was identified based only on laboratory values and glucose-lowering medications. This resulted in a substantial underestimate of the number of cases of incident diabetes in the cohort. The coding issue was corrected, the analysis was repeated, and the corrected code was validated by an independent analyst. After these steps, in agreement with the original article, there remained a statistically significant and positive association of SARS-CoV-2 infection with incident diabetes in the corrected analysis. The largest differences between the original and corrected analysis were seen in the analyses of all male participants in whom the association of SARS-CoV-2 infection with incident diabetes was attenuated in the corrected analysis compared with the original results (odds ratio 120 days: 2.56 [2.32-2.83] original vs. 1.75 [1.63-1.88] corrected; odds ratio all-time: 1.95 [1.80-2.12] original vs. 1.44 [1.36-1.52] corrected). For hospitalized male participants, the differences were smaller. In agreement with the original article, there was no association of SARS-CoV-2 infection with incident diabetes in women in the corrected analysis. Finally, in the corrected models, the P values for the sex * SARS-CoV-2 infection interaction terms were statistically significant except for participants hospitalized in the first 30 days (all available follow-up time). The authors apologize for the error. The online version of the article (https://doi.org/10.2337/dc21-1686) has been updated with the corrected data.

SARS-CoV-2 infection is associated with higher odds of insulin treatment but not with hemoglobin A1c at 120 days in U.S. Veterans with new-onset diabetes.

Aims: To examine associations of SARS-CoV-2 infection/COVID-19 with insulin treatment in new-onset diabetes. Methods: We conducted a retrospective cohort study using Veterans Health Administration data (March 1, 2020-June 1, 2022). Individuals with ≥1 positive nasal swab for SARS-CoV-2 (n = 6,706) comprised the exposed group, and individuals with no positive swab and ≥1 laboratory test of any type (n = 20,518) the unexposed group. For exposed, the index date was the date of first positive swab, and for unexposed a random date during the month of the qualifying laboratory test. Among Veterans with new-onset diabetes after the index date, we modeled associations of SARS-CoV-2 with most recent A1c prior to insulin treatment or end of follow-up and receipt of >1 outpatient insulin prescription starting within 120 days. Results: SARS-CoV-2 was associated with a 40% higher odds of insulin treatment compared to no positive test (95%CI 1.2-1.8) but not with most recent A1c (ß 0.00, 95%CI -0.04-0.04). Among Veterans with SARS-CoV-2, ≥2 vaccine doses prior to the index date was marginally associated with lower odds of insulin treatment (OR 0.6, 95%CI 0.3-1.0). Conclusions: SARS-CoV-2 is associated with higher odds of insulin treatment but not with higher A1c. Vaccination may be protective.

Consensus elements for observational research on COVID-19-related long-term outcomes.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its long-term outcomes may be jointly caused by a wide range of clinical, social, and economic characteristics. Studies aiming to identify mechanisms for SARS-CoV-2 morbidity and mortality must measure and account for these characteristics to arrive at unbiased, accurate conclusions. We sought to inform the design, measurement, and analysis of longitudinal studies of long-term outcomes among people infected with SARS-CoV-2. We fielded a survey to an interprofessional group of clinicians and scientists to identify factors associated with SARS-CoV-2 infection and subsequent outcomes. Using an iterative process, we refined the resulting list of factors into a consensus causal diagram relating infection and 12-month mortality. Finally, we operationalized concepts from the causal diagram into minimally sufficient adjustment sets using common medical record data elements. Total 31 investigators identified 49 potential risk factors for and 72 potential consequences of SARS-CoV-2 infection. Risk factors for infection with SARS-CoV-2 were grouped into five domains: demographics, physical health, mental health, personal social, and economic factors, and external social and economic factors. Consequences of coronavirus disease 2019 (COVID-19) were grouped into clinical consequences, social consequences, and economic consequences. Risk factors for SARS-CoV-2 infection were developed into a consensus directed acyclic graph for mortality that included two minimally sufficient adjustment sets. We present a collectively developed and iteratively refined list of data elements for observational research in SARS-CoV-2 infection and disease. By accounting for these elements, studies aimed at identifying causal pathways for long-term outcomes of SARS-CoV-2 infection can be made more informative.

Does diabetes risk after SARS-CoV-2 infection depend on the viral variant?

SARS-CoV-2 infection is associated with an elevated risk of new-onset diabetes. With infections forecast to rise in the coming months, this may exacerbate an existing public health crisis by increasing rates of diabetes worldwide. Much remains to be learned about a causal link between SARS-CoV-2 and incident diabetes. This is complicated by the rapid evolution of new SARS-CoV-2 variants that may have differential effects on development of diabetes. It is possible that some variants confer an increased risk, while others carry little to no risk. Distinguishing between these possibilities could be key in preventing or screening for new-onset diabetes, and could inform care of at-risk individuals with recent SARS-CoV-2 infection.

Going viral in the islet: mediators of SARS-CoV-2 entry beyond ACE2.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Following initial infection of airway epithelia, SARS-CoV-2 invades a wide range of cells in multiple organs, including pancreatic islet cells. Diabetes is now recognised as a risk factor for severe COVID-19 outcomes, including hospitalisation and death. Additionally, COVID-19 is associated with a higher risk of new-onset diabetes and metabolic complications of diabetes. One mechanism by which these deleterious outcomes may occur is via the destruction of insulin-producing islet ß cells, either directly by SARS-CoV-2 entry into ß cells or indirectly due to inflammation and fibrosis in the surrounding microenvironment. While the canonical pathway of viral entry via angiotensin-converting enzyme 2 (ACE2) has been established as a major route of SARS-CoV-2 infection in the lung, it may not be solely responsible for viral entry into the endocrine pancreas. This is likely due to the divergent expression of viral entry factors among different tissues. For example, expression of ACE2 has not been unequivocally demonstrated in ß cells. Thus, it is important to understand how other proteins known to be highly expressed in pancreatic endocrine cells may be involved in SARS-CoV-2 entry, with the view that these could be targeted to prevent the demise of the ß cell in COVID-19. To that end, this review discusses alternate receptors of SARS-CoV-2 (CD147 and GRP78), as well as mediators (furin, TMPRSS2, cathepsin L, ADAM17, neuropilin-1, and heparan sulphate) that may facilitate SARS-CoV-2 entry into pancreatic islets independent of or in conjunction with ACE2.

Associations of statin use with 30-day adverse outcomes among 4 801 406 US Veterans with and without SARS-CoV-2: an observational cohort study.

OBJECTIVE: To estimate associations of statin use with hospitalisation, intensive care unit (ICU) admission and mortality at 30 days among individuals with and without a positive test for SARS-CoV-2. DESIGN: Retrospective cohort study. SETTING: US Veterans Health Administration (VHA). PARTICIPANTS: All veterans receiving VHA healthcare with ≥1 positive nasal swab for SARS-CoV-2 between 1 March 2020 and 10 March 2021 (cases; n=231 154) and a comparator group of controls comprising all veterans who did not have a positive nasal swab for SARS-CoV-2 but who did have ≥1 clinical lab test performed during the same time period (n=4 570 252). MAIN OUTCOMES: Associations of: (1) any statin use, (2) use of specific statins or (3) low-intensity/moderate-intensity versus high-intensity statin use at the time of positive nasal swab for SARS-CoV-2 (cases) or result of clinical lab test (controls) assessed from pharmacy records with hospitalisation, ICU admission and death at 30 days. We also examined whether associations differed between individuals with and without a positive test for SARS-CoV-2. RESULTS: Among individuals who tested positive for SARS-CoV-2, statin use was associated with lower odds of death at 30 days (OR 0.81 (95% CI 0.77 to 0.85)) but not with hospitalisation or ICU admission. Associations were similar comparing use of each specific statin to no statin. Compared with low-/moderate intensity statin use, high-intensity statin use was not associated with lower odds of ICU admission or death. Over the same period, associations of statin use with 30-day outcomes were significantly stronger among individuals without a positive test for SARS-CoV-2: hospitalisation OR 0.79 (95% CI 0.77 to 0.80), ICU admission OR 0.86 (95% CI 0.81 to 0.90) and death 0.60 (95% CI 0.58 to 0.62; p for interaction all <0.001). CONCLUSIONS: Associations of statin use with lower adverse 30-day outcomes are weaker among individuals who tested positive for SARS-CoV-2 compared with individuals without a positive test, indicating that statins do not exert SARS-CoV-2 specific effects.

Associations of statin use with 30-day adverse outcomes among 4 801 406 US Veterans with and without SARS-CoV-2: an observational cohort study

Objective To estimate associations of statin use with hospitalisation, intensive care unit (ICU) admission and mortality at 30 days among individuals with and without a positive test for SARS-CoV-2. Design Retrospective cohort study. Setting US Veterans Health Administration (VHA). Participants All veterans receiving VHA healthcare with ≥1 positive nasal swab for SARS-CoV-2 between 1 March 2020 and 10 March 2021 (cases;n=231 154) and a comparator group of controls comprising all veterans who did not have a positive nasal swab for SARS-CoV-2 but who did have ≥1 clinical lab test performed during the same time period (n=4 570 252). Main outcomes Associations of: (1) any statin use, (2) use of specific statins or (3) low-intensity/moderate-intensity versus high-intensity statin use at the time of positive nasal swab for SARS-CoV-2 (cases) or result of clinical lab test (controls) assessed from pharmacy records with hospitalisation, ICU admission and death at 30 days. We also examined whether associations differed between individuals with and without a positive test for SARS-CoV-2. Results Among individuals who tested positive for SARS-CoV-2, statin use was associated with lower odds of death at 30 days (OR 0.81 (95% CI 0.77 to 0.85)) but not with hospitalisation or ICU admission. Associations were similar comparing use of each specific statin to no statin. Compared with low-/moderate intensity statin use, high-intensity statin use was not associated with lower odds of ICU admission or death. Over the same period, associations of statin use with 30-day outcomes were significantly stronger among individuals without a positive test for SARS-CoV-2: hospitalisation OR 0.79 (95% CI 0.77 to 0.80), ICU admission OR 0.86 (95% CI 0.81 to 0.90) and death 0.60 (95% CI 0.58 to 0.62;p for interaction all <0.001). Conclusions Associations of statin use with lower adverse 30-day outcomes are weaker among individuals who tested positive for SARS-CoV-2 compared with individuals without a positive test, indicating that statins do not exert SARS-CoV-2 specific effects.

Prior Glucose-Lowering Medication Use and 30-Day Outcomes Among 64,892 Veterans With Diabetes and COVID-19.

OBJECTIVE: To identify preinfection risk factors for adverse outcomes among veterans with diabetes and coronavirus disease 2019 (COVID-19) infection. RESEARCH DESIGN AND METHODS: We identified all Veterans Health Administration patients with diabetes and one or more positive nasal swab(s) for severe acute respiratory syndrome coronavirus 2 (1 March 2020-10 March 2021) (n = 64,892). We examined associations of HbA1c and glucose-lowering medication use with hospitalization, intensive care unit (ICU) admission, and mortality at 30 days using logistic regression models and during 4.4 months of follow-up (range <1-13.1) using proportional hazards models. RESULTS: Compared with HbA1c <7.0%, HbA1c ≥9.0% was associated with higher odds of hospitalization, ICU admission, and death at 30 days (odds ratio [OR] 1.27 [95% CI 1.19-1.35], 1.28 [95% CI 1.15-1.42], 1.30 [95% CI 1.17-1.44], respectively) as well as higher risk of death over 4.4 months (hazard ratio [HR] 1.22 [95% CI 1.12-1.32]). Insulin use was associated with higher odds of hospitalization, ICU admission, and death (OR 1.12 [95% CI 1.07-1.18], 1.12 [95% CI 1.04-1.22], and 1.18 [95% CI 1.09-1.27], respectively) and higher risk of death (HR 1.12 [95% CI 1.07-1.18]). Sodium-glucose cotransporter 2 inhibitor (SGLT2i), glucagon-like peptide-1 receptor agonist (GLP1-RA), or angiotensin receptor blocker use were associated with lower odds of hospitalization (OR 0.92 [95% CI 0.85-0.99], 0.88 [95% CI 0.81-0.96], and 0.94 [95% CI 0.89-0.99], respectively). Metformin and SGLT2i use were associated with lower odds (OR 0.84 [95% CI 0.78-0.91], 0.82 [95% CI 0.72-0.94], respectively) and risk of death (HR 0.84 [95% CI 0.79-0.89], 0.82 [95% CI 0.74-0.92], respectively). CONCLUSIONS: Among veterans with diabetes and COVID-19, higher HbA1c and insulin use were directly associated with adverse outcomes, while use of a GLP1-RA, metformin, and SGLT2i was inversely associated.

Risk factors for adverse outcomes among 35 879 veterans with and without diabetes after diagnosis with COVID-19.

INTRODUCTION: Risk factors and mediators of associations of diabetes with COVID-19 outcomes are unclear. RESEARCH DESIGN AND METHODS: We identified all veterans receiving Department of Veterans Affairs healthcare with ≥1 positive nasal swab for SARS-CoV-2 (28 February-31 July 2020; n=35 879). We assessed associations of diabetes (with and without insulin use) with hospitalization, intensive care unit (ICU) admission, or death at 30 days, and with hazard of death until the censoring date. Among participants with diabetes (n=13 863), we examined associations of hemoglobin A1c and antihyperglycemic medication use with COVID-19 outcomes. We estimated mediation between diabetes and outcomes by comorbidities (cardiovascular disease, heart failure, and chronic kidney disease), statin or ACE inhibitor/angiotensin receptor blocker (ARB) use, and cardiac biomarkers (brain natriuretic peptide and troponin). RESULTS: Diabetes with and without insulin use was associated with greater odds of hospitalization, ICU admission, and death at 30 days, and with greater hazard of death compared with no diabetes (OR 1.73, 1.76 and 1.63, and HR 1.61; and OR 1.39, 1.49 and 1.33, and HR 1.37, respectively, all p<0.0001). Prior sulfonylurea use was associated with greater odds of hospitalization and prior insulin use with hospitalization and death among patients with diabetes; among all participants, statin use was associated with lower mortality and ARB use with lower odds of hospitalization. Cardiovascular disease-related factors mediated <20% of associations between diabetes and outcomes. CONCLUSIONS: Diabetes is independently associated with adverse outcomes from COVID-19. Associations are only partially mediated by common comorbidities.

A Case for Targeting Th17 Cells and IL-17A in SARS-CoV-2 Infections.

SARS-CoV-2, the virus causing COVID-19, has infected millions and has caused hundreds of thousands of fatalities. Risk factors for critical illness from SARS-CoV-2 infection include male gender, obesity, diabetes, and age >65. The mechanisms underlying the susceptibility to critical illness are poorly understood. Of interest, these comorbidities have previously been associated with increased signaling of Th17 cells. Th17 cells secrete IL-17A and are important for clearing extracellular pathogens, but inappropriate signaling has been linked to acute respiratory distress syndrome. Currently there are few treatment options for SARS-CoV-2 infections. This review describes evidence linking risk factors for critical illness in COVID-19 with increased Th17 cell activation and IL-17 signaling that may lead to increased likelihood for lung injury and respiratory failure. These findings provide a basis for testing the potential use of therapies directed at modulation of Th17 cells and IL-17A signaling in the treatment of COVID-19.