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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.

adverse short-term outcomes after COVID-19, including hospitalization, intensive care unit (ICU) admission, and mortality among persons with diabetes by using a large nationwide U.S. cohort of veterans (2). As the pandemic continues, many more individuals with diabetes have been diagnosed with COVID-19. In addition, mortality from COVID-19 has changed over time (3), both of which might impact risk factors for short-term outcomes from COVID-19 among individuals with diabetes. The objective of this report is to expand our previous analysis to identify risk factors for short-term adverse outcomes among veterans with diabetes and COVID-19 infection over additional waves of the epidemic and in a much larger population (n = 64,892).

RESEARCH DESIGN AND METHODS
The Veterans Health Administration (VHA) is the largest integrated health care system in the U.S (4). This analysis used data from the Corporate Data Warehouse (CDW), a data repository derived from the VHA's integrated electronic medical record, including a COVID-19 Shared Data Resource containing analytic variables for all VHA enrollees tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (5). We identified enrollees with diabetes and one or more positive nasal swab(s) for SARS-CoV-2 between 1 March 2020 and 10 March 2021 (n = 64,892). The index date was defined as the date of the first positive COVID-19 test, most of which were performed in Veterans Affairs laboratories using U.S. Food and Drug Administration-approved RealTime (Abbott Laboratories) or Xpert-Xpress (Cepheid) SARS-CoV-2 assays.
Diabetes was defined as present if any of the following criteria were fulfilled: 1) two or more abnormal laboratory values from plasma or serum (random glucose >199 mg/dL, fasting glucose >125 mg/dL, 2-h glucose from an oral glucose tolerance test >199 mg/dL) or whole blood (HbA 1c >6.4%) (6); 2) two outpatient or one inpatient International Classification of Diseases, Ninth Revision Clinical Modification (ICD-9-CM) or ICD-10-CM codes of 250 or E08-E13; or 3) receipt of an initial We fit logistic regression models and Cox proportional hazards models assessing associations of the following exposures with COVID outcomes: most recent HbA 1c in the 2 years before enrollment (<7.0%, 7.0-7.9%, 8.0-8.9%, and $9.0%) and prior glucose-lowering medication use (insulin, metformin, dipeptidyl peptidase 4 inhibitors [DPP4i], glucagon-like peptide-1 receptor agonists [GLP1-RA], sodium-glucose cotransporter 2 inhibitor [SGLT2i], sulfonylureas, or thiazolidinediones). A term for each medication (receipt/no receipt) was included separately in the model such that the odds ratio (OR) or hazard ratio (HR) for each model can be interpreted as the independent association of use of each medication compared with no use of the medication. In addition to terms for most recent HbA 1c and prior glucoselowering medication use, analyses were also adjusted for age, sex, race/ethnicity, BMI, tobacco use, use of an ACE inhibitor (ACEi), angiotensin receptor blocker (ARB), statin, or platelet inhibitor, a history of hypertension, cardiovascular disease, or heart failure defined by ICD-9/ ICD-10 codes; and chronic kidney disease (CKD) defined by categories of estimated glomerular filtration rate (eGFR), facility location, month of SARS-CoV-2 diagnosis, and urban/rural residence by home address. We used multiple imputation with 10 sets of imputations for analyses that included BMI or CKD due to 20% missing values for each of these variables.

Data Resource and Availability
The VHA's and the Department of Veterans Affairs' policies do not permit sharing electronic health record data.

CONCLUSIONS
In this large national cohort of veterans with diabetes and COVID-19, higher HbA 1c (in particular HbA 1c $9.0%) was associated with higher odds of hospitalization, ICU admission, and death by 30 days as well as greater risk of death over an average 4.4 months and up to 13.1 months of follow-up. Use of GLP1- RA, metformin, or SGLT2i was associated with lower odds or hazard of adverse outcomes, while prior insulin use was associated with higher odds or hazard of all outcomes. Prior use of an ACEi, ARB, or statin were all associated with lower odds of 30-day mortality and lower HR for death. We previously reported on associations of glycemia and glucose-lowering medication use in a much smaller cohort of veterans with diabetes and COVID-19 (n = 13,863) as part of a more comprehensive analysis (2). There are some notable differences between the findings seen in our previous report and those in the current analysis. In particular, in our previous analysis, HbA 1c was associated with death but not with hospitalization or ICU admission, and the association was present only among individuals with HbA 1c $9.0%. The current study shows a statistically significant association of HbA 1c $9.0% for all outcomes and larger point estimates ranging from 1.22 to 1.32. This is in line with a population-based study of almost 3 million individuals with type 2 diabetes in the U.K. conducted very early in the pandemic, in which, compared with HbA 1c of 6.5-7.0%, the HR for COVID-19-related mortality was significantly higher in those with HbA 1c of 7.6-8. . No significant association was seen between any of the outcomes and treatment with other classes of diabetes antiglycemic medication use, including metformin, thiazolidinediones, DPP4i, GLP1-RA, and SGLT2i. The discrepancy in findings between this analysis and our earlier one is therefore more likely due to differences in study power than to trends in the relationship between HbA 1c and mortality over time.
Cardiovascular and glucose-lowering medications, including metformin and statins, have been hypothesized to protect against adverse outcomes from COVID-19 (8), for example, by altering viral entry into cells or reducing cardiovascular or renal events through pathways independent of SARS-CoV-2. Consistent with this, in a nationwide U.K. cohort, adjusted HR for death comparing recorded versus no recorded prescription were 0.77 (95% CI 0.73-0.81) for metformin, 1.42 (95% CI 1.35-1.49) for insulin, 0.82 (95% CI 0.74-0.91) for SGLT2i, 0.94 (95% CI 0.89-0.99) for sulfonylureas, 0.94 (95% CI 0.83-1.07) for GLP1-RA, and 1.07 (95% CI 1.01-1.13) for DPP4i (9), quantitatively very similar estimates to those in the current report. An inverse association of prior GLP1-RA and SGLT2i use with 60-day mortality after COVID-19 compared with prior DPP4i use was also recently reported (OR 0.54 [95% CI 0.37-0.80] and 0.66 [95% CI 0.50-0.86], respectively) in a smaller U.S.-based cohort (10). However, protective associations for these and other premorbid medications are not consistently seen across observational cohorts with COVID-19, which is often attributed to differences in study populations or strategies to adjust for confounding. Another possible explanation is that some of these differences may be due to study power. For example, in our previous report, prior use of a GLP1-RA or SGLT2i was not associated with shortterm adverse outcomes in veterans with COVID-19 and diabetes (2) after controlling for confounders including age, BMI, cardiovascular comorbidities, most recent HbA 1c , race/ethnicity, and urban/rural/highly rural residence.
Strengths of the current analysis included 1) a large, well-characterized national sample and 2) availability of medical care/medications without cost or at low cost to all VHA enrollees, which likely decreases the contribution of unmeasured financial factors to differences in the quality of care received.
Limitations include: 1) Prescriptions, hospitalizations, or COVID diagnoses that occurred outside VHA were not captured. 2) Factors related to the diabetes diagnosis, such as duration of diabetes or diabetes subtype (type 1 vs. type 2 diabetes), were not captured, although diabetes in VHA is presumed to predominantly be type 2 diabetes, because persons affected by type 1 diabetes are not eligible for military service. 3) In both our current and previous analyses, we were unable to evaluate whether a given HbA 1c level influenced receipt of a glucose-lowering medication (i.e., was a confounder) or reflected an on-treatment effect (i.e., was a mediator). Associations of prior medication use (GLP1-RA, metformin, SGLT2i, ACEi, ARB, or statin) with short-term outcomes from COVID-19 therefore require further study using rigorous methods to address unmeasured confounding. 4) Finally, given the timing of this study, we were unable to evaluate mediating or moderating effects of vaccination use due to very limited vaccination coverage of our population by the index date.
In conclusion, among veterans with diabetes and COVID-19, higher HbA 1c (in particular HbA 1c $9%) and prior insulin use were associated with adverse outcomes, including hospitalization, ICU admission, and death, while prior use of GLP1-RA, metformin, SGLT2i, ACEi, ARB, or statin were inversely associated with adverse outcomes over up to 13 months of follow-up. Future studies are needed to identify risk factors for long-term adverse outcomes after COVID-19 among individuals with diabetes.