SARS-CoV-2 infection as a trigger of type 2 diabetes in adults: a population-based cohort study in Sweden using a double negative control design

Previous studies suggest an increased risk of new-onset type 2 diabetes (T2D) following SARS-CoV-2 infection, which may be subject to detection bias from increased health care contacts among the infected. We aimed to assess the causal effect of SARS-CoV-2 infection on new-onset T2D using a test-negative design and negative control outcomes. We included all individuals aged ≥ 18 years registered in Sweden on 1 February 2020 without prior T2D who ordered a SARS-CoV-2 test through the Swedish healthcare service between 1 February 2020 and 28 February 2022 (N = 3,175,958). A test-negative design was applied, matching infected individuals with up to five controls based on birth year, sex, region, vaccination status, and test date. Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between infection and new-onset T2D. The influence of COVID-19 severity was assessed using stratified Cox regression. Negative control outcomes anaemia, chronic kidney disease, and thyroid disorder were used to evaluate detection bias. SARS-CoV-2 infection was associated with a 12% (HR 1.12, 95% CI 1.04-1.20) increase in T2D risk, driven by elevated incidence during weeks 1-4 post-infection. Increased risk was concentrated among individuals hospitalized (HR 3.60, 95% CI 2.71-4.78) or admitted to intensive care (HR 4.85, 95% CI 2.60-9.05). Negative control outcomes showed similar patterns. Our findings do not support a causal effect of SARS-CoV-2 infection on new-onset T2D. Instead, observed increases appear largely attributable to increased detection of early-phase, sub-clinical T2D cases during hospitalization or intensive care.