Beyond HbA1c: diabetes subgroups reveal differential risk of neuropathy
Aims: To evaluate and compare long-term comorbidity and mortality risk across the following subgroups of adult-onset diabetes: Severe autoimmune diabetes (SAID), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), and mild obesity-related diabetes (MOD) and mild age-related (MARD) diabetes.
Methods: This large prospective cohort study included 19,076 individuals with newly diagnosed diabetes from the Swedish All New Diabetics in Scania cohort. Participants were classified into the five subgroups (SAID, SIDD, SIRD, MOD, MARD) using clinical variables (HbA1c, BMI, age, HOMA2 indices, GAD antibodies). Prevalent and incident comorbidities, including neuropathy, were assessed using registry data, and associations were analysed using logistic regression and Fine–Gray proportional hazards models with mild age-related diabetes (MARD) as the reference group.
Results: Risk of complications differed across diabetes subgroups. For neuropathy, the highest adjusted risk was observed in SAID) (HR 2.58, 95% CI 1.87–3.56), followed by SIDD (HR 2.13, 95% CI 1.69–2.70) and SIRD (HR 1.54, 95% CI 1.21–1.97). Adjustment for insulin resistance (lnHOMA2-IR) did not alter these associations. After additional adjustment for HbA1c, associations remained significant only for SAID (HR 1.86, 95% CI 1.28–2.70) and SIRD (HR 1.47, 95% CI 1.15–1.88).
Conclusions: Diabetes subgroups show distinct neuropathy risks, highlighting that mechanisms beyond hyperglycaemia contribute to nerve damage and complication risk.
Comments: In this study neuropathy risk differed substantially across biologically defined diabetes subgroups. The increased neuropathy risk in both insulin-deficient (SIDD, SAID) and insulin-resistant (SIRD) subgroups aligns with emerging evidence that metabolic, inflammatory, and vascular pathways contribute alongside hyperglycaemia. Notably, while the association in severe insulin-deficient diabetes (SIDD) appears largely driven by hyperglycaemia, persistent risk in severe autoimmune diabetes (SAID) and severe insulin-resistant diabetes (SIRD) after adjustment for HbA1c suggests that neuropathy risk is not solely glucose-mediated but linked to additional pathophysiological mechanisms.
A key strength is the large, well-characterised prospective cohort of individuals included at the time of diabetes diagnosis with long-term follow-up. Limitations include the use of registry-based diagnoses, which likely underestimate neuropathy and do not allow differentiation between neuropathy subtypes. Additionally, diabetes subgroup classification is based on baseline variables and may evolve over time.
Astrid Wiggers
Reference. Asplund O, Thangam M, Prasad RB, Lejonberg C, Ekström O, Hakaste L, Smith JG, Rosengren AH, Oscarsson J, Carlsson B, Tuomi T, Hansson O, Ahlqvist E. Comorbidities and mortality in subgroups of adults with diabetes with up to 14 years follow-up: a prospective cohort study in Sweden. Lancet Diabetes Endocrinol. 2026 Jan;14(1):29-40. doi: 10.1016/S2213-8587(25)00283-9. Epub 2025 Nov 14. PMID: 41248671.
