Pain phenotypes and chronic pain burden are associated with atherosclerotic cardiovascular disease and vascular disease progression in participants with type 2 diabetes: a UK Biobank cohort study with multistate analysis

Background Chronic pain is common in type 2 diabetes mellitus (T2DM), but its cardiovascular relevance across pain phenotypes and vascular disease-progression pathways remains uncertain. We examined associations of pain chronicity and spatial burden with incident cardiovascular and diabetic microvascular complications. Methods Among 17,699 eligible UK Biobank participants with T2DM, 17,645 had complete data for the four-category pain phenotype and were included in the pain-phenotype and multistate analyses. Pain was categorized as no pain, short-term pain, chronic localized pain, or questionnaire-defined chronic widespread pain (CWP). Chronic pain burden was assessed using chronic pain-site count and multisite chronic pain involving ≥3 sites (MCP ≥ 3). Cox proportional hazards models estimated associations with incident heart failure (HF), atherosclerotic cardiovascular disease (ASCVD), and diabetic microvascular complications. A clock-reset multistate model evaluated transitions from a complication-free baseline state to microvascular complications, ASCVD/HF, and death. Results During a median follow-up of 13.4 years, 4,223 ASCVD events, 1,389 HF events, and 2,632 microvascular events were documented. Compared with no pain, the fully adjusted hazard ratios for ASCVD were 1.16 [95% confidence interval (CI): 1.05–1.27] for short-term pain, 1.32 (1.22–1.41) for chronic localized pain, and 1.77 (1.49–2.10) for CWP. MCP ≥ 3 was also associated with ASCVD risk (hazard ratio: 1.43, 95% CI: 1.22–1.67). Associations with HF and the microvascular composite were weaker and less consistent across pain phenotypes. Among microvascular subtypes, the strongest association was observed for diabetic neuropathy, with a hazard ratio of 2.28 (1.54–3.39) for CWP. In multistate analyses, CWP was associated with transitions from baseline to ASCVD/HF (1.63, 1.36–1.95) and from microvascular complications to ASCVD/HF (1.78, 1.10–2.91), but not with transitions to death. Conclusion Among participants with T2DM, questionnaire-defined CWP and greater chronic pain burden were most consistently associated with incident ASCVD and transitions toward ASCVD/HF. The association with diabetic neuropathy may partly reflect symptom overlap or early/subclinical neuropathic disease rather than a directional relationship. These readily assessed pain characteristics may identify a clinical phenotype associated with higher cardiovascular risk, although their incremental value beyond established risk factors remains to be determined.