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
6 affiliations
- 1The First Affiliated Hospital of Hunan University of Chinese Medicine
- 2School of Traditional Chinese Medicine, Hunan University of Chinese Medicine
- 3Department of Biostatistics, School of Public Health, Fudan University
- 4State Key Laboratory of Biotherapy, Sichuan University
- 5Shanghai Municipal Hospital of Traditional Chinese Medicine
- 6School of Urban Governance and Public Affairs, Suzhou City University
Abstract
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.
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BibTeX
@article{tang2026pain,
title = {{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}},
author = {Binquan Tang and Dingning Liu and Peiyi Zhao and Zengyu Zhang and Chengchen Deng and Jiamin Chen and Yanni Xiao and Jidong Zhang},
journal = {Frontiers in Cardiovascular Medicine},
year = {2026},
month = oct,
doi = {10.3389/fcvm.2026.1942167},
url = {https://www.frontiersin.org/articles/10.3389/fcvm.2026.1942167/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - 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
AU - Binquan Tang
AU - Dingning Liu
AU - Peiyi Zhao
AU - Zengyu Zhang
AU - Chengchen Deng
AU - Jiamin Chen
AU - Yanni Xiao
AU - Jidong Zhang
PY - 2026
DA - 2026/10/27
JO - Frontiers in Cardiovascular Medicine
DO - 10.3389/fcvm.2026.1942167
UR - https://www.frontiersin.org/articles/10.3389/fcvm.2026.1942167/full
AB - 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.
SN - 2297-055X
ER -