Chronic pain, inflammatory biomarkers, and risks of mortality and cardiovascular disease in individuals with type 2 diabetes: a prospective cohort study

BACKGROUND: Chronic pain is common in patients with type 2 diabetes mellitus (T2DM), but its relationship with cardiovascular disease (CVD) remains unclear. We aimed to examine the associations between the number of chronic pain sites and mortality and CVD in T2DM. METHODS: We included 19,899 T2DM participants from UK Biobank without baseline CVD. Pain sites (including hip, knee, back, neck/shoulder, or "all over the body" and pain duration were recorded. Cox proportional hazards models were performed to examine the associations of the number of chronic pain sites with the risks of mortality and CVD. Mediation analyses were conducted to quantify the potential mediation effects of inflammation. RESULTS: Over a median follow-up of 13.9 years, we observed a significant dose-response relationship between the number of chronic pain sites and risks of all-cause mortality and incident CVD. Each additional pain site was associated with a higher risk of all-cause mortality (HR: 1.04, 95% CI: 1.02-1.07). Similarly, greater number of pain sites was linked to higher risks of CVD. The HR (95% CI) with per additional chronic pain site was 1.10 (1.07-1.12) for total CVD, 1.12 (1.09-1.15) for CAD, 1.07 (1.01-1.14) for stroke, 1.04 (1.01-1.08) for AF, and 1.10 (1.06-1.15) for HF. Site-specific analyses indicated that pain "all over the body" and hip pain showed the strongest associations. Inflammatory biomarkers, including C-reactive protein and the low-grade chronic inflammation (INFLA) score, partially mediated these associations, with mediation proportions of 1.71% - 11.12% for CRP and 1.81% - 6.73% for the INFLA score. CONCLUSIONS: A greater number of chronic pain sites was associated with higher risks of all-cause mortality and CVD in T2DM, with pain "all over the body" and hip pain showing the strongest associations. These findings suggest that widespread chronic pain may be an underrecognized cardiovascular risk factor in diabetes.