Parallel disease trajectories of peripheral neurovascular disease and heart failure in type 2 diabetes mellitus: a 12-year prospective follow-up

Background Type 2 diabetes mellitus (T2DM) is characterized by progressive microvascular and macrovascular complications. Peripheral neuropathy reflects systemic microvascular dysfunction, whereas lower extremity arterial disease (LEAD) represents advanced macrovascular involvement driven by insulin resistance and endothelial impairment. Both mechanisms contribute to diabetic cardiomyopathy and heart failure (HF), but their long-term interaction remains insufficiently defined. Purpose To evaluate longitudinal associations between peripheral neuropathy, LEAD, and development of heart failure phenotypes during 12-year follow-up in patients with T2DM. Methods Between 2008 and 2010, 14,321 T2DM patients were screened for vascular complications. Neuropathy was assessed using Neuropathy Disability Score (NDS) and Neuropad testing. LEAD, including arterial stiffness, was evaluated by continuous-wave Doppler and ankle–brachial index. During follow-up, 119 symptomatic patients underwent transthoracic echocardiography. Multivariable Cox regression was performed using LVEF >49% (n=38) as the reference group. Clinical variables, cardiovascular risk factors, diabetic complications, echocardiographic parameters, and limb outcomes were included in the analysis. Results Mean age was 67.1±6.8 years; 62.2% were male; mean diabetes duration 24.9±10.9 years; HbA1c 8.7±1.9%. HFrEF was independently associated with LEAD (HR 4.44; 95% CI 1.97–10.02; p<0.001), larger LV internal diameter (HR 1.17; 95% CI 1.11–1.24; p<0.001), increased mortality risk (HR 4.05; 95% CI 1.50–10.93; p=0.006), and shorter diabetes duration (HR 0.96; 95% CI 0.92–0.99; p=0.041). Neuropathy-related trajectory toward HFrEF was associated with low HDL-cholesterol (HR 5.16; 95% CI 2.25–11.83; p<0.001), higher NDS (HR 2.53; 95% CI 1.16–5.52; p=0.020), increased LV mass index (HR 3.76; 95% CI 1.50–9.43; p=0.005), and lower extremity arterial stiffness (HR 3.66; 95% CI 1.49–8.92; p=0.004). Conclusion In T2DM, peripheral macrovascular and microvascular complications follow distinct but converging trajectories toward HFrEF. LEAD appears to represent a strong systemic vascular driver of systolic dysfunction, whereas neuropathy is linked to adverse metabolic and structural myocardial remodeling. Early vascular phenotyping may improve heart failure risk stratification in diabetic patients.