Microvascular Complications and Predictors for Mortality in Patients with Type 2 Diabetes and Foot Ulcers

Abstract: A diabetic foot ulcer (DFU) is a common and serious complication of diabetes. It is today the leading cause of amputations and is associated with both increased morbidity and mortality. Individuals with DFU have 2.5 times higher mortality rates compared to patients with diabetes but without DFU, a risk that persists even after ulcer healing. Macrovascular complications, such as a higher burden of myocardial infarction, stroke and peripheral vascular disease can partly, but not alone explain this risk in mortality. The overall aim of this thesis is to evaluate risk factors for mortality to enable early risk stratification, in the high-risk population of individuals with type 2 diabetes and DFU. (I). Long-term survival of 214 patients with type 2 diabetes and DFU was evaluated based on baseline HbA1c level and QTc-time. After eight years 70.6% of the entire cohort was diseased. A low HbA1c < 58 mmol/mol (< 7.5%) at baseline was associated with worse survival, particularly among those individuals with QTc interval > 440 ms, with 8-year mortality rates of 92.1%, compared to 48.8% in those with similar HbA1c, but without QTc prolongation (p < 0.0001). (II). This study aimed to evaluate QTc interval as a risk factor for mortality among patients with type 2 diabetes undergoing an above-ankle amputation. In our cohort of 70 patients, we demonstrated that a prolonged QTc-time was independently associated with increased 3-year mortality (HR 2.2 (95% CI 1.11-4.38)), with the highest mortality seen among individuals within the highest quartile of QTc-time. (III). Hyperbaric oxygen (HBO) therapy is a treatment that has been demonstrated to improve tissue oxygenation in hard-to-heal DFUs. The present study is a post-hoc analysis of the randomized, placebo-controlled Hyperbaric Oxygen Treatment in Diabetic patients with Chronic Foot Ulcers (HODFU) study, aiming to evaluate QTc time before and two years after HBO treatment. In this study, 73 patients were evaluated. After two years, median QTc time was significantly shorter in the HBO group compared to placebo group (438 ms vs 453 ms, p < 0.02) and fewer HBO-treated patients had a QTc time > 450 ms (22% vs 53% p < 0.02). (IV). Transcutaneous oxygen pressure (TcPO2) is often used together with ankle-brachial index (ABI) and toe blood pressure (TBP) for bedside vascular evaluation, to identify patients who might benefit from invasive revascularisation. The present study evaluated the predictive value of TcPO2, ABI and TBP on 1-year mortality, in patients with type 2 diabetes and DFU. Of the 236 patients evaluated, 14.8% of them were diseased within one year. Patients with TcPO2 < 25 mmHg had a higher one-year mortality compared to those with TcPO2 ≥ 25 mmHg (27.7% vs. 11.6%, p = 0.003), whereas TBP and ABI did not significantly predict 1-year mortality. Conclusions: The results of the papers included in this thesis, indicate that screening with TcPO2 as well as QTc-interval, might enhance identification of individuals with urgent need for medical assessment. Further, HBO therapy might have a protective effect against QT interval prolongation, however, future studies are needed to confirm this result.

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