Declining incidence of major lower-extremity amputations in the Northern Danish Region between 2016 and 2021: The impact of diabetes and preventive vascular procedures.

BACKGROUND: Preventing lower-extremity amputations (LEAs) is pivotal. In the present study we aimed to examine the recent trends in non-traumatic LEAs seen in the Northern Danish Region. METHODS: Using data from the regional Business Intelligence unit we identified all non-traumatic LEAs (n=689) performed in people above 50 years of age in the Northern Danish Region between January 2016 and December 2021 (approximately 600.000 inhabitants). Persons with diabetes (n=26,025) were identified based on ICD-10 codes and data from The National Health Insurance Service Registry, while preventive vascular procedures (n=1,097) were identified using surgical codes. Major LEA was defined as any amputation above the ankle. Incidence rates were expressed as events per 1.000 person-years. Trends were described as differences between the periods 2016-2018 and 2019-2021. RESULTS: A total of 249 (36%) major LEAs were performed in people with diabetes. People with diabetes were younger (71 vs 77 years, p<0.001) and more frequently male (70% versus 54%, p<0.001). Between 2016-2018 and 2019-2021 the incidence of major LEA declined from 1.76 (95% CI: 1.75-1.76) to 1.39 (1.39-1.39) in people with diabetes, and from 0.47 (0.47-0.47) to 0.20 (0.20-0.20) in people without diabetes (all p<0.001). Simultaneously, the incidence of preventive vascular surgery increased from 2.26 (2.26-2.26) to 3.48 (3.48-3.48) in people with diabetes and declined slightly in people without 0.49 (0.49-0.49) to 0.47 (0.47-0.47) (all p<0.001). CONCLUSION: Despite significant declines in major LEA in both people with and without diabetes, most of the decline was driven by a large reduction in major LEAs in people without diabetes. Diabetic foot, lower extremity amputation, major amputation, minor amputation, preventive vascular procedures, revascularization, vascular surgery.

The co-existence of peripheral and vestibular neuropathy in diabetes: a cross-sectional study.

PURPOSE: Diabetic neuropathy can lead to decreased peripheral sensation and motor neuron dysfunction associated with impaired postural control and risk of falling. However, the relationship between decreased peripheral sensation and impaired vestibular function in diabetes mellitus is poorly investigated. Therefore, the aim of this study was to investigate the relationship between peripheral and autonomic measurements of diabetic neuropathy and measurements of vestibular function. METHODS: A total of 114 participants with type 1 diabetes (n = 52), type 2 diabetes (n = 51) and controls (n = 11) were included. Vestibular function was evaluated by video head impulse testing. Peripheral neuropathy was assessed by quantitative sensory testing and nerve conduction. Autonomic neuropathy using the COMPASS 31 questionnaire. Data were analyzed according to data type and distribution. RESULTS: Measurements of vestibular function did not differ between participants with type 1 diabetes, type 2 diabetes or controls (all p-values above 0.05). Subgrouping of participants according to the involvement of large-, small- or autonomic nerves did not change this outcome. Correlation analyses showed a significant difference between COMPASS 31 and right lateral gain value (ρ = 0.23, p = 0.02,), while no other significant correlations were found. CONCLUSION: Diabetic neuropathy does not appear to impair vestibular function in diabetes, by means of the VOR. CLINICAL TRIALS: NCT05389566, May 25th, 2022.

The Cost-Effectiveness of Subcutaneous Semaglutide Versus Empagliflozin in Type 2 Diabetes Uncontrolled on Metformin Alone in Denmark.

INTRODUCTION: International and Danish guidelines recommend the use of glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors already in second line in the management of type 2 diabetes (T2D). The objective of this study was to evaluate the long-term cost-effectiveness (CE) of subcutaneous (SC) semaglutide (GLP-1 RA) versus empagliflozin (SGLT-2 inhibitor) in individuals with T2D uncontrolled on metformin alone from a Danish payer's perspective. METHODS: Cost-effectiveness analyses (CEA) were conducted from a Danish payer's perspective, using the IQVIA Core Diabetes model (CDM 9.5), with a time horizon of 50 years and an annual discount of 4% on costs and effects. Patients received either SC semaglutide or empagliflozin, in addition to metformin, until HbA1c threshold of 7.5% (58 mmol/mol) was reached, following which treatment intensification with insulin glargine in addition to empagliflozin or SC semaglutide plus metformin was considered. Baseline cohort characteristics and treatment effects were sourced from a published CEA. Utilities and cost of diabetes-related complications were also obtained from published sources. Treatment costs were derived from Danish official sources. Scenario analyses were also performed to test the accuracy of the base case results. RESULTS: Individuals with T2D on SC semaglutide plus metformin gained 0.065 life-years (LYs) and 0.130 quality-adjusted LYs (QALYs), respectively, at an incremental cost of DKK 96,923 (€ 13,031) compared to empagliflozin plus metformin, resulting in an incremental cost-effectiveness ratio (ICER) of DKK 745,561(€ 100,239) per QALY gained. The probabilistic sensitivity analysis (PSA) results showed that the SC semaglutide plus metformin was cost-effective in 19% of simulations assuming a willingness-to-pay (WTP) threshold of DKK 357,100 (€ 48,011)/QALY gained. Duration of therapy with SC semaglutide seems the key driver of results. CONCLUSION: The current analyses suggest that SC semaglutide plus metformin is not cost-effective compared to empagliflozin plus metformin from a Danish payer's perspective.

The cost-effectiveness of oral semaglutide versus empagliflozin in Type 2 diabetes in Denmark.

Aim: To evaluate the cost-effectiveness of oral semaglutide+metformin versus empagliflozin+metformin in people with Type 2 diabetes uncontrolled on msetformin alone. Materials and methods: The IQVIA Core Diabetes Model was populated with efficacy data from a head-to-head study between oral semaglutide+metformin and empagliflozin+metformin. Danish costs and quality-of-life data were sourced from literature. Price per day was Danish Krone (DKK) 25.53 for oral semaglutide and DKK11.40 for empagliflozin. Discounting was fixed at 4%. Scenario and sensitivity analyses were performed. Results: Over a lifetime, Core Diabetes Model projected 8.78 and 8.75 quality-adjusted life-years and a total cost of DKK 447,633 and DKK 387,786, thereby generating an incremental cost-effectiveness ratio of DKK 1,930,548 for oral semaglutide+metformin versus empagliflozin+metformin. Scenario and sensitivity analyses showed the robustness of the outcomes. Duration of treatment with oral semaglutide is the key driver of the analyses. Conclusion: Oral semaglutide+metformin seems not cost effective versus empagliflozin+metformin in patients uncontrolled on metformin in Denmark.

Cardiac vagal tone as a novel screening tool to recognize asymptomatic cardiovascular autonomic neuropathy: Aspects of utility in type 1 diabetes.

AIMS: To test the performance of the cardiac vagal tone (CVT) derived from a 5-minute ECG recording compared with the standardized cardiovascular autonomic reflex tests (CARTs). METHODS: Cross-sectional study included 56 well-phenotyped adults with type 1 diabetes (19-71 years, 2-54 years disease-duration). Autonomic testing included: standardized CARTs obtained with the VAGUS™, CVT, and indices of heart rate variability (HRV) obtained at 24- and 120-hour, and electrochemical skin conductance assessed with SUDOSCAN®. ROC AUC and cut-off values were calculated for CVT to recognize CAN based on ≥ 2 (established CAN, n = 7) or 1 (borderline CAN, n = 9) abnormal CARTs and compared to HRV indices and electrochemical skin conductance. RESULTS: Established CAN: The cut-off CVT value of 3.2LVS showed 67% sensitivity and 87% specificity (p = 0.01). Indices of HRV at either 24-hour (AUC > 0.90) and 120-hour (AUC > 0.88) performed better than CVT. Borderline CAN: The cut-off CVT value of 5.2LVS indicated 88% sensitivity and 63% specificity (p = 0.07). CVT performed better than HRV indices (AUC < 0.72). Electrochemical skin conductance (AUC:0.63-0.72) had lower sensitivity and specificity compared with CVT. CONCLUSIONS: Implementation of CVT with a clinically applicable cut-off value may be considered a quicker and accessible screening tool which could ultimately decrease the number of unrecognized CAN and initiate earlier prevention initiatives.

Circulating Inflammatory Markers Are Inversely Associated with Heart Rate Variability Measures in Type 1 Diabetes.

INTRODUCTION: A neuroimmune communication exists, and compelling evidence suggests that diabetic neuropathy and systemic inflammation are linked. Our aims were (1) to investigate biomarkers of the ongoing inflammation processes including cytokines, adhesion molecules, and chemokines and (2) to associate the findings with cardiovascular autonomic neuropathy in type 1 diabetes by measuring heart rate variability and cardiac vagal tone. MATERIALS AND METHODS: We included 104 adults with type 1 diabetes. Heart rate variability, time domain, and frequency domains were calculated from a 24-hour Holter electrocardiogram, while cardiac vagal tone was determined from a 5-minute electrocardiogram. Cytokines (interleukin- (IL-) 1α, IL-4, IL-12p70, IL-13, IL-17, and tumor necrosis factor- (TNF-) α), adhesion molecules (E-selectin, P-selectin, and intercellular adhesion molecule- (ICAM-) 1), and chemokines (chemokine (C-C motif) ligand (CCL)2, CCL3, CCL4, and C-X-C motif chemokine (CXCL)10) were assessed using a Luminex multiplexing technology. Associations between concentrations of inflammatory biomarkers and continuous variables of heart rate variability and cardiac vagal tone were estimated using multivariable linear regression adjusting for age, sex, disease duration, and smoking. RESULTS: Participants with the presence of cardiovascular autonomic neuropathy had higher systemic levels of IL-1α, IL-4, CCL2, and E-selectin than those without cardiovascular autonomic neuropathy. IL-1α, IL-4, IL-12, TNF-α, and E-selectin were inversely associated with both sympathetic and parasympathetic heart rate variability measures (p > 0.01). Discussion. Our results show that several pro- and anti-inflammatory factors, believed to be involved in the progression of diabetic polyneuropathy, are associated with cardiovascular autonomic neuropathy, suggesting that these factors may also contribute to the pathogenesis of cardiovascular autonomic neuropathy. Our findings emphasize the importance of the neuroimmune regulatory system in the pathogenesis of neuropathy in type 1 diabetes.

Aspects of vincristine-induced neuropathy in hematologic malignancies: a systematic review.

PURPOSE: Vincristine is widely used as anticancer therapy for a variety of hematological malignancies. The treatment is limited by progressive vincristine-induced neuropathy, possibly including both peripheral sensory and motor nerves, autonomic nervous functions, and the central nervous system. This dose-limiting side-effect can diminish quality of life and, furthermore, cause discontinuation of vincristine treatment. The present review elucidates the current knowledge regarding vincristine-induced neuropathy in hematologic malignancies, focusing on neuropathy assessment, clinical and molecular predictive markers, drug-drug interference, prevention, and treatment. METHODS: This review is conducted by a systematic search strategy for the identification of relevant literature in the PubMed and Embase databases. RESULTS: No clinical parameters displayed convincing potential as predictors of vincristine-induced neuropathy; however, preexisting neuropathy was consistently reported to be associated with an increased risk of neurotoxicity. In contrast, molecular markers, including polymorphisms in genes involved in the pharmacodynamics and pharmacokinetics of vincristine, displayed great potential as predictive markers of neuropathy incidence and severity. Furthermore, antifungal drugs, such as itraconazole and voriconazole, decrease the metabolism of vincristine and consequently lead to severe neuropathy when co-administered with vincristine, underscoring why fluconazole should be the antifungal drug of choice. CONCLUSION: Reports from the 71 included studies clearly emphasize the lack of consistency in neuropathy assessment, grading systems, and reporting, making it difficult to interpret results between studies. Thus, truer clinical and molecular markers could emerge if the consistency of neuropathy detection and reporting increases by the use of conventional standardized neuropathy assessment tools and grading scales.

Early Assessment of Cost-effectiveness of Gastric Electrical Stimulation for Diabetic Nausea and Vomiting.

BACKGROUND/AIMS: Recurrent nausea and/or vomiting are common complications of diabetes mellitus. The conditions severely impact the quality of life of patients and often cause repeated admissions to hospital incurring significant healthcare costs. If standard treatment fails, gastric electrical stimulation (GES) may be offered in selected cases, as a minimally invasive, but expensive, therapeutic option. Our aims are to evaluate the clinical effect and the cost-utility of GES as a treatment for severe diabetic recurrent nausea and/or vomiting. METHODS: Among 33 diabetes patients implanted with GES because of recurrent nausea and/or vomiting, 30 were available for evaluation. The effect of treatment was assessed prospectively using symptom-diaries and the SF-36 questionnaires at baseline, after 6 and 12 months, and thereafter yearly. The number of days in hospital due to symptoms related to gastrointestinal dysfunction was calculated using hospital records 12 months prior to and 12 months after implantation. RESULTS: The surgical procedures were performed without mortality or major complications. Six months after surgery 78% of the respondents had at least 50% reduction in time with nausea and 48% had at least 50% reduction in days with vomiting. Symptom relief persisted at follow-up after at least 4 years. Quality adjusted life years improved after GES, which was cost-effective after 24 months. CONCLUSIONS: GES reduces symptoms and improves quality of life in diabetes patients with recurrent nausea and/or vomiting. The procedure is supposed as cost-effective over a 2-year time horizon.

The degree of autonomic modulation is associated with the severity of microvascular complications in patients with type 1 diabetes.

OBJECTIVE: The objective of this study was to elucidate whether the degree of autonomic modulation is associated with the degree of microvascular complications in patients with type 1 diabetes. METHODS: A total of 290 type 1 individuals with diabetes were randomly recruited during normal visits to outpatient clinics at 4 Danish hospitals. The degree of autonomic modulations was quantified by measuring heart rate variability (HRV) during passive spectral analysis and active tests (valsalva ratio [VT], response to standing [RT], and deep breathing [E:I]). To describe possible associations between severity of microvascular complications and measures of autonomic modulation, multivariate analysis was performed. RESULTS: After adjusting for diabetes duration, sex, age, pulse pressure, heart rate, and smoking, autonomic dysfunction remained significantly correlated with severity of retinopathy, nephropathy, and peripheral neuropathy in individuals with type 1 diabetes patients. CONCLUSIONS: Autonomic dysfunction is present in early stages of retinopathy, nephropathy, and peripheral neuropathy in patients with type 1 diabetes.

Cardiovascular autonomic neuropathy is associated with macrovascular risk factors in type 2 diabetes: new technology used for routine large-scale screening adds new insight.

The objective was to identify the presence of cardiovascular autonomic neuropathy (CAN) in a cohort of individuals with diabetes in outpatient clinics from 4 different parts of Denmark and to explore the difference between type 1 and type 2 diabetes in relation to CAN. The DAN-Study is a Danish multicenter study focusing on diabetic autonomic neuropathy. Over a period of 12 months, 382 type 1 and 271 type 2 individuals with diabetes were tested for CAN. Patients were randomly recruited and tested during normal visits to outpatient clinics at 4 Danish hospitals. The presence of CAN was quantified by performing 3 cardiovascular reflex tests (response to standing, deep breathing, and valsalva). To describe possible associations, multivariate analysis with CAN as the dependent variable was performed. The prevalence of CAN was higher among patients with type 2 diabetes (35%) compared to patients with type 1 diabetes (25%). Multivariate analysis revealed significant associations between CAN and different risk markers in the 2 populations. In type 1 diabetes patients CAN was associated with microalbuminuria (P < .001), macroalbuminuria (P = .011), simplex retinopathy (P < .001), proliferative retinopathy (P < .001), and peripheral neuropathy (P = .041). Among type 2 diabetes patients CAN was independently associated with high pulse pressure (P < .01), BMI (P = .006), and smoking (P = .025). In this cross-sectional observational study CAN was independently associated with microvascular complication in type 1, whereas in type 2 CAN was associated with macrovascular risk factors.

A novel model enhances HbA1c-based diabetes screening using simple anthropometric, anamnestic, and demographic information.

BACKGROUND: The sensitivity of HbA1c is not optimal for the screening of patients with latent diabetes. We hypothesize that simple healthcare information could improve accuracy. METHODS: We retrospectively analyzed data, including HbA1c, from multiple years from the National Health and Nutrition Examination Survey (NHANES) database (2005-2010). The data were used to create a logistic regression classification model for screening purposes. RESULTS: The study evaluated data for 5381 participants, including 404 with undiagnosed diabetes. The HbA1c screening data were supplemented with information about age, waist circumference, and physical activity in the HbA1c+ model. Alone, HbA1c alone had a receiver operating characteristics (ROC) curve for the area under the curve (AUC) of 0.808 (95% confidence interval [CI] 0.792-0.834). The HbA1c+ model had an ROC AUC of 0.851 (95% CI 0.843-0.872). There was a significant difference in the AUC between our model and using HbA1c without supplementary information (P < 0.05). CONCLUSIONS: We have developed a novel screening model that could help improve screening for type 2 diabetes with HbA1c. It seems beneficial to systematically add additional patient healthcare information in the process of screening with HbA1c.

The impact of "modern telecommunication" in palliative care--the views of the professionals.

BACKGROUND: Specialized palliative care teams are typically based in larger hospitals, from where home visits, telephone consultations, and support are given directly to patients and relatives, but also to professionals working on the frontline. One of the challenges is the long distances to the patients' homes. Modern telecommunication may help overcome this, but little is known about the perceived advantages and barriers to palliative care. This study analyzed the views on modern telecommunication from specialized palliative care professionals' perspective. MATERIALS AND METHODS: This descriptive study is based on four semistructured group interviews where 17 health professionals from three different palliative care teams in the Central Denmark Region were interviewed from November 2009 to March 2010. RESULTS: We found that face-to-face communication is essential. The participants perceived a potentially added communicative value in visual telecommunication but would never let it replace face-to-face communication. Ethical and practical concerns were expressed on the implementation of "modern telecommunication" and in particular strong reservations against permanent telemonitoring in the patient's home. CONCLUSIONS: Our study underlines the necessity of face-to-face contact in optimal palliative care and that home visits were favored. The participants were generally positive toward telecommunication, although reservations and prerequisites were voiced.

Improved diabetes screening using an extended predictive feature search.

BACKGROUND: Screening entire populations for diabetes is not cost-effective. Hence, an efficient screening process must select those people who are at high risk for diabetes. In this study, we investigated whether screening procedures could be improved using an extended predictive feature search. MATERIALS AND METHODS: In order to develop our model and identify persons with diabetes (prevalence) we used data from years of the National Health and Nutrition Examination Survey (2005-2010), which has not been explored for this purpose before. We calculated all combinations of predictors in order to identify the optimal subset, and we used a linear logistic classification model to predict diabetes. V-fold cross-validation was used for the process of including variables and for validating the final models. This new model was compared with two established models. RESULTS: In total, 5,398 participants were included in this study. Among these, 478 participants had unidentified diabetes. The established models had a receiver operating characteristics curve for the area under the curve (AUC) of 0.74 and 0.71 compared with an AUC of 0.78 for the new model, showing a significant difference (P<0.05). A proposed cutoff point for the established models yielded respective sensitivities/specificities of 63%/72% and 40%/72% compared with the new model, which had a sensitivity/specificity of 70%/72%. CONCLUSIONS: Our data indicate that simple healthcare and economic information such as ratio of family income to poverty can add value in deciding who is at risk of unknown diabetes by using extended investigations of predictor combinations.

Screening for diabetic cardiac autonomic neuropathy using a new handheld device.

BACKGROUND: Cardiac autonomic neuropathy (CAN) is a serious complication of longstanding diabetes and is associated with an increased morbidity and reduced quality of life in patients with diabetes. The present study evaluated the prevalence of CAN diagnosed by reduced heart rate variability (HRV) using a newly developed device in a large, unselected, hospital-based population of patients with diabetes. METHODS: The study examined 323 patients consisting of 206 type 1 diabetes (T1DM) patients and 117 type 2 diabetes (T2DM) patients. The new handheld prototype Vagus™ was used to screen for CAN. Three different standardized cardiac reflex tests were performed to calculate HRV: 30:15 ratio, E:I ratio, and the Valsalva maneuver. An abnormal HRV in one test is indicative of early CAN, and if two or more tests show abnormal HRV, the diagnosis of CAN is established. RESULTS: In total, 86% of examined patients completed all three tests. Each test was completed by more than 90% of the patients. The prevalence of established CAN was 23%, whereas 33% of the patients had early signs of CAN. The prevalence was higher in T2DM patients (27.8%) than in T1DM patients (20.6 %), p = .02. Patients with CAN were older and had a longer duration of diabetes, higher systolic blood pressure, more nephropathy and retinopathy, and a higher vibration threshold. CONCLUSIONS: Cardiac autonomic neuropathy is frequent in both T2DM and T1DM patients, especially in those with other late diabetes complications. Screening for CAN with the new device is feasible.

Paper electrocardiograph strips may contain overlooked clinical information in screen-detected type 2 diabetes patients.

BACKGROUND: A large number of nondigitized electrocardiograph (ECG) strips are routinely collected in larger cohort studies such as the ADDITION study (Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care). These ECG strips are routinely read manually but may contain overlooked information revealing cardiac autonomic dysfunction. The aim of this study was to investigate whether clinical information may be lost using manual R wave to R wave (RR) interval measurements in the calculation of heart rate variability (HRV) in patients with type 2 diabetes mellitus (T2DM). METHOD: From the Danish part of the ADDITION study, we randomly selected 120 T2DM patients at baseline of the ADDITION study. Analysis of the ECG strips was performed using two different methods: (1) by experienced technicians using rulers and (2) by experienced technicians using a high-resolution computer-assisted method. Calculation of heart rate and time domain HRV [standard deviation of normal-to-normal RR intervals (SDNN) and root mean square of successive differences (RMSSD)] were performed with the same software. RESULTS: When comparing results from the two methods, the following values of Pearson's r are obtained: 0.98 for heart rate, 0.76 for SDNN, and 0.68 for RMSSD. These results indicate that heart rate and HRV measurements by the computer-assisted and manually based methods correlate. However, Bland-Altman plots and Pitman's test of difference in variance revealed poor agreements (p < .01) for both HRV measurements (SDNN and RMSSD); only heart rate showed substantiated agreement (p = .54) between the two methods. Low HRV was statistically significantly associated to high heart rate, systolic blood pressure, and diastolic blood pressure in these screen-detected T2DM patients. CONCLUSIONS: Paper ECG strips may contain overlooked clinical information on the status of autonomic function in patients with T2DM. In our study, manual measurements of RR intervals were inferior to the computer-assisted method. Based on this study, we recommend cautiousness in the clinical use and interpretation of HRV based on manual or low resolution measurements of RR intervals from ECG strips. High resolution measurements of RR intervals reveal significant associations between low HRV and high heart rate, systolic blood pressure, and diastolic blood pressure among patients with screen-detected T2DM. It is feasible to use a computer-assisted method to determine RR intervals in patients with T2DM.

Prevalence of neuropathy and peripheral arterial disease and the impact of treatment in people with screen-detected type 2 diabetes: the ADDITION-Denmark study.

OBJECTIVE: There is limited evidence on how intensive multifactorial treatment (IT) improves outcomes of diabetes when initiated in the lead time between detection by screening and diagnosis in routine clinical practice. We examined the effects of early detection and IT of type 2 diabetes in primary care on the prevalence of diabetic peripheral neuropathy (DPN) and peripheral arterial disease (PAD) 6 years later in a pragmatic, cluster-randomized parallel group trial. RESEARCH DESIGN AND METHODS: A stepwise screening program in 190 general practices in Denmark was used to identify 1,533 people with type 2 diabetes. General practices were randomized to deliver either IT or routine care (RC) as recommended through national guidelines. Participants were followed for 6 years and measures of DPN and PAD were applied. RESULTS: We found no statistically significant effect of IT on the prevalence of DPN and PAD compared with RC. The prevalence of an ankle brachial index ≤0.9 was 9.1% (95% CI 6.0-12.2) in the RC arm and 7.3% (5.0-9.6) in the IT arm. In participants tested for vibration detection threshold and light touch sensation, the prevalence of a least one abnormal test was 34.8% (26.7-43.0) in the RC arm and 30.1% (24.1-36.1) in the IT arm. CONCLUSIONS: In a population with screen-detected type 2 diabetes, we did not find that screening followed by IT led to a statistically significant difference in the prevalence of DPN and PAD 6 years after diagnosis. However, treatment levels were high in both groups.