Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Progression of cardiovascular autonomic neuropathy and cardiovascular disease in type 2 diabetes

Abstract Background To examine whether the progression rate of cardiovascular autonomic neuropathy (CAN) stage is an independent predictive factor for cardiovascular disease (CVD) in type 2 diabetes. Methods Standardized cardiovascular autonomic reflex tests (CARTs) using traditional Ewing method were performed at baseline. The follow-up CARTs was recommended once every two years. We estimated the primary CVD endpoint, defined as coronary artery disease and ischemic stroke. The association between the progression rate of CAN stage and CVD was examined using time-dependent Cox proportional hazard models. Results At baseline, 578 patients completed follow-up CARTs; the cohort comprised 329 women (56.9%) with a mean age of 58.3 ± 10.3 years and a mean diabetes duration of 10.1 ± 6.2 years. One hundred and seventy-six patients (30.4%) developed CAN progression between baseline and follow-up CARTs. In the multivariable Cox proportional hazards regression analysis, patients with CAN progression demonstrated a 3.32 times higher risk (95% confidence interval, CI 1.81–6.14, P < 0.001) of CVD than those without CAN progression. Patients who experienced CAN progression from the normal to definite stage had the greatest risk of CVD compared to other patients (hazard ratio 4.91, 95% CI 2.05–11.77, P for trend = 0.001). Conclusions CAN stage progression was associated with an increased risk of CVD in this type 2 diabetes cohort. Patients with rapid CAN progression had the greatest risk of CVD. Thus, regular screening and risk management of CAN progression is necessary to prevent CVD

MOESM1 of Progression of cardiovascular autonomic neuropathy and cardiovascular disease in type 2 diabetes

Additional file 1: Figure S1. Study design summarization of the sample recruitment and follow-up. CART, cardiovascular autonomic reflex test; CVD, cardiovascular diseas

MOESM2 of Progression of cardiovascular autonomic neuropathy and cardiovascular disease in type 2 diabetes

Additional file 2: Table S1. Screening intervals according to the CAN status. Table S2. Descriptive characteristics according to the progression status of cardiovascular autonomic neuropathy including the group with definite CAN. Table S3. Crude and multivariable Cox proportional hazard model for cardiovascular disease and sensitive analysis for cardiovascular disease after exclusion of the patients who developed cardiovascular disease within 2 years

DataSheet_1_External validation and clinical application of the predictive model for severe hypoglycemia.docx

ObjectiveAn internally validated, one-year risk prediction model for severe hypoglycemia (SH) in type 2 diabetes was evaluated in a general hospital setting to externally verify and validate its performance.Research design and methodsBetween December 2017 to December 2019, 2,645 adult patients with type 2 diabetes who visited the diabetes center were enrolled. The receiver operating characteristics curve and Harrell C-statistics were compared to identify the discrimination of the model. The predicted and actual incidence of SH for one year in the development and validation cohorts were compared by ranking participants by deciles of predicted risk.ResultsThe concordance index was 0.878 in the external validation cohort. The sensitivity and specificity of the predictive model were 0.833 and 0.847, respectively. Based on the predicted risk, we stratified the groups into four categories: low (ConclusionOn external validation, the novel one-year SH prediction model showed excellent discrimination in participants with type 2 diabetes and can effectively screen high-risk patients for SH, even in the general hospital setting.</p

A comparison of effects of DPP-4 inhibitor and SGLT2 inhibitor on lipid profile in patients with type 2 diabetes

Abstract Background Previous studies suggest that dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium glucose cotransporter 2 (SGLT2) inhibitors have different effects on the lipid profile in patients with type 2 diabetes. We investigated the effects of DPP-4 inhibitors and SGLT2 inhibitors on the lipid profile in patients with type 2 diabetes. Methods From January 2013 to December 2015, a total of 228 patients with type 2 diabetes who were receiving a DPP-4 inhibitor or SGLT2 inhibitor as add-on therapy to metformin and/or a sulfonylurea were consecutively enrolled. We compared the effects of DPP-4 inhibitors and SGLT2 inhibitors on the lipid profile at baseline and after 24 weeks of treatment. To compare lipid parameters between the two groups, we used the analysis of covariance (ANCOVA). Results A total of 184 patients completed follow-up (mean age: 53.1 ± 6.9 years, mean duration of diabetes: 7.1 ± 5.7 years). From baseline to 24 weeks, HDL-cholesterol (HDL-C) levels were increased by 0.5 (95% CI, −0.9 to 2.0) mg/dl with a DPP-4 inhibitor and by 5.1 (95% CI, 3.0 to 7.1) mg/dl with an SGLT2 inhibitor (p = 0.001). LDL-cholesterol (LDL-C) levels were reduced by 8.4 (95% CI, −14.0 to -2.8) mg/dl with a DPP-4 inhibitor, but increased by 1.3 (95% CI, −5.1 to 7.6) mg/dl with an SGLT2 inhibitor (p = 0.046). There was no significant difference in the mean hemoglobin A1c (8.3 ± 1.1 vs. 8.0 ± 0.9%, p = 0.110) and in the change of total cholesterol (TC) (p = 0.836), triglyceride (TG) (p = 0.867), apolipoprotein A (p = 0.726), apolipoprotein B (p = 0.660), and lipoprotein (a) (p = 0.991) between the DPP-4 inhibitor and the SGLT2 inhibitor. Conclusions The SGLT2 inhibitor was associated with a significant increase in HDL-C and LDL-C after 24 weeks of SGLT2 inhibitor treatment in patients with type 2 diabetes compared with those with DPP-4 inhibitor treatment in this study. Trial registration This study was conducted by retrospective medical record review

Personalized Type 2 Diabetes Management Using a Mobile Application Integrated with Electronic Medical Records: An Ongoing Randomized Controlled Trial

Controlling type 2 diabetes (T2DM) requires a comprehensive approach including patient education, self-monitoring of blood glucose, individualized behavioral strategies, and frequent contact with healthcare professionals (HCPs). We aimed to compare the efficacy of a personalized lifestyle intervention based on a mobile phone application with regular care in participants with T2DM. This is an ongoing randomized controlled open-label parallel-group trial with a target accrual of 282 participants, of which 181 have been enrolled to date. Participants are randomly assigned to one of three groups: (1) regular care; (2) mobile diabetes management; or (3) mobile diabetes management with HCP feedback. The mobile application is enabled to integrate with both electronic medical records (EMR) and a web-based diabetes management system for HCPs. It can send customized messages based on participants’ responses to lifestyle questionnaires administered at the baseline. The intervention period is 26 weeks followed by observation for 26 weeks. We evaluate the intervention’s features in order to assess its clinical utility and efficacy and compare outcomes with regular care considering relevant clinical factors, such as age, baseline HbA1c, etc. We expect our study to provide new evidence in support of customized mobile application tools for the management of T2DM

Diabetic Cardiovascular Autonomic Neuropathy Predicts Recurrent Cardiovascular Diseases in Patients with Type 2 Diabetes.

Cardiovascular autonomic neuropathy (CAN) is a risk factor for cardiovascular disease (CVD) and mortality in patients with type 2 diabetes. This study evaluated the relationship between CAN and recurrent CVD in type 2 diabetes. A total of 206 patients with type 2 diabetes who had a history of CVD within 3 years of enrollment were consecutively recruited from January 2001 to December 2009 and followed-up until December 2015. Cardiovascular autonomic function tests were performed using the following heart rate variability parameters: expiration-to-inspiration ratio, response to Valsalva maneuver and standing. We estimated the recurrence of CVD events during the follow-up period. A total of 159 (77.2%) of the 206 patients enrolled completed the follow up, and 78 (49.1%) patients had recurrent episodes of CVD, with an incidence rate of 75.6 per 1,000 patient-years. The mean age and diabetes duration were 62.5 ± 8.7 and 9.2 ± 6.9 years, respectively. Patients who developed recurrent CVD also exhibited hypertension (P = 0.004), diabetic nephropathy (P = 0.012), higher mean systolic blood pressure (P = 0.006), urinary albumin excretion (P = 0.015), and mean triglyceride level (P = 0.035) than did patients without recurrent CVD. Multivariable Cox hazard regression analysis revealed that definite CAN was significantly associated with an increased risk of recurrent CVD (hazard ratio [HR] 3.03; 95% confidence interval [CI] 1.39-6.60; P = 0.005). Definite CAN was an independent predictor for recurrent CVD in patients with type 2 diabetes who had a known prior CVD event