Semaglutide in patients with overweight or obesity and chronic kidney disease without diabetes: a randomized double-blind placebo-controlled clinical trial.

Semaglutide reduces albuminuria and the risk of kidney disease progression in patients with type 2 diabetes and chronic kidney disease (CKD). We conducted a randomized placebo-controlled double-blind clinical trial in adults with CKD (estimated glomerular filtration rate (eGFR) ≥25 ml min-1 1.73 m-2 and urine albumin-to-creatinine ratio (UACR) ≥30 and <3,500 mg g-1) and body mass index ≥27 kg m-2. Participants were randomized to semaglutide 2.4 mg per week or placebo. The primary endpoint was percentage change from baseline in UACR at week 24. Safety was monitored throughout. Overall, 125 participants were screened, of whom 101 were randomized to semaglutide (n = 51) or placebo (n = 50). Mean age was 55.8 (s.d. 12) years; 40 participants (39.6%) were female; median UACR was 251 mg g-1 (interquartile range 100, 584); mean eGFR was 65.0 (s.d. 25) ml min-1 1.73 m-2; and mean body mass index was 36.2 (s.d. 5.6) kg m-2. Chronic glomerulonephritis (n = 25) and hypertensive CKD (n = 27) were the most common CKD etiologies. Treatment for 24 weeks with semaglutide compared to placebo reduced UACR by -52.1% (95% confidence interval -65.5, -33.4; P < 0.0001). Gastrointestinal adverse events were more often reported with semaglutide (n = 30) than with placebo (n = 15). Semaglutide treatment for 24 weeks resulted in a clinically meaningful reduction in albuminuria in patients with overweight/obesity and non-diabetic CKD. ClinicalTrials.gov registration: NCT04889183 .

The Contribution of Postprandial Glucose Levels to Hyperglycemia in Type 2 Diabetes Calculated from Continuous Glucose Monitoring Data: Real World Evidence from the DIALECT-2 Cohort.

BACKGROUND/OBJECTIVES: Traditional glycemic monitoring in type 2 diabetes is limited, whereas continuous glucose monitoring (CGM) offers better insights into glucose fluctuations. This study aimed to determine the correlations and relative contributions of fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels to hyperglycemia. METHODS: We utilized CGM and recorded carbohydrate intake data from lifestyle diaries of 59 patients enrolled in the Diabetes and Lifestyle Cohort Twente (DIALECT-2). Correlations between FPG and the glucose management indicator (GMI), FPG and Time Above Range (TAR), PPG and GMI, and PPG and TAR were conducted. Daily and mealtime relative contributions of PPG and FPG to glycated hemoglobin (HbA1c) and GMI were determined, considering two ranges: on target (<7.0%, 53 mmol/mol) and not on target (≥7.0%, 53 mmol/mol). Correlations between mealtime PPG and carbohydrate consumption were examined. RESULTS: FPG and PPG correlated with GMI (r = 0.82 and 0.41, respectively, p < 0.05). The relative contribution of PPG in patients with HbA1c, GMI, and TAR values not on target was lower than in patients with HbA1c, GMI, and TAR values on target. When analyzing different mealtimes, patients with target GMI values had a higher PPG (73 ± 21%) than FPG after breakfast (27 ± 21%, p < 0.001). Individuals with elevated GMI levels had lower PPG after lunch (30 ± 20%), dinner (36 ± 23%), and snacks (34 ± 23%) than FPG. PPG after breakfast positively correlated (r = 0.41, p < 0.01) with breakfast carbohydrate intake. CONCLUSIONS: Both PPG and FPG contribute to hyperglycemia, with PPG playing a larger role in patients with better glycemic control, especially after breakfast. Targeting PPG may be crucial for optimizing glucose management.

Consequences of Data Loss on Clinical Decision-Making in Continuous Glucose Monitoring: Retrospective Cohort Study.

BACKGROUND: The impact of missing data on individual continuous glucose monitoring (CGM) data is unknown but can influence clinical decision-making for patients. OBJECTIVE: We aimed to investigate the consequences of data loss on glucose metrics in individual patient recordings from continuous glucose monitors and assess its implications on clinical decision-making. METHODS: The CGM data were collected from patients with type 1 and 2 diabetes using the FreeStyle Libre sensor (Abbott Diabetes Care). We selected 7-28 days of 24 hours of continuous data without any missing values from each individual patient. To mimic real-world data loss, missing data ranging from 5% to 50% were introduced into the data set. From this modified data set, clinical metrics including time below range (TBR), TBR level 2 (TBR2), and other common glucose metrics were calculated in the data sets with and that without data loss. Recordings in which glucose metrics deviated relevantly due to data loss, as determined by clinical experts, were defined as expert panel boundary error (εEPB). These errors were expressed as a percentage of the total number of recordings. The errors for the recordings with glucose management indicator <53 mmol/mol were investigated. RESULTS: A total of 84 patients contributed to 798 recordings over 28 days. With 5%-50% data loss for 7-28 days recordings, the εEPB varied from 0 out of 798 (0.0%) to 147 out of 736 (20.0%) for TBR and 0 out of 612 (0.0%) to 22 out of 408 (5.4%) recordings for TBR2. In the case of 14-day recordings, TBR and TBR2 episodes completely disappeared due to 30% data loss in 2 out of 786 (0.3%) and 32 out of 522 (6.1%) of the cases, respectively. However, the initial values of the disappeared TBR and TBR2 were relatively small (<0.1%). In the recordings with glucose management indicator <53 mmol/mol the εEPB was 9.6% for 14 days with 30% data loss. CONCLUSIONS: With a maximum of 30% data loss in 14-day CGM recordings, there is minimal impact of missing data on the clinical interpretation of various glucose metrics. TRIAL REGISTRATION: ClinicalTrials.gov NCT05584293; https://clinicaltrials.gov/study/NCT05584293.

Use of a diagnostic Puumala virus real-time RT-PCR in an orthohantavirus endemic region in the Netherlands.

Laboratory diagnosis of orthohantavirus infection is primarily based on serology. However, for a confirmed serological diagnosis, evaluation of a follow-up serum sample is essential, which is time consuming and causes delay. Real-time reverse transcription polymerase chain reaction (RT-PCR) tests, if positive, provide an immediate and definitive diagnosis, and accurately identify the causative agent, where the discriminative nature of serology is suboptimal. We re-evaluated sera from orthohantavirus-suspected clinical cases in the Dutch regions of Twente and Achterhoek from July 2014 to April 2016 for the presence of Puumala orthohantavirus (PUUV), Tula orthohantavirus (TULV), and Seoul orthohantavirus (SEOV) RNA. PUUV RNA was detected in 11% of the total number (n = 85) of sera tested, in 50% of sera positive for anti-PUUV/TULV IgM (n = 16), and in 1.4% of sera negative or indeterminate for anti-PUUV/TULV IgM (n = 69). No evidence was found for the presence of TULV or SEOV viral RNA. Based on these findings, we propose two algorithms to implement real-time RT-PCR testing in routine orthohantavirus diagnostics, which optimally provide clinicians with early confirmed diagnoses and could prevent possible further invasive testing and treatment. IMPORTANCE: The addition of a real-time reverse transcription polymerase chain reaction test to routine orthohantavirus diagnostics may better aid clinical decision making than the use of standard serology tests alone. Awareness by clinicians and clinical microbiologists of this advantage may ultimately lead to a reduction in over-hospitalization and unnecessary invasive diagnostic procedures.

Serum T50 predicts cardiovascular mortality in individuals with type 2 diabetes: A prospective cohort study.

BACKGROUND AND AIMS: Individuals with type 2 diabetes (T2D) have a higher risk of cardiovascular disease, compared with those without T2D. The serum T50 test captures the transformation time of calciprotein particles in serum. We aimed to assess whether serum T50 predicts cardiovascular mortality in T2D patients, independent of traditional risk factors. METHODS: We analyzed 621 individuals with T2D in this prospective cohort study. Cox regression models were performed to test the association between serum T50 and cardiovascular and all-cause mortality. Causes of death were categorized according to ICD-10 codes. Risk prediction improvement was assessed by comparing Harrell's C for models without and with T50. RESULTS: The mean age was 64.2 ± 9.8 years, and 61% were male. The average serum T50 time was 323 ± 63 min. Higher age, alcohol use, high-sensitive C-reactive protein, and plasma phosphate were associated with lower serum T50 levels. Higher plasma triglycerides, venous bicarbonate, sodium, magnesium, and alanine aminotransferase were associated with higher serum T50 levels. After a follow-up of 7.5[5.4-10.7] years, each 60 min decrease in serum T50 was associated with an increased risk of cardiovascular (fully adjusted HR 1.32, 95% CI 1.08-1.50, and p = 0.01) and all-cause mortality (HR 1.15, 95%CI 1.00-1.38, and p = 0.04). Results were consistent in sensitivity analyses after exclusion of individuals with estimated glomerular filtration rate <45 or <60 mL/min/1.73 m2 and higher plasma phosphate levels. CONCLUSIONS: Serum T50 improves prediction of cardiovascular and all-cause mortality risk in individuals with T2D. Serum T50 may be useful for risk stratification and to guide therapeutic strategies aiming to reduce cardiovascular mortality in T2D.

Urinary Fetuin-A Fragments Predict Progressive Estimated Glomerular Filtration Rate Decline in Two Independent Type 2 Diabetes Cohorts of Different Ethnicities.

INTRODUCTION: There is a great clinical need for novel markers to predict kidney function decline in patients with type 2 diabetes. We explored the potential of posttranslationally modified fetuin-A fragments in urine (uPTM-FetA) as such a marker. METHODS: We included patients with type 2 diabetes from two independent, nonoverlapping prospective cohort studies. A cut-off for uPTM-FetA, measured via ELISA method, was determined using the Youden index in the primary cohort of patients with type 2 diabetes from Taiwan. Kidney endpoint was defined as an estimated glomerular filtration rate (eGFR) decline ≥30% from baseline, reaching of an eGFR <15 mL/min/1.73 m2, or a need of renal replacement therapy. Prospective associations were assessed in Cox regression models. All analyses were replicated in a cohort of patients with type 2 diabetes from the Netherlands. RESULTS: In total, 294 patients with type 2 diabetes (age 61 ± 10 years, 55% male, eGFR 88 ± 16 mL/min/1.73 m2) were included in the primary cohort. During a follow-up of median 4.6 years, 42 participants (14%) experienced the kidney endpoint. Using the defined cut-off, a high uPTM-FetA was associated with a higher risk of renal function decline (Plog-rank < 0.0001). This association was similar in subgroups depending on albuminuria. This association remained, independent of age, sex, baseline eGFR, albuminuria, HbA1c, and other potential confounders (HR: 9.94; 95% CI: 2.96-33.40; p < 0.001 in the final model). Analyses in the validation cohort (376 patients with type 2 diabetes, age 64 ± 11 years, 66% male, eGFR 76 ± 24 mL/min/1.73 m2) using the same cut-off yielded similar results. CONCLUSION: uPTM-FetA was independently associated with kidney function decline in patients with type 2 diabetes validated in a 2-cohort study. The significant additive predictive power of this biomarker from conventional risk factors suggests its clinical use for renal function progression in patients with type 2 diabetes.

Urinary Post-Translationally Modified Fetuin-A Protein Is Associated with Increased Risk of Graft Failure in Kidney Transplant Recipients.

INTRODUCTION: Urinary fetuin-A has been identified as a biomarker for acute kidney injury and is proposed as a biomarker for early detection of kidney function decline. We investigated whether fetuin-A could serve as a marker of graft failure in kidney transplant recipients (KTRs). METHODS: Data of KTR with a functioning graft ≥1 year that were enrolled in the TransplantLines Food and Nutrition Biobank and cohort study were used. Graft failure was defined as the need for re-transplantation or (re-)initiation of dialysis. Urinary fetuin-A was measured using an enzyme-linked immunosorbent assay kit that detected post-translationally modified fetuin-A in the urine (uPTM-FetA). In the main analyses, 24h uPTM-FetA excretion was used. In the sensitivity analyses, we excluded the outliers in 24h uPTM-FetA excretion, and we used uPTM-FetA concentration and uPTM-FetA concentration indexed for creatinine instead of 24h uPTM-FetA excretion. RESULTS: A total of 627 KTRs (age 53 ± 13 years, 42% females) were included at 5.3 (1.9-12.2) years after transplantation. The estimated glomerular filtration rate (eGFR) was 52 ± 20 mL/min/1.73 m2 and uPTM-FetA excretion was 34 (17-74) µg/24 h. During a median follow-up of 5.3 (4.5-6.0) years after baseline measurements, 73 (12%) KTRs developed graft failure. The association of 24h uPTM-FetA excretion with increased risk of graft failure was not constant over time, with increased risk only observed after 3 years from baseline measurements, independent of potential confounders including kidney function and 24 h urinary protein excretion (hazard ratio per doubling of 24h uPTM-FetA excretion = 1.31; 95% confidence interval = 1.06-1.61). This finding was robust in the sensitivity analyses. CONCLUSIONS: Our findings suggest that uPTM-FetA can be used as a marker for early detection of graft failure in KTR. Further studies are needed to confirm our findings.

NT-proBNP Mediates the Association Between FGF23 and All-Cause Mortality in Individuals With Type 2 Diabetes.

BACKGROUND: FGF23 (fibroblast growth factor 23) is associated with a higher mortality risk in type 2 diabetes, but the mechanism is unclear. We aimed to study whether NT-proBNP (N-terminal pro-brain natriuretic peptide) mediates the association between FGF23 and mortality. METHODS AND RESULTS: We analyzed C-terminal FGF23 and NT-proBNP levels in 399 patients with type 2 diabetes. Cox regression analyses were performed, followed by mediation analyses using Structural Equation Modeling. During follow-up of 9.2 [7.6-11.3] years, 117 individuals died. FGF23 was associated with all-cause mortality, independent of potential confounders (fully adjusted hazard ratio [HR], 2.32 [95% CI, 1.21-4.43], P=0.01). The association was lost upon further adjustment for NT-proBNP (HR, 1.84; 95% CI, 0.91-3.73). NT-proBNP accounted for 26% of the mediation effect between FGF23 and all-cause mortality. CONCLUSIONS: These findings suggest that a higher FGF23 level is associated with increased mortality in individuals with type 2 diabetes through an effect on volume homeostasis.

A Digital Coach (E-Supporter 1.0) to Support Physical Activity and a Healthy Diet in People With Type 2 Diabetes: Acceptability and Limited Efficacy Testing.

BACKGROUND: A healthy lifestyle, including regular physical activity and a healthy diet, is increasingly part of type 2 diabetes (T2D) management. As many people with T2D have difficulty living and maintaining a healthy lifestyle, there is a need for effective interventions. eHealth interventions that incorporate behavior change theories and tailoring are considered effective tools for supporting a healthy lifestyle. The E-Supporter 1.0 digital coach contains eHealth content for app-based eHealth interventions and offers tailored coaching regarding physical activity and a healthy diet for people with T2D. OBJECTIVE: This study aimed to assess the acceptability of E-Supporter 1.0 and explore its limited efficacy on physical activity, dietary behavior, the phase of behavior change, and self-efficacy levels. METHODS: Over a span of 9 weeks, 20 individuals with T2D received daily motivational messages and weekly feedback derived from behavioral change theories and determinants through E-Supporter 1.0. The acceptability of the intervention was assessed using telephone-conducted, semistructured interviews. The interview transcripts were coded using inductive thematic analysis. The limited efficacy of E-Supporter 1.0 was explored using the Fitbit Charge 2 to monitor step count to assess physical activity and questionnaires to assess dietary behavior (using the Dutch Healthy Diet index), phase of behavior change (using the single-question Self-Assessment Scale Stages of Change), and self-efficacy levels (using the Exercise Self-Efficacy Scale). RESULTS: In total, 5 main themes emerged from the interviews: perceptions regarding remote coaching, perceptions regarding the content, intervention intensity and duration, perceived effectiveness, and overall appreciation. The participants were predominantly positive about E-Supporter 1.0. Overall, they experienced E-Supporter 1.0 as a useful and easy-to-use intervention to support a better lifestyle. Participants expressed a preference for combining E-Supporter with face-to-face guidance from a health care professional. Many participants found the intensity and duration of the intervention to be acceptable, despite the coaching period appearing relatively short to facilitate long-term behavior maintenance. As expected, the degree of tailoring concerning the individual and external factors that influence a healthy lifestyle was perceived as limited. The limited efficacy testing showed a significant improvement in the daily step count (z=-2.040; P=.04) and self-efficacy levels (z=-1.997; P=.046) between baseline and postintervention. Diet was improved through better adherence to Dutch dietary guidelines. No significant improvement was found in the phase of behavior change (P=.17), as most participants were already in the maintenance phase at baseline. CONCLUSIONS: On the basis of this explorative feasibility study, we expect E-Supporter 1.0 to be an acceptable and potentially useful intervention to promote physical activity and a healthy diet in people with T2D. Additional work needs to be done to further tailor the E-Supporter content and evaluate its effects more extensively on lifestyle behaviors.

Overall and inter-individual effect of four different drug classes on soluble urokinase plasminogen activator receptor in type 1 and type 2 diabetes.

AIM: To evaluate the effect of four different drug classes on soluble urokinase plasminogen activator receptor (suPAR), a biomarker active in multiple inflammatory processes and a risk factor for complications, in people with type 1 and type 2 diabetes. METHODS: We conducted post hoc analyses of a randomized, open-label, crossover trial including 26 adults with type 1 and 40 with type 2 diabetes with urinary albumin-creatinine ratio ≥30 and ≤500 mg/g assigned to 4-week treatments with telmisartan 80 mg, empagliflozin 10 mg, linagliptin 5 mg and baricitinib 2 mg, separated by 4-week washouts. Plasma suPAR was measured before and after each treatment. SuPAR change after each treatment was calculated and, for each individual, the best suPAR-reducing drug was identified. Subsequently, the effect of the best individual drug was compared against the mean of the other three drugs. Repeated-measures linear mixed-effects models were employed. RESULTS: The baseline median (interquartile range) plasma suPAR was 3.5 (2.9, 4.3) ng/mL. No overall effect on suPAR levels was observed for any one drug. The individual best-performing drug varied, with baricitinib being selected for 20 participants (30%), followed by empagliflozin for 19 (29%), linagliptin for 16 (24%) and telmisartan for 11 (17%). The individual best-performing drug reduced suPAR by 13.3% (95% confidence interval [CI] 3.7, 22.8; P = 0.007). The difference in suPAR response between the individual best-performing drug and the other three was -19.7% (95% CI -23.1, -16.3; P < 0.001). CONCLUSIONS: We demonstrated no overall effect of 4-week treatment with telmisartan, empagliflozin, linagliptin or baricitinib on suPAR. However, individualization of treatment might significantly reduce suPAR levels.

Efficacy of Dapagliflozin by Baseline Diabetes Medications: A Prespecified Analysis From the DAPA-CKD Study.

OBJECTIVE: To determine whether the benefits of dapagliflozin in patients with type 2 diabetes and chronic kidney disease (CKD) in the Dapagliflozin And Prevention of Adverse Outcomes in CKD trial (DAPA-CKD) varied by background glucose-lowering therapy (GLT). RESEARCH DESIGN AND METHODS: We randomized 4,304 adults (including 2,906 with type 2 diabetes) with a baseline estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio of 200-5,000 mg/g to dapagliflozin 10 mg or placebo once daily (NCT03036150). The primary end point was a composite of ≥50% eGFR decline, end-stage kidney disease, and kidney or cardiovascular cause of death. Secondary end points included a kidney composite end point (primary composite end point without cardiovascular death), a cardiovascular composite end point (hospitalized heart failure or cardiovascular death), and all-cause mortality. In this prespecified analysis, we investigated the effects of dapagliflozin on these and other outcomes according to baseline GLT class or number of GLTs. RESULTS: The effects of dapagliflozin on the primary composite outcome were consistent across GLT classes and according to the number of GLTs (all interaction P > 0.08). Similarly, we found consistent benefit of dapagliflozin compared with placebo on the secondary end points regardless of background GLT class or number of GLTs. The same applied to the rate of decline in the eGFR rate and safety end points. Dapagliflozin reduced the initiation of insulin therapy during follow-up compared with placebo (hazard ratio 0.72; 95% CI 0.54-0.96; P = 0.025). CONCLUSIONS: Dapagliflozin reduced kidney and cardiovascular events in patients with type 2 diabetes and CKD across baseline GLT class or classes in combination.

Optimization of Albuminuria-Lowering Treatment in Diabetes by Crossover Rotation to Four Different Drug Classes: A Randomized Crossover Trial.

OBJECTIVE: Renin-angiotensin system (RAS) inhibitors decrease the urinary albumin to creatinine ratio (UACR) but are ineffective in up to 40% of patients. We hypothesized that rotation through different drug classes overcomes RAS inhibitor resistance and tested this in a randomized crossover trial. RESEARCH DESIGN AND METHODS: We assigned 26 adults with type 1 diabetes and 37 with type 2 diabetes and UACR between 30 and 500 mg/g and estimated glomerular filtration rate >45 mL/min/1.73 m2 to 4-week treatment periods with telmisartan 80 mg, empagliflozin 10 mg, linagliptin 5 mg, and baricitinib 2 mg in random order, separated by 4-week washout periods. Each participant was then re-exposed for 4 weeks to the drug that induced that individual's largest UACR reduction. Primary outcome was the difference in UACR response to the best-performing drug during the confirmation period versus UACR response to the other three drugs. RESULTS: There was substantial variation in the best-performing drug. Telmisartan was best performing for 33 participants (52%), empagliflozin and linagliptin in 11 (17%), and baricitinib in 8 participants (13%). The individuals' best-performing drug changed UACR from baseline during the first and confirmatory exposures by a mean of -39.6% (95% CI -44.8, -33.8; P < 0.001) and -22.4% (95% CI -29.7, -12.5; P < 0.001), respectively. The Pearson correlation for first versus confirmatory exposure was 0.39 (P = 0.017). The mean change in UACR with the other three drugs was +1.6% (95% CI -4.3%, 8.0%; P = 0.593 versus baseline; difference versus individuals' best-performing drug at confirmation, 30.9% [95% CI 18.0, 45.3]; P < 0.001). CONCLUSIONS: We demonstrated a large and reproducible variation in participants' responses to different UACR-lowering drug classes. These data support systematic rotation through different drug classes to overcome therapy resistance to RAS inhibition.

A Digital Lifestyle Coach (E-Supporter 1.0) to Support People With Type 2 Diabetes: Participatory Development Study.

BACKGROUND: A healthy lifestyle, including regular physical activity and a healthy diet, is becoming increasingly important in the treatment of chronic diseases. eHealth interventions that incorporate behavior change techniques (BCTs) and dynamic tailoring strategies could effectively support a healthy lifestyle. E-Supporter 1.0 is an eCoach designed to support physical activity and a healthy diet in people with type 2 diabetes (T2D). OBJECTIVE: This paper aimed to describe the systematic development of E-Supporter 1.0. METHODS: Our systematic design process consisted of 3 phases. The definition phase included the selection of the target group and formulation of intervention objectives, and the identification of behavioral determinants based on which BCTs were selected to apply in the intervention. In the development phase, intervention content was developed by specifying tailoring variables, intervention options, and decision rules. In the last phase, E-Supporter 1.0 integrated in the Diameter app was evaluated using a usability test in 9 people with T2D to assess intervention usage and acceptability. RESULTS: The main intervention objectives were to stimulate light to moderate-vigorous physical activities or adherence to the Dutch dietary guidelines in people with T2D. The selection of behavioral determinants was informed by the health action process approach and theories explaining behavior maintenance. BCTs were included to address relevant behavioral determinants (eg, action control, self-efficacy, and coping planning). Development of the intervention resulted in 3 types of intervention options, consisting of motivational messages, behavioral feedback, and tailor-made supportive exercises. On the basis of IF-THEN rules, intervention options could be tailored to, among others, type of behavioral goal and (barriers to) goal achievement. Data on these variables could be collected using app data, activity tracker data, and daily ecological momentary assessments. Usability testing revealed that user experiences were predominantly positive, despite some problems in the fixed delivery of content. CONCLUSIONS: The systematic development approach resulted in a theory-based and dynamically tailored eCoach. Future work should focus on expanding intervention content to other chronic diseases and lifestyle behaviors, enhancing the degree of tailoring and evaluating intervention effects on acceptability, use, and cost-effectiveness.

Low Urinary Potassium Excretion Is Associated with Higher Risk of All-Cause Mortality in Patients with Type 2 Diabetes: Results of the Dutch Diabetes and Lifestyle Cohort Twente (DIALECT).

BACKGROUND: Low 24-h urinary potassium excretion, reflecting low potassium intake, is associated with premature mortality in the general population. OBJECTIVES: To determine whether urinary potassium excretion is associated with all-cause mortality in patients with type 2 diabetes. METHODS: We performed a prospective cohort study in 654 patients with type 2 diabetes in the Diabetes and Lifestyle Cohort Twente (DIALECT). Sex-specific tertiles of 24-h urinary potassium excretion were analyzed in a multivariable Cox regression model with all-cause mortality. The outpatient program of the hospital uses a continuous surveillance system by the municipal registry of death to ensure up-to-date information on the patient's status (alive or deceased). FFQs were used to study associations between urinary potassium excretion and food products. RESULTS: Urinary potassium excretion at baseline was 84 ± 25 mmol/d in males and 65 ± 22 mmol/d in females, corresponding to estimated potassium intakes of 4250 ± 1270 mg/d and 3300 ± 875 mg/d. During a median follow-up of 5.2 (IQR: 2.7-7.9] y, 96 participants died. In a fully adjusted model, patients in the lowest sex-specific tertile had a higher risk of all-cause mortality, compared with patients in the highest sex-specific tertile (HR: 2.09; 95% CI: 1.06, 4.10; P = 0.03). Patients in the lowest sex-specific tertile consumed fewer fruits and vegetables, dairy, coffee, and potato products compared with patients in the highest sex-specific tertile (all P < 0.05). CONCLUSIONS: Low potassium intake is associated with a higher risk of all-cause mortality in Dutch patients with type 2 diabetes. Intervention studies are needed to determine whether potassium supplementation improves longevity in patients with type 2 diabetes. This trial was registered in the Dutch Trial Register as NTR trial code 5855.

Cadmium, active smoking and renal function deterioration in patients with type 2 diabetes.

BACKGROUND: Cadmium is an established nephrotoxin, present in cigarette smoke. We investigated the hazards of cadmium concentration and smoking status on renal function deterioration. We furthermore discerned whether the association of cadmium concentration with renal function deterioration is attributable to smoking status. METHODS: Prospective analyses were performed in data of 226 patients of the DIAbetes and LifEstyle Cohort Twente-1 (DIALECT). Cadmium concentrations were determined from EDTA whole-blood. Smoking status was determined via a self-administered questionnaire. Renal function deterioration was defined as need for renal replacement therapy or a persistent decline of ≥30% in estimated glomerular filtration rate from baseline for at least 3 months. Multivariable Cox regression models were performed to calculate hazard ratios (HRs) for the association between smoking status, cadmium concentration and renal function deterioration. RESULTS: Median (interquartile range) whole-blood cadmium was 2.9 (1.9-5.1) nmol/L. Active smokers had significantly higher cadmium [7.4 (3.3-11.7) nmol/L] compared with never smokers [2.6 (1.6-4.2) nmol/L] and former smokers [2.8 (1.8-4.8) nmol/L]. During median follow-up for 6 (4-8) years, renal function deterioration occurred in 60 persons (27%). Both cadmium and active smoking were associated with an increased hazard for renal function deterioration [HR 1.37, 95% confidence interval (95% CI) 1.06-1.78 and 3.77, 95% CI 1.72-8.29, respectively]. In a multivariable model with both smoking status and cadmium concentration included, active smokers have an increased risk for renal function deterioration (HR 3.00, 95% CI 1.22-7.40), while the association between cadmium and renal function deterioration lost statistical significance (HR 1.16, 95% CI 0.87-1.54). CONCLUSIONS: Active smoking is associated with progressive kidney disease in type 2 diabetes. The association between cadmium concentration and renal function deterioration in large part determined by smoking status. Extensive assessment of smoking status may be useful in patients with type 2 diabetesat high risk of kidney damage.

Identifying relevant determinants of in-hospital time to diagnosis for ANCA-associated vasculitis patients.

Objectives: Diagnosing patients with ANCA-associated vasculitis (AAV) can be challenging owing to its rarity and complexity. Diagnostic delay can have severe consequences, such as chronic organ damage or even death. Given that few studies have addressed diagnostic pathways to identify opportunities to improve, we performed a clinical audit to evaluate the diagnostic phase. Methods: This retrospective, observational study of electronic medical records data in hospitals focused on diagnostic procedures during the first assessment until diagnosis. Results: We included 230 AAV patients from nine hospitals. First assessments were mainly performed by a specialist in internal medicine (52%), pulmonology (14%), ENT (13%) or rheumatology (10%). The overall median time to diagnosis was 13 [interquartile range: 2-49] days, and in patients primarily examined by a specialist in internal medicine it was 6 [1-25] days, rheumatology 14 [4-45] days, pulmonology 15 [5-70] days and ENT 57 [16-176] days (P = 0.004). Twenty-two of 31 (71%) patients primarily assessed by a specialist in ENT had non-generalized disease, of whom 14 (64%) had ENT-limited activity. Two hundred and nineteen biopsies were performed in 187 patients (81%). Histopathological support for AAV was observed in 86% of kidney biopsies, 64% of lung biopsies and 34% of ENT biopsies. Conclusion: In The Netherlands, AAV is diagnosed and managed predominantly by internal medicine specialists. Diagnostic delay was associated with non-generalized disease and ENT involvement at presentation. Additionally, ENT biopsies had a low diagnostic yield, in contrast to kidney and lung biopsies. Awareness of this should lead to more frequent consideration of AAV and early referral for a multidisciplinary approach when AAV is suspected.

Adherence to Statin Therapy and Attainment of LDL Cholesterol Targets in an Outpatient Population of Type 2 Diabetes Patients: Analysis in the DIAbetes and LifEstyle Cohort Twente (DIALECT).

Objective: To assess adherence to statin therapy and its association with sociodemographic data, medical characteristics, LDLc levels, and LDLc target attainment in real-world T2D patients treated in secondary care. Research Design and Methods: Cross-sectional analyses were performed on baseline data of 393 patients in the DIAbetes and LifEstyle Cohort Twente (DIALECT). The medication possession ratio (MPR), calculated with pharmacy dispensing data, was used to determine adherence to statins for an intended period of 24 months. Statins were included in the analyses if they were used for at least six consecutive months with at least three dispenses. Adherence was defined as an MPR ≥80%. Associations with adherence were assessed using descriptive statistics and binary logistic regression. Results: Overall, 80% of the patients had a statin prescription and of those, 89% were adherent. The proportion of patients who reached LDLc targets of ≤2.5 mmol/L and <1.8 mmol/L differed significantly between the adherent, nonadherent and non-statin group (90% vs. 74% vs. 46%; p < 0.01 and 56% vs. 26% vs. 6%; p < 0.01, respectively). Serum LDLc levels were lower in the adherent versus the nonadherent and non-statin group (1.76 ± 0.60 vs. 2.23 ± 0.90 vs. 2.71 ± 0.67 mmol/L; p < 0.01). Higher HbA1c levels were independently associated with nonadherence (OR: 1.05, 95% CI 1.01-1.08; p < 0.01). Mediation adherence (OR: 2.88, 95% CI 1.04-7.97; p = 0.041) and lower BMI (OR: 0.88, 95% CI 0.81-0.96; p < 0.01) were independently associated with attaining the LDLc target of ≤2.5 mmol/L. Conclusion: In patients with T2D treated in secondary care, statin adherence was relatively high and was associated with significantly lower LDLc levels. It is important to identify nonadherence as it appeared an important determinant of failure to reach LDLc targets. The finding that many patients who failed to attain LDLc targets did not receive statin treatment offers an opportunity to improve diabetes care.

Effects of dapagliflozin on volume status and systemic haemodynamics in patients with chronic kidney disease without diabetes: Results from DAPASALT and DIAMOND.

AIMS: To assess the effect of sodium-glucose cotransporter-2 inhibitor dapagliflozin on natriuresis, blood pressure (BP) and volume status in patients with chronic kidney disease (CKD) without diabetes. MATERIALS AND METHODS: We performed a mechanistic open-label study (DAPASALT) to evaluate the effects of dapagliflozin on 24-hour sodium excretion, 24-hour BP, extracellular volume, and markers of volume status during a standardized sodium diet (150 mmol/d) in six patients with CKD. In parallel, in a placebo-controlled double-blind crossover trial (DIAMOND), we determined the effects of 6 weeks of dapagliflozin on markers of volume status in 53 patients with CKD. RESULTS: In DAPASALT (mean age 65 years, mean estimated glomerular filtration rate [eGFR] 39.4 mL/min/1.73 m2 , median urine albumin:creatinine ratio [UACR] 111 mg/g), dapagliflozin did not change 24-hour sodium and volume excretion during 2 weeks of treatment. Dapagliflozin was associated with a modest increase in 24-hour glucose excretion on Day 4, which persisted at Day 14 and reversed to baseline after discontinuation. Mean 24-hour systolic BP decreased by -9.3 (95% confidence interval [CI] -19.1, 0.4) mmHg after 4 days and was sustained at Day 14 and at wash-out. Renin, angiotensin II, urinary aldosterone and copeptin levels increased from baseline. In DIAMOND (mean age 51 years, mean eGFR 59.0 mL/min/1.73 m2 , median UACR 608 mg/g), compared to placebo, dapagliflozin increased plasma renin (38.5 [95% CI 7.4, 78.8]%), aldosterone (19.1 [95% CI -5.9, 50.8]%), and copeptin levels (7.3 [95% CI 0.1, 14.5] pmol/L). CONCLUSIONS: During a standardized sodium diet, dapagliflozin decreased BP but did not increase 24-hour sodium and volume excretion. The lack of increased natriuresis and diuresis may be attributed to activation of intra-renal compensatory mechanisms to prevent excessive water loss.