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

Screening for Common Respiratory Diseases among Israeli Adolescents

BACKGROUND: Respiratory diseases are responsible for a significant proportion of serious morbidity among adolescents. There are few reports on the prevalence of common respiratory disorders in this population. The previous studies focused on specific diseases and screened relatively small samples

Fasting Until Noon Triggers Increased Postprandial Hyperglycemia and Impaired Insulin Response After Lunch and Dinner in Individuals With Type 2 Diabetes: A Randomized Clinical Trial.

Skipping breakfast has been consistently associated with high HbA1c and postprandial hyperglycemia (PPHG) in patients with type 2 diabetes. Our aim was to explore the effect of skipping breakfast on glycemia after a subsequent isocaloric (700 kcal) lunch and dinner

High-energy breakfast based on whey protein reduces body weight, postprandial glycemia and HbA1C in Type 2 diabetes

Acute studies show that addition of whey protein at breakfast has a glucose-lowering effect through increased incretin and insulin secretion. However, whether this is a long-term effect in Type 2 diabetes is unknown. Fifty-six Type 2 diabetes participants aged 58.9±4.5 years, BMI 32.1±0.9 kg/m2 and HbA1C 7.8±0.1% (61.6±0.79 mmol/mol) were randomized to one of 3 isocaloric diets with similar lunch and dinner, but different breakfast: 1) 42 g total protein, 28 g whey (WBdiet, n=19); 2) 42 g various protein sources (PBdiet, n=19); or 3) high-carbohydrate breakfast, 17 g protein from various sources (CBdiet, n=18). Body weight and HbA1C were examined after 12 weeks. All participants underwent three all-day meal challenges for postprandial glycemia, insulin, C-peptide, intact glucagon-like peptide 1 (iGLP-1), ghrelin and hunger and satiety scores. Overall postprandial AUCglucose was reduced by 12% in PBdiet and by 19% in WBdiet, compared with CBdiet (P<.0001). Compared with PBdiet and CBdiet, WBdiet led to a greater postprandial overall AUC for insulin, C-peptide, iGLP-1 and satiety scores, while postprandial overall AUC for ghrelin and hunger scores were reduced (P<.0001). After 12 weeks, HbA1C was reduced after WBdiet by 0.89±0.05% (11.5±0.6 mmol/mol), after PBdiet by 0.6±0.04% (7.1±0.31 mmol/mol) and after CBdiet by 0.36±0.04% (2.9±0.31 mmol/mol) (P<.0001). Furthermore, the participants on WBdiet lost 7.6±0.3 kg, PBdiet 6.1±0.3 kg and CBdiet 3.5±0.3 kg (P<.0001). Whey protein-based breakfast is an important adjuvant in the management of Type 2 diabetes

High-energy breakfast with low-energy dinner decreases overall daily hyperglycaemia in type 2 diabetic patients: a randomised clinical trial

Aims/hypothesis High-energy breakfast and reduced-energy dinner (Bdiet) significantly reduces postprandial glycaemia in obese non-diabetic individuals. Our objective was to test whether this meal schedule reduces postprandial hyperglycaemia (PPHG) in patients with type 2 diabetes by enhancing incretin and insulin levels when compared with high-energy dinner and reduced-energy breakfast (Ddiet). Methods In a randomised, open label, crossover design performed in a clinic setting, 18 individuals (aged 30-70 years with BMI 22-35 kg/m(2)) with type 2 diabetes (< 10 years duration) treated with metformin and/or diet were given either Bdiet or Ddiet for 7 days. Participants were randomised by a person not involved in the study using a coin flip. Postprandial levels of plasma glucose, insulin, C-peptide and intact and total glucagon-like peptide-1 (iGLP-1 and tGLP-1) were assessed. The Bdiet included 2,946 kJ breakfast, 2,523 kJ lunch and 858 kJ dinner. The Ddiet comprised 858 kJ breakfast, 2,523 kJ lunch and 2,946 kJ dinner. Results Twenty-two individuals were randomised and 18 analysed. The AUC for glucose (AUC(glucose)) throughout the day was 20% lower, whereas AUC(insulin), AUC(C-peptide) and AUC(tGLP-1) were 20% higher for the Bdiet than the Ddiet. Glucose AUC(0-180min) and its peak were both lower by 24%, whereas insulin AUC(0-180min) was 11% higher after the Bdiet than the Ddiet. This was accompanied by 30% higher tGLP-1 and 16% higher iGLP-1 levels. Despite the diets being isoenergetic, lunch resulted in lower glucose (by 21-25%) and higher insulin (by 23%) with the Bdiet vs Ddiet. Conclusions/interpretation High energy intake at breakfast is associated with significant reduction in overall PPHG in diabetic patients over the entire day. This dietary adjustment may have a therapeutic advantage for the achievement of optimal metabolic control and may have the potential for being preventive for cardiovascular and other complications of type 2 diabetes