Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

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

Supplementary Material for: Continuous erythropoietin receptor activator for the treatment of chronic dialysis patients with renal anemia in daily clinical practice in Poland: A non-interventional, multi-center, pragmatic NAVIGO trial

Background: Renal anemia is one of the most common complications of chronic kidney disease. This real-life study assessed the effectiveness of methoxy polyethylene glycol-epoetin beta, a continuous erythropoietin receptor activator (C.E.R.A.), for the treatment of chronic kidney disease (CKD)-associated anemia in patients receiving dialysis in daily clinical practice. Methods: 247 patients receiving chronic intermitted dialysis in 26 centers in Poland with CKD-associated symptomatic anemia, ESA-naïve, and with balanced iron stores in the investigators’ opinion were enrolled this real-life study. Over 12 months, the following data were collected: Hb concentration and dosage, route of administration and dosing scheme of C.E.R.A., dialysis adequacy, adverse events, iron therapy, and blood transfusions. Results: During the treatment, a Hb concentration of ≥10 g/dL was noted in 90.9% of hemodialysis patients (n=224) and 96.0% of peritoneal dialysis patients (n=23). At baseline, 7.8% of patients had a Hb concentration of 10–12 g/dL, which increased to 63.3% after 12 months. The median time when Hb concentration was maintained within 10–12 g/dL was 115.2 [IQR 49.1–188.7] days. A Hb concentration ≥12 g/dL was observed after 7 months of treatment in a maximum of 24.1% of hemodialysis patients, and 31.8% of peritoneal dialysis patients. The median time elapsed between the start of treatment and the first Hb concentration >10 g/dL was 42.0 [21.0–78.2] days. C.E.R.A. was well tolerated. Conclusions: C.E.R.A. corrects CKD-associated anemia in dialysis patients, and maintains Hb levels within the recommended target range. The study also confirmed the acceptable safety profile of the drug. Study identifier at ClinicalTrials.gov: NCT0169045

Supplementary Material for: Continuous erythropoietin receptor activator for the treatment of chronic dialysis patients with renal anemia in daily clinical practice in Poland: A non-interventional, multi-center, pragmatic NAVIGO trial

Background: Renal anemia is one of the most common complications of chronic kidney disease. This real-life study assessed the effectiveness of methoxy polyethylene glycol-epoetin beta, a continuous erythropoietin receptor activator (C.E.R.A.), for the treatment of chronic kidney disease (CKD)-associated anemia in patients receiving dialysis in daily clinical practice. Methods: 247 patients receiving chronic intermitted dialysis in 26 centers in Poland with CKD-associated symptomatic anemia, ESA-naïve, and with balanced iron stores in the investigators’ opinion were enrolled this real-life study. Over 12 months, the following data were collected: Hb concentration and dosage, route of administration and dosing scheme of C.E.R.A., dialysis adequacy, adverse events, iron therapy, and blood transfusions. Results: During the treatment, a Hb concentration of ≥10 g/dL was noted in 90.9% of hemodialysis patients (n=224) and 96.0% of peritoneal dialysis patients (n=23). At baseline, 7.8% of patients had a Hb concentration of 10–12 g/dL, which increased to 63.3% after 12 months. The median time when Hb concentration was maintained within 10–12 g/dL was 115.2 [IQR 49.1–188.7] days. A Hb concentration ≥12 g/dL was observed after 7 months of treatment in a maximum of 24.1% of hemodialysis patients, and 31.8% of peritoneal dialysis patients. The median time elapsed between the start of treatment and the first Hb concentration >10 g/dL was 42.0 [21.0–78.2] days. C.E.R.A. was well tolerated. Conclusions: C.E.R.A. corrects CKD-associated anemia in dialysis patients, and maintains Hb levels within the recommended target range. The study also confirmed the acceptable safety profile of the drug. Study identifier at ClinicalTrials.gov: NCT0169045