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

IgM antibodies to oxidized phosphatidylserine as protection markers in cardiovascular disease among 60-year olds.

OBJECTIVE:Phosphatidylserine is exposed on apoptotic cells and is prone to oxidation (OxPS). Here we analyze the association of IgM antibodies against OxPS (anti-OxPS) with the risk of cardiovascular disease (CVD). METHODS:Among sixty-year olds from Stockholm County in Sweden, previously screened for cardiovascular risk factors (2039 men, 2193 women), there were 210 incident CVD-cases identified during a 5-year follow-up. Using a nested case-control design, 622 age- and sex-matched controls were selected. Odds ratios (OR) with 95% intervals (CI) were calculated by conditional logistic regression. IgM anti-OxPS was measured by ELISA. Phagocytosis of apoptotic Jurkat-cells by macrophages was studied by flow cytometry. RESULTS:Anti-OxPS levels were lower among cases (median (interquartile range): 80.7 (60.9-101.0 vs. 84.6 (65.8-109.6); p = 0.047); among men (76.6 (55.8-99.2) vs. 82.0 (63.1-105.1); p = 0.022) and among women 89.6 (72.3-110.1) vs. 89.8 (69.9-114.4); p = 0.79). After adjustment for smoking, BMI, diabetes mellitus type II, hypercholesterolaemia and hypertension, and dividing into quartiles, using the highest quartile (quartile 4) as reference, quartile 3 was associated with a OR of 1.74 (CI 1.08-2.81). Quartiles 2 and 1 had similar associations, the later reaching statistical significance. Among men associations were stronger whereas no significant associations were observed in women. The OR of MI/angina comparing quartile 3 with quartile 4 was 2.31 (CI 1.30-4.11). The OR for quartile 2 and 1, respectively, were similar as for quartile 3. Total IgM increased uptake of apoptotic cells, which was reversed if incubated with OxPS. CONCLUSIONS:IgM anti-OxPS is a novel potential protection marker for CVD, in particular in men. Increased phagocytosis of dying/dead cells could be one potential underlying mechanism

Association between levels of IgM anti-OxPS and risk for stroke, among all participants and men and women separately.

<p>Both cases and controls were included as the basis for division into seven percentiles where the one studied is compared to the rest.</p

IgM antibodies to oxidized phosphatidylserine as protection markers in cardiovascular disease among 60-year olds - Fig 1

<p><b>a. Distribution of IgM anti-OxPS among cases and controls</b>. 0 = controls who did not develop CVD during the follow up time, 1 = controls who did develop CVD. Cases hade significantly lower levels than controls (p = 0.047). Differences were more pronounced when highest quartile was compared with the other quartiles. <b>b. Distribution of IgM anti-OxPS among women, cases and controls</b>. 0 = controls who did not develop CVD during the follow up time, 1 = controls who did develop CVD. Cases hade significantly lower levels than controls (p = 0.047). Differences were more pronounced when highest quartile was compared with the other quartiles. <b>c. Distribution of IgM anti-OxPS among men, cases and controls</b>. 0 = controls who did not develop CVD during the follow up time, 1 = controls who did develop CVD. Cases hade significantly lower levels than controls (p = 0.047). Differences were more pronounced when highest quartile was compared with the other quartiles.</p

Association between levels of IgM anti-OxPS and risk for MI and/or + stroke (CVD), among all participants and men and women separately.

<p>Both cases and controls were included as the basis for division into seven percentiles where the one studied is compared to the rest.</p

Risk of angina/MI in relation to the highest quartile of IgM anti-OxPS.

<p>Association between levels of IgM anti-OxPS and risk for CVD, (as compared to 622 controls) among all participants and men and women separately. In tables, the highest quartile, Q4, is set as 1. Both cases and controls were included angina/MI as the basis for division into quartiles.</p

Baseline characteristics among incident CVD cases and matched controls.

<p>Baseline characteristics among incident CVD cases and matched controls.</p

Risk of stroke in relation to the highest quartile of IgM anti-OxPS.

<p>Association between levels of IgM anti-OxPS and risk for stroke, (as compared to 622 controls) among all participants and men and women separately. In tables, the highest quartile, Q4, is set as 1. Both cases and controls were included as the basis for division into quartiles.</p