Background: This post-hoc study investigated whether biomarkers reflecting extracellular matrix (ECM) turnover predicted cardiovascular disease (CVD), mortality, and progression of diabetic kidney disease (DKD) in individuals with type 2 diabetes (T2D) and microalbuminuria. Methods: Serum levels of specific ECM turnover biomarkers were assessed in 192 participants with T2D and microalbuminuria from an observational study conducted at Steno Diabetes Center Copenhagen from 2007 to 2008. Endpoints included CVD events, mortality, and DKD progression, defined as decline in estimated glomerular filtration rate (eGFR) of >30 %. Results: Participants had a mean age of 59 years, with 75 % males. Over a median follow-up of 4.9 to 6.3 years, the study recorded 38 CVD events, 24 deaths, and 40 DKD events. Elevated levels of a degradation fragment of collagen type I (C1M) were associated with an increased risk of >30 % eGFR decline, although this association was not independent of other risk factors. No significant associations were found between other ECM turnover biomarkers and DKD progression, mortality, or CVD risk. Conclusion: Elevated C1M levels were linked to DKD progression in individuals with T2D and microalbuminuria, but not independently of other risk factors. None of the ECM turnover biomarkers were associated with CVD or mortality.

Aim: Comparing continuous glucose monitoring (CGM)-recorded metrics during treatment with insulin degludec (IDeg) versus insulin glargine U100 (IGlar-100) in people with type 1 diabetes (T1D) and recurrent nocturnal severe hypoglycemia. Materials and methods: This is a multicenter, two-year, randomized, crossover trial, including 149 adults with T1D and minimum one episode of nocturnal severe hypoglycemia within the last two years. Participants were randomized 1:1 to treatment with IDeg or IGlar-100 and given the option of six days of blinded CGM twice during each treatment. CGM traces were reviewed for the percentage of time-within-target glucose range (TIR), time-below-range (TBR), time-above-range (TAR), and coefficient of variation (CV). Results: Seventy-four participants were included in the analysis. Differences between treatments were greatest during the night (23:00-06:59). Treatment with IGlar-100 resulted in 54.0% vs 49.0% with IDeg TIR (70-180 mg/dL) (estimated treatment difference [ETD]: -4.6%, 95% confidence interval [CI]: -9.1, -0.0, P = .049). TBR was lower with IDeg at level 1 (54-69 mg/dL) (ETD: -1.7% [95% CI: -2.9, -0.5], P < .05) and level 2 (<54 mg/dL) (ETD: -1.3% [95% CI: -2.1, -0.5], P = .001). TAR was higher with IDeg compared with IGlar-100 at level 1 (181-250 mg/dL) (ETD: 4.0% [95% CI: 0.8, 7.3], P < .05) and level 2 (> 250 mg/dL) (ETD: 4.0% [95% CI: 0.8, 7.2], P < .05). The mean CV was lower with IDeg than that with IGlar-100 (ETD: -3.4% [95% CI: -5.6, -1.2], P < .05). Conclusion: For people with T1D suffering from recurrent nocturnal severe hypoglycemia, treatment with IDeg, compared with IGlar-100, results in a lower TBR and CV during the night at the expense of more TAR.

AIM:To compare nocturnal glucose profiles according to hourly plasma glucose measurements during treatment with insulin degludec and insulin glargine U100 in a cohort of people with type 1 diabetes prone to nocturnal severe hypoglycaemia.MATERIALS AND METHODS:The HypoDeg trial is a 2-year investigator-initiated, randomized, controlled crossover trial in 149 participants randomized to treatment with insulin degludec and insulin glargine U100 for 12 months each. The 51 participants in this predefined substudy stayed at least one night in hospital during each treatment arm for plasma glucose samples to be taken. Endpoints were glucose profiles, including mean plasma glucose, glycaemic variability and risk of hypoglycaemia.RESULTS:There were no differences between treatments regarding mean plasma glucose. We saw a flatter glucose profile during insulin degludec compared with insulin glargine U100 treatment, which had a nadir at 4:00 AM, with a subsequent rise. During treatment with insulin degludec, the participants had lower glycaemic variability, with an estimated treatment difference of -4.3% (95% confidence interval [CI] -8.1 to -0.5; P < 0.05). Participants treated with insulin degludec were less likely to experience nocturnal hypoglycaemia below 3.0 mmol/L (hazard ratio 0.36 [95% CI 0.17-0.73; P < 0.05]).CONCLUSION:Based on nocturnal plasma glucose measurements, treatment with insulin degludec compared with insulin glargine U100 administered in the evening results in lower glycaemic variability and lower risk of nocturnal hypoglycaemia without differences in mean plasma glucose.

Background Diabetic kidney disease is a major cause of morbidity and mortality. Dysregulated turnover of collagen type III is associated with development of kidney fibrosis. We investigated whether a degradation product of collagen type III (C3M) was a risk marker for progression of chronic kidney disease (CKD), occurrence of cardiovascular disease (CVD), and mortality during follow up in people with type 2 diabetes (T2D) and microalbuminuria. Moreover, we investigated whether C3M was correlated with markers of inflammation and endothelial dysfunction at baseline. Methods C3M was measured in serum (sC3M) and urine (uC3M) in 200 participants with T2D and microalbuminuria included in an observational, prospective study at Steno Diabetes Center Copenhagen in Denmark from 2007–2008. Baseline measurements included 12 markers of inflammation and endothelial dysfunction. The endpoints were CVD, mortality, and CKD progression (>30% decline in eGFR). Results Mean (SD) age was 59 (9) years, eGFR 90 (17) ml/min/1.73m2 and median (IQR) urine albumin excretion rate 102 (39–229) mg/24-h. At baseline all markers for inflammation were positively correlated with sC3M (p≤0.034). Some, but not all, markers for endothelial dysfunction were correlated with C3M. Median follow-up ranged from 4.9 to 6.3 years. Higher sC3M was associated with CKD progression (with mortality as competing risk) with a hazard ratio (per doubling) of 2.98 (95% CI: 1.41–6.26; p = 0.004) adjusted for traditional risk factors. uC3M was not associated with CKD progression. Neither sC3M or uC3M were associated with risk of CVD or mortality. Conclusions Higher sC3M was a risk factor for chronic kidney disease progression and was correlated with markers of inflammation.

Plasma exposure of the endothelin receptor antagonist atrasentan varies between individuals and is associated with nephroprotective effects and the risk of heart failure. We examined the influence of genetic polymorphisms on atrasentan plasma exposure and pharmacodynamic effects. We performed a substudy of the Study of Diabetic Nephropathy With Atrasentan (SONAR) trial which enrolled adults with type 2 diabetes and chronic kidney disease (estimated glomerular filtration rate: 25-75 mL/min/1.73 m(2), and a urine albumin-to-creatinine ratio of 300-5,000 mg/g). Single nucleotide polymorphisms (SNPs) were determined for prespecified membrane transporters, metabolizing enzymes, and the endothelin-1 peptide. The associations among genotype, atrasentan plasma exposure, and the effect of atrasentan on the prespecified kidney and heart failure hospitalization (HHF) outcomes was assessed with Cox proportional hazards regression models. Of 3,668 patients randomized, 2,329 (63.5%) consented to genotype analysis. Two SNPs in the SLCO1B1 gene (rs4149056 and rs2306283), encoding the hepatic organic anion transporter 1B1 (OATP1B1), showed the strongest association with atrasentan plasma exposure. Based on their SLCO1B1 genotype, patients were classified into normal (atrasentan area under the plasma-concentration time curve from zero to infinity (AUC(0-inf)) 41.3 ng center dot h/mL) or slow (atrasentan AUC(0-inf) 49.7 ng center dot h/mL, P < 0.001) OATP1B1 transporter phenotypes. Among patients with a normal OATP1B1 phenotype, the hazard ratio (HR) with atrasentan for the primary kidney and HHF outcomes were 0.61 (95% confidence interval (CI): 0.45-0.81) and 1.35 (95% CI: 0.84-2.13), respectively. In the slow transporter phenotype, HRs for kidney and HHF outcomes were 1.95 (95% CI: 0.95-4.03, P-interaction normal phenotype = 0.004), and 4.18 (95% CI: 1.37-12.7, P-interaction normal phenotype = 0.060), respectively. OATP1B1 gene polymorphisms are associated with significant between-patient variability in atrasentan plasma exposure and long-term efficacy and safety.

Background and Aims: Nocturnal hypoglycemia is mainly a consequence of inappropriate basal insulin therapy in type 1 diabetes (T1D) and may compromise optimal glycemic control. Insulin degludec is associated with a lower risk of nocturnal hypoglycemia in T1D. As nocturnal hypoglycemia is often asymptomatic, we applied continuous glucose monitoring (CGM) to detect a more precise occurrence of nocturnal hypoglycemia in the HypoDeg trial, comparing insulin degludec with insulin glargine U100 in people with T1D and previous nocturnal severe hypoglycemia. Materials and Methods: In the HypoDeg trial, 149 people with T1D were included in an open-label randomized cross-over trial. Sixty-seven participants accepted optional participation in the predefined substudy of 4 × 6 days of blinded CGM requiring completion of at least one CGM period in each treatment arm. CGM data were reviewed for hypoglycemic events. Results: Treatment with insulin degludec resulted in a relative rate reduction (RRR) of 36% (95% confidence interval [CI]: 10%-54%; P < 0.05) in nocturnal CGM-recorded hypoglycemia (≤3.9 mmol/L), corresponding to an absolute rate reduction (ARR) of 0.85 events per person-week. In nocturnal CGM-recorded hypoglycemia (≤3.0 mmol/L), we found an RRR of 53% (95% CI: 36%-65%; P < 0.001), corresponding to an ARR of 0.75 events per person-week. At the lower detection limit of the CGM (≤2.2 mmol/L), treatment with insulin degludec resulted in a significant RRR of 58% (95% CI: 23%-77%; P = 0.005). The reductions were primarily due to significant RRRs in asymptomatic hypoglycemia. Conclusion: In people with T1D, prone to nocturnal severe hypoglycemia, insulin degludec compared with insulin glargine U100 significantly reduces nocturnal CGM-recorded hypoglycemia. www.clinicaltrials.gov (#NCT02192450).

BACKGROUND The endothelin receptor antagonist atrasentan reduced the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease (CKD) in the SONAR (Study of Diabetic Nephropathy with Atrasentan) trial, although with a numerically higher incidence of heart failure (HF) hospitalization. OBJECTIVES The purpose of this study was to assess if early changes in B-type natriuretic peptide (BNP) and body weight during atrasentan treatment predict HF risk. METHODS Participants with type 2 diabetes and CKD entered an open-label enrichment phase to assess response to atrasentan 0.75 mg/day. Participants without substantial fluid retention (> 3 kg body weight increase or BNP increase to > 300 pg/mL), were randomized to atrasentan 0.75 mg/day or placebo. Cox proportional hazards regression was used to assess the effects of atrasentan vs placebo on the prespecified safety outcome of HF hospitalizations. RESULTS Among 3,668 patients, 73 (4.0%) participants in the atrasentan and 51 (2.8%) in the placebo group developed HF (HR: 1.39; 95% CI: 0.97-1.99; P 1/4 0.072). In a multivariable analysis, HF risk was associated with higher baseline BNP (HR: 2.32; 95% CI: 1.81-2.97) and percent increase in BNP during response enrichment (HR: 1.46; 95% CI: 1.081.98). Body weight change was not associated with HF. Exclusion of patients with at least 25% BNP increase during enrichment attenuated the risk of HF with atrasentan (HR: 1.02; 95% CI: 0.66-1.56) while retaining nephroprotective effects (HR: 0.58; 95% CI: 0.44-0.78). CONCLUSIONS In patients with type 2 diabetes and CKD, baseline BNP and early changes in BNP in response to atrasentan were associated with HF hospitalization, highlighting the importance of natriuretic peptide monitoring upon initiation of atrasentan treatment. (C) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

AIMS:The trimethylamine N-oxide (TMAO) pathway is related to intestinal microbiota and has been associated to risk of cardiovascular disease (CVD). We investigated associations between four plasma metabolites in the TMAO pathway and risk of all-cause mortality, CVD and deterioration in renal function in individuals with type 2-diabetes (T2D) and albuminuria. MATERIALS AND METHODS:Plasma concentrations of TMAO, choline, carnitine, and betaine were measured by liquid chromatography-tandem mass spectrometry at baseline in 311 individuals with T2D and albuminuria. Information on all-cause mortality and fatal/non-fatal CVD during follow-up was obtained from registries. The association of each metabolite, and a weighted sum score of all four metabolites, with the endpoints were examined. Serum creatinine was measured at follow-up visits and the renal endpoint was defined as eGFR-decline of ≥30%. Associations were analysed using proportional hazards models adjusted for traditional risk factors. RESULTS:Baseline mean(SD) age was 57.2(8.2) years and 75% were males. Follow-up was up to 21.9 years (median (IQR) follow-up 6.8 (6.1-15.5) years for mortality and 6.5 (5.5-8.1) years for CVD events). The individual metabolites and the weighted sum score were not associated with all-cause mortality (n = 106) or CVD (n = 116) (adjusted p≥0.09). Higher choline, carnitine and the weighted sum score of the four metabolites were associated with higher risk of decline in eGFR (n = 106) (adjusted p = 0.001, p = 0.03 and p<0.001, respectively). CONCLUSIONS:In individuals with T2D and albuminuria, higher choline, carnitine and a weighted sum of four metabolites from the TMAO pathway were risk markers for deterioration in renal function during long-term follow-up. Metabolites from the TMAO pathway were not independently related to risk of all-cause mortality or CVD.

Atrasentan, an endothelin receptor antagonist, showed clinically significant albuminuria reduction with minimal signs of fluid retention in phase II trials. We evaluated whether plasma exposure was associated with long‐term outcomes for kidney protection and heart failure in the phase III SONAR trial (n = 3668) in type 2 diabetics with chronic kidney disease. A population pharmacokinetic model was used to estimate plasma exposure of atrasentan 0.75 mg/day. Parametric time‐to‐event models were used to quantify the association between plasma exposure and long‐term outcomes. Mean atrasentan plasma exposure was 41.4 ng.h/mL (2.5th to 97.5th P: 14.2 to 139.9). Compared with placebo, a mean atrasentan exposure translated in a hazard ratio of 0.76 (95% confidence interval (CI): 0.28–0.85) for kidney events and 1.13 (95% CI: 1.03–2.20) for heart failure events. At the mean atrasentan exposure, the kidney protective effect was larger than the increase in heart failure supporting the atrasentan 0.75 mg/day dose in this population.

To investigate whether the long‐acting insulin analogue insulin degludec compared with insulin glargine U100 reduces the risk of nocturnal symptomatic hypoglycaemia in patients with type 1 diabetes (T1D).

Patients with high albuminuria and low eGFR levels are usually enrolled in clinical trials to enrich the population at risk of ESKD in order to accrue sufficient clinical end points. However, the relatively low event rates in recent nephrology trials suggest that this approach does not completely rule out enrollment of patients without progressive kidney function loss.12–3 The rate of eGFR decline before trial entry (pretrial eGFR slope) is a more direct determinant of ESKD risk and could be a more appropriate approach to select high-risk clinical trial participants, but it has not been used, most likely because of logistical challenges to obtain pretrial eGFR data. However, with the introduction of electronic medical records, obtaining historical eGFR data has become easier and practically more feasible. Using electronic medical record data, we determined pretrial eGFR slope in participants of the Study of Diabetic Nephropathy with Atrasentan (SONAR) trial with high albuminuria and low eGFR. We subsequently determined whether the effect of atrasentan in slowing progressive kidney function loss is higher among participants with a steeper pretrial eGFR slope. We performed a post hoc analysis of the SONAR trial, which determined the effect of the endothelin receptor antagonist atrasentan in patients with type 2 diabetes and CKD on kidney outcomes. The SONAR trial included adult patients with type 2 diabetes who had an eGFR of 25–75 ml/min per 1.73 m2 and a urine albumin-creatinine ratio (UACR) of 300–5000 mg/g.34–5 Participating investigators were asked to participate in a voluntary substudy to record pretrial eGFR data from medical records if available. Each individual's pretrial eGFR slope was estimated using within individual linear regression. We used linear mixed effects models with a random intercept and slope to assess the effect of atrasentan compared with placebo on eGFR slope during the clinical trial. Detailed methods are described in the Supplemental Material. A total of 630 patients (12.3% of total cohort) with at least three serum creatinine values before the start of the trial were included. Over a median pretrial duration of 1.8 years, a mean of 8.1 (SD 4.8) pretrial serum creatinine measurements were collected. Baseline characteristics of the 630 included participants were similar with the overall SONAR cohort (Supplemental Table 1). The mean rate of pretrial eGFR decline was 4.8 (SD 9.6) ml/min per 1.73 m2 per year. We observed a large between-individual variation in pretrial eGFR slopes (Supplemental Figure 1). The annual rate of decline in eGFR prior to the SONAR trial was ≥5 ml/min per 1.73 m2 per year in 259 (41.1%) patients, between 1 and 5 ml/min per 1.73 m2 per year in 183 (29.1%) patients, and <1 ml/min per 1.73 m2 per year in 188 (29.8%) patients (Supplemental Table 2). The event rate for the primary kidney outcome in placebo-treated patients with a fast progression was two-fold higher compared with patients with a stable disease: 6.9 (95% confidence interval [CI], 4.0 to 11.9) versus 3.3 (95% CI, 1.5 to 7.4) events per 100 patients-years. Although patients with a baseline UACR >1000 mg/g had a statistically significantly steeper pretrial eGFR decline than patients with a baseline UACR of ≤1000 mg/g (P=0.001), UACR only explained a modest proportion of the variation in pretrial eGFR slope (R2=2.9%). There was no association between pretrial eGFR slope and baseline eGFR (Supplemental Figure 2, Supplemental Table 2). The effect of atrasentan versus placebo on clinical trial eGFR slope depended on the pretrial eGFR slope. In patients with a pretrial eGFR decline ≥5 ml/min per 1.73 m2 per year, the mean rates of eGFR decline during the double-blind treatment phase of the trial in the atrasentan and placebo groups were 3.3 and 4.9 ml/min per 1.73 m2 per year, respectively, resulting in a between-group difference of 1.6 (95% CI, 0.0 to 3.2) ml/min per 1.73 m2 per year. In contrast, in patients with a pretrial eGFR decline between 1 and 5 ml/min per 1.73 m2 per year and of <1 ml/min per 1.73 m2 per year, the between-group differences in rate of eGFR decline were −0.1 and −0.2 ml/min per 1.73 m2 per year, respectively (P value for interaction of 0.005). Baseline UACR and eGFR did not modify the effect of atrasentan on eGFR decline during the trial (Figure 1).Figure 1.: The effect of atrasentan versus placebo on clinical trial eGFR slope depends on the pretrial eGFR slope, but not on baseline UACR or eGFR. Figure shows the effect of atrasentan compared with placebo on clinical trial eGFR slope stratified by pretrial eGFR decline (<1, between 1 and 5, and ≥5 ml/min per 1.73 m2 per year), baseline UACR (UACR≤1000 and >1000 mg/g), and baseline eGFR (eGFR≤45 and >45 ml/min per 1.73 m2). The circles in the figure represent the hazard ratio and the horizontal line the 95% CI.Endothelin receptor antagonists, including atrasentan, can increase the risk of edema and heart failure in patients with type 2 diabetes and CKD who are at risk of fluid retention.3 Heart failure hospitalizations occurred more frequently in patients with a fast eGFR decline compared with those with a slower decline. However, within fast progressors, these events occurred more frequently in the placebo group (10.8%) compared with the atrasentan group (3.2%; hazard ratio, 0.34; 95% CI, 0.10 to 1.14) (Supplemental Table 3). In this post hoc analysis of 630 SONAR participants with type 2 diabetes, increased albuminuria, and decreased eGFR who were selected for their high risk of kidney failure, our study showed that only 41% had a rapid eGFR decline of at least 5 ml/min per 1.73 m2 per year prior to enrollment into the trial. In other words, despite enriching the SONAR trial for patients with a high UACR, still more than half of the selected patients included had a relatively stable eGFR trajectory and thus, were unlikely to reach kidney failure within the duration of the trial. We also demonstrated that the therapeutic effect of atrasentan on slowing kidney function decline varied by the pretrial eGFR slope, whereas the effect was consistent in subgroups defined by baseline UACR and eGFR as reported previously.3 These data suggest that the pretrial eGFR slope may be a suitable tool to identify patients more likely to benefit from atrasentan. We recognize, however, that the statistical power for these analyses was low, and the results should be considered hypothesis generating. Ongoing prospective clinical trials, such as the Atrasentan in Patients With IgA Nephropathy (ALIGN) trial (NCT04573478), are warranted to confirm if atrasentan more effectively reduces the rate of kidney failure in patients with more progressive kidney function loss. Future research is also required to define the time period and minimal number of eGFR assessments to optimally estimate the pretrial eGFR slope for prognostic enrichment. We also acknowledge that the pretrial eGFR data are not perfectly structured but derived from electronic medical records, which means varying laboratory techniques for serum creatinine measurements per patient or even within one patient, varying numbers and intervals between the creatinine measurements, and potential variation in medications and comorbidities. These variations may have introduced random noise and increased variation in pretrial eGFR slope. In conclusion, the efficacy of atrasentan in slowing progressive kidney function loss was larger in participants with a steeper pretrial eGFR decline, suggesting that the preintervention eGFR slope may be a better tool than UACR or eGFR to select clinical trial participants. Disclosures R. Busch has received research support from AstraZeneca, Kowa, Lilly, and Novo Nordisk and has served on the speaker bureau for Amarin, AstraZeneca, Boehringer-Ingelheim, Lilly, and Novo. L. De Nicola reports consultancy agreements and/or lecturer fees from Astellas, AstraZeneca, Mundipharma, Novo Nordisk, and Vifor Fresenius; and scientific advisor or membership with Abbvie, Astellas, AstraZeneca, Italian Journal of Nephrology, Janssen, and Vifor Fresenius. S.T. de Vries reports funding from the Dutch Medicines Evaluation Board, the European Union's Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant 754425, and ZonMW–The Netherlands Organization for Health Research and Development project 849100006. D. de Zeeuw has served on advisory boards and/or as a speaker for Bayer, Boehringer Ingelheim, Fresenius, Mitsubishi Tanabe, and Mundipharma; has served on steering committees and/or as a speaker for AbbVie and Janssen; has served on data safety and monitoring committees for Bayer; and has consultancy agreements and has received honoraria from Retrophin. R.T. Gansevoort reports consultancy agreements with AstraZeneca, Bayer, Galapagos, Otsuka Pharmaceutical, and Sanofi-Genzyme; receiving research funding and honoraria from Bayer, Galapagos, and Otsuka Pharmaceuticals (all funds paid directly to the institution); and serving as a scientific advisor or member of American Journal of Kidney Diseases, CJASN, Journal of Nephrology, Kidney360, Nephrology Dialysis Transplantation, and Nephron Clinical Practice. J.L. Gorriz reports consultancy agreements with AstraZeneca, Boehringer Ingelheim, Merck, MSD, Mundipharma, and Novo Nordisk; research funding from AstraZeneca; honoraria for giving talks with AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Janssen, Novartis, and Novo Nordisk; scientific advisor or membership with AstraZeneca, Boehringer Ingelheim, and Janssen-Mundipharma; and speakers bureau for AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Janssen, MSD, and Novo Nordisk. H.J.L. Heerspink has served as a consultant for AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Pharma, Dimerix, Fresenius, Gilead, Janssen, Merck, Mitsubishi-Tanabe, Mundipharma, Novo Nordisk, Retrophin, and Travere Pharmaceuticals; has received grant support from AbbVie, AstraZeneca, Boehringer Ingelheim, and Janssen; and has served on speakers bureaus with AstraZeneca. F.F. Hou reports consultancy agreements with AbbVie and AstraZeneca; honoraria from AbbVie and AstraZeneca; and scientific advisor or membership as a member on the editorial boards of Current Opinion in Nephrology and Hypertension, Kidney Diseases (Basel), Kidney International, and Kidney Medicine. G.D. Laverman reports receiving lecture fees from AstraZeneca, Jansen, and Sanofi; has served as a consultant for Abbvie, AstraZeneca, Boehringer Ingelheim, MSD, Novo Nordisk, Sanofi, and Vifor Pharma; reports research funding from AstraZeneca, Novo Nordisk, Sanofi, and Vifor Pharma; and reports honoraria from AstraZeneca, Novo Nordisk, Sanofi, and Vifor Pharma. H.-H. Parving has served as a consultant for Abbott, AbbVie, AstraZeneca, and Novartis; has ownership interest in Merck and Novo Nordisk; and received honoraria from Abbott, AbbVie, AstraZeneca, and Novartis. J. Pascual has served as consultant and received grant support from Biophope Ltd., Chiesi, and Novartis. P.E. Pergola reports consultancy agreements with Akebia, Ardelyx, AstraZeneca, Bayer, Corvidia, Fibrogen, Gilead, Otsuka, Reata, Tricida, and Unicycive as an investigator in multiple clinical trials (his employer receives research support); ownership interest in Unicycive Therapeutics; research funding as a principal or subinvestigator on multiple clinical trials through practice; scientific advisor or membership with Ardelyx and Unicycive; and speakers bureau with AstraZeneca. S.C.W. Tang has served as consultant for George Clinical, Novartis, and Travere Therapeutics; received lecture fees from AstraZeneca; received grant support from Sanofi; reports scientific advisor or membership via editorial board membership with American Journal of Nephrology, CJASN, Journal of Nephrology and Kidney Diseases, and Kidney International; reports scientific advisor or membership via Associate Editor of Glomerular Diseases, Kidney Disease Improving Global Outcomes executive committee member, Editor-in-Chief of Nephrology (Carlton), and theme and subspecialties editor of Nephrology Dialysis Transplantation; and other interests/relationships, such as President-Elect of the Asian Pacific Society of Nephrology and Ex-Officio of the Hong Kong Society of Nephrology. C. Wanner has received consultation and advisory board membership honoraria from Akebia, AstraZeneca, Bayer, Boehringer-Ingelheim, Gilead, GSK, MSD, Sanofi-Genzyme, and Tricida. D. Xie reports other interests/relationships as an International Society of Nephrology (ISN) member. All remaining authors have nothing to disclose. Funding This was supported by Innovative Medicines Initiative 2 Joint Undertaking grant 115974 (Biomarker Enterprise to Attack Diabetic Kidney Disease [BEAt-DKD]); European Union's Horizon 2020 Framework Programme; European Union's European Federation of Pharmaceutical Industries and Associations with Juvenile Diabetes Research Foundation; and College ter Beoordeling van Geneesmiddelen.

BACKGROUND AND OBJECTIVES:Atrasentan reduces the risk of kidney failure but increases the risk of edema and, possibly, heart failure. Patients with severe CKD may obtain greater absolute kidney benefits from atrasentan but may also be at higher risk of heart failure. We assessed relative and absolute effects of atrasentan on kidney and heart failure events according to baseline eGFR and urinary albumin-creatinine ratio (UACR) in a post hoc analysis of the Study of Diabetic Nephropathy with Atrasentan (SONAR) trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:The effect of atrasentan versus placebo in 3668 patients with type 2 diabetes and CKD with elevated albuminuria was examined in the SONAR trial. We used Cox proportional hazards regression analysis to study effects on the primary kidney outcome (composite of doubling of serum creatinine, kidney failure, or kidney death) and heart failure hospitalization across subgroups of eGFR (<30, ≥30-45, and ≥45 ml/min per 1.73 m2) and UACR (<1000, ≥1000-3000, and ≥3000 mg/g). RESULTS:Atrasentan reduced the relative risk of the primary kidney outcome (hazard ratio, 0.71; 95% confidence interval, 0.58 to 0.88) consistently across all subgroups of baseline eGFR and UACR (all P interaction >0.21). Patients in the highest UACR and lowest eGFR subgroups, in whom rates of the primary kidney outcome were highest, showed the largest absolute benefit (all P interaction <0.01). The risk of heart failure hospitalization was higher in the atrasentan group (hazard ratio, 1.39; 95% confidence interval, 0.97 to 1.99) and was consistent across subgroups, with no evidence that relative or absolute risks differed across eGFR or UACR subgroups (all P interaction >0.09). CONCLUSIONS:Atrasentan reduced the relative risk of the primary kidney outcome consistently across baseline UACR and eGFR subgroups. The absolute risk reduction was greater among patients in the lowest eGFR and highest albuminuria category who were at highest baseline risk. Conversely, the relative and absolute risks of heart failure hospitalization were similar across baseline UACR and eGFR subgroups.Clinical Trial registry name and registration number: Study of Diabetic Nephropathy with Atrasentan (SONAR), NCT01858532.

Background and Aims: The risk of nocturnal hypoglycemia (NH) is a limiting factor for achieving good glycemic control in people with type 1 diabetes (T1D). Insulin degludec (IDeg) is proven to lower the risk of self-reported NH. As most episodes of NH are asymptomatic, we assessed differences in occurrence of NH by hourly plasma glucose (PG) measurements at treatments with IDeg or insulin glargine U100 (IGlar) in people with T1D suffering from recurrent nocturnal severe hypoglycemia. Materials and Methods: Pre-defined optional substudy of the HypoDeg trial, a 2-year investigator-initiated, randomized, cross-over trial where 149 participants with T1D were randomized to treatment with IDeg or IGlar. Fifty-one participants (mean (SD) age 58 (13) years, diabetes duration 28 (14) years and HbA1c 7.8 (1) %) were admitted for two nights for hourly blinded plasma glucose measurements for a minimum of one night (23:00h to 07:00h) during each 1-year treatment period. The primary endpoints were NH at level 1 (PG ≤ 3.9 mmol/L) and level 2 (PG < 3.0 mmol/L). Results: We collected data from 196 nights. A total of 57 nights (regardless of level) in 33 participants were hypoglycemic, including 20 nights with symptomatic hypoglycemia. The incidence of NH at level 1 was lower when treated with IDeg [17 events in 97 nights (18%)] as compared to IGlar [36 events in 99 nights (36%)], corresponding to a hazard ratio (HR) of 0.39 (95% CI: 0.22-0.71; p=0.002) during treatment with IDeg. At level 2, the incidence of NH was also lower during treatment with IDeg [8 events in 97 nights (8%)] as compared to IGlar [20 events in 99 nights (20%)], corresponding to an HR of 0.36 [95% CI: 0.16-0.80; p=0.013] during treatment with IDeg. Conclusion: In people with T1D and recurrent nocturnal severe hypoglycemia, treatment with IDeg as compared to IGlar results in a clinically significant lower rate of NH at both levels of hypoglycemia. Disclosure J. M. Brøsen: None. S. Lerche: None. K. Nørgaard: Advisory Panel; Self; Medtronic, Other Relationship; Self; Novo Nordisk Inc., Zealand Pharma A/S, Speaker’s Bureau; Self; Medtronic. H. D. Parving: None. L. Tarnow: None. B. Thorsteinsson: None. U. Pedersen-bjergaard: Advisory Panel; Self; Novo Nordisk A/S, Sanofi-Aventis, Consultant; Self; Abbott, Speaker’s Bureau; Self; Novo Nordisk A/S. R. Agesen: Employee; Self; Novo Nordisk. P. L. Kristensen: Speaker’s Bureau; Self; AstraZeneca, Eli Lilly and Company. A. Alibegovic: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. H. U. Andersen: Stock/Shareholder; Self; Novo Nordisk A/S. P. Gustenhoff: None. C. Hedetoft: None. T. Jensen: Stock/Shareholder; Self; Novo Nordisk A/S. C. B. Juhl: None. Funding Novo Nordisk

Significance Statement This prespecified analysis of the SONAR trial in patients with type 2 diabetes and CKD demonstrated the early albuminuria reduction during an open-label, 6-week run-in period with atrasentan was associated with a reduced risk for long-term kidney outcomes in patients who continued atrasentan after randomization. But because the early albuminuria reduction also associated with long-term kidney outcomes in patients who transitioned from atrasentan to placebo at randomization, atrasentan’s effect on the primary kidney outcome was consistent, regardless of the early albuminuria change, suggesting the early albuminuria response is not a causal predictor for atrasentan’s nephroprotective effect. However, the variable UACR trajectory in the placebo arm, aspects of the SONAR trial design, day-to-day variability in albuminuria, and potential long-lasting effects of atrasentan may have contributed. Background Whether early reduction in albuminuria with atrasentan treatment predicts its long-term kidney-protective effect is unknown. Methods To assess the long-term effects on kidney outcomes of atrasentan versus placebo in the SONAR trial, we enrolled patients who had type 2 diabetes and CKD (stage 2–4) and a urinary albumin creatinine ratio (UACR) of 300–5000 mg/g; participants were receiving maximum tolerated renin-angiotensin system inhibition. After 6 weeks exposure to 0.75 mg/day atrasentan (enrichment period), participants were randomized (stratified by UACR response during enrichment, ranging from ≤60% to >0%) to continue atrasentan or transition to placebo. Primary kidney outcome was a composite of sustained serum creatinine doubling or ESKD. Results UACR response to atrasentan during enrichment persisted throughout the double-blind treatment phase and predicted the primary kidney outcome, whereas UACR levels with placebo remained below pre-enrichment values in the two highest UACR response strata, and exceeded pre-enrichment values in the two lowest strata. As a result, early UACR response to atrasentan during enrichment was also associated with the primary kidney outcome during placebo. Accordingly, the predictive effect of early albuminuria changes during atrasentan was eliminated after placebo correction, leading to a consistent relative risk reduction for the primary kidney outcome with atrasentan compared with placebo, irrespective of the initial UACR response. The difference between atrasentan and placebo in UACR during double-blind treatment was also consistent across UACR response strata. Conclusions Our findings do not support UACR response as a causal predictor of atrasentan’s treatment effect. However, the variable trajectory in UACR with placebo, aspects of the trial design, day-to-day variability in albuminuria, and potential long-lasting effects of atrasentan may have contributed.

Aim To evaluate whether atrasentan plasma exposure explains between-patient variability in urinary albumin-to-creatinine ratio (UACR) response, a surrogate for kidney protection, and B-type natriuretic peptide (BNP) response, a surrogate for fluid expansion. Methods Type 2 diabetic patients with chronic kidney disease (n = 4775) received 0.75 mg atrasentan for 6 weeks in the active run-in period. Individual area under the concentration-time-curve (AUC) was estimated using a population pharmacokinetic model. The association between atrasentan AUC, other clinical characteristics, and UACR and BNP response, was estimated using linear regression. Results The median atrasentan AUC was 43.8 ng.h/mL with a large variation among patients (2.5th-97.5th percentiles [P]: 12.6 to 197.5 ng.h/mL). Median UACR change at the end of enrichment was -36.0% and median BNP change was 8.7%, which also varied among patients (UACR, 2.5th-97.5th P: -76.2% to 44.5%; BNP, 2.5th-97.5th P: -71.5% to 300.0%). In the multivariable analysis, higher atrasentan AUC was associated with greater UACR reduction (4.88% per doubling in ng.h/mL [95% confidence interval {CI}: 6.21% to 3.52%], P < .01) and greater BNP increase (3.08% per doubling in ng.h/mL [95% CI: 1.12% to 4.11%], P < .01) independent of estimated glomerular filtration rate, haemoglobin or BNP. Caucasian patients compared with black patients had greater UACR reduction (7.06% [95% CI: 1.38% to 13.07%]) and also greater BNP increase (8.75% [95% CI: 1.65% to 15.35%]). UACR response was not associated with BNP response (r = 0.06). Conclusion Atrasentan plasma exposure varied among individual patients and partially explained between-patient variability in efficacy and safety response.

Background: Clinical characteristics such as HbA(1c), systolic blood pressure (SBP), albuminuria and estimated glomerular filtration rate (eGFR) are important when treating type 1 diabetes. We investigated the variability in these measures as risk markers for micro- and macrovascular complications. Methods: This prospective study included 1062 individuals with type 1 diabetes. Visit-to-visit variability of HbA(1c), SBP, albuminuria and eGFR was calculated as the SD of the residuals in individual linear regression models using all available measures in a specified period of 3 years (VV). Endpoints included were as follows: cardiovascular events (CVE) defined as myocardial infarction, non-fatal stroke, or coronary or peripheral arterial intervention; end-stage kidney disease (ESKD) defined as eGFR <15 ml/min/1.73 m(2), chronic dialysis or kidney transplantation; eGFR decline >= 30%; and mortality. Adjustment included age, sex, cholesterol, HbA(1c), SBP, body mass index, smoking, albuminuria, eGFR, and mean, intercept, slope of respective exposure variables and regression models. Results: SBP VV was significantly associated with CVE (adjusted hazard ratio per 50% increase, (CI 95%); p: 1.21 [1.05-1.39]; p = 0.008), ESKD (1.51 [1.16-1.96]; p = 0.002) and mortality (1.25 [1.09-1.44]; p = 0.002). HbA(1c) VV was significantly associated with mortality (1.51 [1.30-1.75]; p < 0.001); albuminuria VV with eGFR decline (1.14 [1.08-1.20]; p = 0.024) and ESKD (1.14 [1.02-1.27]; p < 0.001), but neither CVE nor mortality. Adjusted eGFR VV was not associated with endpoints. Conclusion: In type 1 diabetes, higher variability of basic clinical risk markers adds important risk stratification information for the development of micro- and macrovascular complications.

Background: Hypoglycaemia, especially nocturnal, remains a main limiting factor of achieving good glycemic control in type 1 diabetes. The long-acting insulin analog degludec reduces the risk of nocturnal hypoglycemia in patients with type 1 diabetes but is not studied in patients specifically prone to severe nocturnal hypoglycemia. The study aims to investigate whether insulin degludec in comparison with insulin glargine U100 reduces the risk of nocturnal hypoglycaemia in patients with previous severe nocturnal hypoglycaemia.Methods: Investigator-initiated, prospective, randomized, open, blinded endpoint (PROBE), multicenter, cross-over study. A one-year plus one-year treatment period was specified. Each one-year treatment period consisted of a three-month run-in/cross-over period followed by a nine-month maintenance period. A total of 149 adult patients with type 1 diabetes and at least one episode of nocturnal severe hypoglycemia during the preceding two years were included. Participants were randomized 1:1 to basal- bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. The primary endpoint was number of nocturnal symptomatic hypoglycemic episodes during the maintenance period, analysed by intention-to-treat.Findings: Treatment with insulin degludec resulted in a 28% (95%CI: 9-43; p=0·02) and 37% (95%CI: 16-53; p=0·002) relative rate reduction (RRR) of level 1 (≤3·9 mmol/L) and level 2 (≤3·0 mmol/L) nocturnal (00:00 to 05:59) symptomatic hypoglycaemia, respectively, compared to insulin glargine U100. Similar results were demonstrated when defining night-time from 23:00 to 06:59 with a 28% (95%CI: 4-45; p=0·01) and 34% (95%CI:17-48; p<0·001) RRR for level 1 and 2 hypoglycaemia, respectively.Interpretation: Patients with type 1 diabetes prone to nocturnal severe hypoglycaemia have lower rates of nocturnal symptomatic hypoglycaemia with insulin degludec as compared with insulin glargine U100.Trial Registration: The study is registered at www.eudract.ema.europe.eu (#2014-001942-24) and at www.clinicaltrials.gov (# NCT02192450).Funding Statement: Novo Nordisk A/S.Declaration of Interests: HBN, TKH, CH, TJ, AEK, SSL, HHP, ALS, LT and BT have no competing financial interests. ACA and RMA is by 2nd September 2019 employed by Novo Nordisk. HUA owns stocks in Novo Nordisk. HUA is on advisory boards for Novo Nordisk, Abbott and Astra Zeneca and has received a lecture fee from Nordic Infucare. PG has served on advisory boards for Astra Zeneca, Sanofi Aventis, Novo Nordisk, Boehringer Ingelheim and Abbott Laboratories. CBJ serves on advisory boards for Novo Nordisk. KN owns stocks in Novo Nordisk. KN serves as advisor to Medtronic, Abbott and Novo Nordisk. KN has received fees for speaking from Medtronic, Roche Diabetes Care, Rubin Medical, Sanofi, Novo Nordisk, Zealand Pharma and Bayer. UPB has served on advisory boards for AstraZeneca/Bristol Myers Squibb and Novo Nordisk and has received lecture fees from Astra Seneca/Bristol Myers Squibb, Sanofi Aventis and Novo Nordisk. The authors declare no other conflict of interest.Ethics Approval Statement: The study is approved by the Regional Committee on Biomedical Research Ethics (#H-3-2014-101), the Danish Medicines Agency (#2014071615) and the Danish Data Protection Agency (Isuite no: 02945; #NOH-2014-018). All participants gave written informed consent.