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Background: We assessed the effect of once-weekly semaglutide and once-daily liraglutide on kidney outcomes in type 2 diabetes (T2D). Methods: Pooled (N=12,637) and by-trial data from SUSTAIN 6 (N=3297) and LEADER (N=9340) were assessed for albuminuria change, annual slope of estimated glomerular filtration rate (eGFR) change, and time to persistent eGFR reduction (30%, 40%, 50%, and 57%) from baseline. Results: The median follow-up durations were 2.1 and 3.8 years for SUSTAIN 6 and LEADER, respectively. In the pooled analysis, semaglutide/liraglutide lowered albuminuria from baseline to 2 years post-randomization by 24% versus placebo (95% confidence interval [CI] [20%,27% ], p <0.001). Significant reductions were also observed in by-trial data analyses ( p <0.001 for all), the largest being with semaglutide 1.0 mg: 33% (95% CI [24%,40% ], p <0.001) at 2 years. With semaglutide 1.0 mg and liraglutide, eGFR slope decline was significantly slowed by 0.87 and 0.26 mL/min/1.73 m 2 /year ( p <0.0001 and p <0.001), respectively, versus placebo. Effects appeared larger in those with baseline eGFR <60 versus ≥60 mL/min/1.73m 2 ( p interaction =0.06 and 0.008 for semaglutide 1.0 mg and liraglutide, respectively). Semaglutide/liraglutide significantly lowered risk of persistent 40% and 50% eGFR reductions versus placebo (hazard ratio [HR] 0.86, 95% CI [0.75,0.99], p =0.039, and HR 0.80, 95% CI [0.66,0.97], p =0.023, respectively). Similar, non-significant, directional results were observed for 30% and 57% eGFR reductions (HR 0.92, 95% CI [0.84, 1.02], p =0.10, and HR 0.89, 95% CI [0.69, 1.13], p =0.34). In those with baseline eGFR 30−<60mL/min/1.73m 2 , the likelihood of persistent reduction for all thresholds was increased, ranging from a HR 0.71 for 30% reduction (95% CI [0.59,0.85], p =0.0003, pinteraction=0.017) to 0.54 for 57% reduction (95% CI [0.36,0.81], p =0.003, pinteraction=0.035). Conclusions: In patients with T2D, semaglutide/liraglutide offered kidney-protective effects, which appeared more pronounced in those with pre-existing chronic kidney disease.

AimsTo validate the clusters of Swedish individuals with recent‐onset diabetes at differential risk of complications, which were identified in a previous study, in three global populations with long‐standing type 2 diabetes (T2D) who were at high cardiovascular risk, and to test for differences in the risk of major diabetes complications and survival endpoints.Materials and methodsWe assigned participants from recent global outcomes trials (DEVOTE [n = 7637], LEADER [n = 9340] and SUSTAIN‐6 [n = 3297]) to the previously defined clusters according to age at diabetes diagnosis, baseline glycated haemoglobin (HbA1c) and body mass index (BMI). Outcomes were assessed using Kaplan–Meier analysis and log‐rank tests.ResultsThe T2D clusters were consistently replicated across the three trial cohorts. The risk of major adverse cardiovascular events and cardiovascular death differed significantly, in all trials, across clusters over a median follow‐up duration of 2.0, 3.8 and 2.1 years, respectively, and was highest for the cluster of participants with high HbA1c and low BMI (P < 0.05 in DEVOTE and LEADER). In LEADER and SUSTAIN‐6, the risk of nephropathy differed across clusters (P < 0.0001 and P = 0.003, respectively). The risk of severe hypoglycaemia differed in DEVOTE (P = 0.006).ConclusionsPreviously identified clusters can be replicated in three geographically diverse cohorts of long‐standing T2D and are associated with cluster‐specific risk profiles for additional clinical and survival outcomes, providing further validation of the clustering methodology. The external validity and stability of clusters across cohorts provides a premise for future work to optimize the clustering approach to yield T2D subgroups with maximum predictive validity who may benefit from subtype‐specific treatment paradigms.

Kidney failure is an important outcome for patients, clinicians, researchers, healthcare systems, payers, and regulators. However, no harmonized international consensus definitions of kidney failure and key surrogates of progression to kidney failure exist specifically for clinical trials. The International Society of Nephrology convened an international multistakeholder meeting to develop consensus on this topic. A core group, experienced in design, conduct, and outcome adjudication of clinical trials, developed a database of 64 randomized trials and the 163 included definitions relevant to kidney failure. Using an iterative process, a set of proposed consensus definitions were developed and subsequently vetted by the larger multi-stakeholder group of 83 participants representing 18 different countries. The

During chemotherapy for childhood acute lymphoblastic leukemia, all organs can be affected by severe acute side effects, the most common being opportunistic infections, mucositis, central or peripheral neuropathy (or both), bone toxicities (including osteonecrosis), thromboembolism, sinusoidal obstruction syndrome, endocrinopathies (especially steroid-induced adrenal insufficiency and hyperglycemia), high-dose methotrexate-induced nephrotoxicity, asparaginase-associated hypersensitivity, pancreatitis, and hyperlipidemia. Few of the non-infectious acute toxicities are associated with clinically useful risk factors, and across study groups there has been wide diversity in toxicity definitions, capture strategies, and reporting, thus hampering meaningful comparisons of toxicity incidences for different leukemia protocols. Since treatment of acute lymphoblastic leukemia now yields 5-year overall survival rates above 90%, there is a need for strategies for assessing the burden of toxicities in the overall evaluation of anti-leukemic therapy programs.