Richard Pratley

BACKGROUND: Patients with type 2 diabetes and chronic kidney disease are at high risk for kidney failure, cardiovascular events, and death. Whether treatment with semaglutide would mitigate these risks is unknown. METHODS: ), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes. Prespecified confirmatory secondary outcomes were tested hierarchically. RESULTS: in the semaglutide group (P<0.001), the risk of major cardiovascular events 18% lower (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = 0.029), and the risk of death from any cause 20% lower (hazard ratio, 0.80; 95% CI, 0.67 to 0.95, P = 0.01). Serious adverse events were reported in a lower percentage of participants in the semaglutide group than in the placebo group (49.6% vs. 53.8%). CONCLUSIONS: Semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in patients with type 2 diabetes and chronic kidney disease. (Funded by Novo Nordisk; FLOW ClinicalTrials.gov number, NCT03819153.).

BACKGROUND: Chronic kidney disease (CKD) is a common complication of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and lower body weight in people with T2D, and some reduce the risk of cardiovascular (CV) events in those with high CV risk. GLP-1RAs might also have kidney-protective effects. We report the design and baseline data for FLOW (NCT03819153), a trial investigating the effects of semaglutide, a once-weekly (OW) GLP-1RA, on kidney outcomes in participants with CKD and T2D. METHODS: FLOW is a randomised, double-blind, parallel-group, multinational, phase 3b trial. Participants with T2D, estimated glomerular filtration rate (eGFR) ≥50‒≤75 ml/min/1.73 m2 and urine albumin:creatinine ratio (UACR) >300‒<5000 mg/g or eGFR ≥25‒<50 ml/min/1.73 m2 and UACR >100‒<5000 mg/g were randomised 1:1 to OW semaglutide 1.0 mg or matched placebo, with renin-angiotensin-aldosterone system blockade (unless not tolerated/contraindicated). The composite primary endpoint is time to first kidney failure (persistent eGFR <15 ml/min/1.73 m2 or initiation of chronic kidney replacement therapy), persistent ≥50% reduction in eGFR or death from kidney or CV causes. RESULTS: Enrolled participants (N = 3534) had a baseline mean age of 66.6 years [standard deviation (SD) 9.0], haemoglobin A1c of 7.8% (SD 1.3), diabetes duration of 17.4 years (SD 9.3), eGFR of 47.0 ml/min/1.73 m2 (SD 15.2) and median UACR of 568 mg/g (range 2‒11 852). According to Kidney Disease: Improving Global Outcomes guidelines categorisation, 68.2% were at very high risk for CKD progression. CONCLUSION: FLOW will evaluate the effect of semaglutide on kidney outcomes in participants with CKD and T2D, and is expected to be completed in late 2024.

OBJECTIVE A post hoc analysis to investigate the association between 1-year changes in albuminuria and subsequent risk of cardiovascular and renal events. RESEARCH DESIGN AND METHODS LEADER was a randomized trial of liraglutide up to 1.8 mg/day versus placebo added to standard care for 3.5–5 years in 9,340 participants with type 2 diabetes and high cardiovascular risk. We calculated change in urinary albumin-to-creatinine ratio (UACR) from baseline to 1 year in participants with &amp;gt;30% reduction (n = 2,928), 30–0% reduction (n = 1,218), or any increase in UACR (n = 4,124), irrespective of treatment. Using Cox regression, risks of major adverse cardiovascular events (MACE) and a composite nephropathy outcome (from 1 year to end of trial in subgroups by baseline UACR [&amp;lt;30 mg/g, 30–300 mg/g, or ≥300 mg/g]) were assessed. The analysis was adjusted for treatment allocation alone as a fixed factor and for baseline variables associated with cardiovascular and renal outcomes. RESULTS For MACE, hazard ratios (HRs) for those with &amp;gt;30% and 30–0% UACR reduction were 0.82 (95% CI 0.71, 0.94; P = 0.006) and 0.99 (0.82, 1.19; P = 0.912), respectively, compared with any increase in UACR (reference). For the composite nephropathy outcome, respective HRs were 0.67 (0.49, 0.93; P = 0.02) and 0.97 (0.66, 1.43; P = 0.881). Results were independent of baseline UACR and consistent in both treatment groups. After adjustment, HRs were significant and consistent in &amp;gt;30% reduction subgroups with baseline micro- or macroalbuminuria. CONCLUSIONS A reduction in albuminuria during the 1st year was associated with fewer cardiovascular and renal outcomes, independent of treatment. Albuminuria monitoring remains an important part of diabetes care, with great unused potential.

Introduction: Sodium glucose cotransporter inhibitors may increase beta-hydroxybutyrate (BHB) in insulin-requiring patients. We determined factors associated with BHB changes from baseline (ΔBHB) and diabetic ketoacidosis (DKA) in patients with type 1 diabetes (T1D) receiving sotagliflozin as an insulin adjunct. Research Design and Methods: This post hoc analysis compared ΔBHB levels in adults with T1D receiving sotagliflozin 400 mg or placebo for 6 months. We evaluated clinical and metabolic factors associated with ΔBHB and used logistic regression models to determine predictors associated with BHB values &gt;0.6 and &gt;1.5 mmol/L (inTandem3 population; N = 1402) or with DKA events in a pooled analysis (inTandem1–3; N = 2453). Results: From baseline (median, 0.13 mmol/L), median fasting BHB increased by 0.04 mmol/L (95% confidence interval, 0.03–0.05; P &lt; 0.001) at 24 weeks with sotagliflozin versus placebo; 67% of patients had no or minimal changes in BHB over time. Factors associated with on-treatment BHB &gt;0.6 or &gt;1.5 mmol/L included baseline BHB and sotagliflozin use. Age, insulin pump use, sotagliflozin use, baseline BHB, and ΔBHB were significantly associated with DKA episodes. Independent of treatment, DKA risk increased by 18% with each 0.1-mmol/L increase in baseline BHB and by 8% with each 0.1-mmol/L increase from baseline. Conclusion: Incremental increases in baseline BHB and ΔBHB were associated with a higher DKA risk independent of treatment. Adding sotagliflozin to insulin increased median BHB over 24 weeks in patients with T1D and was associated with increased DKA events. These results highlight the importance of BHB testing and monitoring and individualizing patient education on DKA risk, mitigation, identification, and treatment.