Rationale & Objective:Depression is a potential pathophysiologic pathway in type 4 cardiorenal syndrome, ie chronic kidney disease (CKD) resulting in chronic heart failure (HF). We investigated whether depressive symptoms and CKD are independent predictors of HF and whether they augment HF risk when they present together. Study Design:A post-hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT). Setting & Participants:Participants with baseline Patient Health Questionnaire-9 (PHQ-9) data and without baseline HF (N =8,930). Predictors:Depressive symptom severity (baseline PHQ-9 0, 1-4, and 5-27) and CKD (estimated glomerular filtration rate of < 60 mL/min/1.73m2). Outcome:Incident HF events (pre-specified adjudicated secondary SPRINT outcome). Analytical Approach:Multivariable Cox proportional hazards regression models and generalized linear models related PHQ-9 and CKD status to HF events on relative and absolute scales. Results:PHQ-9 scores of 0, 1-4, and ≥ 5 were present in 3,086 (34.6%), 3,775 (42.3%), and 2,069 (23.2%) participants, respectively and baseline CKD in 2,155 (24%). There were 177 HF events over 33,358 person-years. In a multivariable Cox regression model, both CKD (HR 1.60; 95% CI, 1.13-2.28) and PHQ-9 ≥ 5 (HR vs PHQ-9 = 0: 1.92; 95% CI, 1.24-2.98) were independent HF risk factors. In another Cox model, compared to those with PHQ-9 = 0 and no CKD, those with both CKD and PHQ-9 ≥5 had 3.45 times the hazard of HF (HR 3.45, 95% CI 1.70, 7.03) with other subgroups in between. There was no evidence of a synergistic interaction, but they appeared to be additive. Results were largely consistent on the absolute risk scale. Limitations:Bias from post-hoc observational use of data, clinical trial selection bias. Conclusions:Both CKD and depressive symptoms are independent and additive risk factors for HF. Patients with both CKD and a higher burden of depressive symptoms are at greater risk of HF.

AIMS:To compare the risk of all-cause death and cardiovascular events in new users of insulin glargine, glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i), particularly in subgroups defined by baseline haemoglobin A1C (HbA1C), body mass index (BMI) and estimated glomerular filtration rate (eGFR). MATERIALS AND METHODS:We conducted an active comparator, new user design study in a national cohort of 161 405 veterans with type 2 diabetes (T2D) on metformin and initiated insulin glargine (n = 54 375), GLP-1RA (n = 22 145) or SGLT2i (n = 84 885) between 1 January 2018 and 31 December 2021. Patients were followed until 31 March 2023. Inverse probability weighted Cox regression models were used for treatment comparisons on all-cause deaths and cardiovascular events in the entire cohort and above subgroups. RESULTS:There were 20 788 cardiovascular events/414 414 person-years and 15 268 all-cause deaths/446 458 person-years. Insulin glargine had a higher hazard of all-cause death compared to GLP-1RA (hazard ratio [HR] 1.57, 95% confidence interval [CI] 1.48-1.67) or SGLT2i (HR 1.55, 95% CI 1.48-1.61) in the entire cohort and across subgroups, especially in those with HbA1C levels <9.0%. Results were similar for secondary outcomes. Compared to GLP-1RA, SGLT2i had similar risk of all-cause death (HR 1.03, 95% CI 0.97-1.10) but higher hazard of cardiovascular events (HR 1.13, 95% CI 1.08-1.19). Across subgroups, GLP-1RA and SGLT2i had generally similar effects, with SGLT2i showing a slightly higher risk in some cases. CONCLUSIONS:Insulin glargine might be deleterious particularly in those with HbA1C <9.0%. There was no clear evidence for prioritization of SGLT2i versus GLP-1RA across subgroups.

Importance:The head-to-head comparative effectiveness and safety of individual glucagon-like peptide-1 receptor agonists (GLP-1RAs) are not well understood. Objective:To compare risks of kidney, cardiovascular, and death outcomes among patients with type 2 diabetes initiating GLP-1RAs in the Department of Veterans Affairs (VA) health system. Design, Setting, and Participants:This comparative effectiveness study used an active-comparator, new-user target trial-emulation design with national data linked among the VA, Medicare, and US Renal Data System. Participants were GLP-1RA-naive veterans with type 2 diabetes and without end-stage kidney disease treated with metformin who started liraglutide, semaglutide, or dulaglutide between January 1, 2018, and December 31, 2021. Data were analyzed from September 2024 to June 2025. Exposure:Liraglutide, semaglutide, or dulaglutide. Main Outcomes and Measures:Kidney failure (sustained estimated glomerular filtration rate <15 mL/min/1.73 m2 or initiation of kidney replacement therapy), composite cardiovascular and kidney metabolic (CKM) events (kidney failure or major adverse cardiovascular events [MACE]; myocardial infarction, heart failure, or stroke/transient ischemic attack), MACE, all-cause death, and adverse gastrointestinal events (gastroparesis, intestinal obstruction, gallstones, acute cholecystitis, acute pancreatitis) were evaluated separately through March 31, 2023. Results:Of 21 790 included veterans (mean [SD] age, 63.5 [10.8] years, 19 823 [91.0%] male), 5425 (24.9%), 10 838 (49.7%), and 5527 (24.9%) initiated liraglutide, semaglutide, and dulaglutide, respectively. In weighted Cox regression models, compared with initiation of semaglutide, liraglutide initiation had similar hazards for kidney failure (hazard ratio [HR], 0.93; 95% CI, 0.60-1.44), the CKM composite outcome (HR, 0.96; 95% CI, 0.84-1.10), and MACE (HR, 0.95; 95% CI, 0.83-1.09). Results were similar with liraglutide vs dulaglutide and dulaglutide vs semaglutide comparisons. Liraglutide had significantly lower hazard of all-cause death compared with semaglutide under intent-to-treat analyses (HR, 0.83; 95% CI, 0.69-0.99), which lost significance in per-protocol models. Compared with dulaglutide, liraglutide was associated with a lower risk of all-cause mortality in both the intent-to-treat (HR, 0.69; 95% CI, 0.58-0.83) and per-protocol (HR, 0.50; 95% CI, 0.31-0.82) analyses, but compared with semaglutide, dulaglutide had higher hazard of mortality only in the per-protocol model (HR, 1.72; 95% CI, 1.20-2.47). The only observed difference for the gastrointestinal adverse events was a decreased risk for gallstones and acute cholecystitis with dulaglutide vs semaglutide (gallstones: HR, 0.72; 95% CI, 0.54-0.95; acute cholecystitis: HR, 0.62; 95% CI, 0.39-0.99). Conclusions and Relevance:In this comparative effectiveness study in veterans with diabetes, liraglutide, semaglutide, and dulaglutide initiators had similar risks for kidney and cardiovascular outcomes. Head-to-head randomized trials are needed to confirm these findings.

AIMS:To compare the risk of gastrointestinal adverse events in new users of glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT2i) and insulin glargine. MATERIALS AND METHODS:We conducted an active comparator, new user design study in veterans with type 2 diabetes who initiated one of these drug classes between 1 January 2018 and 31 December 2021 (N = 141 080). Inverse probability weighted Cox regression models were used to relate drug class to outcomes of gastroparesis, intestinal obstruction, gallstones, acute cholecystitis, acute pancreatitis and all-cause death. RESULTS:There were 19 765 (14.0%) veterans initiated on GLP-1RA, 75 058 (53.2%) on SGLT2i and 46 257 (32.8%) on insulin glargine. Compared to SGLT2i, GLP-1RA had a higher hazard of gastroparesis (HR 1.65, 95% CI 1.33-2.05) but a similar mortality hazard. Compared to insulin glargine, GLP-1RA had a higher hazard of gastroparesis (HR 1.24, 95% CI 1.02, 1.52), but a lower hazard of all-cause death (HR 0.62, 95% CI 0.58, 0.66). Compared to SGLT2i, insulin glargine had a higher hazard of gastroparesis (HR 1.29, 95% CI 1.07, 1.56), intestinal obstruction (HR 1.26, 95% CI 1.11, 1.43) and all-cause death (HR 1.58, 95% CI 1.50, 1.65). Risks of gallstones, acute cholecystitis and pancreatitis were similar across the classes. CONCLUSIONS:In patients with type 2 diabetes at risk for gastroparesis, SGLT2i might be the preferred agent. In patients for whom SGLT2i is not an option or another agent is needed, patients and providers might need to weigh the higher risk of death with insulin glargine against the higher risk of gastroparesis with GLP-1RA.

Liraglutide, semaglutide and dulaglutide are non-exendin based GLP-1RA that are widely used in type 2 diabetes (T2D) management. GLP-1RA use may be associated with lower risk of dementia, however, intra-class effects of GLP-1RA on AD/ADRD risk need to be further elucidated. We followed the active comparator, new user design to emulate a trial comparing the effect of initiating liraglutide, semaglutide or dulaglutide. Veterans with T2D on metformin who initiated any one of these three agents between 01/01/2018 to 12/31/2021 and did not have baseline dementia, as identified by ICD 9 or 10 codes, were included ( N  = 21,173). Previous use of GLP-1RA, SGLT2i or insulin glargine was an exclusion criterion. Administrative censor date was 03/31/2023. Generalized propensity score based inverse probability weighting (IPW) was employed to control confounding in the observational data and facilitate comparisons among the three agents. In IPW Cox models with adjustment for baseline covariates, the study drug classes were related to the risk of AD/ADRD, death and composite of AD/ADRD/death. Of the 21,173 veterans, 25% were initiated on liraglutide, 50% on semaglutide, and 25% on dulaglutide. The mean age was 63 ± 11 years, with 9% female and 17% African American. There were 679 AD/ADRD events over 62,724 person-years of follow up and 1,428 deaths over 63,579 person-years of follow-up. Semaglutide had the highest unweighted event rate of AD/ADRD compared to liraglutide and dulaglutide. In IPW Cox regression models, liraglutide had a lower risk of AD/ADRD compared to semaglutide (HR 0.68, 95% CI 0.55, 0.83), and similar risk compared to dulaglutide (Table). Semaglutide had a higher risk of AD/ADRD than dulaglutide (HR 1.32, 95% CI 1.08, 1.62). In addition, liraglutide had the lowest risk of death as well as composite AD/ADRD/death compared to both semaglutide and dulaglutide. Liraglutide had a lower risk of AD/ADRD compared to semaglutide as well as a lower risk of death compared to other commonly used GLP-1RA. Dulaglutide had similar risk of AD/ADRD to liraglutide, however death benefit was not seen.

BACKGROUND:Sedentary behavior is highly prevalent and associated with morbidity and mortality in chronic kidney disease (CKD). A Sit Less, Interact and Move More (SLIMM) sedentary activity coaching intervention can reduce sedentary duration among persons with CKD, but preliminary data suggest that effects may not persist. Prior studies have suggested that moderate/vigorous intensity physical activities are not sustainable in persons with CKD. Therefore, we aimed to determine whether guided resistance training ± oral semaglutide co-intervention improves adherence and/or persistence of the SLIMM intervention. METHOD/DESIGN:The SLIMM-2 is a two-center study designed with a 3-month sedentary activity coaching (SLIMM) followed by a 9-month randomized controlled trial with three arms: SLIMM + standard of care resistance training + oral placebo, SLIMM + guided resistance training + oral placebo, or SLIMM + guided resistance training + oral semaglutide. The study is recruiting persons with CKD (eGFR 20 to ≤60 ml/min/1.73 m2). ActivPAL, a wearable tri-axial accelerometer, is used to assess outcomes including sedentary duration (primary outcome), stepping duration and the average number of steps per day. Additional outcomes include 6-min walk distance and body fat percentage. Persons randomized to standard of care resistance training will be encouraged to maintain individualized physical activity goals; those randomized to guided resistance training will attend guided sessions per month and be prescribed daily independent exercises. RESULTS:Enrollment, interventions, and follow-up are ongoing. CONCLUSIONS:Results from the SLIMM-2 study are expected to inform clinical practice, with the potential to enhance physical health and functioning among persons with CKD.