Meir Schechter

Aim: To compare kidney outcomes after GLP‐1 receptor agonists (RA) or tirzepatide (GLP‐1/GIP RAs) versus finerenone initiation in adults with Type 2 diabetes (T2D) and moderate chronic kidney disease (CKD). Methods: In a retrospective TriNetX global network study (July 2021–November 2025), adults with T2D and CKD stages 3–4 initiating GLP‐1/GIP RAs or finerenone were 1:1 propensity‐score matched and followed ≤ 2.5 years. The primary endpoint was a composite of ESKD, Stage 5 CKD, or dialysis initiation. Secondary analyses compared annual total (0–2.5 years) and chronic (0.5–2.5 years) estimated glomerular filtration rate (eGFR) slopes. Sensitivity analyses included positive/negative controls, extended follow‐up, and stratification by age, sex, baseline kidney function, glycated haemoglobin A1c, BMI, specific GLP‐1/GIP RA, and baseline medications. Results: Among 4554 individuals (43.3% women, mean age 70.7 years, mean eGFR 39.4 mL/min/1.73 m ² ), the primary endpoint occurred in 110 (4.8%) GLP‐1/GIP RAs and 136 (6.0%) finerenone initiators (hazard ratio: 0.71 [95% CI: 0.55–0.91]; 2.5‐year absolute risk difference: −1.14% [−2.45 to 0.17]). Between‐group differences in total and chronic eGFR slope with GLP‐1/GIP RA versus finerenone were 1.04 mL/min/1.73 m ² /year [95% CI: 0.32 to 1.75] and −0.08 mL/min/1.73 m ² /year [95% CI, −1.27 to 1.12], respectively. Sensitivity analyses were consistent. Baseline albuminuria data were missing for most participants. Conclusions: In a real‐world cohort, GLP‐1/GIP RAs versus finerenone initiation was associated with a lower relative hazard of adverse kidney outcomes, without evidence of a difference in absolute risk. This was accompanied by total, but not chronic, eGFR slope mitigation. Residual confounding from under‐sampled albuminuria is possible, and findings should be interpreted within this specific matched population.

INTRODUCTION: In people with type 2 diabetes (T2D) without dementia, glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) improved cardiovascular, kidney, and mortality outcomes, with multiple real‐world studies suggesting reduced risk of dementia onset. However, the EVOKE/EVOKE+ randomized‐controlled trials (RCTs) found that oral semaglutide did not slow cognitive decline in individuals with early Alzheimer's disease (AD), most (86%) without T2D. It is unclear whether GLP‐1 RA therapy influences progression to dementia in people with both T2D and mild cognitive impairment (MCI). METHODS: In a target‐trial emulation hypothesis‐generating study using TriNetX global collaborative network data, we compared incident dementia (including AD) in adults with MCI and T2D without dementia, who were new users of GLP‐1 RAs versus dipeptidyl peptidase‐4 inhibitors (DPP4i). RESULTS: We included 1320 propensity‐score‐matched (1:1) individuals who initiated GLP‐1 RAs or DPP4i in the period 2010 to 2021 (702 women; mean age 67.2 years). Over up to 5 years of follow‐up, incident dementia occurred in 101 and 132 participants initiating GLP‐1 RAs and DPP4i, respectively (Cox proportional hazard ratio 0.74 [95% confidence interval [CI]: 0.57 to 0.95]). At a mean follow‐up of 3.9 years, the respective Kaplan‐Meier‐derived cumulative incidences were 15.5% and 20.4% (absolute difference −4.9% [95% CI −9.4 to −0.4], number needed to treat of 21 [11 to 234] individuals to prevent one event). Various sensitivity analyses supported the primary analysis: comparing GLP‐1 RAs with basal insulin, using alternative outcome definitions, repeating the analyses across baseline subgroups, and using a negative control outcome. CONCLUSION: In this hypothesis‐generating study, initiation of GLP‐1 RAs versus DPP4i in people with T2D and MCI without dementia was associated with a lower risk of incident dementia.

Type 2 diabetes (T2D), affecting approximately 12% of the global population and over 30% of older adults, is among the most prevalent and fast-growing risk factors for neurodegenerative disorders. Evidence is lacking on whether specific glucose-lowering agents may reduce the risk of neurodegeneration onset in people living with T2D. In this retrospective cohort study, we utilized the TriNetX platform, which contains electronic health records of over 170 million people worldwide. We propensity-score matched (1:1) people with T2D lacking evidence of neurodegeneration who initiated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or dipeptidyl peptidase-4 inhibitors (DPP4i) (2010–2021). In a separate analytical cohort, we compared individuals initiating GLP-1 RA with those initiating basal insulin. Follow-up continued for ≤ 5 years. We used Cox proportional-hazard regression models to assess the risk of the composite outcome of developing new neurodegenerative conditions, including Alzheimer’s disease, Parkinson’s disease, dementia subtypes, and other synucleinopathies. We also assessed each component individually. Analyses were repeated among subgroups defined by sex, age, and the specific GLP-1 RA initiated. Overall, 214,442 matched individuals initiated GLP-1 RAs or DPP4i (109,731 women, mean age 58.6 years [SD 12], and mean HbA1c 7.7% [1.4]). During a 4.0-year mean follow-up, neurodegenerative disorder onset occurred in 2,393 (2.2%) and 3,062 (2.9%) people initiating GLP-1 RAs and DPP4i, respectively (hazard ratio of 0.81 [95% CI 0.77 to 0.86]; absolute risk difference − 0.6% [− 0.8 to − 0.5]). The associations were separately observed among women (0.78 [0.72 to 0.84]) and men (0.90 [0.83 to 0.98]), individuals aged ≥ 65 years old (0.82 [0.78 to 0.87]) or < 65 years old (0.84 [0.70 to 1.00]), and in those initiating semaglutide (0.75 [0.67 to 0.84]), liraglutide (0.77 [0.70 to 0.84]), or dulaglutide (0.82 [0.77 to 0.88]). The hazard ratios for dementia, Alzheimer's disease, vascular dementia, and Parkinson's disease onset were 0.76 [0.72 to 0.81], 0.77 [0.68 to 0.87], 0.75 [0.67 to 0.85], and 1.04 [0.93 to 1.17] with GLP-1 RAs versus DPP4i, respectively. The results were in the same direction when comparing individuals initiating GLP-1 RAs with those initiating basal insulin. In a real-world cohort of people living with T2D with a multinational representation, the initiation of GLP-1 RAs, compared to DPP4i or basal insulin, was associated with a lower risk of new-onset neurodegeneration. These data support the rationale for dedicated clinical trials to assess the potential neuroprotective properties of GLP-1 RAs in this population.

Aims: Randomized placebo‐controlled clinical trials showed that glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA) reduce kidney risk in patients with type 2 diabetes (T2D), prominently in those with chronic kidney disease. It is unclear whether these findings may apply to broader populations of patients with T2D treated in real‐world settings and compared to active controls. We summarised real‐world data of adverse kidney outcomes among patients with T2D initiating GLP‐1 RA versus other glucose‐lowering agents. Materials and Methods: We searched PubMed and Embase for observational cohort studies (April 2005–January 2025; PROSPERO CRD42023405356). Initiators of GLP‐1 RA were compared to sodium‐glucose cotransporter‐2 inhibitors (SGLT2i), dipeptidyl‐peptidase 4 inhibitors (DPP4i), sulfonylureas, or basal insulin. Outcomes included risks of albuminuria progression, ≥ 40 or ≥ 50% eGFR reduction from baseline, acute kidney injury (AKI), kidney‐related hospitalizations, and end‐stage kidney disease (ESKD), per data availability. We synthesised the data using inverse variance‐weighted averages of logarithmic hazard ratios (HR)s in random‐effect models. Results: Thirty‐one studies were eligible, encompassing 1,601,389 patients (mean age 49–78 years, 5%–64% women), with 21, 6, 5, and 1 of them using SGLT2i, DPP4i, basal insulin, and sulfonylureas as a comparator, respectively. Compared with SGLT2i, GLP‐1 RA initiators had higher risks for AKI (HR [95% CI] 1.12 [1.05–1.20]), kidney‐related hospitalizations (1.66 [1.01–2.73]), and ≥ 40% reduction in eGFR (1.40 [1.27–1.53]), without evidence for differences in risks of ≥ 50% eGFR reduction or ESKD. Compared to DPP4i, GLP‐1 RA initiators had lower risks for experiencing ≥ 50% eGFR reduction (0.84 [0.76–0.92]), kidney‐related hospitalizations (0.73 [0.65–0.83]), and ESKD (0.70 [0.63–0.78]). Similar benefits were observed when comparing GLP‐1 RA to sulfonylureas. Compared to basal insulin, GLP‐1 RA initiation was associated with a lower risk of albuminuria progression (0.89 [0.80–0.99]), with inconsistent data regarding possible benefits in reducing ESKD risk. Conclusions: In patients with T2D, initiation of GLP‐1 RA in real‐world settings may be associated with improved kidney outcomes compared to DPP4i, sulfonylureas, and basal insulin, and worse kidney outcomes compared to SGLT2i.

Aim: To assess the association between urinary albumin‐to‐creatinine ratio (UACR) categories within the normal range with mortality and adverse cardiovascular outcomes. Materials and Methods: PubMed and Embase were systematically searched for real‐world evidence studies. Studies were manually evaluated according to predefined eligibility criteria. We included prospective and retrospective cohort studies of the association between UACR categories <30 mg/g and cardiovascular outcomes or mortality. Published information regarding study design, participants, UACR categorization, statistical methods, and results was manually collected. Two UACR categorization approaches were defined: a two‐category (UACR <10 mg/g vs. 10‐30 mg/g) and a three‐category division (UACR <5 mg/g vs. 5‐10 and 10‐30 mg/g). A random effects meta‐analysis was performed on studies eligible for the meta‐analysis. Results: In total, 22 manuscripts were identified for the systematic review, 15 of which were eligible for the meta‐analysis. The results suggest an association between elevated UACR within the normal to mildly increased range and higher risks of all‐cause mortality, cardiovascular death, and coronary heart disease, particularly in the range of 10‐30 mg/g. Compared with UACR <10 mg/g, the hazard ratio [HR (95% confidence interval, CI)] for UACR between 10 and 30 mg/g was 1.41 (1.15, 1.74) for all‐cause mortality and 1.56 (1.23, 1.98) for coronary heart disease. Compared with UACR <5 mg/g, the risk of cardiovascular mortality for UACR between 10 and 30 mg/g was more than twofold [HR (95% CI): 2.12 (1.61, 2.80)]. Intermediate UACR (5‐10 mg/g) was also associated with a higher risk of all‐cause mortality [HR (95% CI): 1.14 (1.05, 1.24)] and cardiovascular mortality [HR (95% CI): 1.50 (1.14, 1.99)]. Conclusions: We propose considering higher UACR within the normoalbuminuric range as a prognostic factor for cardiovascular morbidity and mortality. Our findings underscore the clinical significance of even mild increases in albuminuria.