What is the clinical evidence from this study?

Study design: Cohort. Population: Type 2 diabetes with low body mass index (n=41856). Intervention: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) vs. Dipeptidyl peptidase-4 inhibitors (DPP-4i). Primary outcome: Major adverse kidney events (MAKE) (HR 0.93, 95% CI 0.89-0.98, p=0.005).

What does this research mean for the field?

GLP-1 receptor agonists reduce the risk of major adverse kidney events by 7% compared to DPP-4 inhibitors in adults with type 2 diabetes and a BMI of 30 kg/m² or less. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to evaluate the effectiveness of glucagon-like peptide-1 receptor agonists in individuals with type 2 diabetes and low body mass index.

April 7, 2026International Journal of Medical Sciences0 citationsOpen Access

Clinical effects of glucagon-like peptide-1 receptor agonist in type 2 diabetes with low body mass index: findings from large-scale emulated target trials

MTMing-Hsien Tsai YFYu-Wei Fang YTYu-Han Tsai

Key Result

GLP-1 receptor agonists reduced the risk of major adverse kidney events by 7% (HR 0.93) compared to DPP-4 inhibitors in adults with type 2 diabetes and BMI ≤ 30 kg/m².

Key Points

This research aims to evaluate the effectiveness of glucagon-like peptide-1 receptor agonists in individuals with type 2 diabetes and low body mass index.
Conducted a retrospective cohort study utilizing the TriNetX US Collaborative Network.
Identified adults with type 2 diabetes and BMI 30 kg/m who initiated GLP-1 RAs or DPP-4 inhibitors.
Performed a 1:1 propensity score matching resulting in two balanced cohorts of patients.
Assessed outcomes over up to four years using Cox regression and Kaplan-Meier analyses.
GLP-1 RA initiation reduced the risk of major adverse kidney events (14.8% vs. 16.8%; HR 0.93, p=0.005).
Significantly decreased risk of progression to dialysis (HR 0.78, p<0.001).
Resulted in lower hospitalization rates (HR 0.84, p<0.001) and sepsis (HR 0.88, p=0.001).
No significant impact on cardiovascular outcomes or all-cause mortality.

Study Design

Type

Cohort (n=41,856)

Multicenter

Yes

Structured PICO

Does GLP-1 RA initiation reduce major adverse kidney events compared to DPP-4i in adults with type 2 diabetes and BMI ≤30 kg/m²?

Population

41,856 adults with type 2 diabetes and BMI ≤30 kg/m² (mean age 61.4, 52.3% male) from the TriNetX US Collaborative Network. Exclusions included prior GLP-1 RA or DPP-4i exposure, kidney failure, transplantation, malignancy, recent cardiovascular events, and concurrent comparator use.

Intervention

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) initiation

Comparator

Dipeptidyl peptidase-4 inhibitors (DPP-4i) initiation (1:1 propensity score matched)

Outcome

Major adverse kidney events (MAKE) (composite of acute kidney injury, end stage of kidney disease, entering dialysis, and death) assessed over up to 4 yearscomposite

In adults with type 2 diabetes and BMI ≤30 kg/m², GLP-1 RAs confer clinically meaningful kidney protection and reduce hospitalization and sepsis, despite neutral cardiovascular effects.

Main Result

Effect estimate: HR 0.93 (95% CI 0.89-0.98)

Absolute Event Rate: 14.8% vs 16.8%

p-value: p=0.005

Limitations

Applicability to Asian populations remains uncertain
BMI defined based on a single recorded measurement rather than longitudinal weight trajectories
Residual confounding cannot be eliminated (e.g., socioeconomic status, physical activity, genetic markers)
Requirement for ≥2 visits may introduce selection-related bias
Outcome definitions relied on diagnostic coding and laboratory data, introducing possibility of misclassification
Urine albumin-to-creatinine ratio (uACR) was available for only a small subset of patients
Evaluated GLP-1 RAs as a class, differences among individual agents could not be examined
Medication adherence, dose escalation, and treatment duration were not fully assessed
Intention-to-treat framework without as-treated or per-protocol analysis

Abstract

Aims: Chronic kidney disease (CKD) is a common and serious complication of type 2 diabetes, yet the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in non-obese or mildly overweight individuals remains uncertain.This study evaluated renal, cardiovascular, and systemic outcomes associated with GLP-1 RA therapy in adults with type 2 diabetes and body mass index (BMI) 30 kg/m.Materials and Methods: We conducted a real-world, target trial emulation, retrospective cohort study using the TriNetX US Collaborative Network.Adults with type 2 diabetes and BMI 30 kg/m initiating GLP-1 RAs or dipeptidyl peptidase-4 inhibitors (DPP-4i) between 2016 and 2023 were identified.After exclusions, 23,103 GLP-1 RA and 44,156 DPP-4i users remained; 1:1 propensity score matching yielded two balanced cohorts of 20,928 patients.Outcomes-including major adverse kidney events (MAKE), progression to dialysis, cardiovascular events, hospitalization, and sepsis-were assessed over up to four years.Cox regression and Kaplan-Meier analyses estimated hazard ratios.Results: GLP-1 RA initiation was associated with lower risks of MAKE (14.8% vs. 16.8%;HR 0.93, p=0.005) and progression to dialysis (HR 0.78, p<0.001).Cardiovascular outcomes and all-cause mortality were similar between groups.GLP-1 RAs significantly reduced hospitalization (HR 0.84, p<0.001) and sepsis (HR 0.88, p=0.001).Benefits were consistent across BMI strata and clinical subgroups, with no evidence of effect modification.Conclusions: In adults with type 2 diabetes and BMI 30 kg/m, GLP-1 RAs confer clinically meaningful kidney protection and reduce hospitalization and sepsis, despite neutral cardiovascular effects.These findings support the use of GLP-1 RAs in non-obese or mildly overweight diabetic populations.

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