Highlights
Survival Advantage
Patients with Type 2 Diabetes (T2D) and a Body Mass Index (BMI) under 25 kg/m² who were treated with semaglutide exhibited a significantly lower 3-year cumulative incidence of all-cause mortality (6.1%) compared to those treated with DPP-4 inhibitors (10.7%).
Weight-Independent Benefit
The study suggests that the clinical benefits of semaglutide, particularly regarding survival, extend to non-overweight populations, challenging the notion that GLP-1 receptor agonists are primarily indicated for weight management in T2D.
Safety Profile
Adverse events, including gastrointestinal symptoms and hypoglycemia, showed no statistically significant difference between the semaglutide and DPP-4 inhibitor groups in this specific lean population.
Background: The GLP-1 Receptor Agonist Paradox in Lean Populations
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, have revolutionized the management of Type 2 Diabetes (T2D) and obesity. Pivotal trials like SUSTAIN-6 and LEADER established their efficacy in reducing major adverse cardiovascular events (MACE). However, these landmark studies predominantly enrolled overweight or obese participants (BMI > 27 or 30 kg/m²). This has led to a clinical bias where GLP-1 RAs are often prioritized for patients with a high BMI, while non-overweight or ‘lean’ patients with T2D are frequently started on dipeptidyl peptidase 4 (DPP-4) inhibitors due to their weight-neutral profile and lower cost.
Non-overweight T2D represents a distinct clinical phenotype, often characterized by more pronounced beta-cell dysfunction rather than primary insulin resistance. Whether the cardioprotective and survival benefits of semaglutide are mediated solely through weight loss or via direct pleiotropic effects remains a critical question for precision medicine. The study by Kishimori et al. addresses this gap by comparing semaglutide to DPP-4 inhibitors specifically in patients with a BMI < 25 kg/m².
Study Design and Methodology
This retrospective cohort study utilized the TriNetX database, a massive global federated health research network providing access to electronic medical records. The researchers identified 340,721 patients diagnosed with T2D and a recorded BMI < 25 kg/m² between 2018 and 2020.
To ensure a rigorous comparison, the researchers employed propensity score matching (PSM). After excluding patients with cross-over treatments (e.g., those who switched from one class to another), 4,194 patients in the semaglutide group were matched with 4,194 patients in the DPP-4 inhibitor group. The matching criteria included age, sex, race, and a comprehensive list of comorbidities such as hypertension, chronic kidney disease, and baseline HbA1c levels.
The primary endpoint was the 3-year cumulative incidence of all-cause mortality. Secondary outcomes included the incidence of acute myocardial infarction (AMI) and stroke. Safety endpoints focused on common adverse events associated with GLP-1 RAs, including nausea, vomiting, diarrhea, and hypoglycemia.
Key Findings: Mortality and Cardiovascular Outcomes
All-Cause Mortality
The most striking finding was the significant reduction in mortality. The semaglutide group demonstrated a 6.1% risk of death over three years, compared to 10.7% in the DPP-4 inhibitor group. This translates to a hazard ratio (HR) of 0.54 (95% CI 0.45–0.65, P < 0.001), indicating a 46% reduction in the risk of death for non-overweight patients treated with semaglutide.
Cardiovascular Specificity
Interestingly, the study did not find a statistically significant difference in the incidence of acute myocardial infarction (6.1% for semaglutide vs. 7.1% for DPP-4i; HR 0.87, P = 0.173) or stroke (8.4% for semaglutide vs. 7.7% for DPP-4i; HR 1.11, P = 0.220). This suggests that while the survival benefit is robust, it may be driven by factors beyond the prevention of acute macrovascular events, or perhaps a longer follow-up period is required to observe divergence in AMI and stroke rates in this lean demographic.
Safety and Tolerability
One of the primary concerns for using GLP-1 RAs in non-overweight patients is the risk of excessive weight loss or intolerable gastrointestinal side effects. However, the data revealed no significant difference in the rates of nausea, vomiting, or diarrhea between the two groups. Furthermore, the risk of hypoglycemia was comparable, reinforcing the safety of semaglutide even in patients with lower baseline adiposity.
Expert Commentary: Mechanistic Insights
Beyond Weight Loss
The 46% reduction in mortality in a population with BMI < 25 kg/m² strongly suggests that semaglutide exerts its protective effects through mechanisms independent of adiposity reduction. Potential pathways include direct anti-inflammatory effects on the vascular endothelium, improvement in mitochondrial function within cardiomyocytes, and the stabilization of atherosclerotic plaques.
Pleiotropic Effects
GLP-1 receptors are expressed in various tissues, including the heart, kidneys, and central nervous system. In lean patients, where the metabolic burden of obesity is absent, the direct modulation of these receptors may play a more visible role in systemic health. The reduction in all-cause mortality might reflect a broader protection against multi-organ failure or chronic inflammatory states that contribute to death in T2D patients.
Study Limitations
While the use of the TriNetX database provides high power, the retrospective nature of the study means that unmeasured confounding factors could influence the results. For instance, socioeconomic status or specific dietary habits were not fully captured. Additionally, the study period (2018–2020) overlaps with the COVID-19 pandemic, which may have influenced mortality data, although the use of a matched control group (DPP-4i) helps mitigate this bias.
Conclusion and Clinical Implications
The findings from Kishimori et al. provide a compelling argument for the use of semaglutide in patients with T2D regardless of their BMI. For years, clinical guidelines and insurance coverage have often prioritized GLP-1 RAs for the ‘obese’ T2D patient. This study suggests that lean patients with T2D are currently an underserved population that stands to gain significant survival benefits from GLP-1 receptor agonism.
Clinicians should reconsider the ‘step-up’ approach that often relegates GLP-1 RAs to third-line therapy in non-overweight individuals. If these results are validated in prospective randomized controlled trials specifically targeting lean cohorts, it could lead to a paradigm shift in diabetes management—moving away from BMI-centric prescribing toward a mortality-reduction strategy for all T2D patients.
References
1. Kishimori T, Kato T, Wada A, et al. Cardiovascular outcomes and safety of semaglutide in non-overweight populations with type 2 diabetes: a comparison with dipeptidyl peptidase 4 inhibitors. Eur Heart J Qual Care Clin Outcomes. 2025;11(8):1319-1328.
2. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-1844.
3. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393(10166):31-39.
