GLP-1 Receptor Agonists Improve Outcomes After Major Limb Events in Diabetes: Study
Taiwan: Researchers have found in a nationwide cohort of patients with diabetes and a history of major adverse limb events that treatment with GLP-1 receptor agonists was associated with significantly lower risks of recurrent limb events, cardiovascular events, all-cause mortality, and kidney disease progression compared to DPP-4 inhibitors. These results support the preferential use of GLP-1 receptor agonists for secondary prevention in this high-risk population.
Patients with diabetes who have already experienced major adverse limb events (MALEs) represent one of the most vulnerable groups, with a markedly elevated risk of further limb complications, cardiovascular events, and death. However, evidence guiding the choice of glucose-lowering therapies for secondary prevention in this population has remained limited. Addressing this gap, a large nationwide cohort study published in JAMA Network Open evaluated whether glucagon-like peptide-1 receptor agonists (GLP-1 RAs) offer superior protection compared with dipeptidyl peptidase-4 (DPP-4) inhibitors among patients with diabetes and prior MALEs.
The retrospective study was conducted by Fu-Chih Hsiao from the Cardiovascular Department, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan, and colleagues, using data from the Taiwan National Health Insurance Research Database between October 2012 and December 2023. The analysis included 17,288 adults with diabetes and a documented history of MALEs, defined as chronic limb-threatening ischemia, lower limb revascularization, or nontraumatic minor or major amputation. Patients who initiated treatment with GLP-1 RAs—specifically liraglutide, dulaglutide, or semaglutide—were compared with those who started DPP-4 inhibitors.
To minimize treatment-selection bias, the investigators used a new-user, active-comparator design with inverse probability of treatment weighting. The primary outcome was a composite of lower limb revascularization and nontraumatic amputation, while secondary outcomes included major adverse cardiovascular events (MACE), all-cause mortality, and progression to long-term dialysis.
The key findings were as follows:
- The mean age of the study population was 70.7 years, with nearly 58% of participants being men.
- A total of 1,583 patients initiated treatment with GLP-1 receptor agonists, while 15,705 patients received DPP-4 inhibitors.
- After statistical adjustment, the use of GLP-1 receptor agonists was associated with a significantly lower risk of recurrent major adverse limb events.
- The reduction in limb events was primarily driven by a notable decrease in amputation rates among patients treated with GLP-1 receptor agonists.
- Patients receiving GLP-1 receptor agonists had substantially lower risks of major cardiovascular events compared with those treated with DPP-4 inhibitors.
- Treatment with GLP-1 receptor agonists was also linked to reduced risks of cardiovascular death and all-cause mortality.
- Kidney outcomes favored GLP-1 receptor agonists, with a significantly lower risk of progression to long-term dialysis.
The authors noted several limitations, including the observational nature of the study, lack of detailed data on lifestyle factors and laboratory parameters, and potential selection bias related to differences between treatment groups. Restrictions within Taiwan’s reimbursement system may also limit generalizability, and causal conclusions cannot be definitively established.
Despite these limitations, the findings suggest that GLP-1 receptor agonists may provide important limb, cardiovascular, and renal protection in patients with diabetes and prior MALEs, supporting their preferential use as a secondary prevention strategy in this exceptionally high-risk population.
Reference:
Hsiao F, Hsu T, Hsieh Y, et al. Glucagon-Like Peptide-1 Receptor Agonists and Prior Major Adverse Limb Events in Patients With Diabetes. JAMA Netw Open. 2026;9(1):e2555952. doi:10.1001/jamanetworkopen.2025.55952
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