A major real-world analysis suggests GLP-1 receptor agonists could offer heart, kidney, and weight benefits in type 1 diabetes without raising hospitalization risk for diabetic ketoacidosis or severe hypoglycemia.
Key takeaways
GLP-1RA initiation in type 1 diabetes associated with lower risks of major cardiovascular events and end-stage kidney disease.
Patients using GLP-1RAs more likely to achieve clinically meaningful weight loss.
GLP-1RA use not associated with more hospitalizations for diabetic ketoacidosis or severe hypoglycemia..
Findings are promising, but randomized trials are still needed because the study is observational.
Brief Communication: Glucagon-like peptide-1 receptor agonists for major cardiovascular and kidney outcomes in type 1 diabetes. Image Credit: Monkey Business Images / Shutterstock
In a recent study published in the journal Nature Medicine, researchers used “target trial emulation” to analyze a decade of clinical data on the long-term outcomes associated with glucagon-like peptide-1 receptor agonists (GLP-1RAs) in type 1 diabetes (T1D).
The study dataset comprised more than 174,000 patients and found that patients using GLP-1RAs demonstrated a 15% reduced risk of major cardiovascular events and a 19% lower risk of end-stage kidney disease. Furthermore, the study found no increased risk of hospitalization for side effects like diabetic ketoacidosis or severe hypoglycemia, suggesting that GLP-1RAs may represent a promising adjunctive therapy warranting further study in T1D management.
Unmet Needs in Type 1 Diabetes Long-Term Outcomes
Decades of research and patient reports have established that living with type 1 diabetes (T1D) is a lifelong balancing act. Even in laboratory-controlled settings with perfect insulin management, the cumulative toll on the body has been found to be significant.
Previous analyses have shown that by middle age, ~31% of individuals with T1D develop major adverse cardiovascular events (MACEs), and 7% report clinically confirmed end-stage kidney disease (ESKD).
Furthermore, while the primary focus of conventional T1D interventions has been on glycemic (blood sugar) control, only about 20-30% of patients in the United States (U.S.) meet these targets. While glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) have become important treatments for type 2 diabetes (T2D) and obesity, their long-term impact on type 1 diabetes (T1D) has remained understudied.
Reviews on the topic highlight two predominant reasons for these discrepancies: 1. T1D patients were excluded from the landmark clinical trials for GLP-1RA drugs, and 2. Early pilot GLP-1RA investigations suggested that these drugs might increase the risk of diabetic ketoacidosis (DKA).
Target Trial Emulation Using Large-Scale Clinical Data
The present study aimed to address these knowledge gaps by leveraging the Optum Labs Data Warehouse (OLDW) dataset. OLDW is a national database containing de-identified electronic health records for over 300 million patients.
The study identified 174,678 individuals with T1D who were followed between January 2013 and March 2024. The study employed a relatively novel statistical methodology termed “sequential target trial emulation”.
This method applies the rigorous design principles of a randomized clinical trial (RCT) to existing (secondary) observational data. The study specifically compared the outcomes of “initiators”, T1D patients who initiated GLP-1RA treatment, with “non-initiators”.
To ensure these groups were comparable despite their significantly different cohort sizes, the analyses employed propensity score weighting, a method that balances baseline characteristics such as age, weight, and existing health conditions to mimic a randomized design.
The study’s primary endpoints were 1. Major Adverse Cardiovascular Events (MACEs), a composite of heart attack, stroke, or death, and 2. End-Stage Kidney Disease (ESKD), herein defined as the patient needing dialysis or a kidney transplant. The study further tracked patient-specific safety outcomes, specifically hospitalizations for severe hypoglycemia (low blood sugar) and DKA.
Reduced Cardiovascular and Kidney Risk with GLP-1RAs
Study findings suggest that GLP-1RAs may offer cardiorenal benefits in T1D that are directionally similar to the benefits seen in T2D. Over the five-year follow-up period, the risk of a major cardiovascular event was 4.3% for GLP-1RA users compared to 5.0% for non-users (Hazard Ratio [HR] = 0.85; 95% CI: 0.77-0.95; 15% risk reduction). Similarly, the five-year risk of end-stage kidney disease was 1.6% for users versus 1.9% for non-users, resulting in an HR of 0.81 (95% CI: 0.69-0.95; 19% risk reduction). Furthermore, the study found that users’ risk of heart failure (HF) decreased by 18% (HR = 0.82), and major adverse liver event risk decreased by 28% (HR = 0.72).
Finally, T1D patients on GLP-1RAs were found to be significantly more likely to achieve clinically meaningful weight loss (5%, 10%, or 15%) compared to their non-user counterparts. Most notably, the study found no increased risk of hospitalization for DKA (HR = 0.83) or severe hypoglycemia (HR = 0.82) among users compared with non-users, although these safety outcomes were limited to events captured through hospitalization records. While the study did identify a slightly higher prevalence of gastrointestinal (GI) issues in the GLP-1RA group, the difference was not statistically significant.
Limitations of Observational Target Trial Emulation Study
The present study provides strong observational evidence that initiation of GLP-1RA therapy was associated with lower cardiorenal risk in T1D, without an increase in hospitalizations for DKA or severe hypoglycemia. However, as an observational target trial emulation, the study cannot establish causality, and residual or unmeasured confounding remains possible. However, the researchers noted some methodological limitations. Most importantly, because this was an observational study, it could not track exact insulin dose adjustments across the study duration. The study also could not determine whether specific GLP-1RA agents or doses differ in their effects.
Future Research on GLP-1RA Use in T1D
Consequently, the researchers called for large-scale randomized controlled trials to confirm these results and determine which specific GLP-1RA or dosage works best for the T1D population. However, despite these limitations, the present study suggests that the benefits of GLP-1RAs may extend beyond their established use in T2D and clinically obese communities, supporting further evaluation of these agents as adjunctive therapy for those who have spent a lifetime managing T1D.