Introduction: The Shifting Paradigm in Cardio-Renal Care
Chronic kidney disease (CKD) is no longer viewed merely as a decline in filtration, but as a potent accelerator of cardiovascular morbidity and mortality. For decades, the therapeutic armamentarium for patients with CKD and type 2 diabetes (T2DM) was limited. However, the emergence of glucagon-like peptide-1 receptor agonists (GLP1-RAs) and sodium-glucose co-transporter 2 inhibitors (SGLT2is) has revolutionized the field. While the cardiovascular benefits of GLP1-RAs are well-established in the general T2DM population, their efficacy across the full spectrum of CKD severity—particularly in real-world settings—and the consistency of their uptake in clinical practice have remained areas of active investigation.
Two landmark studies recently published in the American Journal of Kidney Disease and Diabetes, Obesity and Metabolism provide a dual perspective on this issue: one confirming the profound clinical benefits of GLP1-RAs in CKD populations, and the other highlighting a significant implementation gap in primary care.
Highlights
Significant MACE Reduction
GLP1-RA initiation is associated with a 12% lower risk of Major Adverse Cardiovascular Events (MACE) compared to DPP-4 inhibitors in patients with CKD.
Lower Cardiovascular Mortality
The primary driver of the GLP1-RA benefit in CKD is a 28% reduction in the rate of cardiovascular death.
Consistency Across Subgroups
Cardiovascular benefits remain consistent regardless of CKD stage, level of albuminuria, or concomitant use of SGLT2 inhibitors.
The Implementation Gap
Despite proven benefits, only approximately 10% of eligible CKD patients in primary care settings are currently prescribed GLP1-RAs, with even lower rates observed in advanced CKD stages.
Study 1: GLP1-RAs and MACE Risk in CKD (Yau et al.)
Study Design and Population
Researchers conducted a large-scale retrospective observational cohort study in Ontario, Canada, involving 24,576 new users of GLP1-RAs and 44,367 new users of dipeptidyl peptidase-4 (DPP-4) inhibitors. All participants had an estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2. To minimize confounding, the study utilized inverse probability of treatment weighting (IPTW) based on propensity scores.
Primary and Secondary Outcomes
The primary outcome was MACE, a composite of nonfatal myocardial infarction, unstable angina, nonfatal ischemic stroke or transient ischemic attack, coronary revascularization, and cardiovascular death. Secondary outcomes included individual MACE components, heart failure hospitalizations, peripheral vascular disease interventions, and all-cause mortality.
Key Findings
The study revealed that MACE occurred at a rate of 31.6 per 1,000 person-years among GLP1-RA users, compared to 36.5 per 1,000 person-years among DPP-4 inhibitor users. This translated to a subdistribution hazard ratio (SHR) of 0.88 (95% CI, 0.80-0.97). The most striking finding was the reduction in cardiovascular death, with an SHR of 0.72 (95% CI, 0.62-0.85).
Importantly, the cardiovascular protection offered by GLP1-RAs did not vary by CKD stage (stages 3-5 vs. stage 2) or the presence of albuminuria. Furthermore, the benefit was additive; patients already taking SGLT2 inhibitors still experienced a reduction in MACE when a GLP1-RA was initiated.
Study 2: The Prescription Paradox in Primary Care (Wallace et al.)
Rationale and Methodology
While the clinical evidence for GLP1-RAs and SGLT2is is robust, their real-world utilization is often delayed. Wallace and colleagues analyzed the MedicineInsight dataset, a large Australian primary care database, to assess prescription prevalence among 114,499 adults with T2DM, of whom 32.1% (36,840) had CKD.
Prescription Prevalence Results
The findings highlighted a stark underutilization of evidence-based therapies:
1. SGLT2 Inhibitors: Prescribed in only 14.4% of patients with CKD and 17.8% of those meeting specific trial-target criteria.
2. GLP1-RAs: Prescribed in only 10.1% of patients with CKD and 11.3% of trial-target populations.
The Risk-Treatment Paradox
Perhaps the most concerning finding was that patients with more advanced CKD stages and severely increased albuminuria—those at the highest risk for cardiovascular events—were significantly less likely to be prescribed these medications. This suggests a “risk-treatment paradox” where clinical inertia or concerns over safety in advanced renal disease may be preventing the most vulnerable patients from receiving life-saving interventions.
Expert Commentary: Bridging the Gap
The data from Yau et al. reinforces the biological plausibility of GLP1-RAs as cardio-protective agents in the renal population. Unlike SGLT2 inhibitors, which primarily reduce heart failure hospitalizations and slow eGFR decline through hemodynamic mechanisms, GLP1-RAs likely exert their cardiovascular benefits through anti-atherogenic effects, reduction of systemic inflammation, and improved endothelial function. This makes them particularly effective at reducing atherosclerotic events like myocardial infarction and cardiovascular death.
However, the Australian data by Wallace et al. serves as a wake-up call for the medical community. The low uptake of these therapies in primary care is multi-factorial, likely involving concerns regarding cost, gastrointestinal side effects, and the complexity of managing multiple new drug classes.
Study Limitations
It is important to acknowledge limitations. The study by Yau et al. was retrospective, and despite robust statistical weighting, residual confounding remains possible. Additionally, missing data on albuminuria in real-world databases can complicate the categorization of CKD severity. For the prescription prevalence study, the data represents a specific geographic region (Australia) and may not reflect global trends, although similar gaps have been noted in US and European datasets.
Conclusion and Future Directions
The evidence is clear: GLP1-RAs are effective at reducing major adverse cardiovascular events and cardiovascular death across the spectrum of CKD. These benefits are independent of SGLT2 inhibitor use, suggesting that a combination therapy approach may offer the highest level of protection for high-risk patients.
To translate these findings into clinical practice, health systems must address the implementation gap. This requires multidisciplinary collaboration between primary care physicians, endocrinologists, and nephrologists to ensure that patients with CKD are not only screened for cardiovascular risk but are also initiated on the most effective therapies available. Future research should focus on strategies to overcome clinical inertia and on the long-term safety of these agents in patients with the most advanced stages of kidney failure (eGFR < 15 mL/min/1.73 m2).
References
1. Yau K, Ray JG, Jeyakumar N, et al. Glucagon-like Peptide-1 Receptor Agonists and Risk of Major Adverse Cardiovascular Events in Patients With CKD. Am J Kidney Dis. 2026 Feb;87(2):211-229.e1. doi: 10.1053/j.ajkd.2025.09.010.
2. Wallace H, Wick J, Neuen BL, et al. Prevalence of SGLT2 inhibitor and GLP1 receptor agonist prescriptions in type 2 diabetes patients with and without chronic kidney disease: Analysis of an Australian primary care dataset. Diabetes Obes Metab. 2025 Oct;27(10):5599-5611. doi: 10.1111/dom.16608.
