GLP-1 vs. DPP-4 in Reducing Mortality for T2D Patients with ESRD

Glucagon-like peptide-1 (GLP-1) receptor agonist can reduce mortality and improve cardiovascular outcomes among patients with type 2 diabetes and end-stage kidney disease (ESKD), compared to dipeptidyl peptidase-4 inhibitor use.

Type 2 diabetes is linked to causing CKD, resulting in all-cause mortality, infection, and heart-related issues. Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors can effectively manage blood sugar level, weight control, decrease mortality rate, and reduce heart-related diseases among people with diabetes. American Diabetes Association guidelines recommend using GLP-1 receptor agonist for patients with diabetes and CKD with an estimated glomerular filtration rate less than 60 mL/min/1.73 m²  and for people at risk of having cardiovascular events. Physicians also recommend GLP-1 receptor agonist treatment for individuals who cannot use metformin or SGLT-2 inhibitors. This medication is very effective in treating patients with diabetes and CKD. A recent study reported that GLP-1 receptor agonist and dipeptidyl peptidase-4 (DPP-4) inhibitors use among patients with diabetes showed that GLP-1 receptor agonist was more effective and improved survival rates than DPP-4 inhibitors. However, randomized clinical trials mainly include small groups of people with end-stage kidney disease. Due to the safety and effectiveness of blood glucose control of DPP-4 inhibitors, it is usually recommended for use among patients with advanced-stage CKD. However, few studies have shown the association between GLP-1 receptor agonists treatment with an improved survival rate for patients with ESKD. Also, real-world studies have not been conducted to analyze the use of GLP-1 receptor agonists versus DPP-4 inhibitors to treat patients with  ESKD. This study aims to show the outcome of using the GLP-1 receptor agonist for treating individuals with stage 5 CKD versus the use of DPP-4 inhibitors.

The study was conducted by Huang-Yu Yang, from Kidney Research Institute, Department of Nephrology, Chang Gung University College of Medicine. He analyzed the population constructed from National Health Insurance Research Database (NHIRD) in Taiwan. Data in this study was generated between January 2012 and December 2018, and its Analysis took place between June 2020 and July 2021. In this retrospective cohort study, patients were given either a GLP-1 receptor agonist or a DPP-4 inhibitor before the index data for three months. The definition of the index data was 91 days after the first exposure to either a GLP-1 receptor agonist or a DPP-4 inhibitor. The primary outcome for this study was all-cause mortality after the index date during the investigation period. And the secondary endpoint was sepsis or infection-related mortality and significant advance cardiovascular event mortality. Seventy-five thousand five hundred fifty-six patients who have type 2 diabetes and end-stage kidney disease were on dialysis. Forty-eight thousand two hundred seventy-seven were excluded from the trial, and 27,279 patients were enrolled. Out of the 27,279 patients enrolled in the study, 26 578 participants were assigned in the DPP-4 inhibitor, and 701 were assigned to the GLP-1 receptor agonist group with (54.34% male; mean age, 65 years) and (49.36% male; mean age, 59 years) in both groups respectively.

Data showed that the use of GLP-1 receptor agonist resulted in a lower all-cause mortality rate with (hazard ratio [HR], 0.79; 95% CI, 0.63-0.98) and decrease in sepsis- and infection-related mortality (HR, 0.61; 95% CI, 0.40-0.91). In addition, this Subgroup research shows GLP-1 receptor agonists cause a reduced risk of mortality rate versus the use of DDP-4 inhibitors among individuals that have a cerebrovascular disease than those without cerebrovascular disease with HR, 0.33; 95% CI, 0.12-0.86), and  (HR, 0.89; 95% CI, 0.71-1.12) for both groups respectively. (P = .04 for interaction).

This recent study suggested that treatment with glucagon-like peptide-1 (GLP-1) receptor agonists causes a reduction in all-cause mortality rate among individuals with type 2 diabetes (T2D), advanced-stage chronic kidney disease (CKD), and end-stage kidney disease (ESKD), versus using dipeptidyl peptidase-4 (DPP-4) inhibitors. It also shows that the use of GLP-1 receptor agonists resulted in lower sepsis- and infection-related mortality rates than DPP-4 inhibitors. However, it did not lower major adverse cardiovascular and cerebrovascular events (MACCE)-related mortality. Further well-designed, prospective trials should be conducted to verify the possible benefit of using GLP-1 receptor agonist treatment for patients with advanced or ESKD.

Practice Pearls:

• GLP-1 receptor agonists used for patients with diabetes and advanced chronic diabetes resulted in an improved survival rate compared with the use of DPP-4 inhibitors.
• GLP-1 receptor agonist is an effective alternative treatment to metformin or SGLT-2 inhibitors for patients with diabetes and CKD  with an estimated glomerular filtration rate less than 60 mL/min/1.73 m² and at risk of developing a heart-related disease.
• There has been a lack of real-world studies that compare the effectiveness of GLP-1 receptor agonists with DPP-4 inhibitors for the treatment of patients with ESKD. This study is the first to analyze this comparison, and it shows that GLP-1 receptor agonists had better outcomes versus patients that used DPP-4 inhibitors.

        Jia-Jin Chen, MD. “GLP-1 Receptor Agonists vs. DPP-4 Inhibitors and Mortality in Diabetes and Advanced CKD.” JAMA Network Open, JAMA Network, March 7. 2022, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2789684. doi:10.1001/jamanetworkopen.2022.1169

          Iapoce, Connor. “GLP-1 Receptor Agonists Linked to Low Mortality in Diabetes, CKD Treatment.” HCPLive, HCPLive, March 7. 2022, https://www.hcplive.com/view/glp-1-receptor-agonists-low-mortality-diabetes-ckd.

           Janet Falade, PharmD Candidate, South College School of Pharmacy