Old vs. New: Which T2D Agents Have the Best Renal Outcomes?

How do DPP-4 inhibitors and sulfonylureas compare to SGLT2is and GLP-1 agonists regarding renal outcomes? 

T2D is associated with micro- and macrovascular complications that significantly increase the burden of this disease. Diabetic nephropathy is one such complication associated with increased mortality and reduced quality of life in diabetes patients. Trials such as the CREDENCE and EMPA-REG OUTCOMES trials have shown the benefit of SGLT2is in preventing kidney disease progression and reducing outcomes. There is a lack of evidence that confirms the effectiveness of antihyperglycemic agents in the real world setting or compares current agents’ effectiveness in reducing renal effects. 

 A new study aimed to provide real-world evidence to compare older add-on antihyperglycemic agents’ effectiveness versus newer agents in reducing renal outcomes.  

This comparative-effectiveness analysis compared the use of four add-on antihyperglycemic agents to determine their effectiveness in reducing the risk of kidney outcomes in patients with type 2 diabetes. It was designed to imitate a four-arm RCT comparing the efficacy of the agents. Data for this study was collected from the VA Health Care System Database. Patients were included in the analysis if they were recorded users of sulfonylureas, DPP4-inhibitors, GLP-1 agonists, or SGLT-2 inhibitors after October 1, 2016. Patients with an eGFR < 15 mL/min/1.73m2, or who were on dialysis, or had a kidney transplant were excluded from the analysis. Patients were also excluded if they had no record of relevant outpatient laboratory measurements within a year before the analysis start time, including height, weight, H1c, blood pressure, and eGFR. The follow-up period for the analysis ended on November 30, 2019, and patients were followed until the primary outcome was met or until the follow-up end date. 

The primary outcome was the time to occurrence of a composite 50% reduction in eGFR, ESKD (the first record of eGFR < 15 mL/min/1.73m2 or dialysis), or death from any cause. Both ITT and per-protocol analysis were performed for the primary composite outcome. Sensitivity analyses were performed to test the robustness of the primary analysis. Between the four groups, patients taking SGLT-2 inhibitors and GLP-1 agonists had an increased prevalence of heart failure and albuminuria, and more users were concomitantly using insulin, ACEIs/ARBs, or diuretics. 47.73 % of the study patients were taking metformin, and concomitant metformin use was slightly higher in the SGLT-2 inhibitor group. All other baseline characteristics were consistent between the four groups.  

This study included 216,558 patients. 134,904 patients took sulfonylureas, while 18,544, 23,711, and 39,399 patients took SGLT2is, GLP-1 agonist, and DPP-4 inhibitors, respectively. In the ITT analysis, the composite outcome risk was lower in all groups compared to sulfonylureas. Patients taking SGLT2is and GLP-1 agonists were also at a lower risk of the composite outcome compared to DPP-4 inhibitors (SGLT2is: HR 0.76; 95% CI 0.70 – 0.82; GLP-1: HR 0.79; 95% CI 0.74 – 0.85). There was no significant difference in the overall risk between the SGLT2is and the GLP-1 agonist groups (95% CI 0.87 – 1.04). Within the eGFR category, SGLT2is and GLP-1 agonist had a reduced risk of composite outcomes in all subgroups from an eGFR of ≥ 90 to < 45 mL/min/1.73m2. DPP-4 inhibitors had a significant risk reduction of renal outcomes in patients with an eGFR ≥ 60 but there was no difference in risk in patients with an eGFR < 60 (eGFR ≥ 45 to <60: 95% CI 0.83 – 1.02; eGFR < 45: 95% CI 0.86 – 1.02). Results in the per-protocol analysis were consistent with the risk reduction seen in the ITT analysis. 

Five sensitivity analyses were conducted to test the main analysis results’ strength, including testing the primary composite endpoint’s components, analyses adjusted for time-updated BMI and A1c, and assessing whether the composite endpoint relationship antihyperglycemic class was dependent on BMI or glycemic status. In all sensitivity analyzes, the results were consistent with the primary analysis. 

The generalizability of this study is limited due to the demographics of the cohort. 94.49% of the patients were male, and 71.95% were white, with a mean age of 65 yrs. Even still, the findings of the study were consistent with evidence observed from RCTs, such as the CREDENCE and EMPA-REG OUTCOMES trials. Patients taking DPP-4 inhibitors, SGLT2is, and GLP-1 agonists were associated with having a lower risk of the composite outcome of a 50% reduction in eGFR, ESKD, or death from any cause as compared to sulfonylureas. Though no significant difference was seen between SGLT2is and GLP-1 agonists, both were also associated with lower risk than DPP-4 inhibitors.   

Practice Pearls: 

• SGLT2is and GLP-1 agonists are associated with a lower risk of composite renal outcomes than sulfonylureas and DPP4 inhibitors. 
• Though this study’s generalizability may be limited due to the cohort’s demographics, the study’s findings were consistent with evidence observed from RCTs. 
• DPP-4 inhibitors are associated with a reduced risk of renal outcomes compared to sulfonylureas. 

“Comparative Effectiveness Of SGLT2 Inhibitors, GLP-1 Receptor Agonists, DPP-4 Inhibitors, And Sulfonylureas On Risk Of Kidney Outcomes: Emulation Of A Target Trial Using Health Care Databases”. Diabetes Care, 2020, p. dc201890. American Diabetes Association, https://doi.org/10.2337/dc20-1890.  

Destiny Reed, PharmD. Candidate, Florida A&M College of Pharmacy and Pharmaceutical Sciences