Comparative Effects of Glucose-Lowering Medications on Kidney Outcomes in Type 2 Diabetes: The GRADE Randomized Clinical Trial

Abstract

Importance: Type 2 diabetes (T2D) is the leading cause of kidney disease in the US. It is not known whether glucose-lowering medications differentially affect kidney function.

Objective: To evaluate kidney outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) trial comparing 4 classes of glucose-lowering medications added to metformin for glycemic management in individuals with T2D.

Design, setting, and participants: A randomized clinical trial was conducted at 36 sites across the US. Participants included adults with T2D for less than 10 years, a hemoglobin A1c level between 6.8% and 8.5%, and estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m2 who were receiving metformin treatment. A total of 5047 participants were enrolled between July 8, 2013, and August 11, 2017, and followed up for a mean of 5.0 years (range, 0-7.6 years). Data were analyzed from February 21, 2022, to March 27, 2023.

Interventions: Addition of insulin glargine, glimepiride, liraglutide, or sitagliptin to metformin, with the medication combination continued until the HbA1c was greater than 7.5%; thereafter, insulin was added to maintain glycemic control.

Main outcomes and measures: Chronic eGFR slope (change in eGFR between year 1 and trial end) and a composite kidney disease progression outcome (albuminuria, dialysis, transplant, or death due to kidney disease). Secondary outcomes included incident eGFR less than 60 mL/min/1.73 m2, 40% decrease in eGFR to less than 60 mL/min/1.73 m2, doubling of urine albumin-to-creatinine ratio (UACR) to 30 mg/g or greater, and progression of Kidney Disease Improving Global Outcomes stage. Analyses were intention-to-treat.

Results: Of the 5047 participants, 3210 (63.6%) were men. Baseline characteristics were mean (SD) age 57.2 (10.0) years; HbA1c 7.5% (0.5%); diabetes duration, 4.2 (2.7) years; body mass index, 34.3 (6.8); blood pressure 128.3/77.3 (14.7/9.9) mm Hg; eGFR 94.9 (16.8) mL/min/1.73 m2; and median UACR, 6.4 (IQR 3.1-16.9) mg/g; 2933 (58.1%) were treated with renin-angiotensin-aldosterone inhibitors. Mean chronic eGFR slope was -2.03 (95% CI, -2.20 to -1.86) mL/min/1.73 m2 per year for patients receiving sitagliptin; glimepiride, -1.92 (95% CI, -2.08 to -1.75) mL/min/1.73 m2 per year; liraglutide, -2.08 (95% CI, -2.26 to -1.90) mL/min/1.73 m2 per year; and insulin glargine, -2.02 (95% CI, -2.19 to -1.84) mL/min/1.73 m2 per year (P = .61). Mean composite kidney disease progression occurred in 135 (10.6%) patients receiving sitagliptin; glimepiride, 155 (12.4%); liraglutide, 152 (12.0%); and insulin glargine, 150 (11.9%) (P = .56). Most of the composite outcome was attributable to albuminuria progression (98.4%). There were no significant differences by treatment assignment in secondary outcomes. There were no adverse kidney events attributable to medication assignment.

Conclusions and relevance: In this randomized clinical trial, among people with T2D and predominantly free of kidney disease at baseline, no significant differences in kidney outcomes were observed during 5 years of follow-up when a dipeptidyl peptidase 4 inhibitor, sulfonylurea, glucagonlike peptide 1 receptor agonist, or basal insulin was added to metformin for glycemic control.

Trial registration: ClinicalTrials.gov Identifier: NCT01794143.

Figure 1.. Consolidated Standards of Reporting Trials Diagram

Assignment to the 4 treatment groups, numbers of drop-in/drop-out, and numbers included in intention-to-treat (ITT) and per-protocol analyses. For the ITT analyses, 98 participants in the glargine (n = 36), glimepiride (n = 22), liraglutide (n = 28), and sitagliptin (n = 12) groups were removed from the randomized group (n = 5047) due to not having at least 1 follow-up estimated glomerular filtration rate or 1 follow-up urinary albumin-to-creatinine ratio measure obtained after the baseline visit. For the per-protocol analyses, 247 participants in the glargine (n = 61), glimepiride (n = 44), liraglutide (n = 112), and sitagliptin (n = 30) groups were removed from the randomized group (n = 5047) if they did not attend any follow-up visits or did not take at least 1 dose of their randomized medication. GLP-1 RA indicates glucagonlike peptide-1 receptor agonist; SGLT2, sodium-glucose cotransporter-2.

Figure 2.. Kidney Parameters Over Time in the GRADE Trial and Secondary Kidney Outcomes

A, Estimated glomerular filtration rate (eGFR) over time by treatment group. Shaded areas indicate 95% CI. B, Urinary albumin-to-creatinine ratio (UACR) over time by treatment group. Shaded areas indicate pointwise 95% CI. C, Slope of eGFR by treatment group from year 1. Error bars indicate 95% CI. D, Composite kidney disease progression (Kaplan-Meier cumulative incidence curve). E, Confirmed progression to eGFR less than 60 mL/min/1.73 m². F, Confirmed 40% decline in eGFR relative to baseline. G, Confirmed doubling of UACR to a level greater than or equal to 30 mg/g. H, Confirmed Kidney Disease Improving Global Outcomes (KDIGO) category increase.