Kidney Outcomes in GRADE Study: Comparison of Glucose-Lowering Drugs

In the United States and in most of the world, diabetes is the leading cause of chronic kidney disease and kidney failure. Preventing or delaying the development of diabetic kidney disease (DKD) depends on achieving and maintaining glycemic control. Results of clinical trials in patients with type 1 diabetes and type 2 diabetes have consistently shown that the risk of developing albuminuria is reduced with intensive glycemic control. Long-term follow-up of some cohorts has suggested that intensive glycemic control also prevents a decrease in estimated glomerular filtration rate (eGFR) and kidney failure.

Several classes of glucose-lowering drugs have been shown to have kidney benefits in patients with type 2 diabetes, independent of glycemic effects. The kidney benefit effect has been seen primarily in patients with DKD, atherosclerotic cardiovascular disease, or high atherosclerotic cardiovascualr disease risk. Dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagonlike peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 (SGLT2) inhibitors have all been shown to reduce albuminuria in DKD, compared with placebo or other glucose-lowering drugs. SGLT2 inhibitors have also been shown to slow the decrease in eGFR Over time and GLP-1 receptor agonists have shown potential benefits with regard to eGFR loss in short-term studies and secondary analyses of cardiovascualr outcome trials.

The GRADE (Glycemic Reduction Approaches in Diabetes: A Comparative Effectiveness) study was designed to compare glycemic and other outcomes among four commonly used classes of glucose-lowering medications added to metformin (NCT01794143). Deborah J. Wexler, MD, MSc, and colleagues reported in the effects of GRADE interventions on detailed kidney outcomes in JAMA Internal Medicine.

The GRADE study was a randomized, clinical trial conducted at 36 sites across the United States. Eligible adult participants had type 2 diabetes for less than 10 years, a hemoglobin A1C level between 6.8% and 8.5%, and eGFR ≥60 mL/min/1.73 m² who were receiving metformin treatment. Between July 8, 2013, and August 17, 2027, 5047 participants were enrolled. Follow-up continued for a mean of 5.0 years. Data analysis was conducted from February 21, 2022, to March 27, 2023.

The main outcome of interest was 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 were incident eGFR less than 60 mL/min/1.73 m², 40% decrease in eGFR to <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 stages. Analyses were intention-to-treat.

Of the 5047 participants, 63.6% (n=3210) were men, and 36.4% (n=1887) were women. Mean age was 57.2 years, mean body mass index was 34.3 kg/m², and mean blood pressure was 128.3/77.3 mm Hg. At baseline, 58.1% (n=2933) were treated with renin-angiotensin-aldosterone system (RAAS) inhibitors. Mean baseline eGFR was 94.9 mL/min/1.73 m² and 2.5% of participants (n=125) had a baseline eGFR <60 mL/min/1.73 m². In 14.2% of participants (n=716), UACR was moderately elevated; UACR was severely elevated in 1.7% (n=84). Mean duration of the diagnosis of diabetes was 4.2 years.

Due to missing data, 98 patients were excluded from the analysis. Over the course of the study, mean hemoglobin A1c was 7.2%, mean blood pressure was 128/76 mm Hg, 64.4% of participants (n=2510) were treated with RAAS inhibitors, and 82.2% (n=3201) were treated with any blood-pressure-lowering medications at year 4. There were minor differences across some treatment groups. Mean eGFR was measured 5.4 times per participant and UACR was measured 9.8 times per participant. The rates of permanent discontinuation of assigned study medication were 14% for glargine, 23% for glimepiride, 23% for liraglutide, and 19% for sitagliptin.

Kidney Outcomes

During the study period, mean eGFR decreased, with a chronic slope from year 1 to trial end of –2.01 (95% CI, –2.10 to –1.92) mL/min/1.73 m² per year among all study participants. Mean chronic eGFR slope was –2.03 (95% CI, –2.20 to –1.86) mL/min/1.73 m² for participants receiving sitagliptin; ­–1.92 (95% CI, –2.08 to –1.75) mL/min/1.73 m² for those receiving glimepiride; –2.08 (95% CI, –2.26 to –1.90) mL/min/1.73 m² for those receiving liraglutide; and –2.02 (95% CI, –2.19 to –1.84) mL/min/1.73 m² for those receiving insulin glargine.

There were no significant differences in slope among the treatment groups. Further, there were no significant differences in mean total slope starting from baseline, change in eGFR during the first year of the study, confirmed progression to eGFR less than 60 mL/min/1.73 m², or confirmed 40% decrease in eGFR.

A total of 592 patients experienced the composite kidney disease progression coprimary outcome: 135 (10.6%) in the sitagliptin group; 155 (12.4%) in the glimepiride group; 152 (12.0%) in the liraglutide group; and 150 (11.9%) in the insulin glargine group. Of the 592 events, 82.6% (n=489) consisted of progression from normal to moderately elevated albuminuria. Ninety-three patients (15.8%) developed severely elevated albuminuria, and 10 had dialysis, kidney transplant, or death from kidney disease.

By year 4, the Kaplan-Meier-estimated cumulative incidence of the coprimary outcome of progression of kidney disease was 10.3% in the glargine group, 10.4% in the glimepiride group, 10.1% in the liraglutide group, and 9.3% in the sitagliptin group. There were no significant differences across treatment groups for the duration of study follow-up. At 5 years, the 5-year cumulative incidence of the coprimary composite kidney disease progression was 11.7% overall.

There were no significant differences across treatment groups in secondary outcomes. There were no adverse kidney events attributable to medication assignment.

The researchers cited some limitations to the study, including the relatively short follow-up time and the lack of an SGLT2 inhibitor arm because at the time that GRADE was designed, SGLT2 inhibitors were not approved.

In summary, the authors said, “As a randomized clinical trial of next-step therapy after metformin, GRADE enrolled a low-risk cohort of participants with type 2 diabetes, largely free of cardiac and kidney disease at baseline. The results of GRADE suggest that, in people with type 2 diabetes predominantly without kidney complications at baseline, a DPP-4 inhibitor, sulfonylurea, GLP-1 receptor agonist, or basal insulin added to metformin are equivalent with respect to the development or progression of DKD over 5 years.”

Takeaway Points

1. Researchers reported results of an analysis of kidney outcomes in the GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness) study comparing four classes of glucose-lowering medications added to metformin.
2. The study participants were adults with type 2 diabetes and without kidney disease.
3. There were no significant differences across treatment groups in decreased estimated glomerular filtration rate, progression of albuminuria, dialysis, kidney transplant, or death.

Source: JAMA Internal Medicine