by Diabetes is the leading cause of kidney failure and chronic kidney disease, and proper regulation of the glycemic load in the body prevents or significantly delays the deterioration of kidney function.
Clinical studies in patients with type I and type II diabetes have shown that intensive glycemic control reduces proteinuria, while over the long term it prevents the decline in glomerular filtration rate (an indicator of the ability kidneys to filter waste from the blood and an indicator of kidney damage) and kidney failure.
Recently, several classes of glucose-lowering drugs in type II diabetes mellitus have been shown to have renal benefits independent of the effect of glucose commonly seen in people with diabetic nephropathy, atherosclerotic cardiovascular disease, or at high risk of disease. atherosclerotic cardiovascular disease.
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These classes include dipeptidyl peptidase 4 (DPP-4) inhibitors, glycogen-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 (SGLT2) inhibitors that reduce albuminuria in diabetic nephropathy, compared to placebo or other hypoglycaemic drugs.
Additionally, SGLT2 inhibitors have been clearly shown to slow the decline in glomerular filtration rate (eGFR) over time.
GLP-1 receptor agonists in short-term studies have shown potential protection in lowering eGFR, as well as in secondary analyzes of studies that primarily focused on protecting diabetic patients from cardiovascular disease.
It is unclear whether people with early-onset diabetes and without kidney failure derive different benefits from treatment with different classes of hypoglycemic agents other than the use of SGLT2 inhibitors.
For this reason, the GRADE comparative efficacy study was prepared with the aim of comparing the therapeutic results on both the glycemic load and other health parameters of diabetic patients, by comparing the 4 main classes of antidiabetics added to the basic treatment with metformin.
The study was published in the scientific journal JAMA and compared the main classes of anti-diabetic drugs – except those specific to SGLT2 – in protecting the kidneys against diabetes.
The main classes available at the time of study design and launch in 2013 were the DPP-4 inhibitor sitagliptin, the sulfonylurea glimepiride, the GLP-1 receptor agonist liraglutide, and insulin basal glargine.
As documented, DPP-4 inhibitors and GLP-1 receptor agonists have shown modest renal benefits, primarily reductions in albuminuria, in placebo-controlled trials.
Unlike recent clinical studies of cardiovascular outcomes, GRADE included a diverse group of US patients with shorter duration of diabetes, mostly without cardiovascular and renal complications at baseline, who maintained good overall glycemic control in all 4 treatment groups. treatment. The GRADE study reported modest differences in time to glycemic progression and an insignificant difference in overall microvascular outcomes.
The effect of these categories on kidney outcomes is being evaluated.
The study included 5047 patients with type II diabetes, mostly without kidney disease at baseline, who were treated with metformin. They were then randomly assigned to the sulfonylurea, DPP-4, and GLP-1 treatment groups.
All groups had good management of glycemic load and blood pressure.
There were no significant differences in the decrease in estimated glomerular filtration rate, progression of albuminuria, hemodialysis, kidney transplantation, or death during the 5 years of follow-up.
The randomized clinical trial was conducted at 36 US sites.
Patient characteristics
Participants were adults with type II diabetes for less than 10 years, a glycated hemoglobin A1c level between 6.8% and 8.5% and an estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL /min/1.73 m2 that have been treated with metformin.
A total of 5047 participants were enrolled between July 8, 2013 and August 11, 2017 and were followed for a median of 5 years (range, 0 to 7.6 years). Data was analyzed from February 21, 2022 to March 27, 2023.
Addition of insulin glargine, glimepiride, liraglutide, or sitagliptin to metformin, along with the drug combination, was continued until HbA1c was greater than 7.5%. Insulin was then added to maintain glycemic control.
From the first year of the study to its end – five years later, changes in glomerular filtration rate and a composite outcome of progression of kidney disease (albuminuria, hemodialysis, transplant or death due to kidney disease) were been observed.
Secondary endpoints included incident eGFR less than 60 mL/min/1.73 m2, 40% reduction in eGFR to less than 60 mL/min/1.73 m2, doubling of urinary albumin to creatinine ratio at 30 mg/g or more, with the intent to treat.
Results
Of the 5047 participants, 3210 (63.6%) were men. The average age was 57.2 years.
HbA1c was 7.5% (0.5%).
The duration of diabetes was 4.2 (2.7) years.
Body mass index 34.3 (6.8).
Blood pressure was 128.3/77.3 (14.7/9.9) mm Hg and 2933 patients (58.1%) were treated with renin-angiotensin-aldosterone inhibitors.
eGFR filtration 94.9 (16.8) mL/min/1.73 m2 and median urine albumin to creatinine ratio, 6.4 mg/g.
The mean chronic decline in eGFR glomerular filtration rate was:
- −2.03 (−2.20 to −1.86) mL/min/1.73 m2 per year for patients treated with sitagliptin;
- −1.92 (−2.08 to −1.75) mL/min/1.73 m2 per year for patients receiving glimepiride;
- −2.08 (−2.26 to −1.90) mL/min/1.73 m2 per year for patients receiving liraglutide, and
- −2.02 (−2.19 to −1.84) mL/min/1.73 m2 per year for patients receiving insulin glargine.
The average progression of kidney disease was:
- in 135 (10.6%) patients receiving sitagliptin,
- in 155 (12.4%) patients receiving glimepiride,
- in 152 (12%) patients who received liraglutide and
- in 150 (11.9%) patients who received insulin glargine.
Most of the findings were attributed to the development of albuminuria (98.4%).
