medwireNews: Renal outcomes are comparable in patients with type 2 diabetes undergoing metformin therapy regardless of the type of add-on antidiabetic agent used, suggest the results of the GRADE trial.
At 5 years’ follow-up, the mean annual change in the chronic estimated glomerular filtration rate (eGFR) slope from a starting point of 1 year of treatment was −2.03 mL/min per 1.73m2 for the dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin, –1.92 mL/min per 1.73m2 for the sulfonylurea glimepiride, −2.08 mL/min per 1.73m2 for the glucagon-like peptide (GLP)-1 receptor agonist liraglutide, and −2.02 mL/min per 1.73m2 for insulin glargine.
There were also no differences between the adjunctive medication types in terms of the development of a composite endpoint that included albuminuria, the need for dialysis, kidney transplant, or death because of diabetic kidney disease (DKD). This was recorded in 10.6% of patients treated with sitagliptin, 12.4% treated with glimepiride, 12.0% with liraglutide, and 11.9% with insulin glargine. In most cases, this endpoint was due to albuminuria.
“We evaluated many participants and a range of complementary early sensitive kidney outcomes, but we did not observe any significant differences by treatment assignment in intention-to-treat analyses,” report Deborah Wexler (Harvard Medical School, Boston, Massachusetts, USA) and co-authors in JAMA Internal Medicine.
GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness) was a parallel-group, randomized clinical trial conducted at 36 sites in the USA. A total of 5047 participants (64% men) aged a mean 57.2 years at recruitment were included; all had type 2 diabetes for less than 10 years, were being treated with metformin, and had a glycated hemoglobin of between 6.8% and 8.5% (50.8 and 69.4 mmol/mol).
Patients with a history of cardiovascular disease and existing renal disease were excluded, and the latter might explain why some of the trial’s findings appear at odds with those of others, such as the LEADER and REWIND trials, Wexler and co-authors suggest. It could be that drugs such as the GLP-1 agonists, for example, are “more effective at slowing the progression of established DKD than at preventing the development of DKD.”
The lack of data for sodium-glucose transport protein 2 (SGLT-2) inhibitors as an add-on to metformin is a limitation, says the team. This is because these drugs were not approved for clinical use at the time the GRADE trial was being designed and rolled out. A few participants used SGLT-2 inhibitors and while there was no effect on kidney function, the researchers caution that there was a lack of statistical power to properly evaluate this.
“These results suggest that neither DPP-4 inhibitor, GLP-1 receptor agonist, sulfonylurea, nor basal insulin has a substantial comparative advantage when added to metformin for preventing the development or progression of DKD in [type 2 diabetes] in the first decade after diagnosis,” Wexler et al conclude.
Other effects of these drugs, such as on total cardiovascular events and weight loss, however, “may influence the selection of one medication over another,” they add.
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