Glucose-lowering medications and comparative kidney outcomes in type 2 diabetes

Diabetic kidney disease (DKD) is a serious complication of diabetes that can progress to kidney failure. In people with diabetes, achieving and maintaining glycaemic control is central to prevent or delay its development. 

There is evidence that several classes of glucose-lowering medications have kidney benefits in established type 2 diabetes that appear to be independent of glycaemic effects. It is not known, however, whether there are differential benefits from treatment with non-SGLT2 inhibitor glucose-lowering medication classes in people who are at an earlier stage of type 2 diabetes, and are largely free of DKD.

The GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness) trial compared glycaemic and other outcomes in four commonly used medication classes when added to metformin. The trial recruited 5047 adults (63.6% men) across 36 US sites. At baseline, participants had had type 2 diabetes for <10 years, an HbA1c between 6.8% and 8.5% (51 and 69 mmol/mol), an eGFR ≥60 mL/min/1.73 m² and were receiving metformin. They were randomised to start sitagliptin (a DPP-4 inhibitor), glimepiride (a sulfonylurea), liraglutide (a GLP-1 receptor agonist) or insulin glargine (100 U/mL), in addition to metformin. Basal and prandial insulin were added thereafter, if needed. The mean follow-up time was 5.0 years.

The co-primary outcomes were chronic eGFR slope (change in eGFR between year 1 and the trial end) and a composite of kidney disease progression (albuminuria, dialysis, transplant or death due to kidney disease). No significant differences were found between groups in these outcomes.

Nor were there significant differences by treatment assignment in the secondary outcomes. These included confirmed progression to eGFR ≤60 mL/min/1.73 m², a 40% decrease in eGFR, doubling of urine albumin-to-creatinine ratio to ≥30 mg/g and progression of KDIGO category. No adverse kidney events due to treatment assignment were recorded.

These null results suggest that, in people with type 2 diabetes predominantly without kidney complications at baseline, there is no substantial comparative advantage of a DPP-4 inhibitor, sulfonylurea, GLP-1 receptor agonist or insulin glargine, when added to metformin for preventing the development or progression of DKD in the first decade after diagnosis.

The full study can be read here.