The effects of dipeptidyl peptidase-4(DPP-4) inhibitorson the progression of diabetic nephropathy

Abstract

I studied the effects of the DPP-4 inhibitor Linagliptin on hypoglycaemic incidence, overall glycaemic control and glycaemic variability, when compared to the sulfonylurea Gliclazide (in the randomised controlled GLOOCOSE study), and when compared to other anti-diabetic treatment regimens that do not include DPP-4 inhibitors (in the observational LINDA-CKD study). I also studied the effects of Linagliptin on the levels of inflammatory and fibrotic biomarkers associated with the progression of diabetic nephropathy. These studies were undertaken using CGM in participants with type 2 diabetes and moderate to severe CKD, or on haemodialysis. Linagliptin did not make any significant difference to hypoglycaemic incidence or glycaemic variability. In the GLOOCOSE study, randomisation to Linagliptin was significantly associated with worsening glycaemic control (higher fasting CBGs; p=0.001, higher mean CGM glucose; p=0.023, higher estimated CGM HbA1c; p=0.016) and significantly increased urine MCP- 1/creatinine ratio (p=0.002). Participants on Linagliptin in the LINDA-CKD study did not have significantly different serum or urinary MCP-1 or TGF-β1 levels compared to those not on Linagliptin. Therefore, there was insufficient evidence that Linagliptin modifies the progression of diabetic nephropathy separately from its glucose lowering actions. LINDA-CKD CKD participants had significantly more hypoglycaemic episodes than haemodialysis participants (p=0.025), however, this was in the context of haemodialysis participants spending significantly less time in normoglycaemia (47.0% vs. 65.5%; p<0.001) and more time in hyperglycaemic ranges (51.8% vs. 32.3%; p<0.001 for time above 10.0 mmol/L, 22.0% vs. 9.4%; p=0.001 for time above 13.9 mmol/L). Serum HbA1c in haemodialysis participants did not reflect their poorer glycaemic control (59 mmol/mol vs. 58 mmol/mol; p=0.649), but estimated CGM HbA1c (69 mmol/mol vs. 56 mmol/mol; p<0.001) and mean CGM glucose did (10.8 mmol/L vs. 9.0 mmol/L; p<0.001). The LINDA-CKD study results support the use of CGM in the haemodialysis population to accurately capture dynamic glucose changes and evaluate diabetes control.