Postprandial renal haemodynamic effect of lixisenatide vs once‐daily insulin‐glulisine in patients with type 2 diabetes on insulin‐glargine: An 8‐week, randomised, open‐label trial

Abstract

Aim: To determine whether lixisenatide, a prandial short‐acting glucagon‐like peptide receptor agonist ( GLP‐1RA ), ameliorates postprandial glomerular hyperfiltration in patients with type 2 diabetes mellitus ( T2DM ) compared with insulin‐glulisine ( iGlu ). Methods: Postprandial renal haemodynamic effects of 8‐week treatment with lixisenatide 20 µg vs once‐daily titrated iGlu were measured in 35 overweight patients with T2DM inadequately controlled on insulin‐glargine, with or without metformin [mean ± SD age 62 ± 7 years, HbA1c 8.0% ± 0.9%, estimated glomerular filtration rate ( GFR ) 85 ± 12 mL /min/1.73 m 2 , median ( IQR ) urinary albumin/creatinine ratio 1.5 (0.9‐3.0) mg/mmol]. After a standardised breakfast, GFR (primary endpoint) and effective renal plasma flow ( ERPF ) were determined by inulin and para‐aminohippuric acid renal clearance, respectively, based on timed urine sampling. Intrarenal haemodynamic functions were estimated using Gomez equations. Results: Compared with iGlu , lixisenatide did not affect GFR [+0.1 mL /min/1.73 m 2 (95% CI −9 to 9)], ERPF [−17 mL /min/1.73 m 2 (−61 to 26)], other (intra‐)renal haemodynamics or renal damage markers, but increased fractional sodium excretion [+0.25% (0.09‐0.41)] and urinary pH [+0.7 (0.3‐1.2)]. Plasma renin, angiotensin‐ II and aldosterone were unchanged. Lixisenatide and iGlu reduced HbA1c similarly, by 0.8% ± 0.1% and 0.6% ± 0.1%, respectively, while postprandial glucose was lower with lixisenatide ( P = .002). Compared with iGlu , lixisenatide reduced bodyweight [−1.4 kg (−2.5 to −0.2)] and increased postprandial mean arterial pressure [+9 mm Hg (4‐14)]. Conclusion: Eight‐week lixisenatide treatment does not affect postprandial (intra‐)renal haemodynamics compared with iGlu when added to insulin‐glargine in patients with T2DM without overt nephropathy. Prolonged lixisenatide treatment has a sustained natriuretic effect, which is in contrast to previous reports on long‐acting GLP‐1RA , reduces body weight and increases postprandial blood pressure compared with iGlu . Trial registration : ClinicalTrials.gov identifier NCT02276196