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

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 20μg 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±7years, HbA1c 8.0%±0.9%, estimated glomerular filtration rate (GFR) 85±12mL/min/1.73m2, 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 [+0.1mL/min/1.73m2 (95% CI -9 to 9)], ERPF [-17mL/min/1.73m2 (-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 [-1.4kg (-2.5 to -0.2)] and increased postprandial mean arterial pressure [+9mm 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

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