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

• Published in: Diabetes, obesity & metabolism Vol. 19; no. 12; pp. 1669 - 1680
• Main Authors: Tonneijck, Lennart, Muskiet, Marcel H. A., Smits, Mark M., Hoekstra, Trynke, Kramer, Mark H. H., Danser, A. H. Jan, Diamant, Michaela, Joles, Jaap A., van Raalte, Daniël H.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.12.2017; Wiley Subscription Services, Inc
• Subjects: Aged; Biomarkers - blood; Body Mass Index; Diabetes; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - physiopathology; Diabetic Nephropathies - epidemiology; Diabetic Nephropathies - prevention & control; Drug Administration Schedule; Drug Therapy, Combination - adverse effects; Evidence-based medicine; Female; Follow-Up Studies; glomerular filtration rate; Glomerular Filtration Rate - drug effects; glomerular hyperfiltration; glomerular pressure; GLP‐1 receptor agonist; Glucagon-Like Peptide-1 Receptor - agonists; Glucagon-Like Peptide-1 Receptor - metabolism; glucagon‐like peptide‐1; Hemodynamics; Humans; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - therapeutic use; Insulin; Insulin - adverse effects; Insulin - analogs & derivatives; Insulin - therapeutic use; Insulin Glargine - adverse effects; Insulin Glargine - therapeutic use; insulin‐glulisine; Kidney - drug effects; Kidney - physiopathology; lixisenatide; Male; Middle Aged; natriuresis; Netherlands - epidemiology; Overweight - chemically induced; Overweight - complications; Overweight - prevention & control; Peptides - adverse effects; Peptides - therapeutic use; Postprandial Period; renal function; renal haemodynamics; Renal Insufficiency - complications; Renal Insufficiency - epidemiology; Renal Insufficiency - prevention & control; Risk Factors; type 2 diabetes; Vascular Resistance - drug effects; natriuresis; type 2 diabetes; glomerular filtration rate; insulin-glulisine; lixisenatide; glomerular pressure; glucagon-like peptide-1; renal function; GLP-1 receptor agonist; diabetes; glomerular hyperfiltration; renal haemodynamics
• ISSN: 1462-8902; 1463-1326; 1463-1326
• DOI: 10.1111/dom.12985

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 m2, 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 m2 (95% CI −9 to 9)], ERPF [−17 mL/min/1.73 m2 (−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