Effects of glucagon-like peptide-1 receptor agonists on renal function

Table 1 Studies of the effects of exenatide on renal function

Ref.	Study details	Main findings
Li et al[57]	Administration of exendin-4 in human mesangial cells.	Exendin-4 decreased mRNA and protein levels of TGF-β1 and connective tissue growth factor. These effects were mainly dependent on the activation of adenylate cyclase[57].
Carraro-Lacroix et al[70]	Investigation of the role of exendin-4 in modulating the activity of Na+/H+ exchanger NHE3 in LLC-PK(1) cells.	GLP-1 receptor agonists modulate sodium homeostasis most likely by affecting NHE3 activity.
Liu et al[60]	In vitro administration of exendin-4 in spontaneously hypertensive rat renal arteries and aortic endothelial cells. Additionally, exendin-4 administration in renal arteries from hypertensive patients.	In vitro exendin-4 improved endothelium-dependent relaxation and restored renal blood flow in spontaneously hypertensive rat renal arteries and increased nitric oxide production in spontaneously hypertensive rat aortic endothelial cells[60]. Ex vivo exendin-4 administration improved endothelial function of renal arteries from hypertensive patients.
Park et al[58]	Administration of exendin-4 for 8 wk in a mouse model of diabetes (male db/db mice).	Exendin-4 improved intraperitoneal glucose tolerance test and decreased urinary albumin excretion in a dose-dependent manner. It also reduced glomerular hypertrophy, mesangial matrix expansion, TGF-β1 expression and type IV collagen accumulation, whereas it increased the renal immunoreactivity of peroxisome proliferator-activated receptor α and GLP-1 receptor-positive cells in the glomeruli of db/db mice.
Kodera et al[59]	Administration of exendin-4 in a streptozotocin-induced rat model of type 1 diabetes.	Exendin-4 improved albuminuria, glomerular hyperfiltration, glomerular hypertrophy and mesangial matrix expansion, reduced macrophage infiltration and protein levels of intercellular adhesion molecule-1 and type IV collagen and decreased oxidative stress and nuclear factor- κB activation in kidney tissue of the diabetic rats.
Mima et al[61]	Mice overexpressing protein kinase Cβ2 (results in a reduction of GLP-1 receptor expression) in endothelial cells (EC-PKCβ2Tg).	In vivo treatment with exendin-4 was partially effective to reduce glomerular pathology of both diabetic wild type and EC-PKCβ2Tg mice.
Hirata et al[62]	Exendin-4 for 12 wk in db/db mice (they have increased intra-renal angiotensin II concentration) and in angiotensin II-infused non-diabetic mice.	Exendin-4 inhibited the development of hypertension in db/db mice. Exendin-4 attenuated the delay of the urinary sodium excretion and elevation of blood pressure induced by a high-salt load. Exendin-4 prevented hypertension in angiotensin II-infused non-diabetic mice.
Liu et al[64]	A peptide analogue with exenatide (AC3174) was given for 4 wk via subcutaneous infusion in Dahl salt-sensitive rats.	The combination of AC3174 with captopril produced the most effective improvement in renal morphology (reduction of extensive sclerosis) in high salt diet rats compared with monotherapy. The combination of AC3174 with captopril also reduced the deleterious effects of high salt on posterior wall thickness and left ventricular mass.
Vaghasiya et al[66]	Exenatide treatment (14 d) in T2DM rats with induced renal ischemia for 30 min followed by reperfusion for 24 h.	Exenatide treatment normalized serum creatinine phosphokinase activity, liver function enzymes and antioxidant enzymes such as glutathione, superoxide dismutase, catalase and glutathione peroxidase (all P < 0.01).
Rieg et al[72]	Parenteral exendin-4 in wild-type mice and in mice lacking GLP-1 receptor. Additionally, administration of exendin-4 in diabetic db/db mice.	Parenteral exendin-4 in wild-type mice induced diuresis and natriuresis. These effects were associated with renal membrane expression of the Na+/H+ NHE3, a site for cAMP-dependent protein kinase A. These effects were abolished in mice lacking the GLP-1 receptor. The administration of exendin-4 in diabetic db/db mice resulted in a reduction of renal fluid and Na+ reabsorption.
Thomson et al[73]	Exenatide infusion in hydropenic male Wistar and Wistar-Froemter rats.	Exenatide infusion increased single-nephron glomerular filtration rate, early distal flow rate and urine flow rate and reduced proximal tubular reabsorption. These effects were observed without altering the efficiency of glomerulotubular balance, tubuloglomerular feedback responsiveness or the tonic influence of tubuloglomerular feedback.
Marina et al[78]	Exenatide administration in Wistar rats with normal serum concentration of glucose and potassium and in Wistar rats with hyperkalemia produced by intraperitoneal injection of 1.25% KCl solution.	Exenatide increased renal excretion of potassium in Wistar rats with normal serum concentration of glucose and potassium. Exenatide enhanced excretion of potassium in Wistar rats with hyperkalemia.
Simonsen et al[34]	Exendin-4 administration in anesthetised pigs (n = 9).	Exenatide is solely cleared by glomerular filtration.
Linnebjerg et al[35]	Exenatide administration in 31 subjects (one with T2DM).	No dosage adjustment of exenatide is required for patients with mild to moderate renal impairment. In contrast, even the recommended starting dosage of 5 μg may not be suitable for patients with ESRD or severe renal impairment (creatinine clearance < 30 mL/min).
Linnebjerg et al[36]	Placebo-controlled, crossover study of elderly patients (≥ 75 yr, n = 15) or controls (≥ 45 to ≤ 65 yr, n = 15) with T2DM who received single subcutaneous doses of exenatide before a standardized breakfast.	Exenatide dose adjustments should be based on renal function rather than age in elderly T2DM patients.
Zhang et al[65]	31 patients with T2DM and microalbuminuria randomly received exenatide (n = 13) or glimepiride (n = 18) for 16 wk.	Similar reductions of fasting plasma glucose and HbA1c were observed between the two groups. Exenatide reduced body mass index (-5.95%), urinary type IV collagen and 24-h urinary albumin and urinary TGF-β1 (all P < 0.01).
Mendis et al[74]	Double-blind, randomized, crossover study of a single 10 μg subcutaneous injection of exenatide in healthy male volunteers (n = 8).	Exenatide significantly increased after 2 h the urinary sodium/creatinine ratio compared with placebo (P < 0.05). Exenatide administration was also associated with a significant increase of heart rate (+ 8.2 beats/min) and cardiac output, whereas a reduction in total peripheral resistance was observed (all P < 0.05). No change in blood pressure levels was observed.
US FDA[32]	Case reports of exenatide-induced acute kidney injury.	78 cases of altered kidney function (62 cases of acute renal failure and 16 cases of renal insufficiency) were reported with exenatide between April 2005 and October 2008.
Macconell et al[49]	Pooled analysis of 19 randomized, controlled trials of exenatide twice daily (5 μg and 10 μg) with 5594 intent-to-treat patients followed for 12-52 wk.	The incidence of renal impairment-related adverse events, including acute renal failure, was low (1.6 per 100 person-year for both groups) with no significant difference between groups (95%CI: -0.98-0.96). The most frequent adverse event with exenatide was transient, mild-to-moderate nausea (36.9% vs 8.3% in the pooled comparator).
Pendergrass et al[50]	Retrospective cohort of a large medical and pharmacy claims database including 491539 patients.	The adjusted risk for acute kidney injury among the patients with T2DM was not different between patients who received exenatide compared with patients who received other agents (hazard ratio = 0.77, 95%CI: 0.42-1.41, P = 0.40). Kaplan–Meier curves of time to acute kidney injury showed no significant differences between exenatide and other drugs.

TGF-β1: Transforming growth factor beta 1; GLP-1: Glucagon-like peptide 1; T2DM: Type 2 diabetes mellitus; ESRD: End-stage renal disease; FDA: Food and Drug Administration; NHE3: Exchanger isoform 3.

Table 2 Studies of the effects of liraglutide on renal function

Author	Study details	Main findings
Kim et al[89]	Liraglutide administration in Glp1r(-/-), Nppa(-/-) or wild type mice.	Liraglutide leaded to relaxation of aortic rings through a GLP-1 receptor-dependent but endothelium-independent manner. Liraglutide did not induce ANP secretion and did not result in vasorelaxation or blood pressure reduction in Glp1r(-/-) or Nppa(-/-) mice. Refeeding was associated with an increase in ANP levels in wild-type mice, whereas this effect was not observed in Glp1r(-/-) mice. Liraglutide administration led to increase of urine sodium excretion in wild-type, whereas this effect was abolished in Nppa(-/-) mice. These findings suggest a gut-heart axis, which is both GLP-1 receptor-dependent and ANP-dependent and regulates blood pressure.
Hendarto et al[90]	Liraglutide administration in streptozotocin-induced type 1 diabetes rats. Additionally, incubation of cultured renal mesangial cells with liraglutide for 48 h.	Liraglutide administration in streptozotocin-induced diabetic rats normalized the increased urinary albumin excretion and oxidative stress markers, as well as the expression of NADPH oxidase components, TGF-β1 and fibronectin in renal tissues. The incubation of cultured renal mesangial cells with liraglutide inhibited NADPH-dependent superoxide production in a dose-dependent manner, an effect that was abolished by a protein kinase A inhibitor and an adenylate cyclase inhibitor.
Malm-Erjefalt et al[82]	Administration of radio-labelled liraglutide in seven healthy males.	Liraglutide is metabolized by DPP-IV similarly with the native GLP-1, but at a much slower rate. No intact liraglutide was excreted in urine and feces.
Jacobsen et al[83]	A single dose of liraglutide 0.75 mg was given subcutaneously in 30 subjects (24 with varying degrees of renal impairment and 6 with normal renal function).	No significant effect of reduced creatinine clearance on the pharmacokinetics of liraglutide was observed. No association was found between the degree of renal impairment and the risk of adverse events.
Davidson et al[84]	A meta-analysis of the 6 LEAD (Liraglutide Effect and Action in Diabetes) studies which analysed data from patients with T2DM administered once-daily liraglutide (1.2 or 1.8 mg) or placebo as either monotherapy or in combination with oral antidiabetic drugs for 26 wk.	Mild renal impairment (determined by the Cockcroft-Gault equation) had no significant effect on the efficacy and safety of liraglutide. No significant differences in the rates of nausea, renal injury or minor hypoglycemia were observed between liraglutide and placebo in patients with mild renal impairment. No significant effect of mild renal impairment on HbA1c reduction was observed. However, a trend towards increased nausea was observed with liraglutide in the small number of patients with moderate or severe renal impairment.

GLP-1: Glucagon-like peptide 1; ANP: Atrial natriuretic peptide; TGF-β1: Transforming growth factor beta 1; DPP-IV: Dipeptidyl peptidase IV; T2DM: Type 2 diabetes mellitus; HbA1c: Glycated haemoglobin.