Effect of the Urotensin Receptor Antagonist Palosuran in Hypertensive Patients With Type 2 Diabetic Nephropathy
The urotensin system has been hypothesized to play an important role in the pathophysiology of diabetic nephropathy. In this multicenter, randomized, double-blind, placebo-controlled, 2-period crossover study, the effects of the urotensin receptor antagonist palosuran on urinary albumin excretion and blood pressure in hypertensive patients with type 2 diabetic nephropathy treated with a single blocker of the renin-angiotensin-aldosterone system were assessed. Patients with 24-hour albuminuria >0.5 and <3.0 g, systolic blood pressure >135 and <170 mm Hg, and/or diastolic blood pressure >85 and <110 mm Hg received both palosuran 125 mg BID and placebo for 4 weeks each. Fifty-four patients (20% women; mean age: 61.6 years, blood pressure: 155/84 mm Hg, and albuminuria: 1016 mg per 24 hours) were included in the per-protocol analysis. Palosuran did not affect albuminuria, blood pressure, glomerular filtration rate, or renal plasma flow significantly. These results question whether urotensin receptor antagonism represents a new treatment strategy in this high-risk patient population.
Urotensin II, initially described as the most potent vasoconstrictor known in mammals,1,2 is upregulated in hypertension and diabetic nephropathy and, therefore, has been hypothesized to be involved in the development of albuminuria.3–5 Palosuran (ACT-058362) is an oral, selective, competitive, nonpeptidic antagonist of the human urotensin receptor and has been extensively studied in experimental models of renal failure. In these models, palosuran displayed renoprotective potential by beneficial effects on renal blood flow, proteinuria, and development of glomerular and tubulointerstitial damage.6,7 Thus far, no controlled data in humans are available. This multicenter, randomized, double-blind, placebo-controlled, 2-period crossover, proof-of-concept study was designed to assess whether palosuran would reduce urinary albumin excretion (UAE) and/or systemic blood pressure in hypertensive patients with type 2 diabetic nephropathy on stable treatment with either an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II–receptor type 1 antagonist.
Patients of both sexes, age >30 to <75 years, with type 2 diabetes mellitus (with or without insulin treatment) and hemoglobin A1c <10%, hypertension (systolic/diastolic blood pressure ≥135 to <170 mm Hg and/or ≥85 to <110 mm Hg), macroalbuminuria (UAE ≥0.5 and <3.0 g/24 hours), and a measured creatinine clearance ≥30 mL/min per 1.73 m2 were recruited. Diabetic nephropathy was defined as the presence of macroalbuminuria. Renal biopsy for confirmation was not required. All of the patients gave their written informed consent. The study was conducted in full adherence to the principles of the Declaration of Helsinki. Patients had to be on stable single renin-angiotensin-aldosterone system (RAAS) blockade for ≥3 months. Any treatment with other antihypertensives, statins, and nonsteroidal anti-inflammatory drugs had to be stable. Patients had stable renal function in the last 6 months. Exclusion criteria included combined angiotensin II–receptor type 1 antagonist and angiotensin-converting enzyme inhibitor therapy, as well as clinically relevant signs of nephrotic syndrome, significant renal artery stenosis, hepatic dysfunction, and serum potassium ≥5.5 mmol/L. Randomization, according to a permuted block method, and drug packaging were performed by an independent person. Treatment was allocated in consecutive order starting with the lowest provided randomization number. After screening, eligible patients entered a 4-week run-in period. Thereafter, patients were randomly treated during 2 treatment periods of 4 weeks each with palosuran (ACT-058362) 125 mg and placebo twice daily, separated by a 6-week washout period. On the basis of plasma concentration-time profiles of palosuran and an expected effective daily dose of 50 mg,8,9 palosuran dosing of 125 mg twice daily was chosen. Finally, patients entered a 4-week follow-up recovery period. At the end of each study period, patients visited the outpatient clinic in the morning after overnight fasting, not taking any medication.
To reduce the intraindividual variability of UAE, UAE was assessed as the mean albuminuria calculated from 3 consecutive 24-hour urine collections measured locally using the same center-specific method throughout the study. Trough semisupine systemic blood pressure was measured every 3 minutes during 15 minutes by an automated oscillometric device, using the mean of the 3 last measurements. Plasma urotensin II was measured by an in-house developed radioimmunoassay by Actelion Pharmaceuticals Ltd using polyclonal antiserum directed against human UII (Phoenix Pharmaceuticals, RAB-071-05).
A single ancillary study was performed in the 22 patients included at the Mario Negri institute in Ranica. Glomerular filtration rate and renal plasma flow were measured by inulin and para-aminohippuric acid clearance methods, respectively,10 and blood pressure was measured by 24-hour ambulatory blood pressure monitoring (A&A Medical, TM-2430).
The main analysis was performed on the per-protocol population. On the basis of previous clinical experience, a 30% (log-transformed [estimated SD]: 0.357 [1.000]) difference in the mean change from baseline in the 24-hour UAE was considered clinically relevant. Fifty patients were needed to demonstrate this hypothesis, using a 2-sided paired t test with a type 1 error of 10% and a power of 80%. Data are summarized as arithmetic means with SD, except for the UAE and UAE/creatinine ratio, which were log-transformed before analysis to take into account the nonnormal distribution of UAE. UAE change from baseline to the end of treatment on the log scale is expressed as loge(end value/baseline value). Its summary statistics are the geometric mean and coefficient of variation. The paired t test was used for the main treatment comparison between palosuran and placebo. The linear mixed model was used to test for period and carryover effects, including the following covariates: sex, blood pressure, creatinine clearance, and hemoglobin A1c.
Sixty-two patients, of 118 screened patients, were included in the study in 11 centers from Italy (n=24), The Netherlands (n=10), Israel (n=12), Australia (n=7), France (n=7), and Switzerland (n=2), of whom 54 could be analyzed. Demographic characteristics at screening, background therapy during the study, and results are summarized in Tables 1 and 2⇓, and the Figure. Mean UAE remained stable during the study. The intrapatient and interpatient variabilities of UAE were high, comparable with previous studies.11 Palosuran did not significantly affect UAE with palosuran over placebo treatment effect ratio (geometric mean of log-transformed data) of 0.99 (95% CI: 0.85 to 1.14) or placebo-corrected systolic or diastolic blood pressure (mean [SD]): −1.9 mm Hg (16.5) and −0.2 mm Hg (9.5), respectively, or heart rate. Plasma urotensin II levels remained stable. The linear mixed model could not identify period, treatment carryover, or baseline effects. In the ancillary study, in 19 and 20, respectively, of 22 patients, no significant 24-hour ambulatory blood pressure monitoring or renal plasma flow and glomerular filtration rate changes were observed. Palosuran was well tolerated, and no adverse event led to study drug discontinuation.
Here we report on the first randomized placebo-controlled study assessing the effect of the urotensin receptor antagonist palosuran in diabetic nephropathy. Four-week treatment with palosuran did not show any effect on UAE or blood pressure in patients on single RAAS blockade. No significant renal hemodynamic effects were observed. Our results do not support the hypothesis that urotensin receptor antagonism would counteract the potential deleterious effects of urotensin II in the pathophysiology of diabetic nephropathy. On the basis of experimental and preclinical data, we hypothesized that, similar to angiotensin II, human urotensin II might contribute to kidney damage by successively triggering elevation of intraglomerular hydraulic pressure, albuminuria, and glomerular and interstitial lesions. The mechanism by which proteinuria develops in diabetic nephropathy seems not solely pressure dependent; in addition to enhanced intraglomerular pressure, injury to endothelial cells, mesangial cells, and podocytes has been demonstrated.12,13 The role of the urotensin system on these factors is not known. One cannot rule out that 4-week palosuran exposure was too short to observe an effect on albuminuria, because potential antifibrotic action of urotensin antagonism might need longer treatment. At the time that the study was conducted, the available preclinical toxicology data did not allow for a longer exposure of patients to palosuran. Furthermore, the facts that all of the patients received RAAS blockade, not allowing study of independent effects of urotensin receptor blockade, and no dose-titration for albuminuria was performed might influence interpretation of the results. Finally, inadequately regulated diabetes mellitus, high body weight, or high sodium intake may have influenced potential responsiveness to palosuran.
This study suggests that inhibition of the urotensin system may not represent a new treatment strategy in hypertensive patients with type 2 diabetic nephropathy. RAAS blockade remains the cornerstone in treatment modalities protecting cardiac and renal function in this high-risk patient population. Despite different attempts to improve the efficacy of RAAS blockade, diabetic patients still progress to end-stage renal disease. This unmet medical need demands an intensified search for new treatment strategies that can be added to RAAS blockade in this high-risk patient population.
Sources of Funding
Actelion Pharmaceuticals Ltd sponsored this study.
H.C.-B., P.D., J.D., and E.N. are full-time employees of Actelion Pharmaceuticals Ltd. S.H., H.K., P.R., A.J.W., R.Z., G.R., and D.d.Z. have acted as a consultant to and have received speaker fees and/or research support from Abbott, Amgen, Astra Zeneca, Biotronik, Bristol Meyers Squibb, Dexon Israel, Eli Lilly, Glaxo Smith Kline, Hemocue, Johnson & Johnson, Medtronic, Merck Sharp & Dohme, Nicox, Novartis, Novo-Nordisk, Noxxon, Roche, Sanofi-Aventis, Schering-Plough, Servier, Siemens, and/or Solvay.
The investigators have interpreted the data and written this publication independent of Actelion.
- Received December 24, 2009.
- Revision received January 11, 2010.
- Accepted February 18, 2010.
Ames RS, Sarau HM, Chambers JK, Willette RN, Aiyar NV, Romanic AM, Louden CS, Foley JJ, Sauermelch CF, Coatney RW, Ao Z, Disa J, Holmes SD, Stadel JM, Martin JD, Liu WS, Glover GI, Wilson S, McNulty DE, Ellis CE, Elshourbagy NA, Shabon U, Trill JJ, Hay DW, Ohlstein EH, Bergsma DJ, Douglas SA. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature. 1999; 40: 282–286.
Totsune K, Takahashi K, Arihara Z, Sone M, Ito S, Murakami O. Increased plasma urotensin II levels in patients with diabetes mellitus. Clin Sci. 2003; 104: 1–5.
Clozel M, Binkert C, Birker-Robaczewska M, Boukhadra C, Ding SS, Fischli W, Hess P, Mathys B, Morrison K, Müller C, Müller C, Nayler O, Qiu C, Rey M, Scherz MW, Velker J, Weller T, Xi JF, Ziltener P. Pharmacology of the urotensin-II receptor antagonist palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt): first demonstration of a pathophysiological role of the urotensin system. J Pharmacol Exp Ther. 2004; 311: 204–212.
Clozel M, Hess P, Qiu C, Ding SS, Rey M. The urotensin-II receptor antagonist palosuran improves pancreatic and renal function in diabetic rats. J Pharmacol Exp Ther. 2006; 316: 1115–1121.
Perico N, Benigni A, Zoja C, Delaini F, Remuzzi G. Functional significance of exaggerated renal thromboxane A2 synthesis induced by cyclosporin A. Am J Physiol. 1986; 251: 581–587.
Zandi-Nejad K, Eddy AA, Glassock RJ, Brenner BM. Why is proteinuria an ominous biomarker of progressive kidney diease? Kidney Int. 2004; 92 (suppl): S76–S89.
Perico N, Benigni A, Remuzzi G. Present and future drug treatments for chronic kidney diseases: evolving targets in renoprotection. Nature Reviews. 2007; 7: 936–953.