title: Effect on blood pressure of combined inhibition of endothelin-converting enzyme and neutral endopeptidase with daglutril in patients with type 2 diabetes who have albuminuria: a randomised, crossover, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  Effective reduction of albuminuria and blood pressure in patients with type 2 diabetes who have nephropathy is seldom achieved with available treatments. We tested the effects of treatment of such patients with daglutril, a combined endothelin-converting enzyme and neutral endopeptidase inhibitor.
  
  
  METHODS
  We did this randomised, crossover trial in two hospitals in Italy. Eligibility criteria were: age 18 years or older, urinary albumin excretion 20-999 μg/min, systolic blood pressure (BP) less than 140 mm Hg, and diastolic BP less than 90 mm Hg. Patients were randomly assigned (1:1) with a computer-generated randomised sequence to receive either daglutril (300 mg/day) then placebo for 8 weeks each or vice versa, with a 4-week washout period. Patients also took losartan throughout. Participants and investigators were masked to treatment allocation. The primary endpoint was 24-h urinary albumin excretion in the intention-to-treat population. Secondary endpoints were median office and ambulatory (24 h, daytime, and night-time) BP, renal haemodynamics and sieving function, and metabolic and laboratory test results. This study is registered with ClinicalTrials.gov, number NCT00160225.
  
  
  RESULTS
  We screened 58 patients, of whom 45 were enrolled (22 assigned to daglutril then placebo, 23 to placebo then daglutril; enrolment from May, 2005, to December, 2006) and 42 (20 vs 22) were included in the primary analysis. Daglutril did not significantly affect 24-h urinary albumin excretion compared with placebo (difference in change -7·6 μg/min, IQR -78·7 to 19·0; p=0·559). 34 patients had complete 24-h BP readings; compared with placebo, daglutril significantly reduced 24-h systolic (difference -5·2 mm Hg, SD 9·4; p=0·0013), diastolic (-2·5, 6·2; p=0·015), pulse (-3·0, 6·3; p=0·019), and mean (-3·1, 6·2; p=0·003) BP, as well as all night-time BP readings and daytime systolic, pulse, and mean BP, but not diastolic BP. Compared with placebo, daglutril also significantly reduced office systolic BP (-5·4, 15·4; p=0·028), but not diastolic (-1·8, 9·9; p=0·245), pulse (-3·1, 10·6; p=0·210), or mean (-2·1, 10·4; p=0·205) BP, and increased big endothelin serum concentration. Other secondary outcomes did not differ significantly between treatment periods. Three patients taking placebo and six patients taking daglutril had mild treatment-related adverse events--the most common was facial or peripheral oedema (in four patients taking daglutril).
  
  
  CONCLUSIONS
  Daglutril improved control of BP in hypertensive patients with type 2 diabetes and nephropathy and had an acceptable safety profile. Combined endothelin-converting enzyme and neutral endopeptidase inhibition could provide a new approach to hypertension in this high-risk population.
  
  
  BACKGROUND
  Solvay Pharmaceuticals.
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro di Ricerche Cliniche per le Malattie Rare Aldo e Cele Daccò, Bergamo, Italy.
authors.forename: Aneliya
authors.initials: A
authors.lastname: Parvanova
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro di Ricerche Cliniche per le Malattie Rare Aldo e Cele Daccò, Bergamo, Italy; Department of Internal Medicine, Division of Nephrology, HAGA Hospital, Den Haag, Netherlands.
authors.forename: Irene M
authors.initials: IM
authors.lastname: van der Meer
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro di Ricerche Cliniche per le Malattie Rare Aldo e Cele Daccò, Bergamo, Italy.
authors.forename: Ilian
authors.initials: I
authors.lastname: Iliev
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro di Ricerche Cliniche per le Malattie Rare Aldo e Cele Daccò, Bergamo, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Perna
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro di Ricerche Cliniche per le Malattie Rare Aldo e Cele Daccò, Bergamo, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Gaspari
authors.affiliation: Unit of Diabetology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Trevisan
authors.affiliation: Unit of Diabetology of Treviglio Hospital, Bergamo, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Bossi
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro di Ricerche Cliniche per le Malattie Rare Aldo e Cele Daccò, Bergamo, Italy; Unit of Nephrology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy. Electronic address: giuseppe.remuzzi@marionegri.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro di Ricerche Cliniche per le Malattie Rare Aldo e Cele Daccò, Bergamo, Italy.
authors.forename: Ariela
authors.initials: A
authors.lastname: Benigni
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro di Ricerche Cliniche per le Malattie Rare Aldo e Cele Daccò, Bergamo, Italy; Unit of Nephrology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Ruggenenti
mesh_terms: D000368:Aged; D000419:Albuminuria / Q000188:drug therapy* / Q000201:enzymology / Q000453:epidemiology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology / Q000453:epidemiology; D004311:Double-Blind Method; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008875:Middle Aged; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011446:Prospective Studies; D016896:Treatment Outcome
chemical_list: D001552:Benzazepines; D004791:Enzyme Inhibitors; C405520:SLV 306; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes