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Endothelin-converting enzyme and neutral endopeptidase inhibitor: effect on blood pressure of Daglutril in patients with type 2 diabetes who have albuminuria


Effective reduction of albuminuria and blood pressure in patients with type 2 diabetes mellitus who have nephropathy is seldom achieved with available treatments.
Researchers tested the effects of treatment of such patients with Daglutril, a combined endothelin-converting enzyme and neutral endopeptidase inhibitor.

Randomised, crossover trial was performed in two hospitals in Italy. Eligibility criteria were: age 18 years or older, urinary albumin excretion 20-999 mcg/min, systolic blood pressure less than 140 mmHg, and diastolic blood pressure less than 90 mmHg.
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 ) blood pressure, renal haemodynamics and sieving function, and metabolic and laboratory test results.

Researchears screened 58 patients, of whom 45 were enrolled ( 22 assigned to Daglutril then placebo, 23 to placebo then Daglutril; enrolment during the period 2005-2006 ) 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 mcg/min; p=0.559 ).

A total of 34 patients had complete 24-h blood pressure readings; compared with placebo, Daglutril significantly reduced 24-h systolic ( difference -5.2 mmHg; p=0.0013 ), diastolic ( -2.5; p=0.015 ), pulse ( -3.0; p=0.019 ), and mean (-3.1; p=0.003 ) blood pressure, as well as all night-time blood pressure readings and daytime systolic, pulse, and mean blood pressure, but not diastolic blood pressure.

Compared with placebo, Daglutril also significantly reduced office systolic blood pressure (-5.4; p=0.028 ), but not diastolic (-1.8; p=0.245 ), pulse (-3.1; p=0.210 ), or mean (-2.1; p=0.205 ) blood pressure, 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 ).

In conclusion, Daglutril improves control of blood pressure 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. ( Xagena )

Parvanova A et al, The Lancet Diabetes & Endocrinology 2013; 1: 19-27

XagenaMedicine_2013



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