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.

Findings

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).

Interpretation

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.

8-week treatment with daglutril plus losartan and other antihypertensive drugs did not significantly affect urinary albumin excretion, nor renal haemodynamic measures or sieving function, but it did decrease ambulatory blood pressure in hypertensive patients with type 2 diabetes mellitus and albuminuria. Treatment was safe and well tolerated in all participants.

Because dietary salt intake and concomitant anti-hypertensive treatment were not systematically changed and 24-h urinary sodium excretion was stable during the study, we can reasonably exclude any confounding effect of intensified hypertension treatment or reduced sodium exposure. Moreover, we detected no substantial carry-over effect and the crossover design avoided confounding related to interpatient data heterogeneity. Thus, the reduction of blood pressure associated with daglutril seems to be a genuine treatment effect.

To the best of our knowledge, this study is the first randomised clinical trial reporting the beneficial effects of daglutril on arterial hypertension in patients with type 2 diabetes mellitus (panel). Hypertension affects most patients with diabetes and almost all of those with some renal involvement;1, 3 systolic hypertension is almost always present. When combined with increased pulse pressure, it is almost always a result of increased vascular stiffness—a major risk factor for cardiovascular morbidity and mortality in this population.19 Systolic hypertension is often resistant to drug treatment,19 especially in patients with diabetes with renal involvement; in our study, systolic blood pressure averaged 140 mm Hg, despite background treatment with losartan, plus two or more antihypertensive drugs, and also a diuretic in most cases. This blood pressure exceeds the 130 mm Hg target that was recommended when the study was designed, but accords with the most recent guidelines,20 which recommend less stringent control of blood pressure in patients with diabetes.

Thus, daglutril effectively improved both office and ambulatory systolic hypertension with much smaller effects on diastolic blood pressure. Reduction in systolic blood pressure is normally associated with a concomitant reduction in diastolic blood pressure, which can result in decreased left ventricular perfusion and a heightened risk of cardiovascular events—the so called J curve.21 Therefore, availability of a drug that can reduce systolic and pulse pressure with marginal effects on diastolic blood pressure might have major clinical implications. Indeed, a 10 mm Hg reduction in systolic blood pressure has been associated with a 22% reduction in coronary heart disease and 41% reduction in stroke.22 Whether the effect of daglutril observed in our study is a result of improved vascular stiffness should be investigated. The treatment effect of daglutril on ambulatory blood pressure was larger during night-time, and was achieved on top of full-dose losartan plus two or more additional hypotensive drugs in most patients. This might also have clinical implications, because night-time hypertension is a strong cardiovascular risk factor independent of trough, 24-h, or daytime blood pressure control, especially in patients with diabetes who have renal disease.23

We recorded a significant increase in office blood pressure, and a non-significant increase in other blood pressures, during placebo treatment, which might be a result of progression of renal disease with a consequent worsening of hypertension. Daglutril maintained all measures of office blood pressure and decreased ambulatory systolic and pulse blood pressure, an effect that translated into net differences compared with placebo that were larger for ambulatory than for office blood pressure.

The increase in serum concentrations of big EDN1 suggests that the treatment effect was mainly sustained by inhibition of endothelin-converting enzyme. In the vasculature, EDNRA and EDNRB are expressed on vascular smooth-muscle cells and mediate the vasoconstrictory effects of EDN1. ENDRB is also located on vascular endothelial cells, where its activation promotes vasodilation through release of nitric oxide and prostacyclin.10 In patients with mild-to-moderate hypertension without antihypertensive treatment, the mixed endothelin receptor antagonist bosentan has been reported to significantly reduce office and 24-h systolic and diastolic blood pressure compared with placebo, and to a similar extent as the angiotensin-converting enzyme inhibitor, enalapril.24 Furthermore, the selective EDNRA antagonist darusentan—when added to at least three other antihypertensive drugs—significantly reduced office and 24-h systolic and diastolic blood pressure in patients with treatment-resistant hypertension, and to a larger extent than had been shown for bosentan.25 Finally, avosentan—an EDNRA antagonist that is less selective than darusentan—improved albuminuria when given with angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers in patients with overt diabetic nephropathy, but had no antihypertensive effect.26 Theoretically, avoiding inhibition of EDNRB would be preferable, because it also mediates the clearance of circulating EDN1 in people, and in animal studies it has a role in regulation of natriuresis and diuresis. Thus, endothelin-converting enzyme inhibitors are promising new drugs—they will antagonise endothelin without affecting EDNRB-mediated clearance of EDN1.10

Blood pressure reduction during daglutril treatment was not associated with any significant change in 24-h albuminuria, renal haemodynamics, or albumin and IgG fractional clearances compared with placebo. One explanation could be that patients had increased bioavailability of pro-atrial natriuretic peptide secondary to inhibition of neutral endopeptidase, which could have increased glomerular permeability to plasma macromolecules.27 The consequent increase in albumin ultrafiltration might have offset the reduction in albuminuria expected from decreased kidney perfusion pressure and postglomerular vasodilatation from antagonism of endothelin.28, 29 Natriuretic peptides might also induce preglomerular vasodilatation that maintains glomerular perfusion and filtration despite reduced blood pressure.30 This hypothesis might explain why glomerular filtration rate and renal plasma flow were not reduced by daglutril treatment.

Our safety data compare favourably to the side-effects reported during treatment with endothelin receptor antagonists.24,25 Darusentan has been associated with a doubled incidence of fluid overload or oedema compared with placebo. Another study28 examining the effects of avosentan on progression of overt diabetic nephropathy had to be stopped prematurely because of an excess of fluid overload and congestive heart failure in the avosentan group. Kohan and colleagues29 reported that oedema occurred in up to 46% of patients receiving increasing doses of the highly selective EDNRA antagonist atrasentan. Notably, no angio-oedema occurred during our study, a finding of clinical relevance, because combined inhibition of angiotensin-converting enzyme and neutral endopeptidase has previously been associated with increased incidence of angio-oedema caused by decreased breakdown of bradykinin, leading to increased nitric oxide concentrations.31 Additional inhibition of endothelin-converting enzyme—as provided by daglutril—might alleviate this effect by reducing activation of EDNRB, thus decreasing production of nitric oxide.13

Further studies should be done to address whether higher doses of daglutril than were used in this study are needed to detect the antiproteinuric effects previously reported in animal studies and whether daglutril’s blood-pressure lowering effects apply to patients with non-diabetic nephropathies.14 The predominance of men in our study could be a result of the excess of men in the average population of patients with type 2 diabetes mellitus who have nephropathy and perhaps environmental factors that result in more men than women consenting to take part in the study. However, the large number of men does not affect the internal validity of the study and should not affect the generalisability of the findings to both sexes; no evidence exists of sex-specific effects of endothelin on hypertension, and previous studies25 of endothelin receptor antagonists showed the same antihypertensive effects in both men and women. Our results from autoregressive modelling18 provide additional evidence that daglutril has an antihypertensive effect—particularly on systolic blood pressure—throughout the whole 24-h observation period, independent of rhythmical (circadian) and non-rhythmical changes in blood pressure. Our sensitivity analyses confirmed the robustness of these results. The study design, measurement of 24-h blood pressure, and the gold-standard procedures used to measure albuminuria and renal haemodynamic and sieving function parameters are major strengths. Results of our per-protocol analyses of efficacy variables were similar to those of the modified intention-to-treat analyses, which confirmed the robustness of our findings. Long-term clinical trials are needed to test whether the blood-pressure lowering effect of daglutril provides consistent nephroprotection and cardioprotection in this high-risk population.

Soure: Lancet