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Entresto, a first-in-class angiotensin receptor neprilysin inhibitor: safety and efficacy in patients with hypertension and renal dysfunction


A 8-week, multicenter, open-label study has assessed the safety and efficacy of LCZ696 ( Entresto ), a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction.

Patients ( n=32 ) with mean sitting systolic blood pressure ( msSBP ) greater than or equal to 140 mm Hg ( after a 2-5-week washout of previous antihypertensive medications ) and estimated glomerular filtration rate ( eGFR ) greater than or equal to 15 and less than 60  ml min(-1) 1.73 m(-2) received LCZ696 100 mg with an optional titration to 200 and 400 mg in a sequential manner starting from Week 2 in patients with inadequate BP control ( msSBP greater than or equal to 130 mm Hg and mean sitting diastolic blood pressure ( msDBP ) greater than or equal to 80 mm Hg ) and without safety concerns.

Safety was assessed by monitoring and recording all adverse events and change in potassium and creatinine. Efficacy was assessed as change from baseline in msSBP/msDBP.

The mean baseline blood pressure was 151.6/86.9  mm Hg, urinary albumin/creatinine ratio ( UACR ) geometric mean was 7.3 mg mmol(-1) and eGFR was greater than or equal to 30 and less than 60 in 25 ( 78.1% ) patients and was greater than or equal to 15 and less than 30 in 7 ( 21.9% ) patients.

Fourteen ( 43.8% ) patients reported at least one adverse effect, which were mild in severity. No severe adverse reactions or deaths were reported.

There were no clinically meaningful changes in creatinine, potassium, blood urea nitrogen and eGFR. The geometric mean reduction in UACR was 15.1%, and the mean reduction in msSBP and msDBP was 20.5±11.3 and 8.3±6.3 mm Hg, respectively, from baseline to Week 8 end point.

The results suggest that LCZ696 may be a promising therapeutic approach in patients with hypertension and renal dysfunction and may offer beneficial renal effects in addition to blood pressure lowering.
In addition to the cardiovascular and renal benefits of AT1 receptor blockade, LCZ696 provides NEP inhibition, which enhances the actions of natriuretic peptides. These peptides promote natriuresis and diuresis and inhibit the sympathetic nervous system and aldosterone secretion.
Natriuretic peptides also may provide renal protection in patients with renal dysfunction by reducing intraglomerular pressure and through antiproliferative and antihypertrophic effects.

Potential limitations of this study include its open-label design, small sample size and relatively short duration.

However, this 8-week study has demonstrated that LCZ696, a first-in-class angiotensin receptor NEP inhibitor, is generally safe and efficacious in Japanese patients with hypertension and renal dysfunction while maintaining renal function. ( Xagena )

Ito S et al, Hypertens Res 2015;38:269-275

XagenaMedicine_2015



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