LCZ696 is used to treat chronic heart failure in adults to help reduce the risk of death and hospitalization. This medicine is also used to treat children with symptomatic heart failure. Valsartan is an angiotensin II receptor blocker (ARB). It works by blocking a substance in the body that causes blood vessels to tighten. As a result, valsartan relaxes the blood vessels. This lowers blood pressure and increases the supply of blood and oxygen to the heart. Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking LCZ696, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. LCZ696 may cause serious side effects. Call your doctor at once if you have: feeling like you might pass out; high blood potassium--nausea, weakness, tingly feeling, chest pain, irregular heartbeats, loss of movement; or kidney problems--swelling, urinating less, feeling tired or short of breath. Common side effects of LCZ696 may include: kidney problems; high potassium levels in your blood; dizziness, feeling like you might pass out; or cough.

LCZ696, a promising novel agent in treating hypertension

Hypertension is one of the most common cardiovascular diseases. Although it can be treated with a variety of drugs, there is ongoing and intensive research to develop drugs that reduce blood pressure (BP) more effectively. One of these is LCZ696, which is a novel angiotensin receptor-neprilysin inhibitor (ARNI).Many clinical trials have been carried out to test the effectiveness of LCZ696 for the treatment of hypertension, but only a few have been large-scale clinical trials. To determine the effectiveness and safety of LCZ696 for the clinical treatment of hypertension, we performed a meta-analysis of the previous clinical trials. Unfortunately, omapatrilat has a number of side effects, including an elevated risk of angioedema, which have restricted its application. Consequently, at present, a number of other drugs that can inhibit both neprilysin and the RAAS are under development or are being tested. In addition, unlike omapatrilat, an angiotensin converting enzyme-neprilysin inhibitor, the administration of LCZ696 would not increase the risk of angioedema. So, we think LCZ696 as a promissing novel agent in treating hypertension.[1]

In the study by Zhao et al., two drugs, including valsartan and olmesartan were used in ARB group, and the dose of olmesartan varied at 80mg, 160mg and 320mg in NCT00549770. The category and dose of drugs is likely to affect the effectiveness of reducing blood pressure. In this meta-analysis, olmesartan was only administered at a dose of 20mg, which can more objectively reflect the effectiveness of LCZ696 and olmesartan in reducing blood pressure. In this meta-analysis, the effectiveness and safety of it and placebo in reducing blood pressure were compared, which contributes to the evaluation of the effectiveness and safety of it in directly reducing blood pressure. A study of the effectiveness of LCZ696 in treating hypertension showed that LCZ696 combined with amlodipine outperformed amlodipine alone in terms of reducing BP. Moreover, there was no significant difference between the two therapy strategies in terms of adverse events. However, this study did not assess whether it combined with amlodipine outperforms LCZ696 alone in terms of reducing BP. Future studies on this issue are still wanted, especially since it has been shown that combining LCZ696 with HCTZ, amlodipine, or carvedilol is safe.

LCZ696, an angiotensin receptor-neprilysin inhibitor

Diabetic cardiomyopathy (DCM) is one of the most frequent and typical clinical features of diabetic cardiovascular complications and contributes to the impairment of both the function and the structure of the heart, increasing morbidity and mortality risks in diabetic patients. Evidence has demonstrated that the excessive cardiac inflammation, reactive oxygen species (ROS) generation, apoptosis, calcium ion regulation abnormalities, fatty acid metabolism abnormalities, and fibrotic reactions may play pivotal roles during the heart remodeling observed in DCM. LCZ696, an angiotensin receptor-neprilysin inhibitor (ARNi), has been tested in clinical trials. LCZ696 is a combination of valsartan and AHU377, at a ratio of 1:1, which is synthesized through a complex chemical reaction, and it inhibits the excessive activation of the renin-angiotensin-aldosterone system (RAAS) while simultaneously increasing the cardiovascular protection provided by the natriuretic peptide system. Neprilysin inhibitors (NEPi) have been used as an adjunctive approach to the inhibition of the renin-angiotensin system (RAS), although the independent use of NEPis has failed in the market because their effectiveness has been determined to be unacceptably low.[2]

However, its therapeutic mechanism during DCM remains to be studied. Therefore, this study investigated the underlying mechanisms through which LCZ696 exerts anti-inflammatory, antioxidant, and antiapoptotic effects in an experimental model of DCM. In the present study, we used STZ-induced diabetic mice and high glucose (HG)-treated H9C2 cardiomyocytes to examine the effects of LCZ696 on cardiac inflammation, oxidative stress, and apoptosis and their associated signaling pathways. The results demonstrate that LCZ696 could potentially be used to treat DCM. Whether LCZ696 has direct effects on the TAK1/MKK4-JNK/p38MAPK or IKK/IκBα-NF-κB pathways or whether it effects downstream molecules, such as MCP-1, remains to be studied. Although our study showed that LCZ696 improved DCM through its anti-inflammatory, anti-oxygenation, and anti-apoptotic effects, the effects of the enhanced natriuretic peptide system on these pathways and the identifying the specific mechanisms of action require further research. This study showed that LCZ696 can protect against DCM by inhibiting inflammation, oxidative stress, and apoptosis (Supplementary Figure 2) without toxic effects. Therefore, LCZ696 might represent a potential new drug for the treatment of DCM.

LCZ696 As a New Treatment for Hypertension and Heart Failure

LCZ696 had been tested to utilize the beneficial properties of natriuretic peptides in combination with angiotensin receptor antagonism. It induces even greater blood pressure reductions and decreased mortality and morbidity in patients with heart failure with reduced ejection fraction, while patients with heart failure with preserved ejection fraction show lowered blood pressure and decreased NT-pro-BNP levels. Although long-term studies remain to be performed, these initial data suggest that there is a potential clinical benefit of LCZ696 in the treatment of hypertension and heart failure. A recent indirect comparisons of LCZ696 with a putative placebo by McMurray et al. revealed striking reductions in cardiovascular and all-cause mortality by LCZ696, and also HF hospitalization. These benefits were obtained even though LCZ696 was added to existing β-blocker and mineralocorticoid receptor antagonist therapy.[3]

References

[1]Ye L, Wang J, Chen Q, Yang X. LCZ696, a promising novel agent in treating hypertension (a meta-analysis of randomized controlled trials). Oncotarget. 2017 Nov 14;8(64):107991-108005. doi: 10.18632/oncotarget.22442. PMID: 29296218; PMCID: PMC5746120.

[2]Ge Q, Zhao L, Ren XM, Ye P, Hu ZY. LCZ696, an angiotensin receptor-neprilysin inhibitor, ameliorates diabetic cardiomyopathy by inhibiting inflammation, oxidative stress and apoptosis. Exp Biol Med (Maywood). 2019 Sep;244(12):1028-1039. doi: 10.1177/1535370219861283. Epub 2019 Jul 1. PMID: 31262190; PMCID: PMC6879777.

[3]Andersen, Mathilde Borring et al. “LCZ696 (Valsartan/Sacubitril)--A Possible New Treatment for Hypertension and Heart Failure.” Basic & clinical pharmacology & toxicology vol. 118,1 (2016): 14-22. doi:10.1111/bcpt.12453