Journal of Family Medicine and Primary Care

REVIEW ARTICLE
Year
: 2019  |  Volume : 8  |  Issue : 7  |  Page : 2184--2188

Fimasartan: A new armament to fight hypertension


Akshyaya Pradhan, Vikas Gupta, Rishi Sethi 
 Department of Cardiology, King George Medical University, Lucknow, Uttar Pradesh, India

Correspondence Address:
Dr. Akshyaya Pradhan
Department of Cardiology, King George's Medical University, Lucknow - 226 003, Uttar Pradesh
India

Abstract

Hypertension is a major public health problem of modern era. Fimasartan is a new Angiotensin Receptor Blocker approved for treatment of hypertension. It is more potent and longer acting angiotensin receptor blocker with effects lasting over 24 hours. Many clinical studies have affirmed its role in pharmacotherapy of hypertension. Further, it is renoprotective and has proven beneficial in diabetes also. This article briefly discusses the pharmacology and clinical evidence with fimasartan with a short summary of previous angiotensin receptor blockers.



How to cite this article:
Pradhan A, Gupta V, Sethi R. Fimasartan: A new armament to fight hypertension.J Family Med Prim Care 2019;8:2184-2188


How to cite this URL:
Pradhan A, Gupta V, Sethi R. Fimasartan: A new armament to fight hypertension. J Family Med Prim Care [serial online] 2019 [cited 2019 Aug 20 ];8:2184-2188
Available from: http://www.jfmpc.com/text.asp?2019/8/7/2184/263756


Full Text



 Introduction



Hypertension is a major public health problem of modern era. Up to 28% of the world's adult population had uncontrolled hypertension in a study published in 2011.[1] Anchala et al. reported an overall hypertension prevalence of 29.8% in India in their meta-analysis.[2] The prevalence of hypertension in this study was significantly higher in urban Indians than in rural Indians (33.8% vs. 27.6%, respectively).[2]

Hypertension if left untreated can lead to end organ damage, such as retinopathy, chronic kidney disease, cerebrovascular disease, heart failure, coronary artery disease, and atrial fibrillation. Various classes of drugs are available for treatment of hypertension. Among these angiotensin receptor blockers (ARBs) are most widely used antihypertensive drugs and have maximal patient acceptability profile. ARBs hold class I recommendation for pharmacological management of hypertension in various guidelines including European and American guidelines.[3],[4],[5]

 Mechanism of Action of ARBs



The ARBs selectively inhibit angiotensin II by competitive antagonism of the angiotensin receptors [Figure 1]. Thereby, they antagonize angiotensin II-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, and water retention. These mechanisms reduce adverse effects and possibly improve clinical efficacy in comparison to angiotensin convertase enzyme inhibitors (ACEIs). The currently available ARBs are summarized briefly in [Table 1].{Figure 1}{Table 1}

 Fimasartan - the Latest “sartan”



Fimasartan is a latest [9] angiotensin II receptor antagonist with selectivity for the AT(1) receptor subtype, developed by a korean company Boryung Pharmaceutical as an oral antihypertensive drug. [Figure 2] demonstrates journey of ARBs from first marketed ARB molecule to recently introduced fimasartan. Fimasartan has been approved for use in patients with hypertension by FDA of Korea. Boryung has also got approval for this molecule in many other countries such as China, Singapore, and Russia. Fimasartan has also been approved in India by CDSCO (Central Drugs Standard Control Organization) recently.{Figure 2}

Fimasartan is a biochemical derivative of losartan in which the imidazole ring has been replaced. This change provides higher potency and longer duration of action to this molecule. Fimasartan is selective angiotensin II type 1 (AT1) receptor antagonist.[10] In contrast to other ARBs, it did not show agonistic action to AT2 receptor in animal models.[11]

 Pharmacokinetics and Dynamics



The pharmacokinetics and pharmacodynamics of fimasartan are highlighted in [Table 2]. It is a long acting drug, requiring once daily dosing. It is usually given in dosage of 60–120 mg OD. The onset of action of fimasartan is faster that it's congeners. It is usually well tolerated in mild to moderate renal dysfunction, but dose reduction is required in severe renal dysfunction (<30 mL/min creatinine clearance starting dose is 30 mg OD). It is safe in mild hepatic dysfunction. Fimasartan should be avoided in severe hepatic dysfunction, patients on hemodialysis, pregnant or nursing mothers, and patients with hypersensitivity reaction.{Table 2}

The drug has been well tolerated in clinical studies. Most adverse reactions were transient and not dose related. Headache and dizziness were the most common ones reported. Other reported side effects include nausea, pain abdomen, cough, pruritus, hot flushes, increased liver enzymes, etc.

 Clinical Evidence for Use in Hypertension



We have now accumulated data for fimasartan use in close to 20,000 patients. Fimasartan was found to have an excellent efficacy and tolerability profile in a large-scale observational population study - Safe-KanArb. In this study, a total of 14,151 patients with mean age of 59 ± 12 years were evaluated. This study established the safety, efficacy, and compliance of this molecule. The Systolic blood pressure (SBP) fell by an average of -18.65 mm of Hg and Diastolic blood pressure by - 9.73 mm of Hg with drug therapy at 2 months. Interestingly, the pulse rate declined from 74.4 to 71.9 beats per min in the treatment arm. The benefits were attained irrespective of age, sex, comorbidities and background antihypertensive therapy. It should be noted that more than half of the study population (63%) was on background anti-hypertensive therapy underscoring the potency and efficacy of the drug. The drug was found to be excellent in patients potentially at higher risk for adverse events.[12]

The K-MetS study of 10601 patients was planned to evaluate long-term effects of fimasartan on major adverse cardiovascular outcomes. The study also evaluated long-term metabolic effects of fimasartan. Three-year follow-up was planned in this study. At 1-year follow-up, in a sub group analysis published in 2017, fimasaratn significantly decreased the albumin/creatinine ratio. The systolic blood pressure fell from 143.7 ± 17.2 mm of Hg to 126.7 ± 12.6 mm of Hg at 1 year (a fall of around 17 mm of Hg). On a similar note, the diastolic BP decreased from 88.4 ± 11.48 at baseline to 78.6 ± 8 mm of Hg. Waist circumference and triglyceride levels were also diminished simultaneously.[13]

In another study, the drug was associated with reduction in day to day BP variability independent of absolute BP reduction.[14] Fimasartan was similarly effective in reducing Systolic as well as diastolic BP in hypertensive elderly patients compared with nonelderly patients in a sub group analysis of K-MetS study. It also resulted in better pulse pressure reduction with similar home blood pressure reduction efficacy and safety in hypertensive elderly patients.[22]

One recent study evaluated the effects of fimasartan and amlodipine therapy on carotid atherosclerotic plaque inflammation using 18F-fluorodeoxyglucose positron emission tomography imaging. Both drugs were found to decrease carotid atherosclerotic plaque inflammation similarly in patients with acute coronary syndrome.[23] The major studies done with fimasartan so far are depicted in [Table 3].{Table 3}

 Implications for Clinical Practice



The prevalence of hypertension is continuously rising, yet the proportion of patient's with their blood pressures under target remains low. The ACC/AHA 2017 hypertension guidelines suggest that most of the hypertensive patients will need combination therapy for attaining BP goals. In real world, primary care physician (not the cardiologist) is usually the first contact of a patient for hypertension consultation. So longer acting, potent antihypertensive drugs with least side effect profile are needed to make the task of hypertension control easy. ARBs have proven their efficacy in treatment of hypertension for past two decades. They have most favorable side effect profile among current antihypertensive portfolio. Fimasartan is newer longer acting and potent ARB. So, it can be safely used by primary care physician in an efficient manner for management of hypertension.

 Future Directions



FANTASTIC study will assess renoprotective effect of fimasartan and the target blood pressure to reduce adverse outcomes in hypertensive diabetic chronic kidney disease patients with overt proteinuria.[24]

The safety and efficacy of drug in elderly patients (>70 years) against perindopril is being evaluated in FITNESS study (NCT 03246555). The FRESH (FimasaRtan-basEd BP Targets After Drug SwitcHing) study aimed to find proportion of patients achieving BP goals after switching to fimasartan-based regimens in patients with uncontrolled hypertension (NCT 03649646).

 Conclusion



A good number of clinical evidences support the use of this newer, potent, longer acting ARB- Fimasartan [See [Figure 3]]. Fimasartan achieved clinically significant blood pressure reduction in various studies with effect persisting over 24 h dosing interval. It was also shown to be renoprotective too. Apart from being efficacious, it has also demonstrated safety in elderly and high risk populations. So, this newer ARB has shown promising results in terms of efficacy, safety, and tolerability in clinical studies. The molecule is currently being used in number of countries in treatment of hypertension. In India, it has been launched recently. Fimasartan appears as a promising drug for management of hypertension for future in our country.{Figure 3}

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Danaei G, Finucane MM, Lin JK, Singh GM, Paciorek CJ, Cowan MJ, et al. National, regional, and global trends in systolic blood pressure since 1980: Systematic analysis of health examination surveys and epidemiological studies with 786 country-years and 5.4 million participants. Lancet 2011;377:568-77.
2Anchala R, Kannuri NK, Pant H, Khan H, Franco OH, Di Angelantonio E, et al. Hypertension in India: A systematic review and meta-analysis of prevalence, awareness, and control of hypertension. J Hypertension 2014;32:1170-7.
3Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2018;71:1269-324.
4Williams B, Mancia G, Spiering W, Rosei EA, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 2018;39:3021-104.
5James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: Report From the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311:507-20.
6Olin BR. Drug Facts and Comparisons. St. Louis: JB Lippincott Co; 2002. p. 514-8.
7Bumier M. Angiotensin II type 1 receptor blockers. Circulation 2001;103:904-12.
8Jones JD, Jackson SH, Agboton C, Martin TS. Azilsartan medoxomil (Edarbi): The eighth angiotensin II receptor blocker. P T 2011;36:634-40.
9Fimasartan. Am J Cardiovasc Drugs 2011;11:249-52.
10Kim TH, Shin S, Bashir M, Chi YH, Paik SH, Lee JH, et al. Pharmacokinetics and metabolite profiling of fimasartan, a novel antihypertensive agent, in rats. Xenobiotica 2014;44:913-25.
11Chi YH, Lee H, Paik SH, Lee JH, Yoo BW, Kim JH, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of fimasartan following single and repeated oral administration in the fasted and fed states in healthy subjects. Am J Cardiovasc Drugs 2011;11:335-46
12Park JB, Sung K-C, Kang SM, Cho EJ. Safety and efficacy of fimasar-tan in patients with arterial hypertension (Safe-KanArb Study) Am J Cardiovasc Drugs 2013;13:47-56.
13Park JB, Kim S-A, Sung K-C, Kim JY. Gender-specific differences in the incidence of microalbuminuria in metabolic syndrome patients after treatment with fimasartan: The K-MetS study. PLoS One 2017;12:e0189342.
14Shin MS, Kang DR, Kim C, Cho EJ, Sung KC, Kang SM, et al. Fimasartan for independent reduction of blood pressure variability in mild-to-moderate hypertension. Drug Des Devel Ther 2016;10:1573-80.
15Cardona-Munoz EG, Lopez-Alvarado A, Conde-Carmona I, Sánchez-Mejorada G, Pascoe-González S, Banda-Elizondo RG, et al. Safety and efficacy of fimasartan in Mexican patients with grade 1–2 essential hypertension. Arch Cardiol Mex 2017;87:316-25.
16Durán AM, Corcuera JO. Antihypertensive efficacy of fimasartan and additional benefits in patients with renal dysfunction. Ann Clin Exp Hypertension 2017;5:1046.
17Lee HY, Kim CH, Song JK, Chae SC, Jeong MH, Kim DS, et al. 24-Hour blood pressure response to lower dose (30 mg) fimasartan in Korean patients with mild to moderate essential hypertension. Korean J Intern Med 2017;32:1025-36.
18Lee H, Kim KS, Chae SC, Jeong MH, Kim DS, Oh BH. Ambulatory blood pressure response to once-daily fimasartan: An 8-week, multicenter, randomized, double-blind, active-comparator, parallel-group study in Korean patients with mild to moderate essential hypertension. Clin Ther 2013;35:1337-49.
19Rhee MY, Baek SH, Kim W, Park CG, Park SW, Oh BH, et al. Efficacy of fimasartan/hydrochlorothiazide combination in hypertensive patients inadequately controlled by fimasartan monotherapy. Drug Des Devel Ther 2015;9:2847-54.
20Kim K, Shin MS, Ihm SH, Youn HJ, Sung KC, Chae SC, et al. A randomized, double-blind, multicenter, phase III study to evaluate the efficacy and safety of fimasartan/amlodipine combined therapy versus fimasartan monotherapy in patients with essential hypertension unresponsive to fimasartan monotherapy. Clin Ther 2016;38:2159-70.
21Yang YS, Lim MH, Lee SO, Roh E, Ahn CH, Kwak SH, et al. Fimasartan increases glucose-stimulated insulin secretion inpatients with type 2 diabetes and hypertension comparedwith amlodipine. Diabetes Obes Metab 2018;20:16707.
22Cho EJ, Sung KC, Kang SM, Shin M-S, Joo SJ, Park JB. Fimasartan reduces clinic and home pulse pressure in elderly hypertensive patients: A K-MetS study. PLoS One 2019;14:e0214293.
23Oh M, Lee CW, Ahn JM, Park DW, Kang SJ, Lee SW, et al. Comparison of fimasartan and amlodipine therapy on carotid atherosclerotic plaque inflammation. Clin Cardiol 2019;42:241-6.
24Kim JY, Son JW, Park S, Yoo TH, Kim YJ, Ryu DR, et al. FimAsartaN proTeinuriA SusTaIned reduCtion in comparison with losartan in diabetic chronic kidney disease (FANTASTIC): Study protocol for randomized controlled trial. Trials 2017;18:632.