**2. Anti-hypertensive effect of olive leaf extract**

There are lots of animals and human trials conducted to inquire about the antihypertensive effect of OLE. The animal studies are mostly conducted on rats. In 2002, Khayyal et al. performed an 8-week investigation into the effects of oral administration of OLE at different levels (25, 50 or 100 mg/kg/day) on blood pressure in rats rendered hypertensive by oral doses of 4-week L-NAME (NG-nitro-L-arginine methyl ester, 50 mg/kg/day). They reported a dose-dependent prophylactic influence against the ascent in blood pressure induced by L-NAME and the greatest effect was related to the 100 mg/kg of the extract [13]. Besides these observations, the effect of OLE has also been researched in 2016 by Romero et al. In this study, a 5-week investigation on OLE (15% w/w OL) in spontaneously hypertensive rats at 30 mg/kg body weight reported a significant reduction of systolic blood pressure (−21.6 ± 5.5 mmHg) [14]. Although there are many other animal studies in this field, we intend to talk more about human clinical trials. Here, we collected a systematic review on a number of human randomised controlled trials (RCTs), which have been conducted to investigate the effect of OLE compared to placebo on systolic and diastolic blood pressure as primary or secondary outcomes in adults.

In 2008, an open, controlled, parallel-group, co-twin trial was carried out for 8 weeks on the anti-hypertensive effect of OLE in 40-borderline hypertensive monozygotic twins (age: 16–60) by Perrinjaquet-Moccetti et al. There were two parallel experiments, the first being the effect of a 500 mg OLE tablet (equivalent to 104 mg OL) once daily compared with no medication. The second experiment involved a 500 mg OLE tablet once daily compared with that of 1000 mg (equivalent to 208 mg OL) divided

*The Effect of Olive Leaf Extract on Systolic and Diastolic Blood Pressure in Adults: A Systemic... DOI: http://dx.doi.org/10.5772/intechopen.102769*

into two distinct doses. As a result, they revealed a significant dose-dependent decrease in blood pressure within pairs, with mean systolic differences of ≤6 mmHg (500 mg vs control) and ≤13 mmHg (1000 vs 500 mg), and diastolic differences of ≤5 mmHg. Also, mean blood pressure had significantly decreased just for the high dose group [3].

Elsewhere, in 2008, Saberi et al. verified the anti-hypertensive effect of OLE in another way. They enrolled 64 mild to moderate hypertensive patients with normal treatment resistance. They randomised the patients into two distinct groups (n=32 intervention & n=32 placebo). In the intervention group, each person received a 1000 mg OLE capsule divided into three doses daily. Consequently, the study demonstrated a significant decrease in mean systolic blood pressure. They found no remarkable effect on diastolic blood pressure and mean arterial pressure in the intervention group compared to before OLE treatment, despite the fact that there was meaningful diastolic blood pressure reduction in the OLE group compared to the placebo group [5].

In contrast, De Bock et al. who performed a 12-week randomized, placebocontrolled, crossover trial in 2013, demonstrated a different result. They assessed the effect of an OLE capsule (51.1 mg oleuropein; 9.7 mg hydroxytyrosol) daily on cardiovascular risk factors and insulin action in middle-aged overweight men. 46 participants (aged 35–55 years; BMI 25–30 kg/m2) randomly consumed OLE or placebo for 12 weeks with crossing over to the alternate arm after a 6-week washout. As a result, there were no remarkable changes in ambulatory (24-hour) blood pressure [15].

Further, in 2017, Lockyer et al. performed a randomised, double-blind, controlled, crossover trial to investigate the influence of a liquid-form OLE (136mg oleuropein; 6mg hydroxytyrosol) on blood pressure in prehypertensive patients. They used ambulatory blood pressure as the primary endpoint. The participants were 60 male subjects aged 45.3 ± 12.7, and body mass index (BMI) 27.0 ± 3.4 kg/m2 . They received either OLE or placebo for 6 weeks before switching to the other treatment after a 4-week washout. After tracking down the 24-hour and daytime blood pressure in patients, they represented a marked daytime and 24-hour systolic and diastolic blood pressure reduction (about 3 mmHg) compared to the control group (placebo) [7].

In 2020, Yaghoobzadeh et al. performed a 12-week investigation into the effect of OLE on cardiometabolic profiles in patients (aged 30–60) with essential HTN. The trial participants were randomly selected regarding intervention and control groups. (n= 30 intervention & n=30 placebo). As a result, a 250 mg OLE capsule, twice daily, could decrease systolic blood pressure significantly. However, it did not show a meaningful effect on the diastolic part [4].

As you notice, all of these studies show the anti-hypertensive effect of OLE, except the experiment conducted by De Bock et al. [15]. The most important differences between this study and other studies might be related to the study design, type of disease, nature of OLE, duration of extract in-take, patients' compliance and inclusion/exclusion criteria [4]. There is a systemic review and meta-analysis conducted by Muhammad Asyraf Ismail et al. in 2021 to show the effect of OLE on cardiometabolic profile in prehypertensive and hypertensive adults [1]. However, with all due respect to the authors of this study, there were a number of cases that encouraged us to make some updates with more accurate results. To clarify, the previous meta-analysis included 5 trials. Among these trials, in 2019, Javadi et al. did not investigate the effect of OLE on blood pressure [16]. Wong et al., studied a combined extract [17]. So, this study is not able to show us the pure effect of OLE. Susalit et al., compared OLE effect with a very strong anti-hypertensive drug (captopril) [6]. These three trials made the previous meta-analysis non-accurate, and they also excluded three useful RCTs for

different reasons. De Bock et al. [15] were deleted because of not involving prehypertensive or hypertensive group in the study. Saberi et al. [5], was also deleted due to being a non-English RCT in addition to Lockyer et al. [7], who could not retrieve data after contacting the author [1]. Ultimately, the previous meta-analysis could not demonstrate the accurate effect of OLE on blood pressure. Hence, to determine the OLE effect on systolic and diastolic blood pressure, we aimed to perform a meta-analysis of these 5 human trials (**Figures 1** and **2**).

Our meta-analysis shows that OLE has a significant effect on the reduction of systolic blood pressure. But, its effect on diastolic blood pressure is not meaningful. The anti-hypertensive property of the olive leaf is due to its phenolic compounds.
