Olive leaf extract effect on cardiometabolic profile among adults with prehypertension and hypertension: a systematic review and meta-analysis

Eligibility criteria

The inclusion criteria were adults aged 18 years old of any sex and any ethnicity considered eligible if diagnosed with elevated BP (≥ 120/80 mmHg; classified as prehypertension and hypertension based on the JNC-7). The types of interventions were olive leaf extract (either alone or in combination with other active ingredients), placebo, antihypertensive drugs or no treatment. The extract was administered orally, in either tablet or liquid form. The follow-up period for primary outcomes was at least six weeks after treatment. The exclusion criteria were patients with cardiovascular complications and stroke.

Search strategy

We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 4) and MEDLINE (1966 to April week 1, 2020) (see appendix 1). We restricted the publications to those published in the English language only and searched the reference list of identified RCTs and review articles to find unpublished trials or trials not identified by electronic searches. We also searched for ongoing trials through the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; http://www.who.int/ictrp/en) and (NLM; http://www.clinicaltrials.gov).

Trial selection

Two review authors (MAI, NMN) scanned the titles and abstracts from the searches and obtained full-text articles when they appeared to meet the eligibility criteria, or when there was insufficient information to assess eligibility. We assessed the eligibility of the trials independently and documented any reasons for exclusion. We resolved any disagreements between the review authors by discussion, contacting the authors for clarification if needed.

Data extraction

From each of the selected trials, we extracted study settings, participant characteristics (age, sex, and ethnicity), methodology (the number of participants randomized and analyzed, the duration of follow-up), whether olive leaf extract was used alone or in combination with other active ingredients, and the method used for diagnosing prehypertension and hypertension. Predefined primary outcomes were changes in systolic BP and diastolic BP. The secondary outcomes were changes in lipid profiles (Total cholesterol (TC), Triglyceride (TG), LDL, and HDL), inflammatory markers for CVD (IL-6 and IL-8), TNF-alpha, kidney and liver function safety parameters (creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and glucose metabolism (fasting blood sugar (FBS), homeostatic model of assessment-insulin resistance (HOMA-IR) and insulin).

Risk of bias assessment

We assessed the risk of bias based on random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, completeness of outcome data, the selectivity of outcome reporting and other bias (Higgins et al., 2019).

Statistical analysis

We performed the meta-analysis using Review Manager 5.3 software (The Nordic Cochrane Centre, Copenhagen) and reported the results of the random-effects model. Since our meta-analysis measures continuous outcomes, we used the inverse variance for the outcomes. We drew forest plots for the trials with numerical outcomes using mean differences (MD) and 95% confidence intervals (CI) (Higgins et al., 2019). There was no missing data from the trials. We were able to retrieve data on one trial via a supplementary file attached to the article (Wong et al., 2014).

The planned subgroup analyses would have compared prehypertension with hypertension and high dose (1,000 mg per day) with a low dose (500 mg per day). However, we were unable to perform these analyses due to insufficient trials. We were also unable to perform a sensitivity analysis to investigate the impact of bias risk for sequence generation and allocation concealment of the included studies due to insufficient trials.

Assessment of heterogeneity

We assessed the presence of heterogeneity in two steps. First, we assessed apparent heterogeneity at face value by comparing populations, settings, interventions and outcomes. Second, we assessed statistical heterogeneity through the I² statistic (Higgins et al., 2019). We used the following guide to interpret heterogeneity, as mentioned in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins et al., 2019) 0% to 40% signified negligible importance, 30% to 60% signified moderate heterogeneity, 50% to 90% indicated substantial heterogeneity and 75% to 100% indicated considerable heterogeneity.

Grading evidence quality

We assessed evidence quality for primary and secondary outcomes according to GRADE methodology (Schünemann, Guyatt & Oxman, 2013) for risk of bias, inconsistency, indirectness, imprecision and publication bias. The quality of evidence was classified as one of four certainty levels: very low, low, moderate or high. Quality could be downgraded depending on the presence of four factors: (i) limitations in the design and implementation of available studies, (ii) evidence indirectness, (iii) unexplained result heterogeneity or inconsistency and (iv) imprecise results.

Study descriptions

We retrieved 489 records from the electronic database search and five from other sources (Fig. 1) and screened a total of 494 records. We reviewed full copies of 12 studies, identifying six articles with the potential of meeting the review inclusion criteria and excluding the other six. Of those excluded, three were published in a non-English language (Cabrera-Vique et al., 2015; Saberi, Kazemisaleh & Bolurian, 2008; Schulz, 2011), one did not involve a prehypertensive or hypertensive group (De Bock et al., 2012), one was a non-RCT (Zam & Ali, 2017) and one was a conference abstract (Saibandith et al., 2016). We were not able to retrieve the data for the conference abstract after contacting the authors (Saibandith et al., 2016). A trial was also excluded due to being a crossover trial that we were unable to retrieve data on after contacting the author (Lockyer et al., 2017). Therefore, we only included five trials in this review.

Included studies

The five trials included in this review (Javadi et al., 2019; Perrinjaquet-Moccetti et al., 2008; Susalit et al., 2011; Wong et al., 2014; Yaghoobzadeh et al., 2020) had met the eligibility criteria. One trial included monozygotic twins with untreated suboptimal blood pressure, exceeding 120 mmHg systolic or 80 mmHg diastolic at rest (Perrinjaquet-Moccetti et al., 2008). One trial included stage-1 hypertension either naïve or being under treatment with any anti-hypertensive medication and exclusions were participants with a history of secondary hypertension, presence of target-organ damage, second- or third-degree heart block, valvular heart disease, diabetic subjects, hepatic dysfunction, pregnant and breastfeeding female subjects (Susalit et al., 2011). One trial included participants with BP between 130–160 mmHg systolic and 85–100 mmHg diastolic and excluded participants that smoke or took nicotine therapy, taking anti-hypertensive medication or insulin, pregnant or currently breastfeeding and currently consuming dietary supplements containing extracts of olive leaf, green coffee bean or beet (Wong et al., 2014). One trial included participants with hypertension and exclusions were hypertensive patients who had complications such as diabetes, kidney disease, and hypo and/or hyperthyroidism (Javadi et al., 2019). One trial included patients with essential hypertension (Yaghoobzadeh et al., 2020). Two trials had declared funding from olive leaf extract manufacturers (Perrinjaquet-Moccetti et al., 2008; Susalit et al., 2011; Wong et al., 2014). Table 1 shows the characteristics of the included studies.

Participants

Two trials were conducted in high-income countries (Perrinjaquet-Moccetti et al., 2008; Wong et al., 2014) and three trials were conducted in moderate-income countries (Javadi et al., 2019; Susalit et al., 2011; Yaghoobzadeh et al., 2020). Three trials recruited patients from healthcare settings (Javadi et al., 2019; Susalit et al., 2011; Yaghoobzadeh et al., 2020) and two trials recruited patients from a research institute (Perrinjaquet-Moccetti et al., 2008; Wong et al., 2014). Two trials reported the exclusion of participants due to hypertension with complications, such as diabetes mellitus, kidney disease, and heart disease (Javadi et al., 2019; Susalit et al., 2011). The five trials involved 325 participants, 220 of which were female and 105 were male.

Intervention

Trial participants were randomized regarding intervention and control groups. Olive leaf extract was given in 1,000 mg (Susalit et al., 2011; Wong et al., 2014) and 500 mg per day doses (Javadi et al., 2019; Perrinjaquet-Moccetti et al., 2008; Yaghoobzadeh et al., 2020). For the 1,000 mg per day dose, one trial used a combined formulation of 500 mg olive leaf extract with green coffee bean extract and beetroot tablet to be taken twice daily (Wong et al., 2014) and one trial used a 500 mg olive leaf extract tablet twice daily (Susalit et al., 2011). For the 500 mg per day dose, one trial used the olive leaf extract 500 mg tablet once daily (Perrinjaquet-Moccetti et al., 2008) and two trials used the 250 mg olive leaf extract tablet twice daily (Javadi et al., 2019; Yaghoobzadeh et al., 2020). Three trials used a placebo as a control (Javadi et al., 2019; Wong et al., 2014; Yaghoobzadeh et al., 2020). One trial advocated lifestyle modification to the control group (Perrinjaquet-Moccetti et al., 2008) and one trial gave an antihypertensive (captopril) to the control group (Susalit et al., 2011). In all five trials included, there was no information about harvesting area and seasons. Three trials mentioned olive leaf extract manufactured by Frutarom Switzerland Ltd (Perrinjaquet-Moccetti et al., 2008; Susalit et al., 2011; Wong et al., 2014). From the three trials, one trial mentioned that 500 mg of olive leaf extract comprised 16%–24% oleuropein and ≥30% other polyphenols (Wong et al., 2014). One trial stated that 500 mg olive leaf extract manufactured comprised 16–24% (m/m) oleuropein and the batch used had a content of 19.9% (m/m) (Susalit et al., 2011). One trial mentioned that characteristic components in the 500 mg olive leaf extract were 18–26% (m/m) oleuropein, 30–40% (m/m) polyphenols as well as verbascoside and luteolin-7-glucoside whereby, the batch used had oleuropein content of 20.8% (m/m) (Perrinjaquet-Moccetti et al., 2008). Two trials manufactured olive leaf extract by Barij medicinal plant research center, Kashan, Iran (Javadi et al., 2019; Yaghoobzadeh et al., 2020), whereby one trial mentioned that 250 mg olive leaf extract contains 16% oleuropein (Javadi et al., 2019) and another trial did not mention the components of olive leaf extract (Yaghoobzadeh et al., 2020).

Outcomes

All five trials performed the intervention for a minimum of six weeks, and these were grouped according to three comparisons. The first comparison, which involved only one trial, compared a placebo with the 1,000 mg per day combined formulation of olive leaf extract, and it measured both primary outcomes and secondary outcomes (Wong et al., 2014). The secondary outcomes measured in the first comparison were the lipid profile and glucose metabolism. The second comparison, which involved three trials, compared the 500 mg per day olive leaf extract with a placebo or with no treatment (Javadi et al., 2019; Perrinjaquet-Moccetti et al., 2008; Yaghoobzadeh et al., 2020). In the second comparison, two trials measured both primary and secondary outcomes, whereby the secondary outcome was only the lipid profile (Perrinjaquet-Moccetti et al., 2008; Yaghoobzadeh et al., 2020). One trial in the second comparison measured only secondary outcomes, which were glucose metabolism, inflammatory markers, kidney and liver functions (Javadi et al., 2019). In the third comparison, which involved one trial, 1,000 mg per day of olive leaf extract was compared with an antihypertensive drug, and it measured both primary outcomes and secondary outcomes (Susalit et al., 2011). The secondary outcomes in the third comparison were the lipid profile, kidney and liver functions.

We were able to analyze two out of three trials from the second comparison as the two trials measured primary outcomes and lipid profile. Another trial in the second comparison only measures other secondary outcomes on which a review was performed. Meta-analysis was intended for the first and third comparison, but there were insufficient trials, thus only a review was performed.

Risk of bias in included studies

The assessment of the risk of bias is shown in Figs. 2 and 3. Figure 2 shows the proportion of studies that were assessed as having a low, high or unclear risk of bias with regard to each risk-of-bias indicator. Figure 3 shows the risk-of-bias indicators for individual studies.

Effects of interventions

Comparison 2: Olive leaf extract vs placebo or no treatment

There were two trials of a 500 mg per day olive leaf extract (Perrinjaquet-Moccetti et al., 2008; Yaghoobzadeh et al., 2020) that measured primary and secondary outcomes, while one trial of the 500 mg per day olive leaf extract (Javadi et al., 2019) measured only the secondary outcomes. For the primary outcomes, the olive leaf extract reported decreases in systolic BP (MD −5.78 mmHg, 95% CI [−10.27 to −1.30]; I² = 0%, p = .01; two trials, 80 participants; low certainty of evidence) [Fig. 4 and Table 3] and no significant effect on diastolic BP in comparison to the control [Fig. 5 and Table 3]. For the secondary outcomes, the olive leaf extract reported no significant effect on TC [Fig. 6 and Table 3], LDL [Fig. 7 and Table 3], HDL [Fig. 8 and Table 3), FBS, HOMA-IR, ALT or AST in comparison to the control. However, the olive leaf extract reported decreases in IL-6 (MD −6.83 ng/L, 95% CI [−13.15 to −0.51], p = .03; one trial, 60 participants), IL-8 (MD −8.24 ng/L, 95% CI [−16.00 to −0.48], p = .04; one trial, 60 participants) and TNF-alpha (MD −7.40 ng/L, 95% CI [−13.23 to −1.57], p = .01; one trial, 60 participants) in comparison to the control. Overall, the quality of evidence showed low certainty (Table 3). We were unable to analyze any difference between the 500 mg, single dose per day olive leaf extract and 250 mg, twice daily dose olive leaf extract due to limited trials.

Table 3:

Summary of findings including GRADE quality assessment for comparison between olive leaf extract and placebo or no treatment.

		No. of participants		Anticipated absolute effects *
Outcomes	No. of participants (studies)	Placebo or no treatment	Olive leaf extract 500 mg per day dosage	MD	95% CI	P-value	Certainty of the evidence (GRADE)	Comments
Systolic blood pressure (mmHg)	80 (2 RCTs)	40	40	5.78 lower	−10.27 to -1.3, I2= 0%	0.01	⊕⊕$○$$○$ LOWa	Risk of bias: not serious Inconsistency: seriousa; indirectness: not serious; imprecision: seriousa;
Diastolic blood pressure (mmHg)	80 (2 RCTs)	40	40	1.69 lower	−5.73 to 2.34, I2= 0%	0.41	⊕⊕$○$$○$ LOWa,b	Risk of bias: not serious Inconsistency: seriousa,b; indirectness: not serious; imprecision: seriousa;
Total cholesterol (mg/dl)	80 (2 RCTs)	40	40	4.97 lower	−17.28 to 7.34, I2= 81%	0.43	⊕⊕$○$$○$ LOWa,b	Risk of bias: not serious Inconsistency: seriousa,b; indirectness: not serious; imprecision: seriousa;
LDL (mg/dl)	80 (2 RCTs)	40	40	0.29 higher	−0.2 to 0.79, I2= 0%	0.25	⊕⊕$○$$○$ LOWa,b	Risk of bias: not serious Inconsistency: seriousa,b; indirectness: not serious; imprecision: seriousa;
HDL (mg/dl)	80 (2 RCTs)	40	40	0.98 higher	−1.63 to 3.6, I2= 78%	0.46	⊕⊕$○$$○$ LOWa,b	Risk of bias: not serious Inconsistency: seriousa,b; indirectness: not serious; imprecision: seriousa;
Fasting blood glucose (mmol/l)	60 (1 RCT)	30	30	0.08 higher	−0.25 to 0.4	0.65	⊕⊕$○$$○$ LOWa	Risk of bias: not serious Inconsistency: seriousa; indirectness: not serious; imprecision: seriousa;
HOMA-IR	60 (1 RCT)	30	30	0.17 higher	−0.17 to 0.51	0.33	⊕⊕$○$$○$ LOWa	Risk of bias: not serious Inconsistency: seriousa; indirectness: not serious; imprecision: seriousa;
Insulin (µu/ml)	60 (1 RCT)	30	30	0.61 higher	−0.84 to 2.06	0.41	⊕⊕$○$$○$ LOWa	Risk of bias: not serious Inconsistency: seriousa; indirectness: not serious; imprecision: seriousa;
creatinine (mg/dl)	60 (1 RCT)	30	30	0.09 higher	−0.18 to 0.36	0.52	⊕⊕$○$$○$ LOWa	Risk of bias: not serious Inconsistency: seriousa; indirectness: not serious; imprecision: seriousa;
ALT (U/L)	60 (1 RCT)	30	30	0.3 higher	−2.26 to 2.86	0.82	⊕⊕$○$$○$ LOWa	Risk of bias: not serious Inconsistency: seriousa; indirectness: not serious; imprecision: seriousa;
AST (U/L)	60 (1 RCT)	30	30	0.57 higher	−2 to 3.14	0.66	⊕⊕$○$$○$ LOWa	Risk of bias: not serious Inconsistency: seriousa; indirectness: not serious; imprecision: seriousa;
IL-6 (ng/L)	60 (1 RCT)	30	30	6.83 lower	−13.15 to −0.51	0.03	⊕⊕$○$$○$ LOWa	Risk of bias: not serious Inconsistency: seriousa; indirectness: not serious; imprecision: seriousa;
IL-8 (ng/L)	60 (1 RCT)	30	30	8.24 lower	−16 to -0.48	0.04	⊕⊕$○$$○$ LOWa	Risk of bias: not serious Inconsistency: seriousa; indirectness: not serious; imprecision: seriousa;
TNF-alpha (ng/L)	60 (1 RCT)	30	30	7.4 lower	−13.23 to -1.57	0.01	⊕⊕$○$$○$ LOWa	Risk of bias: not serious Inconsistency: seriousa; indirectness: not serious; imprecision: seriousa;

DOI: 10.7717/peerj.11173/table-3

Notes:

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; MD: Mean difference.

Explanations

asmall population.

bwide CI.

GRADE Working Group grades of evidence

High certainty: We are very confident that the true effect lies close to that of the estimate of the effect

Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different

Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect

Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Applicability of evidence

In the global perspective, dietary risks were reported to be associated with 2.1 million cardiovascular deaths in the WHO European Region that accounts for 49.2% of CVD deaths and 22.4% of all deaths (Meier et al., 2019). Recognizing the increasing burden of non-communicable disease, WHO had emphasized the importance of dietary modifications as strategies to combat the non-communicable disease (Waxman, 2004). In Malaysia, the Clinical Practice Guideline on Primary and Secondary Prevention of CVD 2017s also emphasized that dietary habits have beneficial effects on cardiometabolic risk factors, such as weight, blood pressure, glucose metabolism, cholesterol, oxidative stress and inflammation. As there were ongoing research and interest in olive leaf extract, in the future it can act as a daily supplement to prevent CVD in addition to dietary modifications and lifestyle changes. Olive leaf, which originates from the olive tree, may have beneficial effects on cardiometabolic risk factors that had been used traditionally and contemporary globally as medicine which acts as folks remedy in the community for example to treat hypertension, diabetes and acts as an anti-inflammatory (Hashmi et al., 2015). However, in Malaysia there has been no reported use of olive leaf extract among the community.

In this review, we included both prehypertensive and hypertensive populations because of the increased risk of cardiovascular morbidity and mortality in comparison to the normotensive population (Zhang & Li, 2011). In addition, systolic BP is said to be superior to diastolic BP as a predictor of cardiovascular outcomes (Mourad, 2008). Furthermore, it was reported that, increased systolic BP was the leading risk factor for women and the second leading risk factor for men globally whereby, IHD was the largest source attributable to increased systolic BP, followed by hemorrhagic stroke and ischemic stroke (GBDRF Collaborators, 2017). The analysis of two trials has shown that 500 mg per day dose of olive leaf extract is beneficial for the reduction of systolic BP (around 5.78 mmHg). This is comparable to conventional perindopril monotherapy, as reported in the perindopril protection against recurrent stroke study, where perindopril monotherapy reduced systolic BP by five mmHg (PROGRESS, 2001). Furthermore, one review has shown a linear association between systolic BP and risk of cardiovascular disease and mortality, with the lowest risk at a systolic BP of 120 to 140 mmHg (Bundy et al., 2017). Only one trial found that LDL was reduced, with no other effects on the rest of the lipid profile, as the 1,000 mg dosage of olive leaf extract shows a reduction of LDL by 6 mg/dl in comparison to captopril. The reduction of LDL is important, as a reduction of LDL by 38.7 mg/dl ( one mmol/L) in a patient without known atherosclerotic cardiovascular disease will lead to predicted risk of major vascular events of 15% and of hard cardiovascular events (cardiovascular death, MI, or stroke) of 10% in the next 10 years, which indicates risk reductions of approximately 3.5% and 2.3%, respectively (Silverman et al., 2016). This review also shows that olive leaf extract confers some effects on the inflammatory markers involved in atherosclerosis. In terms of safety, this review shows that consuming olive leaf extract did not have a significant effect on creatinine, AST or ALT, which indicates a possible use for patients with liver and kidney disorders who have hypertension. Thus, there is a possible benefit from olive leaf extract in terms of modifying the cardiometabolic profile to reduce the risk of CVD.

Quality of evidence

Applying the Cochrane methodology was a major strength of this systematic review, comprising a pre-published protocol, a non-restricted and up-to-date literature search, independent data extraction by at least two authors and risk of bias assessment leading to (Grading of Recommendations, Assessment, Development and Evaluation) GRADE evaluations of important outcomes. However, the findings of the review are limited by the small number of trials involved. Overall, there was low bias among the trial’s domains. There were two trials with an unclear risk of random sequence generation. There was no evidence of selective reporting bias. Attrition bias was low for all trials. Three of the trials declared funding from natural health manufacturers. We used random-effects meta-analysis, in which we encountered low to substantial heterogeneity in the analysis. For the substantial heterogeneity, we were unable to do sensitivity analysis due to the limited number of similar trials for comparison. Hence, the overall quality of evidence contributing to this review as assessed using the GRADE approach was low.

Limitations

There were limited trials on olive leaf extracts that met the inclusion criteria for the review. They further differed in terms of the olive leaf extract and comparator formulation, which meant we could not combine trials for analysis. Furthermore, two trials were funded by olive leaf extract companies. The component analysis was mentioned in four out of five trials. None of the trials mentioned olive leaf harvesting area and season. Lipoprotein subfractions- sdLDL, VLDL and vascular inflammation marker CRP could not be evaluated. It was reported as a positive correlation between lipoprotein subfractions and inflammatory markers may contribute to increasing cardiovascular risk (Zhang et al., 2015). IL8 has been reported not to be associated with cardiovascular events in a recent cohort study (Moreno Velásquez et al., 2019). In the future, further similar trials are needed to ensure more concrete evidence.