The effects of olive leaf extract on cardiovascular risk factors in the general adult population: a systematic review and meta-analysis of randomized controlled trials

Literature flow

The primary search identified 723 articles, and after removing duplicates (n = 314), 344 records were excluded through screening of the titles and abstracts. We were unable to obtain the full-text of one article, despite contacting the corresponding author, and so, finally, 64 studies were reviewed in full-text. Twenty additional articles were excluded due to the irrelevant endpoints and design (Additional file 2. References 1–20). A further 32 articles were excluded for the following reasons: two studies were conducted on children (Additional file 2: References 21–22) and one among athletes (Additional file 2: Reference 23); ten articles applied multi-supplementation in the intervention group (Additional file 2: References 24–33); three studies used olives or olive extracts (Additional file 2: References 34–36), and four studies used olive pollen as the supplement (Additional file 2: References 37–40); one study was in-vitro research (Additional file 2: Reference 41), and two studies were food-industry investigations (Additional file 2: References 42–43). Seven studies did not consider any control group (Additional file 2: References 44–50); one study had insufficient data (Additional file 2: Reference 51), and another study had duplicate data from a previous publication (Additional file 2: Reference 52).

Finally, twelve eligible studies were included in the systematic review and meta-analysis [19,20,21, 23, 24, 34,35,36,37, 42,43,44]. The study selection process is presented in Fig. 1.

Fig. 1figure 1

Flow diagram for the study selection process

Characteristics of the included studies

The characteristics of the included studies are outlined in Table 1. All of the included studies were in English, except for three, which were in Japanese [34] and Farsi [24, 37]. Studies were conducted in Iran [24, 35, 37], the Netherlands [42, 43], Australia and New Zealand [20, 23], Japan [19, 34], Switzerland [21], Indonesia [36], and Israel [44]. Except for two studies that used the liquids [23] or beverages [34] of OLE, the rest of the studies used either tablets or capsules of OLE. All but two studies applied a parallel design [20, 23]. The duration and dose of OLE supplementation varied from 6 to 48 weeks, and 500 mg to 5 g per day, respectively. Two studies included males [20, 23], one study included females [42], and the rest of the studies enrolled both males and females. Studies were conducted among patients with type-2 diabetes mellitus [19, 44], hypertension [21, 23, 24, 35,36,37], dyslipidemia [34, 43], obesity [20], and osteopenia [42]. Eight studies considered placebo controls in their investigations [20, 21, 23, 24, 35, 37, 43, 44], and one study used a low concentration of green tea as the comparator [34]. One study examined the effect of OLE supplementation in combination with calcium, in which the calcium supplements were given to both the intervention and the control groups [42]. One investigation used captopril in the control group, which was excluded in the analysis of blood pressure [36]. None of the included studies assessed the pure bioactive compounds of OLE, and none reported any related adverse effects.

Table 1 Characteristics of eligible randomized controlled trials that investigated the effect of OLE intervention on cardiovascular-risk factors in adultsRisk of bias and quality of evidence

According to the overall quality assessment based on the Cochrane Collaboration Risk of Bias tool (Additional file 3), six studies were classified as “low” risk of bias (i.e., low risk of bias for all domains) [20, 23, 36, 37, 42, 43], three studies were classified as “some concerns” [24, 35, 44], and the three remaining studies were classified as “high” risk of bias [19, 21, 34]. To explain the details of the observed biases, three studies did not clearly explain the randomization and allocation concealment processes [19, 21, 34]. The blinding process was not considered in one study [21] and was not clearly explained in two investigations [19, 34]. One study had a “high” risk of bias [21] and three studies had “some concerns” risk of bias [19, 34, 35] due to the measurements of the outcomes where outcome assessors were not blinded to the study. One study did not clearly report the number of participants with missing outcome data [21] and three studies [21, 24, 44] were also shown to have insufficient data regarding the pre-specified analysis plan (bias due to the selection of the reported results).

According to the evaluation of the quality of evidence based on the GRADE system, the quality of evidence was found to be very low for the effect of OLE supplementation on HbA1c a, high sensitive C-reactive protein (hs-CRP), TNF-α, IL-6, and IL-8. A low quality of evidence was also observed for insulin, AST, ALT, ALP, and creatinine, as well as LDL-ox. A moderate quality of evidence was observed for that of OLE supplementation on FBS, LDL-C, HDL-C, TC, TG, and blood pressure (SBP and DBP) levels (Additional file 3).

Meta-analysisLipid profileTC

Meta-analysis of seven studies [20, 21, 23, 36, 37, 42, 43], including 520 participants, showed that OLE supplementation had no significant effect on the levels of TC, and the heterogeneity between studies was found to be moderate (WMD = − 3.95 mg/dl, 95% CI − 9.97, 2.07; P = 0.2; I2 = 65.6%; P-heterogeneity = 0.008) (Fig. 2a). Subgroup analyses showed a significant reducing effect of OLE supplementation on TC levels in normal-weight participants (4 studies; WMD = − 6.69 mg/dl, 95% CI − 11.90, − 1.49; P = 0.01; I2 = 0.0%; P-heterogeneity = 0.45), and in patients with hypertension (4 studies; WMD = − 9.14 mg/dl, 95% CI − 13.80, − 4.47; P < 0.001; I2 = 7.5%; P-heterogeneity = 0.36) (Additional file 4).

Fig. 2figure 2

Forest plot of randomized controlled trials (RCTs) illustrating weighted mean differences in a total cholesterol, b LDL-c, c HDL-c, and d triglyceride between OLE supplementation and control groups for all eligible studies. Analysis was conducted using a random effects model

LDL-C

Nine RCTs [19,20,21, 23, 34, 36, 37, 42, 43], including 616 participants, evaluated the effect of OLE on LDL-C levels. Results indicated that OLE supplementation yielded in an insignificant reduction in LDL-C measures and the between-study heterogeneity was reported to be medium (WMD = − 1.30 mg/dl, 95% CI − 5.25, 2.65; P = 0.52; I2 = 53.6%; P-heterogeneity = 0.03) (Fig. 2b). Subgroup analyses showed that LDL-C concentration decreased significantly in patients with hypertension (4 studies; WMD = − 4.60 mg/dl, 95% CI − 8.26, − 0.94; P = 0.014; I2 = 11.7%; P-heterogeneity = 0.33). Other potential sources of heterogeneity are reported in Additional file 4.

HDL-C

Among the included studies, nine investigations [19,20,

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