Effect of Hesperidin on blood pressure and lipid pro�le: A systematic review and meta-analysis of randomized controlled trials

Abstract


Introduction
As per the WHO fact sheet, cardiovascular diseases (CVDs) are the major cause of death globally (WHO, 2021).WHO estimated that 17.9 million people died from CVDs in the year 2016, which was 31% of allcause deaths globally (WHO, 2021).Cardiovascular disorder is a broad term that covers coronary heart disease, rheumatic heart disease, cerebrovascular disease, deep vein thrombosis/pulmonary embolism, congenital heart disease, and peripheral arterial disease.Coronary heart disease is most common among these CVDs, (Prabhakaran et al., 2016).Most CVDs are easily preventable regardless of being a foremost cause of mortality globally (Kinoshita et al., 2017) with dietary control (Clar et al., 2017), highintensity workouts, active lifestyle (Lavie et al., 2015), and stress management.CVDs are often due to metabolic imbalance (Zhang et al., 2008).Under such conditions, there is a nutritive disparity between supply and demand, which leads to heart-related disorders such as obesity, atherosclerosis, hypertension, ischemic heart disease, and occasionally heart failure (Brandhorst et al., 2019).These disorders are associated with oxidative stress at the cellular level due to mitochondrial dysfunction (Ferrari et al., 1996).
Hesperidin is a polyphenolic compound found most abundantly in citrus fruits that exerts many medicinal uses.Hesperidin has been found to possess many pharmacological activities like hypolipidemic, anti-diabetic, anti-in ammatory, and anti-hypertensive.Relevant to this study, to date there are thirteen clinical studies are available related to the cardioprotective activity of hesperidin in humans.Also, there is a meta-analysis study has been published so far (Mohammadi et.al., 2019).However, the meta-analysis performed by Mohammadi et.al.considered the studies on orange juice and hesperidin, the comparisons were not solely between hesperidin vs placebo/control.Further, there are two additional randomized controlled trials, Zahra Yari et.al.,2019 and Zahra Yari et.al.,2020 have been published on hesperidin related to its cardiovascular bene ts after the publication of the above-cited meta-analysis papers.Therefore, there is a scope for performing a systematic review and meta-analysis on hesperidin related to its cardiovascular bene ts when compared to placebo/control.With this background, the present study was undertaken to carry out a systematic review and meta-analysis to determine the bene cial role of hesperidin in treating cardiovascular diseases.

Literature search
The literature search was performed in detail using the search term 'Hesperidin' in combination with cardiovascular disease, heart, and clinical trials in online databases such as PubMed and Google Scholar for studies published up to April 2023.Initially, total articles obtained from the above databases were screened with the 'abstract' or 'full-length copy', and irrespective of the type of experimental model, the articles tting into the inclusion criteria were considered for the study.Further, cross-references in the articles and reviews were searched wherever additional data was required.
The literature search completely was performed by H Shylaja, GL Viswanatha, and Sunil V; however, after concerning all the co-authors, the nal selection of articles for systematic review and meta-analysis was performed with inclusion and exclusion articles.

Inclusion criteria (Data items)
The original research articles published until April 2023 involving randomized controlled studies conducted on hesperidin against various cardiovascular disorders including metabolic disorders in healthy/diseased individuals having a comparison to placebo/control were included.

Parameters
The meta-analysis was performed for cardiovascular parameters such as blood pressure (both systolic blood pressure (SBP) and diastolic blood pressure (DBP) and lipid pro le (LDL, HDL, Total cholesterol (TC), Triglycerides (TG)).The above-listed parameters were compared between the control and hesperidin-treated group.

Risk of Bias (RoB) of included studies
The risk of bias shall be assessed with the Cochrane Collaboration risk assessment tool for RCTs

Data collection and analysis
All the studies were critically scrutinized distinctly as per the inclusion and exclusion criteria by the reviewers.The analysis was done initially at the title and abstract level, and later at the full-text level.
Data to be pulled out from the studies included details of experimental conditions, methods used, interventions, and outcome measurements.Wherever necessary, the numerical data from the graphs was extracted using Adobe Acrobat's XI in-built measuring tool (Adobe Systems Incorporated, San Jose, CA, USA)).Further, in the absence of a standard error of the mean (SEM) or standard deviation (SD), a default value of 10% of the mean was considered as SD for both hesperidin and control groups, instead of assigning zero.

Statistical analysis
The meta-analysis was performed using Review Manager (RevMan, version 5.4; Nordic Cochrane Centre [Cochrane Collaboration], Copenhagen, Denmark; 2014).For continuous, variables, inverse variance (IV) was estimated using the random-effects model with a standardized mean difference (SMD) as the effect measure.A random-effects model was used to calculate the pooled prevalence with a 95% con dence interval (CI).Heterogeneity was calculated with the I 2 statistic.This test evaluated the percentage of the difference between the results of the study that is due to heterogeneity than sampling error.I 2 of less than 40% was considered as not signi cant.On the other hand, the I 2 value of more than 40% was regarded as moderate to high heterogeneity.

Selection of articles
During the electronic search, we identi ed a total of 2905 records across various databases, namely, PubMed/Medline (n = 84) and Google Scholar (n = 2820) based on the pre-de ned search criteria.Upon applying the inclusion and exclusion criteria a total of 9 research articles were selected for systematic review meta-analysis out of 2905 records identi ed during the preliminary search.The duration of included studies varied from a single day to multiple days.In all the included studies the pure form of hesperidin was used at different dose levels.The search strategy and descriptions of the studies included in this review have been summarized in Figure . 1 and Table 1 respectively.

Risk of bias in the included studies
The risk of bias assessment for included studies is included in Figure .2.

Effect of Hesperidin on Blood Pressure
The effect of hesperidin on blood pressure has been evaluated across various studies.Interestingly, hesperidin administration has signi cantly reduced the systolic blood pressure (SBP) (IV: -0.86 (-1.53 to -0.18) at 95% CI, p = 0.01, I 2 = 100%), however, there was no statistically signi cant difference in the diastolic blood pressure (DBP) (IV: 0.52 (-1.78 to 2.83) at 95% CI, p = 0.06, I 2 = 100%) compared with control.The lack of statistical signi cance in the diastolic blood pressure compared to control is considered due to signi cant heterogenicity among the included studies.Based on the available evidence hesperidin administration has shown potential bene t in reducing systolic blood pressure.The results are depicted as forest plots in Figure.
The results are illustrated as forest plots in Figure .5,6,7, and 8.

Discussion
There are several clinical studies published on the cardiovascular bene ts of hesperidin.In addition, there is a meta-analysis published by Mohamaddi et.al., 2019 has reported that hesperidin supplementation does not affect blood pressure and lipid pro le (Mohamaddi et.al., 2019).However, Mohammadi et.al.have considered the studies published on both orange juice and hesperidin, and secondly, the comparisons were not solely between hesperidin vs placebo/control.Furthermore, there are two additional randomized control trials published on hesperidin related to its cardiovascular effects after the publication of the above-cited meta-analysis.The present systematic review and meta-analysis were performed to determine the bene cial effect of hesperidin in alleviating the altered blood pressure and lipid pro le among patients with cardiovascular diseases.Considering the clinical studies published up to 2021, having a comparison between hesperidin vs placebo/control.Worldwide, there are about 1.28 billion people who have hypertension whose age is between 30-79 years.Hypertension is one of the major causes of premature death and cardiovascular disease globally.
Hypertension can cause damage to the arteries cells of the inner lining.When fat enters the bloodstream through diet, it can accumulate in these damaged arteries.Eventually, the walls of the arteries become less elastic and limit the ow of blood throughout the body which leads to cerebrovascular diseases like coronary artery diseases (angina, arrhythmia, and heart attack), heart failure, transient ischemic attack, stroke, dementia, and mild cognitive impairment.As per the available literature, treatment for lowering blood pressure signi cantly reduces the risk of cardiovascular disease and death (WHO; 2023).Reduction of systolic blood pressure by 10 /mm Hg reduces the risk of heart failure by 28%, cardiovascular disease by 20%, stroke by 27%, coronary heart disease by 17%, and all-cause mortality by 13% (Ettehad et.al., 2016).Lifestyle modi cations like quitting smoking, and tobacco, being more active, and having a healthier diet may reduce the risk of hypertension.Some patients still need medicines to lower their blood pressure.Medicines that are commonly used to treat hypertension are ACE inhibitors (Ex.enalapril and lisinopril), Calcium channel blockers (Ex.amlodipine and felodipine), Angiotensin-2 receptor blockers (ARBs) (Ex.losartan and telmisartan), and diuretics (Ex.hydrochlorothiazide and chlorthalidone) (WHO 2023).Apart from these allopathic medicines, some herbs and their supplements are also used to treat hypertension.The most commonly used herbs for the treatment of hypertension are garlic (Allium sativum), custard apple (Annona muricate), Tea (Camellia sinensis), Ajwain (Carum copticum), Carrot (Daucus carota), Flaxseed (Linum usitatissimum), Tomato (Lycopersicon esculentum), Basil (Ocimum basilicum), Pomegranate (Punica granatum), Radish (Raphanus sativus), avonoids, polyphenols, and so on (Tabassum et.al., 2011).Hesperidin reduces blood pressure by decreasing oxidative stress through ther enin-angiotensin system cascade suppression (Mas-Capdevila et.al., 2020).
Notably, this meta-analysis revealed that hesperidin administration has signi cantly reduced the systolic blood pressure, however, there was no statistically signi cant difference in the diastolic blood pressure compared with control.The lack of statistical signi cance in the diastolic blood pressure compared to control is considered due to signi cant heterogenicity among the included studies.
Numerous studies show that the increase in the levels of triglyceride (TG) and total cholesterol (TC) might affect the contraction of blood vessels in the heart, which is signi cantly associated with the risk of cardiovascular disease.Furthermore, increases in the level of LDL could induce arteriosclerosis due to the buildup of LDL in the intima-media of the arteries, which in turn leads to thrombocytopoiesis.As per available scienti c data, HDL is inversely proportional to cardiovascular disease.Higher the HDL level, the lesser the risk of emerging cardiovascular disease.It is also believed that HDL acts by reverse cholesterol transport where HDL interacts with cells in systemic vasculature by a series of reactions and disposes of excess cholesterol as bile salts by transferring it to the liver (Filippatos et.al).Medicines that are used to lower the lipid pro le are of two types namely statins (Ex.lovastatin, simvastatin, uvastatin, atorvastatin, rosuvastatin, etc.) and brates (Ex.cipro brate, clo brate, feno brate, etc.).Based on the available literature some of the herbs and herbal supplements can also be used for lowering lipid pro le.Some of the herbs containing hypolipidemic agents are basil, ginger, dill oil, tea, grapes, and so on.
This systematic review and meta-analysis revealed that the administration of hesperidin has alleviated the triglycerides levels compared to placebo/control in the subjects with cardiovascular diseases compared.However, hesperidin administration has not elicited a bene cial effect on LDL, HDL, and total cholesterol compared to the placebo/control.In summary, this systematic review and meta-analysis revealed that the administration of hesperidin has alleviated systolic blood pressure and triglycerides in subjects with cardiovascular diseases.However, there is no better bene cial effect of the administration of hesperidin on diastolic blood pressure, LDL, HDL, and total cholesterol compared with the placebo/control.However, the heterogenicity between the studies is considered one of the concerns for all the parameters evaluated except triglycerides.The outcome of this meta-analysis is slightly in contrast to the ndings of Mohammadi et.al, related to systolic blood pressure and triglycerides.The possible reasons may be rstly Mohammadi et.al., have considered the studies published on both orange juice and hesperidin; secondly, in Mohammadi et.al., the comparisons were not solely between hesperidin vs placebo/control, and lastly, in this meta-analysis there are two additional randomized controlled trials published on hesperidin have been included.

Limitations
Though there are several clinical studies published on hesperidin related to its cardiovascular bene ts.In this meta-analysis, we found hesperidin is bene cial in alleviating only elevated systolic blood pressure and serum triglycerides.However, the trend shows that hesperidin has also got the potential to alleviate diastolic blood pressure and other lipid parameters, while these changes are not re ected in the summary because of the signi cant heterogenicity between the available studies.The possible reasons may be differences in the population included (both diseases and healthy individuals), and the available studies are conducted at different locations by different study groups with different study characteristics.There is further scope for conducting multicentric, double-blind placebo-controlled trials involving patients/subjects with underlying cardiovascular conditions.

Conclusion
Based on the available evidence, the present systematic review and meta-analysis suggest that hesperidin supplementation could be an adjuvant in alleviating elevated systolic blood pressure and triglycerides in patients suffering from cardiovascular diseases.

Figure 2 Risk
Figure 2

Figure 3 Effect
Figure 3

Figure 7 Effect
Figure 7