The effects of raspberry consumption on lipid profile and blood pressure in adults: A systematic review and meta‐analysis

Abstract Research into the effects of raspberry on blood pressure and lipid profiles is inconclusive. This meta‐analysis was aimed to determine whether raspberry has beneficial effects in clinical practice and to what extent these effects are associated with blood pressure and lipid profiles. A systematic literature search up to September 2023 was completed in PubMed/Medline, Scopus, and Web of Science, to identify eligible RCTs. Heterogeneity tests of the selected trials were performed using the I 2 statistic. Random effects models were evaluated based on the heterogeneity tests, and pooled data were determined as weighted mean differences with a 95% confidence interval. Eleven randomized controlled trials (with 13 arms) were eligible for this meta‐analysis. Our findings revealed that Raspberry consumption had no significant effects on the blood pressure and lipid profile markers, including systolic blood pressure (SBP) (WMD, −0.37 mm Hg; 95%CI: −2.19 to 1.44; p = .68), diastolic blood pressure (DBP) (WMD, −2.14 mm Hg; 95%CI: −4.27 to 0.00; p = .05), total cholesterol (TC) (WMD, −6.83 mg/dL; 95%CI: −15.11 to 1.44; p = .10), triglycerides (TG) (WMD, −5.19 mg/dL: 95%CI: −11.76 to 1.37; p = .12), low‐density lipoprotein‐cholesterol (LDL‐C) (WMD, −5.19 mg/dL; 95%CI: −11.58 to 1.18; p = .11), and high‐density lipoprotein‐cholesterol (HDL‐C) (WMD, 0.82 mg/dL; 95%CI: −1.67 to 3.32; p = .51), compared to control groups. Subgroup analysis showed that raspberry consumption significantly decreased total cholesterol and LDL‐C levels in people with elevated TC levels, metabolic syndrome, and andropause symptoms, as well as those older than 35, while the consumption of raspberries led to a significant increase in HDL‐C levels in females, obese, under 35, and healthy individuals. Raspberry can improve lipid profile and blood pressure, but it is important to keep in mind that further research is necessary to fully understand the exact mechanism of action and a definite conclusion in this regard.


| INTRODUC TI ON
Hypertension and dyslipidemia are the principal risk factors for cardiovascular diseases (CVD) (Ke et al., 2018).Despite extensive research, diagnostic tools, and effective treatment, they are the leading causes of CVD mortality and disability-adjusted life years worldwide (Forouzanfar et al., 2016).When hypertension and dyslipidemia coexist, their combined negative effect on the cardiovascular system is greater than the sum of their separate effects (Borghi, 2002;Ke et al., 2018).Interestingly, it has been demonstrated that CVD risk can be significantly reduced using therapeutic approaches that target both hypertension and dyslipidemia (Borghi et al., 2022;Schwalm et al., 2016).This bidirectional synergistic effect indicates endothelial dysfunction plays a crucial role in the development of both hypertension and dyslipidemia (Dąbrowska & Narkiewicz, 2023).
In contrast to the noticeable negative effects of pharmaceutical treatments, nutritional interventions for disease management are often well-tolerated (McInnes, 2005).Dietary Approaches to Stop Hypertension (DASH) diet, losing weight, and getting more exercise are the main ways to treat high blood pressure.Numerous randomized controlled trials on humans have shown that certain foods reduce blood pressure and protect the heart (Mansour et al., 2015;Wightman & Heuberger, 2015).Raspberry was among the foods that gained attention.Raspberry bioactive compounds like polyphenols, anthocyanins, and dietary fiber (Nile & Park, 2014) have been proposed to impact lipid metabolism, With the potential to improve lipid profile through modulating enzymes involved in lipid digestion, absorption, and synthesis (Teng et al., 2017), raspberry has been found to be effective in treating dyslipidemia, hypertension, diabetes, and obesity, and it also has anti-inflammatory and antioxidant properties (Harasym & Oledzki, 2014).The prevention and treatment of atherosclerosis and the improvement of endothelial cell function have both been linked to raspberry.Raspberry extract was shown to reduce blood pressure in a rat model of essential hypertension (Lee et al., 2014).Raspberry's impact on blood pressure has only been evaluated in a small number of human-controlled studies (Basu et al., 2010;Erlund et al., 2008).Blood pressure was successfully reduced in a clinical trial using a mixture of berries that included black raspberry.Eight weeks after starting treatment, prehypertensive patients who consumed black raspberries had significantly reduced 24-hour blood pressure (Jeong, Hong, et al., 2016;Jeong, Kim, et al., 2016).The use of raspberries has been shown in one human clinical trial to improve vascular endothelial function and reduce total cholesterol and inflammatory cytokines levels in patients with metabolic syndrome (Myung et al., 2016).Black raspberry has been shown to improve vascular function, lipid profiles, and blood pressure in a few studies (Ash et al., 2011;McAnulty et al., 2014).
While the aforementioned points do raise the possibility of positive outcomes, research into the effects of raspberry on blood pressure and lipid profiles remains inconclusive.Accordingly, this meta-analysis was conducted to determine whether raspberry has beneficial effects in clinical practice and to what extent these effects are associated with blood pressure and lipid profiles.

| ME THODS
All stages of designing and conducting this systematic review were based on the Preferred Reporting Items of Systematic Reviews and Meta-Analysis (PRISMA) method (Moher et al., 2009).The protocol of this meta-analysis was registered in the PROSPERO database with registration code: CRD42023470302.

| Search strategy
To find relevant studies, Web of Science, Medline, and Scopus databases were comprehensively searched until September 2023.This search was designed using the PICOS method framework (Participant: adults, Intervention: raspberry consumption, Comparison: control group, Outcome: lipid profile and blood pressure, Type of study: Randomized controlled trials (RCTs)) (Methley et al., 2014).
Two researchers independently (M.Sh.J and H.B) screened the found studies based on their titles and abstracts.The reference of the final related articles was checked to reduce the possibility of missing related studies.Also, the Google Scholar search engine was searched manually.

| Study selection
The inclusion criteria for this review included (a) interventional studies, (b) raspberry consumption, (c) RCTs, and (d) adult participants.
Animal interventions, non-interventional studies (observational studies, review articles, short communication, letters to the editors), absence of a control group, lack of reporting related outcomes, and conducting studies in people under 18 years of age were the exclusion criteria of this systematic review.

| Data extraction
Data related to this review were independently extracted by two authors (H.B and M.R).Relevant information includes the first author's name, study country, publication date, study design, sample size and number of subjects in each group, characteristics of participants (gender, mean age, mean BMI, and health status), type and duration of intervention with raspberry, type of the control group, and the mean difference and the standard deviation (SD) of the outcomes during the intervention with raspberry (or the mean levels of the outcomes and the standard deviation at the beginning and the end of the intervention).The cases of disagreement were discussed until reaching a consensus.

| Quality assessment
The quality of the studies was assessed by two researchers (M.Sh.J and H.B) independently using the Cochrane Collaboration risk of bias tool (Higgins & Green, 2010).This tool assessed the risk of bias in seven subclasses including random sequence generation, allocation concealment, selective reporting, incomplete outcome data, blinding of participants and personnel, blinding of outcome assessor, and other potential sources of bias in three levels: low, unclear, and high.If the number of high-risk bias items for each study was less than 2, it is considered as general low risk of bias; if it was 2, it is considered as moderate, and if it was greater than 2, it is considered as general high risk of bias.Disagreements were discussed in consultation with a third author (M.M).

| Statistical analysis
The overall effect of raspberry intake on lipid markers and blood pressure was estimated by employing the weighted mean differences (WMD) and 95% confidence interval (95%CI) in each group based on the random effects model (DerSimonian & Laird, 1986).
If the mean changes were not reported, it was calculated by subtracting the parameters' mean levels at the interventions beginning from the end.SD changes were estimated using the following formula: SD change = square root [(SDbaseline) 2 + (SDfinal) 2 − (2 × R × S Dbaseline × SDfinal)] (Borenstein et al., 2021).
The standard error (SEs), interquartile range (IQRs), and 95%CI were converted to SDs using the method of Hozo et al. (2005).The units of all reported lipid markers (TC, TG, LDL-C, and HDL-C) were converted to mg/dL and blood pressure to mmHg.Heterogeneity between studies was evaluated by performing Cochran's Q test and the measure of the I-square (I 2 ) statistic (Higgins et al., 2003).
Subgroup analysis to identify the source of heterogeneity based on predetermined criteria (Higgins & Thompson, 2002), including country (Korea and None-Korea), age (≥35 and <35), gender (both sexes, males, and females), study design (parallel and crossover), baseline BMI (normal, overweight, and obese), health status, duration of intervention (≤8 and >8 weeks), type of intervention (black raspberry and none-black raspberry), general risk of bias (low and moderate), and outcome values at baseline.Egger's regression and visual interpretation of the funnel plots were used to check the publication bias (Egger et al., 1997).Sensitivity analysis was conducted to investigate the influence of the sample size and quality of each study on the outcomes' pooled effect sizes using the leave-one-out method (Duval, 2005;Tobias, 1999).All the analyses performed in this meta-analysis were performed using Stata version 17 software, and the p-values <.05 were considered statistically significant.

| Certainty assessment
The quality of certainty of the studies investigating the effect of raspberry consumption on lipid profile and blood pressure included in this review was evaluated using the GRADE guideline (Grading of Recommendations Assessment, Development, and Evaluation) (Guyatt et al., 2008).The certainty quality of the evidence used for each of the five areas (Risk of bias, Publication Bias, Inconsistency, Indirectness, and Imprecision) was classified into three groups: no serious limitation, serious limitation, and very serious limitation.The overall quality of the evidence was leveled into four: high, moderate, low, and very low.

| Study selection
Among the 121 studies found by the initial search, 40 duplicate results were removed.The remaining 81 research were used to be screened.
The general risk of bias of Mosah et al. (2015) was considered moderate, while the rest of the general risk of bias was low.Also, the majority of the included studies were deemed to be of good quality, although the studies conducted by Franck et al. (2022), and Mosah et al. (2015) were assessed as being of fair quality.
The details of the risk of bias assessment in each subclass are presented in Table 2.

| Adverse events
Among the included studies, five did not report the adverse effects that occurred (Franck et al., 2022;Jeong et al., 2014;Mosah et al., 2015;Park et al., 2015;Schell et al., 2019), no adverse events occurred in four studies (Cho et al., 2020;Franck et al., 2020;Jeong, Hong, et al., 2016;Jeong, Kim, et al., 2016), and complications were reported in only two studies (An et al., 2016;Jung et al., 2023).In An et al. (2016), the side effects in the group that received raspberry with a high dose included insomnia, nausea, and skin rash, and in the group that received raspberry with a low dose, it included diarrhea, nausea, abdominal pain, skin rash, and fever.In this study, complaints of fatigue, skin rash, and abdominal pain were reported even in the placebo control group.In another study conducted by Jung et al. (2023), although the relationship between intervention and complaint was ruled out, complications including oral leukoplakia, heartburn, elevated T-PSA, upper respiratory infection, and dysuria were reported in the group receiving black raspberry extract.Abbreviations: L, Low; H, High; U, Unclear.

|
However, significant heterogeneity was observed among the included studies (I 2 = 67.8%;p = .002)(Figure 2a).The subgroup analysis, which was conducted to find the source of heterogeneity, showed a significant reducing effect of raspberry consumption on total cholesterol levels in participants with metabolic syndrome, borderline-high cholesterol, andropause symptoms, overweight, older than 35 years, and with the baseline elevated serum cholesterol levels (>200 mg/dL) (Table 3).

| Effect of raspberry consumption on serum TG levels
Meta-analyzing 10 effect sizes showed that raspberry consumption could not significantly change serum TG levels compared to control groups (WMD, −5.19 mg/dL; 95%CI, (−11.76 to 1.37); p = .12;402 participants).Also, heterogeneity among the included studies was not significant (I 2 = 12.6%; p = .32)(Figure 2b).Subgroup analysis indicated that raspberry intake significantly decreased serum TG levels in studies conducted on both sexes (Table 3).

| Effect of raspberry consumption on serum LDL-C levels
The combination of nine effect sizes showed that receiving raspberry had no significant effect on serum LDL-C levels (WMD, −5.19 mg/dL; 95%CI, (−11.58 to 1.18); p = .11;380 participants).While heterogeneity between studies was significant (I 2 = 53.7%;p = .02)(Figure 2c), the subgroup analysis reported the significant effect of raspberry intake on LDL reduction in studies with more than 8-week duration, and those conducted on participants with metabolic syndrome, borderline-high cholesterol, andropause symptoms, overweight, and more than 35 years (Table 3).

| Effect of raspberry consumption on serum HDL-C levels
The combination of eight effect sizes demonstrated a nonsignificant effect of raspberry consumption on serum HDL-C levels (WMD, 0.82 mg/dL; 95%CI, (−1.67 to 3.32); p = .51;303 participants).
However, significant heterogeneity was detected among the included studies (I 2 = 69.2%;p = .002)(Figure 2d).The significant increasing effect of raspberry intake on serum HDL levels in studies conducted in non-Korean countries, with moderate general risk of bias, interventions with none-exclusively black raspberries, and in obese, females, 35 years old or younger, and healthy subjects, was reported by subgroup analysis (Table 3).

| GRADE analysis
The assessment of the quality of evidence examined in this metaanalysis was done based on the GRADE protocol (Guyatt et al., 2008).
The certainty of the evidence of the effect of raspberry consumption on total cholesterol, LDL-C, and HDL-C was downgraded to low due to serious limitations in inconsistency and imprecision.The evidence used to investigate the effect of raspberry consumption on TG, SBP, and DBP moderate quality was mentioned due to serious limitations in imprecision.The grade profile for the evidence included in this meta-analysis is shown in Table 4.In the meta-analysis study by Nikparast et al. (2023) published in 2023, the review of six RCTs showed that raspberry and blackcurrant have no effect on lowering blood pressure.In another review (2020) that investigated the effect of berries, including raspberries, on cardiovascular risk factors, no significant effect on the improvement of these factors was seen (Wang et al., 2021).It should be mentioned that in this review, only one RCT that investigated the effect of raspberries on DBP and SBP was included (Jeong, Hong, et al., 2016).
Raspberry, specifically red raspberry (Rubus idaeus), has been studied for its potential health benefits, including its role in improving hypertension and lipid profile.The mechanism of action by which raspberry may exert this effect is not fully understood.Some studies have provided insights into its potential mechanisms.The authors highlighted that raspberries are abundant sources of bioactive compounds such as polyphenols, anthocyanins, and dietary fiber, which have been presented to influence lipid metabolism.They suggested that these compounds may modulate enzymes involved in lipid digestion, absorption, and synthesis, ultimately leading to the improvement of lipid profile (Teng et al., 2017).The cholesterol-lowering effect of raspberry might be attributed to the inhibition of hepatic cholesterol synthesis by inhibiting β-hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase and increased fecal excretion of bile acids (Wang et al., 2012).Also, upregulate the hepatic LDL-C receptor expression (Tu et al., 2019).
The researchers found that raspberry ketone treatment significantly reduced intracellular lipid accumulation by inhibiting fatty acid synthesis, promoting fatty acid oxidation, and inhibiting lipogenesis by decreasing the levels of the peroxisome proliferator-activated receptor γ (PPARγ) mRNA in adipose tissues (Askar et al., 2023).These findings suggest that raspberry ketone may contribute to lowering blood cholesterol levels by modulating lipid metabolism.Raspberry ketone treatment significantly decreased triglyceride accumulation (e) (f) and increased lipolysis.The researchers proposed that these effects were mediated by activating adiponectin signaling, a hormone involved in regulating lipid metabolism (Park, 2010).Moreover, the expression of the CCATT/enhancer-binding protein α (C/EBPα), sterol regulatory element-binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) mRNAs was decreased (Oh et al., 2016).Also, phosphorylation of 5′ adenosine monophosphate-activated protein kinase (AMPK) in the liver increased.This, in turn, led to a decrease in cholesterol biosynthesis due to the inhibition of SREBP-2 activation (Cho et al., 2020).
As shown in the results of the present meta-analysis and also mentioned in the first paragraph of the discussion, the effect of raspberry in improving the lipid profile, including the reduction of TC and LDL-C in people who are exposed to lipid disorders, such as overweight people and over 35 years old.It is more obvious that this shows the regulating effect of raspberry on the lipid profile, and it cannot be concluded that it only reduces the level of TC and LDL-C.Also, long-term intervention (more than 8 weeks) is more effective.One of the factors that are effective in increasing the level of HDL-C is dietary antioxidants.In this meta-analysis, it was also shown that red raspberry, which is thought to have a higher level of antioxidants, significantly increased the level of HDL-C.Also, in general, the level of HDL-C in women is higher than that of men due to hormonal factors, and their response to raspberry was also significant in increasing the level of HDL-C.
The polyphenolic compounds present in raspberries enhanced nitric oxide production and improved endothelial function (Lee et al., 2014).Nitric oxide helps relax blood vessels, resulting in better blood flow and potentially lower blood pressure.Furthermore, polyphenols inhibited enzymes like endothelin-1 related to vasoconstriction, enhancing vasodilation, and reducing oxidative stress (Nikparast et al., 2023).Delphinidin-3-O-sambubiosides and cyanidin-3-O-sambubiosides in black raspberry play an effective role in regulating blood pressure through the inhibition of reninangiotensin system (Lee et al., 2014).These mechanisms collectively promote a healthier cardiovascular system and may contribute to blood pressure reduction.
Based on the information provided, it seems that the meta-analysis conducted on the effect of raspberry on lipid profile and blood pressure had some limitations.These include a small number of eligible studies for meta-analysis and low quality of the most included RCTs.
The heterogeneity among the included RCTs was also high.
Furthermore, the sensitivity analysis results for TC, TG, and LDL-C did not allow for a definite conclusion regarding the effectiveness of raspberry.The grade test indicated moderate-to-lowquality results, suggesting that more and better RCTs are needed in this field to draw a definitive conclusion.

| CON CLUS ION
While this study provides some insights into the potential mechanisms underlying raspberry's effects on improving lipid profile and blood pressure, it is critical to consider that further research TA B L E 4 GRADE profile of raspberry consumption for lipid profile and blood pressure.
Meta-analysis3.4.1 | Effect of raspberry consumption on serum TC levelsPooling of nine effect sizes showed a non-significant effect of raspberry consumption on serum total cholesterol levels (WMD, −6.83 mg/dL; 95%CI, (−15.11 to 1.44); p = .10;380 participants).TA B L E 2 Risk of bias assessment.General Low risk <2 high risk, General moderate risk = 2 high risk, General high risk >2 high risk.
review and meta-analysis study with the review of 13 RCTs showed that the consumption of raspberries reduces the serum level of TC in subjects who are overweight, over 35 years old and with high cholesterol level.LDL-C is reduced in the intervention group for more than 8 weeks with raspberries and in subjects with overweight and aged over 35 years.The level of HDL-C increases in black raspberry group, women, obese, subjects over 35 years old, and healthy group.Also, the intervention with raspberry has been effective in reducing DBP in less than 8-week intervention and in men and healthy subjects.

1
Flowchart of study selection for inclusion trials in this meta-analysis.
studies in meta-analysis.
(Schell et al., 2019)ell et al., 2019), Subgroup analyses of raspberry consumption on lipid profile and blood pressure in adults.