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The effect of cinnamon supplementation on blood pressure in adults: A systematic review and meta-analysis of randomized controlled trials
Clinical Nutrition ESPEN xxx (xxxx) xxx
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Review
The effect of cinnamon supplementation on blood pressure in adults: A systematic review and meta-analysis of randomized controlled trials Amir Hadi a, Marilyn S. Campbell b, Bahar Hassani c, d, Makan Pourmasoumi e, f, Ammar Salehi-sahlabadi g, Seyed Ahmad Hosseini h, * a
Halal Research Center of IRI, FDA, Tehran, Iran Department of Kinesiology and Health Promotion, University of Kentucky, Lexington, KY, USA Department of Nutrition, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran d Department of Health Safety and Environment (HSE), Razi Petrochemical Company, Mahshahr, Iran e Food Security Research Center and Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran f Universal Scientific Education and Research Network (USERN), Tehran, Iran g Student Research Committee, Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran h Nutrition and Metabolic Disease Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran b c
a r t i c l e i n f o
s u m m a r y
Article history: Received 22 October 2019 Accepted 3 January 2020
Background & aims: Several clinical trials have shown that cinnamon can reduce blood pressure, but the results are controversial. Therefore, we conducted a systematic review and meta-analysis to provide a more precise estimate of the overall effects of cinnamon supplementation on blood pressure in adults. Methods: We searched PubMed, Scopus, Cochrane Library, ISI Web of Science, and Google Scholar databases through September 2019 to identify randomized clinical trials (RCTs) investigating the effect of cinnamon supplementation on blood pressure. Data were pooled by using the random-effects model, and weighted mean difference (WMD) was considered as the summary effect size. Sensitivity analysis was conducted using the leave-one-out method. Results: Meta-analysis of 9 RCTs with 641 participants showed significant reductions in both systolic (WMD: 5.17 mmHg, 95% CI: 9.35 to 0.99, P ¼ 0.01) and diastolic blood pressure (WMD: 3.36 mmHg, 95% CI: 5.67 to 1.04, P 0.001) after cinnamon supplementation. Subgroup analyses indicated that these results were significant only when cinnamon was administered at the dosages of 2 g/day, for a period longer than 8 weeks, and in participants with a baseline BMI of 30 kg/m2. Conclusion: The present meta-analysis suggests that cinnamon supplementation can improve blood pressure by a modest degree. However, due to limited availability of studies with hypertensive cases and relatively small sample sizes of available studies, well designed trials with adequate sample sizes aimed at hypertensive populations are recommended. © 2020 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
Keywords: Cinnamon Blood pressure Systematic review Meta-analysis
1. Introduction High blood pressure, commonly known as hypertension (HTN), is a global health problem that affects more than one billion individuals and causes an estimated 9.4 million deaths per year [1]. Accumulating evidence has also suggested that
* Corresponding author. E-mail address: [email protected] (S.A. Hosseini).
there is a positive association between HTN and the risk of chronic diseases, including cardiovascular disease [2], stroke [3], and kidney dysfunction [4], which are leading causes of mortality worldwide. Therefore, HTN not only has an impact directly on the individual but also incurs a significant cost to the government and a burden to the community [5]. As result, adopting appropriate strategies to control blood pressure is important for any healthcare system. Lifestyle modifications, including adherence to a healthy diet (rich in fruits, vegetables and low-fat dairy products with
https://doi.org/10.1016/j.clnesp.2020.01.002 2405-4577/© 2020 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Hadi A et al., The effect of cinnamon supplementation on blood pressure in adults: A systematic review and metaanalysis of randomized controlled trials, Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2020.01.002
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sodium restriction) and increased physical activity, as well as pharmacotherapy, are regarded as the most important strategies for blood pressure management [6,7]. However, given the undesirable side effects of synthetic drugs [8], the number of people choosing plant based-therapies as an alternative to control blood pressure is increasing [9]. In this regard, herbs and spices have attracted significant attention recently, both in the scientific and consumer communities due to their safety, popularity, ease of access, and reduced number of side effects [10]. Cinnamon, from the genus Cinnamomum and Lauraceae family, is a spice derived from the inner bark of a tropical evergreen tree [11]. It is one of the most widely used flavoring agents in the food and beverage industry worldwide [12]. This spice was reported as a traditional remedy for several diseases including the common cold, gastrointestinal disorders, and diabetes [12,13]. The main components found in cinnamon are cinnamaldehyde, cinnamic acid, eugenol, and coumarin, which play key roles in different biological activities, such as anti-microbial, anti-inflammatory, antioxidant, antifungal, and anti-diabetic activities [14,15]. Cinnamon also exhibits hypotensive effects, and it is postulated that anti-oxidant and anti-inflammatory properties of cinnamon might be responsible for these hypotensive effects [16]. However, in clinical settings, the effects of cinnamon on blood pressure are controversial. Some clinical trials have found that cinnamon supplementation can decrease blood pressure [17e21], but others [22e25] have not reported any beneficial effects on blood pressure after cinnamon supplementation. In 2013, Akilen et al. [26] published a metaanalysis on this topic that included only 3 clinical trials representing 139 participants. The results indicated that cinnamon supplementation significantly decreased systolic blood pressure (SBP) and diastolic blood pressure (DBP) relative to the control group. However, the limited number of trials included in the aforementioned meta-analysis suggests that their findings could be biased by sample size. In addition, more randomized controlled trials (RCTs) with larger samples sizes have been published since then. Therefore, we conducted an updated systematic review and meta-analysis to provide a more precise estimate of the overall effects and safety of cinnamon supplementation on blood pressure in adults.
2. Methods The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [27] were followed to perform and report the current meta-analysis.
2.1. Search strategy Studies published from inception to September 2019 were identified through electronic searches of six databases: PubMed, Scopus, Cochrane Library, ISI Web of Science, and Google Scholar. No restrictions on the language, publication date, or other filters were applied. For this purpose, we used MESH (Medical Subject Heading) and non-MESH keywords including the following: ("Cinnamomum zeylanicum" OR "Cinnamomum" OR "Cinnamon" OR "Cinnamons" OR "Cinnamomum verum") AND ("blood pressure" OR "systolic blood pressure" OR "diastolic blood pressure" OR "hypertension"). In addition, references from the articles retrieved and previous review articles were manually reviewed to identify further relevant studies.
2.2. Study selection A two-stage screening process consisting of a title and abstract scan and a full-text review was used to ensure the accurate identification of eligible studies. Studies were included if they met all of the following inclusion criteria: a) Study design: RCT with either a parallel or crossover design; b) Population: adult participants (aged 18 years) (healthy or otherwise); c) Intervention: investigated cinnamon as an intervention for over 4 weeks; d) Comparators: placebo or a comparison group were used; and e) Outcomes: including SBP and DBP. The exclusion criteria included: a) nonrandomized, non-control, or experimental studies; b) studies on cinnamon in combination with other herbs or ingredients as a mixture; and c) studies with lack of sufficient data required for meta-analysis. If duplicate publications from the same study were identified, the publication with the largest number of cases from the study was included. Two investigators (A.H. and M.P.) conducted study selection and held further discussion to resolve any disagreement after reviewing the original article. 3. Data extraction Data were extracted by two independent reviewers (A.H. and M.P.) using a pre-defined form. Any disagreement regarding the data extraction was discussed until agreement was reached. The following characteristics were extracted from each selected study: first author's name, year of publication, study design, sample size, age, body mass index (BMI), sex of participants, health status of subjects, study duration, details of the strategy administered to the intervention and the control groups, and results observed. When these characteristics were not reported in available publications, we contacted the corresponding author to acquire the necessary data. 3.1. Quality assessment The Cochrane risk of bias tool [28] was used to assess each study as having low, high, or unclear risk of bias on 7 criteria: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessments, incomplete outcome data, selective reporting, and other biases. Finally, the overall quality of the studies was categorized into weak, fair, or good, if < 3, 3, or 4 domains were rated as low risk, respectively. Two authors (A.H. and M.P.) independently conducted the quality assessment. When disagreement occurred, final scores were discussed by the authors until consensus was reached. 3.2. Statistical analyses Data were analyzed using Stata version 12.0 software (StataCorp, College Station, Texas, USA). Blood pressure was measured in mmHg. The effect size of each study was calculated from mean and standard deviation (SD) of the outcomes before and after the intervention and presented as weighted mean difference (WMD) with 95% confidence intervals (CI). If only SD for the baseline and final values was provided, SD for the net changes was assigned based on the Follmann method [29] using a correlation coefficient of 0.5. In studies where the standard error (SE) was reported, SD was calculated as follows: SD ¼ SE sqrt (n), where n is the number of participants in each group. Due to the fact that selected RCTs were carried out in different settings, the random-effects model was employed to calculate the overall effect from effect sizes. Heterogeneity was examined using the I-squared (I2) index [30]. Subgroup analyses based on cinnamon dosage, duration of supplementation, and baseline BMI of subjects were conducted to
Please cite this article as: Hadi A et al., The effect of cinnamon supplementation on blood pressure in adults: A systematic review and metaanalysis of randomized controlled trials, Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2020.01.002
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determine the source of heterogeneity if the I2 value was >50%. Sensitivity analysis was also performed to evaluate the potential bias and robustness of the overall effect estimate by omitting one study at a time. Given that the effect size of each outcome was less than 10, we were not able to create funnel plots, and the existence of publication bias was inspected only through Egger's regression model [31]. All tests were two-sided. A P value < 0.05 was considered statistically significant. 4. Results Our search yielded 321 studies for an initial review. Following the removal of duplicates, 186 were retained. We excluded 173 irrelevant references by reading titles and abstracts. In the next step, 4 papers were excluded based on the full-text review. These exclusions were due to the following reasons: administered cinnamon in combination with other components (n ¼ 2), no control group (n ¼ 1), and insufficient data for outcomes (n ¼ 1). As a result, a total of nine articles consisting of 641 participants, with 318 participants in the intervention group and 323 in the control group, were identified as eligible for the present meta-analysis. The detailed steps of the selection process are summarized in Fig. 1.
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22 to 135 participants, with a mean age ranging from 44.3 to 61.7 years. The trials were from six different countries including Iran [18,22,23], USA [20,24], UK [21], India [19], Thailand [17], and Israel [25]. Eight studies included both male and female participants [17,19e25], and one study included only female participants [18]. The baseline BMI of the participants indicated that all trials except one [17] examined primarily overweight and obese subjects (BMI >25 kg/m2). The length of interventions ranged from 8 to 16 weeks, and cinnamon supplementation dosage ranged from 0.5 to 10 g/ day. Participants in these studies were patients with type 2 diabetes [17,21e23], individuals with metabolic syndrome [19], patients with rheumatoid arthritis [18], and pre-diabetic subjects [20,24]. 4.2. Risk of bias and quality of evidence According to the Cochrane risk of bias tool, seven trials were classified as good quality [17e19,21,22,24,25] and two [20,23] as fair quality. Table 2 presents details of the study quality assessment of the included studies. 5. Meta-analysis results 5.1. Systolic blood pressure
4.1. Study characteristics
Identification
The characteristics of the included studies are outlined in Table 1. All trials adopted a parallel study design, and they were conducted between 2006 and 2018. The sample sizes ranged from
The pooled estimate from the random-effects model performed on 9 trials showed that cinnamon supplementation significantly decreased SBP (WMD: 5.17 mmHg, 95% CI: 9.35 to 0.99, P ¼ 0.01) with a significant between-study heterogeneity
Articles identified through database searches (n=321)
Eligibility
Screening
Records after duplicates removed (n=186)
Articles removed by title/abstract (n=173) Records screened (n=186)
Full-text articles assessed for eligibility (n=13)
Without sufficient data (n=1) Without control group (n=1)
Included studies in qualitative synthesis (n=9)
Included
Articles removed after full-text review (n=4):
In combination with other components (n=2)
Included studies in quantitative synthesis (metaanalysis) (n=9)
Fig. 1. PRISMA flow diagram of study selection process.
Please cite this article as: Hadi A et al., The effect of cinnamon supplementation on blood pressure in adults: A systematic review and metaanalysis of randomized controlled trials, Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2020.01.002
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Table 1 Characteristics of included studies. First author (publication year)
Country
RCT design (blinding)
Ziegenfuss (2006)
USA
Parallel (Yes) 22
Both
46.3
32.3
12
Pre-diabetes
10 g/day cinnamon
Akilen (2010)
UK
Parallel (Yes) 58
Both
54.6
32.7
12
T2DM
2 g/day cinnamon
Wainstein (2011)
Israel
Parallel (Yes) 59
Both
61.7
29.8
12
T2DM
1.2 g/day cinnamon
Vafa (2012)
Iran
Parallel (Yes) 37
Both
54.1
29.2
8
T2DM
3 g/day cinnamon
Anderson (2015)
USA
Parallel (Yes) 135
Both
61.3
25.3
9
Pre-diabetes
0.5 g/day cinnamon
Sengsuk (2016)
Thailand Parallel (Yes) 99
Both
57.1
24.7
9
T2DM
1.5 g/day cinnamon
Azimi (2016)
Iran
Parallel (No)
Both
54.1
28.8
8
T2DM
Jain (2017)
India
Parallel (Yes) 116
Both
44.3
33.6
16
Metabolic syndrome
3 g/day cinnamon þ black tea 3 g/day cinnamon
Parallel (Yes) 36
Female
46.9
29.1
8
Rheumatoid arthritis 2 g/day cinnamon
Shishehbor (2018) Iran
Sample Gender Mean age Mean BMI Duration Target population size (years) (kg/m2) (weeks)
79
Intervention (name and Control daily dose)
Results
SBP 4 DBP 4 Placebo SBP Y DBP 4 Placebo SBP 4 DBP 4 Placebo SBP 4 DBP 4 Placebo SBP 4 DBP 4 Placebo SBP Y DBP Y Black tea SBP [ DBP Y Placebo SBP Y DBP Y Placebo SBP Y DBP Y
Placebo
RCT, randomized controlled trial; BMI, body mass index; T2DM, type 2 diabetes mellitus; SBP, systolic blood pressure; DBP, diastolic blood pressure.
Table 2 Quality assessment of included studies based on Cochrane guidelines. Study
Random sequence generation
Allocation concealment
Blinding of participants, personnel
Blinding of outcome assessment
Incomplete outcome data
Selective outcome reporting
Other sources of bias
Ziegenfuss (2006) Akilen (2010) Wainstein (2011) Vafa (2012) Anderson (2015) Sengsuk (2016) Azimi (2016) Jain (2017) Shishehbor (2018)
U L L U U L L U L
U L L U L L U L L
L L L L L L H L L
U L L L U L U L L
L L L L L L L L L
L L L L L L L L L
U L U L L U U L U
U, unclear risk of bias; L, low risk of bias; H, high risk of bias.
(I2 ¼ 87.3%, P < 0.001) (Fig. 2). Subgroup analyses indicated that when the studies were stratified according to cinnamon dosage, interestingly, the reduction of SBP was significant only in studies using 2 g/day of cinnamon (WMD: 5.99 mmHg, 95% CI: 10.18 to 1.80, I2 ¼ 49.8%), and no significant effect was detected in doses higher than 2 g/day. In addition, SBP was significantly decreased relative to the control group when the intervention duration was ˃8 weeks (WMD: 6.06 mmHg, 95% CI: 9.33 to 2.87, I2 ¼ 44.3%). Results of subgroup analyses also indicated that cinnamon supplementation could significantly decrease SBP only in participants with a baseline BMI 30 kg/m2 (WMD: 7.41 mmHg, 95% CI: 10.00 to 4.82, I2 ¼ 0.0%). All these findings are provided in Table 3. 5.2. Diastolic blood pressure Combining effect sizes from 9 trials, we showed that cinnamon supplementation significantly decreases DBP (WMD: 3.36 mmHg, 95% CI: 5.67 to 1.04, P 0.001), with a significant betweenstudy heterogeneity (I2 ¼ 81.5%, P < 0.001) (Fig. 3). Thus, subgroup analyses were performed to identify the source of heterogeneity (Table 3). Results showed that the effect of cinnamon administration on DBP was significant at the dosages of 2 g/day (WMD: 3.80 mmHg, 95% CI: 6.22 to 1.37, I2 ¼ 34.5%) and in trials with intervention duration <8 weeks (WMD: 4.05 mmHg, 95% CI: 6.61 to 1.59, I2 ¼ 51.8%). Additionally, cinnamon reduced DBP in subjects with BMI 30 kg/m2 (WMD: 4.98 mmHg, 95%
CI: 8.17 to 1.79, I2 ¼ 46.8%) more significantly than subjects with BMI <30 kg/m2 (WMD: 2.40 mmHg, 95% CI: 4.54 to 0.26, I2 ¼ 62.4%). 5.3. Sensitivity analysis and publication bias The results following the systematic removal of each study did not significantly change the overall effects of cinnamon supplementation on SBP and DBP, which ranged from (WMD: 4.31 mmHg, 95% CI: 8.52 to 0.11) to (WMD: 5.95 mmHg, 95% CI: 10.75 to 1.15) and (WMD: 2.85 mmHg, 95% CI: 5.17 to 0.52) to (WMD: 3.89 mmHg, 95% CI: 6.17 to 1.60), respectively. Furthermore, the results of Egger's regression test indicated no publication bias for SBP (P ¼ 0.08) or DBP (P ¼ 0.06). 6. Discussion To our knowledge, the present study is the most comprehensive meta-analysis to date evaluating the effects of cinnamon supplementation on blood pressure; the previously published metaanalysis was based on merely three trials and focused on those with specific underlying health conditions, including prediabetes and type 2 diabetes. Our findings, however, do corroborate the previous, smaller scale meta-analysis in reporting a significant effect of cinnamon on SBP and DBP. To assess the impact of trial-level covariates on results, we carried out subgroup analyses. The results
Please cite this article as: Hadi A et al., The effect of cinnamon supplementation on blood pressure in adults: A systematic review and metaanalysis of randomized controlled trials, Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2020.01.002
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Study name
ES (95% CI)
Weight %
Ziegenfuss et al (2006)
-14.00 (-29.64, 1.64)
4.91
Akilen et al (2010)
-5.00 (-9.75, -0.25)
13.04
Wainstein et al (2011)
-5.70 (-12.27, 0.87)
11.31
Vafa et al (2012)
0.13 (-6.41, 6.67)
11.34
Anderson et al (2015)
-0.70 (-5.64, 4.24)
12.87
Sengsuk et al (2016)
-13.50 (-25.41, -1.59)
6.90
Azimi et al (2016)
1.30 (0.75, 1.85)
15.64
Jain et al (2017)
-8.20 (-11.35, -5.05)
14.40
Shishehbor et al (2018)
-12.50 (-20.90, -4.10)
9.60
Overall (I-squared = 87.3%, p = 0.000)
-5.17 (-9.35, -0.99)
100.00
NOTE: Weights are from random effects analysis -29.6
0
29.6
Fig. 2. Forest plot of the effects of cinnamon supplementation on systolic blood pressure.
Table 3 Subgroup analyses to assess the effect of cinnamon supplementation on SBP and DBP. Sub-grouped by No. of Effect 95% CI trials sizea SBP Baseline BMI <30 kg/m2 6 30 kg/m2 3 Duration 8 weeks 3 >8 weeks 6 Cinnamon dosage 2 g/day 5 >2 g/day 4 DBP Baseline BMI <30 kg/m2 6 30 kg/m2 3 Duration 8 weeks 3 >8 weeks 6 Cinnamon dosage 2 g/day 3 >2 g/day 4
P for effect size
I2 (%) P for heterogeneity
3.58 7.97 to 0.82 0.11 76.2 7.41 10.00 to 4.82 <0.001 0.0
<0.001 0.38
2.70 9.65 to 4.26 6.06 9.33 to 2.87
0.44 80.8 <0.001 44.3
<0.001 0.11
5.99 10.18 to 1.80 <0.001 49.8 3.70 10.44 to 3.03 0.28 92.0
0.09 <0.001
2.40 4.54 to 0.26 4.98 8.17 to 1.79
0.02 62.4 <0.001 46.8
0.02 0.15
2.34 5.80 to 1.13 4.05 6.61 to 1.59
0.18 76.5 <0.001 51.8
0.01 0.06
3.80 6.22 to 1.37 2.62 6.49 to 1.26
<0.001 34.5 0.18 89.8
0.19 <0.001
SBP, systolic blood pressure; DBP, diastolic blood pressure. a Calculated by Random-effects model.
indicate that cinnamon reduces both SBP and DBP at dosages of 2 g/day when administered for ˃8 weeks. In addition, we found a greater reduction in SBP and DBP in subjects with a baseline BMI 30 kg/m2. The magnitude of blood pressure reductions in response to cinnamon supplementation in this meta-analysis are moderate but detectable. The findings from the Heart Outcome Prevention Evaluation study revealed that a modest reduction of SBP (3.3 mmHg) and DBP (1.4 mmHg) can lead to a 22% reduction in
relative risk of cardiovascular mortality, stroke, and myocardial infarction. Precise biological mechanisms for the hypotensive effects of cinnamon have not yet been established. However, several possible mechanisms have been suggested. Higher levels of inflammatory markers and oxidative stress in the body lead to increased blood homocysteine and arterial stiffness, which are well known mechanisms for hypertension [32e34]. A variety of studies have suggested that cinnamon is a powerful antioxidant that can neutralize reactive oxygen species by donating electrons; thus, cinnamon attenuates oxidative stress, leading to improved production and bioavailability of nitric oxide (NO), a molecule with vasodilatory properties [12,13]. The antioxidant potential of cinnamon can also promote a reduction in endothelial dysfunction, thereby lowering blood pressure [26,35]. In addition, cinnamon supplementation improves lipid profile characteristics, potentially lowering lipid oxidation and vascular blockage [36]. Previous studies have suggested that cinnamon has Ca2þ antagonistic activity, which could influence endothelium dependent vasodilation, and thereby improve blood pressure [13,37]. Moreover, the high potassium content of cinnamon increases sodium excretion and decreases the contractility of the arterial smooth muscle, potentially decreasing blood pressure [38]. Additionally, cinnamon appears to improve glycemic control among diabetics, and improved glycemic control may be partially responsible for lower blood pressure seen among diabetic subjects [21]. Studies designed to explore the mechanisms by which cinnamon can lower blood pressure are needed to elucidate which of the proposed mechanisms, or unexplored mechanisms, contribute most to the reductions that are seen in SBP and DBP. Cinnamon is labelled by the United States’ Food and Drug Administration as “Generally Recognized as Safe” and no serious adverse effects were reported among the included studies. Only one trial [21] reported mild, short-lived gastric upset and
Please cite this article as: Hadi A et al., The effect of cinnamon supplementation on blood pressure in adults: A systematic review and metaanalysis of randomized controlled trials, Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2020.01.002
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Study name
ES (95% CI)
Weight %
Ziegenfuss et al (2006)
-2.00 (-10.88, 6.88)
4.89
Akilen et al (2010)
-3.00 (-6.79, 0.79)
11.91
Wainstein et al (2011)
-1.40 (-6.10, 3.30)
10.17
Vafa et al (2012)
-0.23 (-3.92, 3.46)
12.13
Anderson et al (2015)
-2.50 (-5.34, 0.34)
13.86
Sengsuk et al (2016)
-10.50 (-20.77, -0.23)
3.94
Azimi et al (2016)
-0.80 (-1.08, -0.52)
17.47
Jain et al (2017)
-6.90 (-9.10, -4.70)
15.13
Shishehbor et al (2018)
-7.50 (-12.02, -2.98)
10.50
Overall (I-squared = 81.5%, p = 0.000)
-3.36 (-5.67, -1.04)
100.00
NOTE: Weights are from random effects analysis -20.8
0
20.8
Fig. 3. Forest plot of the effects of cinnamon supplementation on diastolic blood pressure.
headache after the intervention with cinnamon. However, at high doses (< 10 g/day), precautions should be taken, as previous reports indicate side effects such as irritation and allergies, increased heart rate, and liver problems [39,40]. Furthermore, individuals taking blood thinning medication should consult a physician before implementing cinnamon supplements, as cinnamon has an apparent blood thinning capacity. Cinnamon may also interact with certain medications, including antibiotics, medications for diabetes, and heart medications, so patients should speak to physicians about potential risks before starting a cinnamon supplementation regimen [39]. Our review and meta-analysis has several limitations. While our pooled sample size was of sufficient size to detect a statistically significant effect, the total number of studies analyzed and the overall sample size was relatively small. Additionally, the relatively small total number of studies available for each subgroup analysis may have affected the results. Furthermore, the longest supplement duration in our current analysis was 16 weeks, with the majority of studies implementing supplementation durations of 8e12 weeks. Given the relatively short durations of the available studies, the long-term effects of cinnamon supplementation on blood pressure and safety are uncertain. At baseline, most subjects were normotensive, making a stratified analysis by hypertension status unreasonable for the current analysis, and normotensive individuals also may not have as much room for improvement in blood pressure. Finally, confounding factors and their influence were nor reported and analyzed in the majority of trials, precluding their analysis in our study. We suggest that future suggest should consider the influence of confounding factors such as physical activity and smoking status. 7. Conclusion In conclusion, the present analysis provides support for cinnamon to reduce SBP and DBP, particularly when administered at
dosages of 2 g/day, for a period longer than 8 weeks, and in participants with a baseline BMI of 30 kg/m2. However, due to limited availability of studies with hypertensive cases and relatively small sample sizes, well designed trials with adequate sample sizes aimed at hypertensive populations are recommended. Grant and funding No external funding supported this work. Author contributions A.H and SA.M contributed to the study concept and design. A.H, M.P, A.S and B.H contributed to the acquisition, analysis and interpretation of the data. A.H drafted the manuscript. A.H and M.S.C critically revised the manuscript. Declaration of Competing Interest All authors confirm that they have no conflict of interests to declare. Acknowledgements None. References [1] Campbell NR, Lackland DT, Niebylski ML, League WH, Committees ISoHE. High blood pressure: why prevention and control are urgent and importantda 2014 fact sheet from the World Hypertension League and the International Society of Hypertension. J Clin Hypertens 2014;16:551e3. [2] Kjeldsen SE. Hypertension and cardiovascular risk: general aspects. Pharmacol Res 2018;129:95e9. [3] Pistoia F, Sacco S, Degan D, Tiseo C, Ornello R, Carolei A. Hypertension and stroke: epidemiological aspects and clinical evaluation. High Blood Press Cardiovasc Prev 2016;23:9e18.
Please cite this article as: Hadi A et al., The effect of cinnamon supplementation on blood pressure in adults: A systematic review and metaanalysis of randomized controlled trials, Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2020.01.002
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[22] Vafa M, Mohammadi F, Shidfar F, Sormaghi MS, Heidari I, Golestan B, et al. Effects of cinnamon consumption on glycemic status, lipid profile and body composition in type 2 diabetic patients. Int J Prev Med 2012;3:531. [23] Azimi P, Ghiasvand R, Feizi A, Hosseinzadeh J, Bahreynian M, Hariri M, et al. Effect of cinnamon, cardamom, saffron and ginger consumption on blood pressure and a marker of endothelial function in patients with type 2 diabetes mellitus: a randomized controlled clinical trial. Blood Press 2016;25:133e40. [24] Anderson RA, Zhan Z, Luo R, Guo X, Guo Q, Zhou J, et al. Cinnamon extract lowers glucose, insulin and cholesterol in people with elevated serum glucose. J Tradit Complementary Altern Med 2016;6:332e6. [25] Wainstein J, Stern N, Heller S, Boaz M. Dietary cinnamon supplementation and changes in systolic blood pressure in subjects with type 2 diabetes. J Med Food 2011;14:1505e10. [26] Akilen R, Pimlott Z, Tsiami A, Robinson N. Effect of short-term administration of cinnamon on blood pressure in patients with prediabetes and type 2 diabetes. Nutrition 2013;29:1192e6. [27] Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 2009;151:264e9. [28] Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. Bmj 2011;343:d5928. [29] Follmann D, Elliott P, Suh I, Cutler J. Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol 1992;45:769e73. [30] Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. Bmj 2003;327:557e60. [31] Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. Bmj 1997;315:629e34. [32] Grundy SM. Inflammation, hypertension, and the metabolic syndrome. Jama 2003;290:3000e2. [33] Soeki T, Sata M. Inflammatory biomarkers and atherosclerosis. Int Heart J 2016:15e346. [34] Fallah AA, Sarmast E, Dehkordi SH, Engardeh J, Mahmoodnia L, Khaledifar A, et al. Effect of Chlorella supplementation on cardiovascular risk factors: a meta-analysis of randomized controlled trials. Clin Nutr 2018;37:1892e901. [35] Schiffrin EL. Antioxidants in hypertension and cardiovascular disease. Mol Interv 2010;10:354. [36] Maierean SM, Serban M-C, Sahebkar A, Ursoniu S, Serban A, Penson P, et al. The effects of cinnamon supplementation on blood lipid concentrations: a systematic review and meta-analysis. J Clin Lipidol 2017;11:1393e406. [37] Shen Y, Jia L-N, Honma N, Hosono T, Ariga T, Seki T. Beneficial effects of cinnamon on the metabolic syndrome, inflammation, and pain, and mechanisms underlying these effectsea review. J Tradit Complementary Altern Med 2012;2:27e32. [38] Filippini T, Violi F, D'Amico R, Vinceti M. The effect of potassium supplementation on blood pressure in hypertensive subjects: a systematic review and meta-analysis. Int J Cardiol 2017;230:127e35. [39] Hajimonfarednejad M, Ostovar M, Raee MJ, Hashempur MH, Mayer JG, Heydari M. Cinnamon: a systematic review of adverse events. Clin Nutr 2019;38:594e602. [40] Singletary K. Cinnamon: update of potential health benefits. Nutr Today 2019;54:42e52.
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Review
The effect of cinnamon supplementation on blood pressure in adults: A systematic review and meta-analysis of randomized controlled trials Amir Hadi a, Marilyn S. Campbell b, Bahar Hassani c, d, Makan Pourmasoumi e, f, Ammar Salehi-sahlabadi g, Seyed Ahmad Hosseini h, * a
Halal Research Center of IRI, FDA, Tehran, Iran Department of Kinesiology and Health Promotion, University of Kentucky, Lexington, KY, USA Department of Nutrition, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran d Department of Health Safety and Environment (HSE), Razi Petrochemical Company, Mahshahr, Iran e Food Security Research Center and Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran f Universal Scientific Education and Research Network (USERN), Tehran, Iran g Student Research Committee, Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran h Nutrition and Metabolic Disease Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran b c
a r t i c l e i n f o
s u m m a r y
Article history: Received 22 October 2019 Accepted 3 January 2020
Background & aims: Several clinical trials have shown that cinnamon can reduce blood pressure, but the results are controversial. Therefore, we conducted a systematic review and meta-analysis to provide a more precise estimate of the overall effects of cinnamon supplementation on blood pressure in adults. Methods: We searched PubMed, Scopus, Cochrane Library, ISI Web of Science, and Google Scholar databases through September 2019 to identify randomized clinical trials (RCTs) investigating the effect of cinnamon supplementation on blood pressure. Data were pooled by using the random-effects model, and weighted mean difference (WMD) was considered as the summary effect size. Sensitivity analysis was conducted using the leave-one-out method. Results: Meta-analysis of 9 RCTs with 641 participants showed significant reductions in both systolic (WMD: 5.17 mmHg, 95% CI: 9.35 to 0.99, P ¼ 0.01) and diastolic blood pressure (WMD: 3.36 mmHg, 95% CI: 5.67 to 1.04, P 0.001) after cinnamon supplementation. Subgroup analyses indicated that these results were significant only when cinnamon was administered at the dosages of 2 g/day, for a period longer than 8 weeks, and in participants with a baseline BMI of 30 kg/m2. Conclusion: The present meta-analysis suggests that cinnamon supplementation can improve blood pressure by a modest degree. However, due to limited availability of studies with hypertensive cases and relatively small sample sizes of available studies, well designed trials with adequate sample sizes aimed at hypertensive populations are recommended. © 2020 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
Keywords: Cinnamon Blood pressure Systematic review Meta-analysis
1. Introduction High blood pressure, commonly known as hypertension (HTN), is a global health problem that affects more than one billion individuals and causes an estimated 9.4 million deaths per year [1]. Accumulating evidence has also suggested that
* Corresponding author. E-mail address: [email protected] (S.A. Hosseini).
there is a positive association between HTN and the risk of chronic diseases, including cardiovascular disease [2], stroke [3], and kidney dysfunction [4], which are leading causes of mortality worldwide. Therefore, HTN not only has an impact directly on the individual but also incurs a significant cost to the government and a burden to the community [5]. As result, adopting appropriate strategies to control blood pressure is important for any healthcare system. Lifestyle modifications, including adherence to a healthy diet (rich in fruits, vegetables and low-fat dairy products with
https://doi.org/10.1016/j.clnesp.2020.01.002 2405-4577/© 2020 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Hadi A et al., The effect of cinnamon supplementation on blood pressure in adults: A systematic review and metaanalysis of randomized controlled trials, Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2020.01.002
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A. Hadi et al. / Clinical Nutrition ESPEN xxx (xxxx) xxx
sodium restriction) and increased physical activity, as well as pharmacotherapy, are regarded as the most important strategies for blood pressure management [6,7]. However, given the undesirable side effects of synthetic drugs [8], the number of people choosing plant based-therapies as an alternative to control blood pressure is increasing [9]. In this regard, herbs and spices have attracted significant attention recently, both in the scientific and consumer communities due to their safety, popularity, ease of access, and reduced number of side effects [10]. Cinnamon, from the genus Cinnamomum and Lauraceae family, is a spice derived from the inner bark of a tropical evergreen tree [11]. It is one of the most widely used flavoring agents in the food and beverage industry worldwide [12]. This spice was reported as a traditional remedy for several diseases including the common cold, gastrointestinal disorders, and diabetes [12,13]. The main components found in cinnamon are cinnamaldehyde, cinnamic acid, eugenol, and coumarin, which play key roles in different biological activities, such as anti-microbial, anti-inflammatory, antioxidant, antifungal, and anti-diabetic activities [14,15]. Cinnamon also exhibits hypotensive effects, and it is postulated that anti-oxidant and anti-inflammatory properties of cinnamon might be responsible for these hypotensive effects [16]. However, in clinical settings, the effects of cinnamon on blood pressure are controversial. Some clinical trials have found that cinnamon supplementation can decrease blood pressure [17e21], but others [22e25] have not reported any beneficial effects on blood pressure after cinnamon supplementation. In 2013, Akilen et al. [26] published a metaanalysis on this topic that included only 3 clinical trials representing 139 participants. The results indicated that cinnamon supplementation significantly decreased systolic blood pressure (SBP) and diastolic blood pressure (DBP) relative to the control group. However, the limited number of trials included in the aforementioned meta-analysis suggests that their findings could be biased by sample size. In addition, more randomized controlled trials (RCTs) with larger samples sizes have been published since then. Therefore, we conducted an updated systematic review and meta-analysis to provide a more precise estimate of the overall effects and safety of cinnamon supplementation on blood pressure in adults.
2. Methods The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [27] were followed to perform and report the current meta-analysis.
2.1. Search strategy Studies published from inception to September 2019 were identified through electronic searches of six databases: PubMed, Scopus, Cochrane Library, ISI Web of Science, and Google Scholar. No restrictions on the language, publication date, or other filters were applied. For this purpose, we used MESH (Medical Subject Heading) and non-MESH keywords including the following: ("Cinnamomum zeylanicum" OR "Cinnamomum" OR "Cinnamon" OR "Cinnamons" OR "Cinnamomum verum") AND ("blood pressure" OR "systolic blood pressure" OR "diastolic blood pressure" OR "hypertension"). In addition, references from the articles retrieved and previous review articles were manually reviewed to identify further relevant studies.
2.2. Study selection A two-stage screening process consisting of a title and abstract scan and a full-text review was used to ensure the accurate identification of eligible studies. Studies were included if they met all of the following inclusion criteria: a) Study design: RCT with either a parallel or crossover design; b) Population: adult participants (aged 18 years) (healthy or otherwise); c) Intervention: investigated cinnamon as an intervention for over 4 weeks; d) Comparators: placebo or a comparison group were used; and e) Outcomes: including SBP and DBP. The exclusion criteria included: a) nonrandomized, non-control, or experimental studies; b) studies on cinnamon in combination with other herbs or ingredients as a mixture; and c) studies with lack of sufficient data required for meta-analysis. If duplicate publications from the same study were identified, the publication with the largest number of cases from the study was included. Two investigators (A.H. and M.P.) conducted study selection and held further discussion to resolve any disagreement after reviewing the original article. 3. Data extraction Data were extracted by two independent reviewers (A.H. and M.P.) using a pre-defined form. Any disagreement regarding the data extraction was discussed until agreement was reached. The following characteristics were extracted from each selected study: first author's name, year of publication, study design, sample size, age, body mass index (BMI), sex of participants, health status of subjects, study duration, details of the strategy administered to the intervention and the control groups, and results observed. When these characteristics were not reported in available publications, we contacted the corresponding author to acquire the necessary data. 3.1. Quality assessment The Cochrane risk of bias tool [28] was used to assess each study as having low, high, or unclear risk of bias on 7 criteria: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessments, incomplete outcome data, selective reporting, and other biases. Finally, the overall quality of the studies was categorized into weak, fair, or good, if < 3, 3, or 4 domains were rated as low risk, respectively. Two authors (A.H. and M.P.) independently conducted the quality assessment. When disagreement occurred, final scores were discussed by the authors until consensus was reached. 3.2. Statistical analyses Data were analyzed using Stata version 12.0 software (StataCorp, College Station, Texas, USA). Blood pressure was measured in mmHg. The effect size of each study was calculated from mean and standard deviation (SD) of the outcomes before and after the intervention and presented as weighted mean difference (WMD) with 95% confidence intervals (CI). If only SD for the baseline and final values was provided, SD for the net changes was assigned based on the Follmann method [29] using a correlation coefficient of 0.5. In studies where the standard error (SE) was reported, SD was calculated as follows: SD ¼ SE sqrt (n), where n is the number of participants in each group. Due to the fact that selected RCTs were carried out in different settings, the random-effects model was employed to calculate the overall effect from effect sizes. Heterogeneity was examined using the I-squared (I2) index [30]. Subgroup analyses based on cinnamon dosage, duration of supplementation, and baseline BMI of subjects were conducted to
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determine the source of heterogeneity if the I2 value was >50%. Sensitivity analysis was also performed to evaluate the potential bias and robustness of the overall effect estimate by omitting one study at a time. Given that the effect size of each outcome was less than 10, we were not able to create funnel plots, and the existence of publication bias was inspected only through Egger's regression model [31]. All tests were two-sided. A P value < 0.05 was considered statistically significant. 4. Results Our search yielded 321 studies for an initial review. Following the removal of duplicates, 186 were retained. We excluded 173 irrelevant references by reading titles and abstracts. In the next step, 4 papers were excluded based on the full-text review. These exclusions were due to the following reasons: administered cinnamon in combination with other components (n ¼ 2), no control group (n ¼ 1), and insufficient data for outcomes (n ¼ 1). As a result, a total of nine articles consisting of 641 participants, with 318 participants in the intervention group and 323 in the control group, were identified as eligible for the present meta-analysis. The detailed steps of the selection process are summarized in Fig. 1.
3
22 to 135 participants, with a mean age ranging from 44.3 to 61.7 years. The trials were from six different countries including Iran [18,22,23], USA [20,24], UK [21], India [19], Thailand [17], and Israel [25]. Eight studies included both male and female participants [17,19e25], and one study included only female participants [18]. The baseline BMI of the participants indicated that all trials except one [17] examined primarily overweight and obese subjects (BMI >25 kg/m2). The length of interventions ranged from 8 to 16 weeks, and cinnamon supplementation dosage ranged from 0.5 to 10 g/ day. Participants in these studies were patients with type 2 diabetes [17,21e23], individuals with metabolic syndrome [19], patients with rheumatoid arthritis [18], and pre-diabetic subjects [20,24]. 4.2. Risk of bias and quality of evidence According to the Cochrane risk of bias tool, seven trials were classified as good quality [17e19,21,22,24,25] and two [20,23] as fair quality. Table 2 presents details of the study quality assessment of the included studies. 5. Meta-analysis results 5.1. Systolic blood pressure
4.1. Study characteristics
Identification
The characteristics of the included studies are outlined in Table 1. All trials adopted a parallel study design, and they were conducted between 2006 and 2018. The sample sizes ranged from
The pooled estimate from the random-effects model performed on 9 trials showed that cinnamon supplementation significantly decreased SBP (WMD: 5.17 mmHg, 95% CI: 9.35 to 0.99, P ¼ 0.01) with a significant between-study heterogeneity
Articles identified through database searches (n=321)
Eligibility
Screening
Records after duplicates removed (n=186)
Articles removed by title/abstract (n=173) Records screened (n=186)
Full-text articles assessed for eligibility (n=13)
Without sufficient data (n=1) Without control group (n=1)
Included studies in qualitative synthesis (n=9)
Included
Articles removed after full-text review (n=4):
In combination with other components (n=2)
Included studies in quantitative synthesis (metaanalysis) (n=9)
Fig. 1. PRISMA flow diagram of study selection process.
Please cite this article as: Hadi A et al., The effect of cinnamon supplementation on blood pressure in adults: A systematic review and metaanalysis of randomized controlled trials, Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2020.01.002
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Table 1 Characteristics of included studies. First author (publication year)
Country
RCT design (blinding)
Ziegenfuss (2006)
USA
Parallel (Yes) 22
Both
46.3
32.3
12
Pre-diabetes
10 g/day cinnamon
Akilen (2010)
UK
Parallel (Yes) 58
Both
54.6
32.7
12
T2DM
2 g/day cinnamon
Wainstein (2011)
Israel
Parallel (Yes) 59
Both
61.7
29.8
12
T2DM
1.2 g/day cinnamon
Vafa (2012)
Iran
Parallel (Yes) 37
Both
54.1
29.2
8
T2DM
3 g/day cinnamon
Anderson (2015)
USA
Parallel (Yes) 135
Both
61.3
25.3
9
Pre-diabetes
0.5 g/day cinnamon
Sengsuk (2016)
Thailand Parallel (Yes) 99
Both
57.1
24.7
9
T2DM
1.5 g/day cinnamon
Azimi (2016)
Iran
Parallel (No)
Both
54.1
28.8
8
T2DM
Jain (2017)
India
Parallel (Yes) 116
Both
44.3
33.6
16
Metabolic syndrome
3 g/day cinnamon þ black tea 3 g/day cinnamon
Parallel (Yes) 36
Female
46.9
29.1
8
Rheumatoid arthritis 2 g/day cinnamon
Shishehbor (2018) Iran
Sample Gender Mean age Mean BMI Duration Target population size (years) (kg/m2) (weeks)
79
Intervention (name and Control daily dose)
Results
SBP 4 DBP 4 Placebo SBP Y DBP 4 Placebo SBP 4 DBP 4 Placebo SBP 4 DBP 4 Placebo SBP 4 DBP 4 Placebo SBP Y DBP Y Black tea SBP [ DBP Y Placebo SBP Y DBP Y Placebo SBP Y DBP Y
Placebo
RCT, randomized controlled trial; BMI, body mass index; T2DM, type 2 diabetes mellitus; SBP, systolic blood pressure; DBP, diastolic blood pressure.
Table 2 Quality assessment of included studies based on Cochrane guidelines. Study
Random sequence generation
Allocation concealment
Blinding of participants, personnel
Blinding of outcome assessment
Incomplete outcome data
Selective outcome reporting
Other sources of bias
Ziegenfuss (2006) Akilen (2010) Wainstein (2011) Vafa (2012) Anderson (2015) Sengsuk (2016) Azimi (2016) Jain (2017) Shishehbor (2018)
U L L U U L L U L
U L L U L L U L L
L L L L L L H L L
U L L L U L U L L
L L L L L L L L L
L L L L L L L L L
U L U L L U U L U
U, unclear risk of bias; L, low risk of bias; H, high risk of bias.
(I2 ¼ 87.3%, P < 0.001) (Fig. 2). Subgroup analyses indicated that when the studies were stratified according to cinnamon dosage, interestingly, the reduction of SBP was significant only in studies using 2 g/day of cinnamon (WMD: 5.99 mmHg, 95% CI: 10.18 to 1.80, I2 ¼ 49.8%), and no significant effect was detected in doses higher than 2 g/day. In addition, SBP was significantly decreased relative to the control group when the intervention duration was ˃8 weeks (WMD: 6.06 mmHg, 95% CI: 9.33 to 2.87, I2 ¼ 44.3%). Results of subgroup analyses also indicated that cinnamon supplementation could significantly decrease SBP only in participants with a baseline BMI 30 kg/m2 (WMD: 7.41 mmHg, 95% CI: 10.00 to 4.82, I2 ¼ 0.0%). All these findings are provided in Table 3. 5.2. Diastolic blood pressure Combining effect sizes from 9 trials, we showed that cinnamon supplementation significantly decreases DBP (WMD: 3.36 mmHg, 95% CI: 5.67 to 1.04, P 0.001), with a significant betweenstudy heterogeneity (I2 ¼ 81.5%, P < 0.001) (Fig. 3). Thus, subgroup analyses were performed to identify the source of heterogeneity (Table 3). Results showed that the effect of cinnamon administration on DBP was significant at the dosages of 2 g/day (WMD: 3.80 mmHg, 95% CI: 6.22 to 1.37, I2 ¼ 34.5%) and in trials with intervention duration <8 weeks (WMD: 4.05 mmHg, 95% CI: 6.61 to 1.59, I2 ¼ 51.8%). Additionally, cinnamon reduced DBP in subjects with BMI 30 kg/m2 (WMD: 4.98 mmHg, 95%
CI: 8.17 to 1.79, I2 ¼ 46.8%) more significantly than subjects with BMI <30 kg/m2 (WMD: 2.40 mmHg, 95% CI: 4.54 to 0.26, I2 ¼ 62.4%). 5.3. Sensitivity analysis and publication bias The results following the systematic removal of each study did not significantly change the overall effects of cinnamon supplementation on SBP and DBP, which ranged from (WMD: 4.31 mmHg, 95% CI: 8.52 to 0.11) to (WMD: 5.95 mmHg, 95% CI: 10.75 to 1.15) and (WMD: 2.85 mmHg, 95% CI: 5.17 to 0.52) to (WMD: 3.89 mmHg, 95% CI: 6.17 to 1.60), respectively. Furthermore, the results of Egger's regression test indicated no publication bias for SBP (P ¼ 0.08) or DBP (P ¼ 0.06). 6. Discussion To our knowledge, the present study is the most comprehensive meta-analysis to date evaluating the effects of cinnamon supplementation on blood pressure; the previously published metaanalysis was based on merely three trials and focused on those with specific underlying health conditions, including prediabetes and type 2 diabetes. Our findings, however, do corroborate the previous, smaller scale meta-analysis in reporting a significant effect of cinnamon on SBP and DBP. To assess the impact of trial-level covariates on results, we carried out subgroup analyses. The results
Please cite this article as: Hadi A et al., The effect of cinnamon supplementation on blood pressure in adults: A systematic review and metaanalysis of randomized controlled trials, Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2020.01.002
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5
Study name
ES (95% CI)
Weight %
Ziegenfuss et al (2006)
-14.00 (-29.64, 1.64)
4.91
Akilen et al (2010)
-5.00 (-9.75, -0.25)
13.04
Wainstein et al (2011)
-5.70 (-12.27, 0.87)
11.31
Vafa et al (2012)
0.13 (-6.41, 6.67)
11.34
Anderson et al (2015)
-0.70 (-5.64, 4.24)
12.87
Sengsuk et al (2016)
-13.50 (-25.41, -1.59)
6.90
Azimi et al (2016)
1.30 (0.75, 1.85)
15.64
Jain et al (2017)
-8.20 (-11.35, -5.05)
14.40
Shishehbor et al (2018)
-12.50 (-20.90, -4.10)
9.60
Overall (I-squared = 87.3%, p = 0.000)
-5.17 (-9.35, -0.99)
100.00
NOTE: Weights are from random effects analysis -29.6
0
29.6
Fig. 2. Forest plot of the effects of cinnamon supplementation on systolic blood pressure.
Table 3 Subgroup analyses to assess the effect of cinnamon supplementation on SBP and DBP. Sub-grouped by No. of Effect 95% CI trials sizea SBP Baseline BMI <30 kg/m2 6 30 kg/m2 3 Duration 8 weeks 3 >8 weeks 6 Cinnamon dosage 2 g/day 5 >2 g/day 4 DBP Baseline BMI <30 kg/m2 6 30 kg/m2 3 Duration 8 weeks 3 >8 weeks 6 Cinnamon dosage 2 g/day 3 >2 g/day 4
P for effect size
I2 (%) P for heterogeneity
3.58 7.97 to 0.82 0.11 76.2 7.41 10.00 to 4.82 <0.001 0.0
<0.001 0.38
2.70 9.65 to 4.26 6.06 9.33 to 2.87
0.44 80.8 <0.001 44.3
<0.001 0.11
5.99 10.18 to 1.80 <0.001 49.8 3.70 10.44 to 3.03 0.28 92.0
0.09 <0.001
2.40 4.54 to 0.26 4.98 8.17 to 1.79
0.02 62.4 <0.001 46.8
0.02 0.15
2.34 5.80 to 1.13 4.05 6.61 to 1.59
0.18 76.5 <0.001 51.8
0.01 0.06
3.80 6.22 to 1.37 2.62 6.49 to 1.26
<0.001 34.5 0.18 89.8
0.19 <0.001
SBP, systolic blood pressure; DBP, diastolic blood pressure. a Calculated by Random-effects model.
indicate that cinnamon reduces both SBP and DBP at dosages of 2 g/day when administered for ˃8 weeks. In addition, we found a greater reduction in SBP and DBP in subjects with a baseline BMI 30 kg/m2. The magnitude of blood pressure reductions in response to cinnamon supplementation in this meta-analysis are moderate but detectable. The findings from the Heart Outcome Prevention Evaluation study revealed that a modest reduction of SBP (3.3 mmHg) and DBP (1.4 mmHg) can lead to a 22% reduction in
relative risk of cardiovascular mortality, stroke, and myocardial infarction. Precise biological mechanisms for the hypotensive effects of cinnamon have not yet been established. However, several possible mechanisms have been suggested. Higher levels of inflammatory markers and oxidative stress in the body lead to increased blood homocysteine and arterial stiffness, which are well known mechanisms for hypertension [32e34]. A variety of studies have suggested that cinnamon is a powerful antioxidant that can neutralize reactive oxygen species by donating electrons; thus, cinnamon attenuates oxidative stress, leading to improved production and bioavailability of nitric oxide (NO), a molecule with vasodilatory properties [12,13]. The antioxidant potential of cinnamon can also promote a reduction in endothelial dysfunction, thereby lowering blood pressure [26,35]. In addition, cinnamon supplementation improves lipid profile characteristics, potentially lowering lipid oxidation and vascular blockage [36]. Previous studies have suggested that cinnamon has Ca2þ antagonistic activity, which could influence endothelium dependent vasodilation, and thereby improve blood pressure [13,37]. Moreover, the high potassium content of cinnamon increases sodium excretion and decreases the contractility of the arterial smooth muscle, potentially decreasing blood pressure [38]. Additionally, cinnamon appears to improve glycemic control among diabetics, and improved glycemic control may be partially responsible for lower blood pressure seen among diabetic subjects [21]. Studies designed to explore the mechanisms by which cinnamon can lower blood pressure are needed to elucidate which of the proposed mechanisms, or unexplored mechanisms, contribute most to the reductions that are seen in SBP and DBP. Cinnamon is labelled by the United States’ Food and Drug Administration as “Generally Recognized as Safe” and no serious adverse effects were reported among the included studies. Only one trial [21] reported mild, short-lived gastric upset and
Please cite this article as: Hadi A et al., The effect of cinnamon supplementation on blood pressure in adults: A systematic review and metaanalysis of randomized controlled trials, Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2020.01.002
6
A. Hadi et al. / Clinical Nutrition ESPEN xxx (xxxx) xxx
Study name
ES (95% CI)
Weight %
Ziegenfuss et al (2006)
-2.00 (-10.88, 6.88)
4.89
Akilen et al (2010)
-3.00 (-6.79, 0.79)
11.91
Wainstein et al (2011)
-1.40 (-6.10, 3.30)
10.17
Vafa et al (2012)
-0.23 (-3.92, 3.46)
12.13
Anderson et al (2015)
-2.50 (-5.34, 0.34)
13.86
Sengsuk et al (2016)
-10.50 (-20.77, -0.23)
3.94
Azimi et al (2016)
-0.80 (-1.08, -0.52)
17.47
Jain et al (2017)
-6.90 (-9.10, -4.70)
15.13
Shishehbor et al (2018)
-7.50 (-12.02, -2.98)
10.50
Overall (I-squared = 81.5%, p = 0.000)
-3.36 (-5.67, -1.04)
100.00
NOTE: Weights are from random effects analysis -20.8
0
20.8
Fig. 3. Forest plot of the effects of cinnamon supplementation on diastolic blood pressure.
headache after the intervention with cinnamon. However, at high doses (< 10 g/day), precautions should be taken, as previous reports indicate side effects such as irritation and allergies, increased heart rate, and liver problems [39,40]. Furthermore, individuals taking blood thinning medication should consult a physician before implementing cinnamon supplements, as cinnamon has an apparent blood thinning capacity. Cinnamon may also interact with certain medications, including antibiotics, medications for diabetes, and heart medications, so patients should speak to physicians about potential risks before starting a cinnamon supplementation regimen [39]. Our review and meta-analysis has several limitations. While our pooled sample size was of sufficient size to detect a statistically significant effect, the total number of studies analyzed and the overall sample size was relatively small. Additionally, the relatively small total number of studies available for each subgroup analysis may have affected the results. Furthermore, the longest supplement duration in our current analysis was 16 weeks, with the majority of studies implementing supplementation durations of 8e12 weeks. Given the relatively short durations of the available studies, the long-term effects of cinnamon supplementation on blood pressure and safety are uncertain. At baseline, most subjects were normotensive, making a stratified analysis by hypertension status unreasonable for the current analysis, and normotensive individuals also may not have as much room for improvement in blood pressure. Finally, confounding factors and their influence were nor reported and analyzed in the majority of trials, precluding their analysis in our study. We suggest that future suggest should consider the influence of confounding factors such as physical activity and smoking status. 7. Conclusion In conclusion, the present analysis provides support for cinnamon to reduce SBP and DBP, particularly when administered at
dosages of 2 g/day, for a period longer than 8 weeks, and in participants with a baseline BMI of 30 kg/m2. However, due to limited availability of studies with hypertensive cases and relatively small sample sizes, well designed trials with adequate sample sizes aimed at hypertensive populations are recommended. Grant and funding No external funding supported this work. Author contributions A.H and SA.M contributed to the study concept and design. A.H, M.P, A.S and B.H contributed to the acquisition, analysis and interpretation of the data. A.H drafted the manuscript. A.H and M.S.C critically revised the manuscript. Declaration of Competing Interest All authors confirm that they have no conflict of interests to declare. Acknowledgements None. References [1] Campbell NR, Lackland DT, Niebylski ML, League WH, Committees ISoHE. High blood pressure: why prevention and control are urgent and importantda 2014 fact sheet from the World Hypertension League and the International Society of Hypertension. J Clin Hypertens 2014;16:551e3. [2] Kjeldsen SE. Hypertension and cardiovascular risk: general aspects. Pharmacol Res 2018;129:95e9. [3] Pistoia F, Sacco S, Degan D, Tiseo C, Ornello R, Carolei A. Hypertension and stroke: epidemiological aspects and clinical evaluation. High Blood Press Cardiovasc Prev 2016;23:9e18.
Please cite this article as: Hadi A et al., The effect of cinnamon supplementation on blood pressure in adults: A systematic review and metaanalysis of randomized controlled trials, Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2020.01.002
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Please cite this article as: Hadi A et al., The effect of cinnamon supplementation on blood pressure in adults: A systematic review and metaanalysis of randomized controlled trials, Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2020.01.002