PPT | Integrative Med

November 29, 2020



Allen R.W., Schwartzman, E., Baker, W.L., Coleman C.I., and Phung O.J.

INTRODUCTION

    The widespread use of cinnamon in healthcare has helped it earn its title as the eternal tree of tropical medicine¹. More than being a spice, cinnamon is also an essential oil and can be used as a fragrance. It is a naturally occurring product that is obtained from the bark of the tree of the genus Cinnamomum.

There are two major varieties namely, Cinnamon ceylon, and Cinnamon cassia, with the former grown in Sri Lanka and the latter found in Indonesia, China, and Vietnam. Most clinical studies among humans used C. cassia. In vitro studies, studies in mice and in tissue culture have been done using C.ceylon and studies in humans subjects are under way. The major difference of these two species lies on their coumarin content.

Coumarin is a precursor of anticoagulants, which in significant amounts, causes liver damage and is higher in C.cassia. Cinnamon has a variety of clinical uses. It has antioxidant, antimicrobial, antineoplastic, and antidiabetic properties¹. Its antioxidant property is highlighted by its ability to increase cardiac and hepatic antioxidant enzymes as well as glutathione. Their aqueous and alcoholic extracts inhibit fatty acid oxidation and lipid peroxidation and the ethanolic extract can be compared to Vitamin E. Cinnamon is also rich in polyphenols and flavonoids which have free radical scavenging activity. A metabolite of the major bioactive component cinnamaldehyde reduces inflammation by decreasing nitric oxide via inhibition of the inflammatory marker nuclear factor kappa B (NFkB). Compounds extracted from another species, C. ramulus, inhibit inducible nitric oxide synthesis as well as carbon dioxide in the central nervous system showing therapeutic potential and preventive strategy for inflammation-induced neurodegenerative diseases. Apart from its antioxidant and anti-inflammatory properties, several compounds from cinnamon show neuroprotective effects.

Cinnamophilin, a compound extracted from C. philippinensis, functions as a thromboxane A2 receptor antagonist that has been shown to protect versus ischemia or infarct from the studies done on the brain of mice. Furthermore, sodium benzoate from cinnamon upregulates the expression of a gene that expresses a neuroprotective protein which is helpful among patients with Parkinson Disease. In addition to that, cinnamon has potential for preventing Alzheimer Disease¹. Compounds extracted from the aqueous form reduce beta amyloid formation, tau aggregation, and filament formation in animal and in vitro studies. The antimicrobial activity of cinnamon is exhibited by its essential oil which has been found to be bactericidal for Staphylococcus aureus. It also has antifungal properties on Candida species. Its antineoplastic property can be explained by the ability of the aqueous extract to inhibit vascular endothelial growth factor receptor (VEGFR) activity and consequently reducing the angiogenesis of cancer cells. Cinnamon together with cardamom, has been studied in mice for their lipid peroxidation and glutathione activity in colon cancer¹.

Majority of the abovementioned health benefits of cinnamon have been tested in vitro or in animals. But the antidiabetic, cardiovascular, and cholesterol lowering effects of cinnamon have been extensively studied in human subjects. Cinnamon has inherent insulin characteristic via its derivatives methyl hydroxychalcone and polyphenol that enhances insulin signaling and glucose transport through beta receptor phosphorylation. Cinnamaldehyde has insulinotropic properties that promote the release of insulin and enhances its sensitivity. Furthermore, the aqueous extracts increase the expression of peroxisome proliferator-activated receptors (PPAR) This, in turn, regulate and adipogenesis and insulin resistance which results to improvement in overall lipid and glucose metabolism².

Cinnamon’s role in cardiovascular health is mediated by the peripheral vasodilating property of cinnamaldehyde. This supports the antihypertensive characteristic of cinnamon.  It also shows a therapeutic potential for myocardial ischemia and re perfusion injury. Total cholesterol, LDL –cholesterol, and triglycerides are also reported to have significant reductions with the use of cinnamon while HDL-cholesterol had significant improvement. Diabetes mellitus is the leading metabolic disease that poses a threat to overall cardiovascular health. A 2014 report by the World Health Organization estimates the prevalence of diabetes at 8.5% of the adult population. This is equivalent to about 422 million people worldwide. In 2012, diabetes has claimed 1.5 million lives³. Much importance has been given to the prevention and treatment of diabetes due to the disease’s heavy burden. Studies utilizing cinnamon in human subjects have evaluated its role in diabetes mellitus. A systematic review and meta analysis in 2013 by Allen R. et al investigates the role of cinnamon in type 2 diabetes and dyslipidemia. The results of the study are discussed in this technical review article. RELEVANCE Naturally occurring products like cinnamon prove to be beneficial in specific disease conditions such as diabetes. The global burden of diabetes is undeniable and has prodded researchers to conduct studies that provide sufficient evidence for the use of cinnamon for the prevention and treatment of diabetes.

OBJECTIVES The aim of this study is to update a prior systematic review which did not show any statistically significant result with regard to cinnamon use in diabetes mellitus. This new review and metaanalysis is updated with newly published evidence from recent randomized clinical trials. 

HIGHLIGHTS This study is both a systematic review and a metaanalysis. MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) are the databases utilized to search potential studies in the literature. The search strategy was performed using cinnamon and diabetes as medical subject headings and keywords. Ten randomized controlled trials met the inclusion criteria. The first criterion is that they should be randomized controlled trials in patients with type 2 diabetes. Secondly, they should use cinnamon supplement via oral intake regardless of any formulation, dosage, and other intervention. Lastly, they should have an outcome on any of these: fasting plasma glucose, HbA1c (glycosylated hemoglobin), total cholesterol, triglycerides, low density lipoprotein (LDL-Cholesterol), and high density lipoprotein (HDL-Cholesterol). A total of 543 study subjects were included. Studies were validated by two independent reviewers using Cochrane Risk of Bias Tool. The two independent reviewers used a standardized data abstraction tool for each trial where specific information where obtained such as sample size, duration of study, and cinnamon dose and formulation. Comprehensive Meta-Analysis, version 2 (Biostat) was used to statistically analyze the data where a p value of <0.05 was identified to be statistically significant.

Eight trials had reported HbA1c level, as well as HDL-C and LDL-C. Nine trials reported data on total cholesterol, triglyceride, and fasting plasma glucose. The formulation of cinnamon varied from aqueous extract or raw powder form. The dosage of cinnamon in the trials ranged from 120 mg/day to 6g/day and the study duration lasted from 4 to 18 weeks. Only two trials reported an intention to treat analysis with only one specifying the number lost to follow up. The rest of the trials did not perform an intention-to-treat analysis. One trial accounted all patients in their analysis and had no subjects lost to follow-up. A statistically significant decrease in fasting plasma glucose was noted in those taking cinnamon compared with their counterparts in the control group with a weighted mean difference (WMD) of = –24.59 mg/dL.  Total cholesterol (WMD=–15.60 mg/dL), LDL-C (WMD=–9.42 mg/dL), and triglycerides (WMD=–29.59 mg/dL) also had significant reductions compared with their respective control. HDL-C levels, on the other hand, had a statistically significant improvement (WMD=1.66 mg/dL).

However no significant effect was seen in terms of HbA1c (WMD –0.16%)  

Heterogeneity was detected when HbA1c, fasting plasma glucose, triglycerides, total cholesterol, and LDL-C were analyzed but this was not statistically significant in HDL-C. The dose of cinnamon and its formulation may also contribute to heterogeneity. Potential publication bias was detected for fasting plasma glucose analysis (P=.004) but not for the other parameters. The bias may be due to the analysis of the results of one trial as three separate comparisons. In return, this resulted in a lower effect size. The reductions in fasting plasma glucose can be compared with standard therapies. Reductions in fasting plasma glucose levels (–24.59 mg/dL) in this metaanalysis using cinnamon are less than that of metformin (–58 mg/dL) but is greater than new oral agents, such as sitagliptin (–16 to –21 mg/dL). In terms of lipid profile, cinnamon has been shown to decrease LDL-C by 9.4 mg/dL and triglyceride levels by 29.6 mg/dL. Standard agents against dyslipidemia, such as pravastatin and gemfibrozil, decrease LDL-C and triglyceride by 50 mg/dL. The metaanalysis also stresses out the differences in the amount of the active component, cinnamaldehyde. Furthermore it points out the less rigorous manufacturing oversight of herbal supplements compared to that of pharmacological products. There are also some issues in terms of the administration of oral cinnamon. The side effects of cinnamon have not been well established in human population but the studies in animal subject identified the following: decreased platelet counts with increased risk of bleeding; allergic reactions particulary urticara; and hepatotoxicity from significant amounts of coumarin.

Therefore, liver enzyme studies should be established first before embarking on supplementation with cinnamon. Caution must be exercised by patients on oral hypoglycemic agents, those who are on antidyslipidemic agents, and those with known liver failure in terms of using cinnamon. The study recommends the need to conduct further trials on a long-term basis to establish safety data of various oral formulations of cinnamon. In future studies, a multivariate analysis can be completed to control for multiple factors, such as dose, formulation, and duration of treatment. The duration could have affected any potential and significant reduction in the HbA1c since the individual trials were done only for 4 to 18 weeks even if HbA1c reflects blood glucose for 3 months.

CONCLUSION    

Cinnamon intake whether in aqueous or powdered form significantly reduced fasting plasma glucose among type 2 diabetic patients. However, it did not reduce HbA1c to a significant value. This may be attributed to the short duration of the individual studies which range from 4 to 18 weeks. On one end, use of cinnamon significantly decreased levels of total cholesterol, LDL-Cholesterol, triglycerides and significantly increased HDL-Cholesterol. The application of this metaanalysis to clinical practice is limited by the heterogeneity of the studies in terms of the dosage of the cinnamon, its formulation, and the duration of treatment.

REFERENCES:

1. Rao Pand Gan S. (2014). Cinnamon: A Multifaceted Medicinal Plant. Evidence-Based Complementary and Alternative Medicine Volume 2014.

2. Allen R., et. al (2013). Cinnamon Use in Type 2 Diabetes: An Updated Systematic Review and Meta-Analysis. Annals of Family Medicine Vol. 11, No. 5

3. World Health Organization. (WHO 2014). Global Report on Diabetes.

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