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Deeper Dive: Cinnamon may improve biomarkers of metabolic diseases

Study under review: The beneficial effects of cinnamon among patients with metabolic diseases: A systematic review and dose-response meta-analysis of randomized-controlled trials

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Metabolic diseases[1] affect over a billion people worldwide, and the prevalence of metabolic diseases has increased dramatically during the last decades. The costs and burden[2] to governments and communities are tremendous, with diabetes accounting for a global cost of over $1.3 trillion USD of global gross domestic product[3]. Lifestyle modifications such as a healthy diet, physical activity, stress management, and pharmacotherapy are currently the most prevalent interventions for treating metabolic diseases[4]. Since pharmacological interventions are often accompanied by unwanted side effects, scientists have been exploring alternative treatment options[5]. Plant-based therapeutics[6] such as cinnamon[7] have recently become more popular and could be used as an alternative or complementary therapy to treat metabolic diseases.

Cinnamon is one of the most common flavorings worldwide and may also have potential health benefits due to its high amounts of bioactive compounds[8]. In traditional medicine, cinnamon has been used for centuries[8] as an antitussive, antiarthritic, antimicrobial, antifungal, anti-oxidant, and anti-inflammatory agent[7]. The main bioactive components of cinnamon include cinnamaldehyde, cinnamic acid, eugenol, and coumarin[9]. These compounds influence various biological pathways and exert antimicrobial[10], anti-inflammatory[11], antioxidant[12], and anti-diabetic effects[13]. However, as shown in Figure 1, cinnamon species contain different amounts of these bioactive compounds, most notably coumarin, which can be toxic in higher doses[14].

Figure 1: Some major bioactive compounds and their amounts found in different cinnamon species

References: Wang et al. J Agric Food Chem. 2013 May.[15]
Zhu et al. Pharmacol Res. 2017 Aug.[16]
Doyle et al. Fitoterapia. 2019 Nov. [17]
Shreaz et al. Fitoterapia. 2016 Jul.[18]
Adisakwattana. Nutrients. 2017 Feb.[19]
De et al. Curr Med Chem. 2011.[20]
Anlar et al. Turk J Med Sci. 2018 Feb.[21]
Fujisawa et al. Adv Exp Med Biol. 2016.[22]
Barboza et al. Oxid Med Cell Longev. 2018 Oct.[23]
Shen et al. J Tradit Complement. Med. 2012. Jan.[24]

The two most widely used cinnamon species are Cinnamomum zeylanicum (typical baker’s or Ceylon cinnamon, sometimes also called C. verum) and Cinnamomum cassia (Chinese cinnamon). The two species differ significantly in their coumarin content. Since C. cassia contains high amounts of coumarin[25] (7–18 mg of coumarin per teaspoon), consuming too much could exceed the daily tolerable limit[26] of 0.1 mg of coumarin per kilogram of bodyweight. On the other hand, Ceylon cinnamon has a lower coumarin content, which makes it appear safer at first glance. However, C. cassiaalso contains higher amounts of other bioactive compounds, which could explain why studies found higher anti-diabetic effects of C. cassia than Ceylon. This is why there is still controversy as to which cinnamon species to use for optimal outcomes and sufficient safety in clinical practice. However, the current evidence suggests Ceylon is the safer option and that the bioactive compounds of cinnamon have beneficial properties to treat various metabolic diseases[8].

In particular, the potential beneficial effects of cinnamon on lipid profiles[27], glycemic status[28], blood pressure[29], and body composition[30] attract the most research attention and have been studied in detail. Experimental evidence suggests that cinnamon may positively affect lipid metabolism[24]. Studies have shown that the bioactive compounds of cinnamon can decrease fatty acid synthesis by influencing critical enzymes involved in hepatic lipid degradation[31]. For example, cinnamaldehyde[16], one of the main bioactive compounds that give cinnamon its odor and flavor, may stimulate lipolysis (the breakdown of fatty acids) by inhibiting the synthesis of fatty acids[24]. Also, evidence suggests that cinnamon could help treat dyslipidemia, as bioactive compounds of cinnamon were shown to inhibit lipoprotein lipase[32], an enzyme involved in lipolysis and secretion of lipids into systemic circulation. Two recent meta-analyses from 2017[33] and 2020[27] provide clinical evidence that cinnamon may improve lipid profiles in both healthy adults and participants with type 2 diabetes.

Experimental studies[34] showed that cinnamon improves glucose metabolism and insulin sensitivity via various biological mechanisms such as enhancing insulin receptor[35] activity, increasing secretion of glucagon-like peptide-1 (GLP-1)[36], improving glucose uptake[37], and modulation of glycolysis (e.g., by stimulating peroxisome proliferation[38] and inhibiting the gene expression of pyruvate kinase[39]). In addition, cinnamon extract has been shown to inhibit glucosidase[37] (an enzyme breaking down starch to glucose) in rats with diabetes, leading to decreased carbohydrate digestion and thus avoiding postprandial hyperglycemia, a major risk factor for diabetic complications. Cinnamon’s ability to slow digestion was observed in another study reporting that cinnamon reduced postprandial glucose response and delayed gastric emptying without affecting satiety[40]. However, these metabolic processes are complex, and the exact mechanism of cinnamon is not fully understood yet. Nevertheless, the experimental evidence incentivized scientists to conduct RCTs to investigate whether cinnamon could help manage type 2 diabetes and related aspects of metabolic syndrome in clinical practice. Two recent[41][28] studies meta-analyzed the clinical evidence and found that cinnamon improved the glycemic status of participants with type 2 diabetes, showing reduced fasting serum glucose levels. However, both meta-analyses report high heterogeneity, so these findings should be viewed with caution.

Cinnamon may also improve blood pressure. Two recent[42][29] meta-analyses from 2020 investigated the anti-hypertensive effects of cinnamon supplementation in healthy adults and found significant reductions in blood pressure. A possible biological mechanism is that cinnamon has a high antioxidant capacity[43] and may neutralize reactive oxygen species and increase nitric oxide levels[44], thus improving vasodilation and decreasing blood pressure. However, the two meta-analyses also report significant heterogeneity between the RCTs, most notably for disease state and type of cinnamon used. So, cinnamon may be a potent anti-hypertensive compound with clinical relevance, but further studies are required to confirm these properties.

Overall, there is still controversy regarding whether cinnamon has beneficial effects in terms of treating metabolic diseases. For example, the most recent Cochrane Review on cinnamon[45] did not find a disease-protective or curative effect of cinnamon in the context of type 2 diabetes due to a lack of pertinent evidence. Ever since the review was published, though, the clinical evidence has substantially grown, and more recent[41][28] meta-analyses found beneficial effects of cinnamon in this regard. Other meta-analyses[28][33] report controversial and mixed effects on different outcomes. So, there exists a ‘cinnamon controversy’, in that the efficacy of cinnamon as a preventive or medicinal compound for metabolic syndrome is still widely debated.

The present study[46] was designed to shed more light on the cinnamon controversy. The researchers meta-analyzed 35 placebo-controlled RCTs that investigated the effects of cinnamon on various cardiometabolic risk markers in adults with metabolic diseases. Unlike previous meta-analyses, the present study focused on metabolic disorders in general and analyzed multiple outcomes. In contrast, previous studies either focused on specific conditions like type 2 diabetes[28] or particular outcomes such as lipid profiles[27] and blood pressure[29]. Thus, the present study is one of the most comprehensive meta-analyses on the effects of cinnamon in metabolic diseases to date.

Metabolic diseases affect over a billion people worldwide and pose a severe economic and healthcare burden. Cinnamon could ameliorate critical features of metabolic disorders, thus improving outcomes and increasing quality of life while cutting healthcare costs. Even though the putative biological mechanisms of cinnamon are promising, there is still controversy about cinnamon’s practical efficacy, with some studies showing beneficial effects and others showing mixed results. The present study was designed to clarify this cinnamon controversy by meta-analyzing 35 RCTs, more than any meta-analysis had tackled before, on the various effects of cinnamon in adults with metabolic diseases.

What was studied?

The present study is a systematic review and meta-analysis of 35 RCTs published between 2003 and 2020 that investigated the effects of cinnamon among adults with metabolic diseases. Notably, the researchers did not specify which type of cinnamon was used in the included RCTs. The researchers assessed the changes in lipid profiles (total cholesterol, total triglycerides, HDL-C, and LDL-C), markers of glycemic status (fasting serum glucose, fasting serum insulin, HbA1c, and HOMA-IR), blood pressure (systolic and diastolic blood pressure), and waist circumference. Studies that lacked sufficient data for the outcomes of interest or were not placebo-controlled were excluded. The pooled sample size was 2,282 participants with metabolic diseases, ranging from 17 to 200 participants per study, with follow-ups of 6–26 weeks and doses of 0.12–12 grams per day. The most common metabolic disease was pre-diabetes and type 2 diabetes (26 of 35 RCTs), with the remaining studies including polycystic ovary syndrome, obesity, rheumatoid arthritis, and others.

The researchers used a random-effects model for the meta-analysis and reported their findings based on the Preferred Reporting Items of Systematic Reviews and Meta-Analysis (PRISMA)[47] statement guidelines. The researchers also conducted subgroup analyses to delineate the effects of cinnamon at different doses, study durations, and types of metabolic diseases. Notably, the researchers did not preregister their meta-analysis. To evaluate the quality of the included RCTs, the researchers used the Cochrane scoring system[48] to assess risk of bias as high risk, low risk, or unclear risk. The risk of publication bias was judged by visual inspection of funnel plots and Egger’s test[49]. The researchers also performed a sensitivity analysis to investigate the effect of individual RCTs on the overall effect estimates.

The present study is a meta-analysis of 35 RCTs investigating the effects of cinnamon in 2,282 adults with metabolic diseases. Specifically, the researchers assessed the effects of cinnamon on lipid profiles, markers of glycemic status, blood pressure, and waist circumference. Subgroup analysis was used to examine the effects of melatonin on different doses, study durations, and types of diseases.

What were the findings?

As shown in Figure 2, cinnamon significantly improved the lipid profiles, glycemic status, blood pressure, and waist circumference of adults with metabolic diseases. Also, serum insulin dropped by 7.6 pmol/L and HOMA-IR changed by -0.6. Overall, the effects of cinnamon on these risk factors may be large enough to have clinical relevance for participants with metabolic diseases.

Figure 2: Effect of cinnamon on metabolic markers (with 95% confidence intervals)

However, the researchers found considerable heterogeneity in all outcomes except for waist circumference, meaning the effects of cinnamon varied widely between the RCTs used in the meta-analysis. The researchers state two reasons to explain this heterogeneity: First, the risk of bias was unclear for most RCTs (31 of 35), with only three studies showing a low risk of bias, suggesting that the quality of the included RCTs is questionable. Second, the researchers identified the dose and study duration as two possible factors that could explain some of the heterogeneity. RCTs using doses of no more than 1.5 grams per day and study durations of more than 8 weeks showed more pronounced effects of cinnamon in terms of reducing total cholesterol (-18.4 and -15.7 mg/dL), triglycerides (-20.0 and -18.1 mg/dL), and LDL-C (-8.5 and -8.6 mg/dL). Daily doses of no more than 1.5 grams taken for more than 8 weeks also reduced fasting serum glucose (-12.4 and -15.0 mg/dL) more effectively than the overall effect estimate. However, blood pressure and waist circumference were not influenced by cinnamon dose and study duration. Notably, dose and duration could not explain all the heterogeneity observed for these outcomes, indicating that other confounding factors may be present.

The researchers assessed the dose-response relationship in more detail to better understand the effects of dose and duration on the effects of cinnamon. Interestingly, a non-linear dose-response relationship was found between changes in triglycerides and LDL-C with dose and changes in LDL-C and fasting serum glucose with duration. These findings could explain why cinnamon was more effective in the context of doses of no more than 1.5 grams per day for durations of more than 8 weeks. The relevance of these findings is discussed further in the next section.

Cinnamon significantly improved lipid profiles, markers of glycemic status, blood pressure, and waist circumference in adults with metabolic diseases. However, the researchers found substantial heterogeneity for all outcomes except waist circumference and an unclear risk of bias for most of the included RCTs. Different doses and study durations could, in part, explain the heterogeneity. Daily doses of no more than 1.5 grams supplemented for more than 8 weeks significantly improved the beneficial effects of cinnamon in terms of reducing total cholesterol, triglycerides, LDL-C, and fasting serum glucose compared to the overall effect estimate. However, dose and duration did not influence blood pressure and waist circumference and could not explain all of the heterogeneity, indicating that other confounding factors may play a role.

The bigger picture

The positive findings of the present study seem promising. Cinnamon showed various beneficial effects on lipid profiles, glycemic status, blood pressure, and waist circumference. However, the attentive reader may raise some justified questions: If cinnamon has such beneficial effects on these risk markers, why was there so much controversy regarding its efficacy? How does the present study stand concerning previous meta-analyses? And how relevant are the measured effects in clinical practice? Answering these questions requires diving deeper into the study under review in order to assess it in relation to the current body of literature.

The present study is in good agreement with two previous meta-analyses from 2017[33] (in adults) and 2020[27] (in participants with type 2 diabetes). All three meta-analyses found that cinnamon significantly reduced total cholesterol (-12 to -14 mg/dL), triglycerides (-16 to -26 mg/dL), and LDL (-6 mg/dL). However, the two previous meta-analyses did not find any statistically significant improvements in HDL-C, while the present study reports a significant increase in HDL-C (+1.35 mg/dL). That said, the 95% confidence intervals from each study shown in Figure 3 indicate that the studies are still roughly compatible with each other, even if the previous two didn’t find statistically significant results.

Figure 3: HDL-C changes in this study compared to two previous meta-analyses (with 95% confidence intervals)

So how relevant are these effects? Given the American Heart Association’s recommendations (see Table 1), the effects of cinnamon on cholesterol and triglycerides may be clinically relevant. Notably, cinnamon reduced triglycerides most significantly by 16 to 26 mg/dL, which could make a clear difference in participants with dyslipidemia, characterized by triglyceride levels of more than 200 mg/dL, aiming for levels of less than 150 mg/dL. Cinnamon’s effect on total cholesterol (-16.3 mg/dL) and LDL-C (-6.4mg/dL) is also considerable and could make a difference. Based on a recent cohort study of 12.8 million adults[50], a change in total cholesterol of -16 mg/dL in adults with blood levels of more than 200 mg/dL would be associated with approximately 5% lower all-cause mortality risk. Similarly, the reduced LDL-C levels found for cinnamon could lead to approximately 8% lower risk for coronary artery diseases (CAD), based on a recent Mendelian randomization analysis. The small yet significant increase in HDL-C caused by cinnamon may not be as clinically relevant as its lipid-lowering effects. Overall, the beneficial effects of cinnamon on lipid profiles are promising, but must be interpreted with caution. As decreasing risk markers do not necessarily lead to improved clinical outcomes, future RCTs investigating the effect of cinnamon on hard clinical outcomes such as decreased mortality rates are needed.

Besides blood lipids, cinnamon could be beneficial to improve the glycemic status of people with type 2 diabetes. Animal studies showed that cinnamon could inhibit numerous digestive enzymes, such as alpha-glucosidase[51] and sucrase[52], and decrease the influx of glucose into the systemic circulation, thus avoiding high insulin spikes. Like previous meta-analyses, the present study found a significant reduction in fasting serum glucose (-11.4 mg/dL) caused by cinnamon. If supplemented for more than 8 weeks, this glucose-lowering effect of cinnamon was even more pronounced (-15.0 mg/dL). As diabetes is diagnosed when fasting serum glucose levels are above 126 mg/dL (see Table 2), cinnamon could be clinically relevant for diabetes management. A recent Mendelian randomization study and meta-analysis[53] found that a 18 mg/dL higher fasting glucose was causally linked to an 48% higher risk of ischaemic stroke. That means it’s possible that the fasting glucose-lowering effect in the present study could meaningfully lower stroke risk by up to 40%, if cinnamon is supplemented for a prolonged period of time, although this is not confirmed.

In contrast to the previous meta-analyses, which probably lacked statistical power, the present study also found significant improvements for HbA1c (-0.23%), serum insulin (-7.6 pmol/L), and HOMA-IR (-0.59). These effect estimates could be clinically relevant, e.g., by improving the parameters of a participant with diabetes from moderate to slight insulin resistance. However, it remains an open question as to whether cinnamon could improve clinical outcomes such as disease progression or mortality rates. The positive findings of the present study could incentivize scientists to conduct further research on this topic.

Cinnamon may also have an effect on blood pressure. In 2020, two meta-analyses[29][30] were published that assessed the anti-hypertensive effects of cinnamon in adults. The findings were somewhat incompatible and created some controversy: While the first study found significant improvements for both systolic (-6.2 mmHg) and diastolic blood pressure (-3.9 mmHg), the other reported only a slight effect on diastolic blood pressure (-0.9 mmHg) and no significant effect on systolic blood pressure. The present study now provides a third perspective: cinnamon improved both systolic (-4.0 mmHg) and diastolic blood pressure (-3.4 mmHg) significantly. The effect was even more pronounced in studies of more than 8 weeks in duration (-6.7 and -8.9 mmHg, respectively). These findings are in good agreement with the other meta-analysis that showed positive effects of cinnamon on blood pressure. Also, both studies found that longer supplementation periods yielded more pronounced blood pressure improvements, indicating that cinnamon may exert biological effects, which emerge only after long-term administration.

Based on current evidence, the blood pressure-lowering benefits of cinnamon may have clinical relevance (see Table 3 for reference values). A meta-analysis of 123 studies including more than 613,000 participants[54] found a 13% risk reduction in all-cause mortality for a 10 mmHg decrease in systolic blood pressure. The anti-hypertensive effects of cinnamon could thus lead to an approximately 5–9% reduced risk for all-cause mortality, assuming a linear dose-response relationship between blood pressure and all-cause mortality risk. However, due to the high heterogeneity (i.e., the included studies varied a lot in design and findings) and unclear risk of bias, the effect estimates of cinnamon on blood pressure cannot be taken for granted and need to be viewed with caution.

Overall, the present meta-analysis has several strengths. Most notably, the present study is one of the most extensive meta-analyses of 35 RCTs that investigated the effects of cinnamon in 2,282 participants with different metabolic diseases. The sample size of the present meta-analysis allowed the researchers to identify significant changes where previous meta-analyses may have lacked the statistical power to do so.

However, there are three important limitations to consider when interpreting the reported effect estimates. First, the heterogeneity of the overall effect estimates was high, thus limiting the explanatory power of the results. A possible explanation that could account for part of the high heterogeneity may be the broad range of metabolic diseases analyzed. Apparently, the effects of cinnamon may vary for different metabolic diseases. Second, the researchers did not specify the type of cinnamon (C. verum or C. cassia), probably because most RCTs did not report on the type of cinnamon used. However, the type of cinnamon is a crucial factor that could account for some of the heterogeneity observed. In addition, different types of cinnamon differ by their bioactive compound content, most notably the potentially toxic coumarin. In fact, the non-linear dose response and upper limit of no more than 1.5 grams of cinnamon daily could be explained by most RCTs using C. cassia (high in coumarin) instead of Ceylon cinnamon. Future RCTs should thus carefully outline which type of cinnamon was used to make subgroup analyses and thus more specific supplement recommendations popular. Third, the complex multitude of biological mechanisms cinnamon is involved in makes it difficult to study the effects of cinnamon, especially in the context of such complex diseases as metabolic syndrome. Future studies may shed more light on the complex mechanisms and effects of cinnamon that could provide important information about general efficacy, the kind of people who benefit most, optimal dosage, and maybe even ideal timing.

The present study is one of the most comprehensive meta-analyses on cinnamon and metabolic diseases to date. Overall, the present study’s findings are in broad agreement with previous research but provide higher statistical power. This may be why the present study found significant effects that were previously only assumed, but not established. Cinnamon’s positive effects on lipid profiles, glycemic status, and blood pressure may have clinical relevance, especially if taken in the optimal dose (no more than 1.5 grams) over more extended periods (more than 8 weeks). However, the present study’s findings are limited by the high heterogeneity of the effects, unclear risk of bias for most the included RCTs, and unknown type of cinnamon used in the studies. Future studies should address these limitations to shed more light on the possible positive effects of cinnamon to treat metabolic diseases.

Frequently asked questions

Q. What is the optimal dose of cinnamon?

The precise dose to benefit from the optimal effects of cinnamon is still being debated. The present study suggests that doses of up to 1.5 grams per day may be sufficient for optimal health effects. However, the type of cinnamon (C. zeylanicum vs. C. cassia) is crucial to consider. As C. cassia contains higher amounts of the bioactive compound coumarin[25] (7–18 mg of coumarin per teaspoon), which can be toxic to the liver[26]. However, there is also a debate ongoing regarding whether coumarin may also be the bioactive agent responsible for most of the health benefits conveyed by cinnamon. This hypothesis is supported by recent evidence showing higher anti-diabetic effects of C. cassia than Ceylon.

However, considering the possible side effects of cinnamon, such as headache and diarrhea caused by high doses of its bioactive compounds, and the present study’s findings, lower amounts (no more than 1.5 grams per day) may be sufficient to reap the health benefits of cinnamon while staying on the safe side. This upper limit reported in the present study could indeed be explained by most RCTs using C. cassia instead of Ceylon cinnamon. Yet until more evidence is available, a precise number cannot be given at this time.

What should I know?

Over one billion people worldwide live with metabolic diseases, and incidence rates are steadily increasing. Cinnamon has been recommended to treat metabolic disorders due to its high content of bioactive compounds showing antimicrobial, anti-inflammatory, antioxidant, and anti-diabetic effects.

The present study meta-analyzed 35 RCTs of 2,282 participants with metabolic diseases to assess the effects of cinnamon on lipid profiles, glycemic status, blood pressure, and waist circumference. Cinnamon significantly improved all of the investigated risk markers, showing the most pronounced effects with doses of no more than 1.5 grams of cinnamon per day taken over more than 8 weeks. However, the researchers found considerable heterogeneity in the effects, indicating that the included RCTs differed widely in design and outcome and potentially the presence of confounding factors.

If future studies confirm the positive results of cinnamon, its effects may have clinical relevance as an adjunct therapy due to its anti-hypertensive effects, ability to reduce cholesterol and blood glucose, and its beneficial effect on insulin sensitivity. However, more RCTs validating the positive effects of cinnamon, and preferably showing clinical outcomes, must confirm cinnamon as an adjunct therapeutic in clinical practice.

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