|Year : 2016 | Volume
| Issue : 5 | Page : 16-21
Safety and efficacy of health supplement (Stevia rebaudiana)
Mazlina Mukhtar1, Chua Say Tiong2, Sarah I Bukhari3, Amir Heberd Abdullah2, Long Chiau Ming4
1 Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, Selangor, Malaysia
2 Department of Environmental Health, Faculty of Health Sciences, Universiti Teknologi MARA, Bertam, Penang; Vector-borne Diseases Research Group (VERDI), Pharmaceutical and Life Sciences CoRe, Universiti Teknologi MARA, Shah Alam, Selangor, Malaysia
3 Department of Pharmaceutics, College of Pharmacy, King Saud University, Saudi Arabia
4 Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam; Vector-borne Diseases Research Group (VERDI), Pharmaceutical and Life Sciences CoRe, Universiti Teknologi MARA, Shah Alam, Selangor, Malaysia
|Date of Web Publication||26-May-2016|
Dr. Long Chiau Ming
Level 11, FF1 Building, Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam, Selangor
Source of Support: None, Conflict of Interest: None
Purpose: The aim of this review is to evaluate the safety and efficacy of a product containing Stevia rebaudiana and its related marketing restriction governed by laws.
Methods: An electronic search was conducted through searching at Cochrane Library, EMBASE, PUBMED to assess the literature of Stevia rebaudiana.
Results: Stevia was considered safe to be used as sugar substitution in patients with diabetes. No serious adverse events and health risk were reported. However, until now, most of the beneficial results were from the study conducted in short-term. Not many studies conducted to assess the health risk of consuming stevia for long-term effect. Therefore, consumers must be warned to used stevia product cautiously and not exceed the recommended dose as instructed. No definite findings yet regarding dose range, minimum and maximum, to achieve optimal outcome and avoid risk of hypoglycemia.
Conclusion: Although some countries still banned the use of stevia since lack of toxicology profile, it was credited with the various health benefits. The Joint Expert Committee on Food Additives revealed that stevia extracts containing 95% steviol glycosides are safe for human use in the range of 4 mg/kg of body weight/day.
Keywords: Blood glucose, diabetes mellitus, HbA1c, herbal product, traditional medicine
|How to cite this article:|
Mukhtar M, Tiong CS, Bukhari SI, Abdullah AH, Ming LC. Safety and efficacy of health supplement (Stevia rebaudiana). Arch Pharma Pract 2016;7, Suppl S1:16-21
|How to cite this URL:|
Mukhtar M, Tiong CS, Bukhari SI, Abdullah AH, Ming LC. Safety and efficacy of health supplement (Stevia rebaudiana). Arch Pharma Pract [serial online] 2016 [cited 2019 Jun 20];7, Suppl S1:16-21. Available from: http://www.archivepp.com/text.asp?2016/7/5/16/183032
| Background of Disease|| |
Diabetes mellitus is a chronic disease characterized by hyperglycemia and metabolic abnormalities, resulting from insulin defects in secretion and action, insulin resistance, as well as increased in hepatic of glucose uptake supported by venous plasma glucose level ≥7 mmol/L during fasting and/or ≥11.1 mmol/L at random. It manifested by thirst, polyuria, polydipsia, blurring of vision, and weight loss. In severe cases of diabetes, ketoacidosis may occur when acids called ketones build up in the blood and urine because of no or not enough insulin produced. In this case, fat was used as a fuel instead of insulin. Over time, diabetes mellitus can lead to serious microvascular complications including nephropathy, neuropathy, and retinopathy as well as macrovascular complications such as ischemic heart disease and cerebrovascular and peripheral vascular disease.
Based on the 2014 World Health Organization (WHO) report, the global prevalence of diabetes was 9% with 347 million of population already diagnosed with diabetes and death due to diabetes was estimated double from 2005 to 2030.
| Treatment Guidelines|| |
Management of patient with diabetes should include combination of nonpharmacological, pharmacological, and dietary supplement to achieve and maintain normal sugar level that can minimize the risk of diabetes complications. According to the Malaysia Clinical Practice Guideline for diabetes, oral medication should be initiated for a patient who failed to achieve glycemic target (HbA1c <6.5%, fasting plasma glucose 16 <6 mmol/L), with nonpharmacological management. Combination therapy with either insulin or another oral agents has to consider if patient still does not reach the target after 3 months intensification with monotherapy.
| Product Background|| |
Stevia rebaudiana Bertoni is the herbs from Asteraceae family, native to the Amambay region in Paraguay. Stevia extracts consisted of stevioside, rebaudioside C, rebaudioside A, and dulcoside A. However, only stevioside and rebaudioside A have the sweetening effect which is 200–300 times more than sucrose. For many years, South Americans have been used stevia extracts as a treatment for diabetes. Until now, stevioside and rebaudioside A were used as sugar substitution or food additive in several countries such as Japan, China, Taiwan, South Korea, Malaysia, and South America. However, the Food and Drug Administration only approved the use of whole stevia or stevia extracts as dietary supplement and not for food additive. Despite some issue questioning on stevia safety profile, numerous studies were published regarding health benefit of stevia as antihyperglycemia, antihypertensive, anti-inflammatory, antitumor, and immunomodulatory effects.,,,,,
| Clinical Pharmacology|| |
Mechanism of action
Reduction of intestinal mucosal adenosine triphosphate (ATP) content would inhibit the absorption of glucose and lead to decrease accumulation of glucose in the intestine.,
Suppress phosphoenolpyruvate carboxykinase gene will slow down the gluconeogenesis in the liver.
Insulin secretion and sensitivity
Stimulate excretion on insulin from β-cells and increase insulin sensitivity in peripheral tissue will promote glucose utilization. Stevia also has a direct effect on glucagon reduction.
Since gastric juices and digestive enzymes in the intestine were unable to hydrolyzed stevioside, they were hydrolyzed to aglycone for absorption by the colon microflora at the lower intestinal tract. Tmax of aglycone was 0.25 h.
Stevioside was accumulated in the small and large intestine.
Metabolism in the liver by cytochrome P450 was carried out in two phases. Stevioside was metabolized to steviol glucuronide as a major metabolite. Median peak concentration is 8 h.,
In Phase 1 metabolism, 62% of steviol was excreted in the urine after 72 h ingestion. More steviol is conjugated with glucuronide for urinary excretion after Phase 2 metabolism. Excretion process involved of renal organic anion transporters.
| Promotion of Stevia Use|| |
Cultivation of stevia was spread to Canada, Europe, and Asia region including Malaysia, Japan, Thailand, China, and South Korea since it first discovered in Paraguay in the early 90's. Japan became the first Asian country marketed stevia as sweetener in food and drug industry. In Malaysia, stevia was marketed via various channels and became a phenomenon since consumers nowadays are demanding healthier and natural food. Multilevel marketing one of the strategies used to attract consumers becomes a distributor with various advantages such as membership commission, bonus, and reward to market their products.
The advertisement is one-way of marketing strategy. Medicines Advertisement Board (MAB) Legislation and Approval guideline was used to regulate the content of advertising and ensure safe use of medicines/products. Advertisements of stevia in Malaysia need some aspects for amendments to adhere with MAB requirements. Marketers would advertise their products in different sources to attract the different target groups. At present, Facebook dominates as a source of social traffic and sale for all kinds of products including health, fashion, and even household. Since stevia promising various health benefits, advertising via Facebook with attractive messages would become the great platform to generate interest of the consumers. Interactive communication as in Facebook would make consumers more appeal to buy that product. In Malaysia, stevia was only approved to be used as food additive/sugar substitution. Advertiser promotes stevia as herbs product which is not allowed (clause 7.3) unless approved by the Drug Control Authority. Nature of stevia which is noncaloric sweetener benefits diabetic patient in maintaining of the glucose level. However, advertising the product with the claim for the treatment of illness is not allowed according to the MAB guideline. Advertiser failed to adhere clause 4.4 (a) as they claim that stevia can be used not only to reduce the glucose level but also to prevent and treat diabetes.
There is also illustration of diabetic wound with the statement “stevia proved to cure wound of the diabetes patient.” Advertisers also tend to use exaggerated word and safety claims to attract more consumers, for example, “sedap,” “sangat berkesan,” safe and no side effect which are conflicted with the MAB guideline (clause 7.6). Putting up customer testimonials or reviews in the newspaper, radio, and online shopping website allowed consumers to research more thoroughly with those honest opinions and increase their confidence to buy the product. Stevia was advertised using celebrities as promotional strategy, but no statement “the effect of the product may vary among individuals” for the user and celebrity testimonial (clause 5.1). Furthermore, no information regarding name, identity certificate/passport number, signature, and contact number was included (clause 5.3). The only information available was name and contact number. Certified HALAL logo by JAKIM was published, but no KKLIU number was displayed in Internet advertisement (clause 4.14).
Placement of banner and handing out flyers regarding stevia at strategic area for targeted group of consumer was the other way to introduce the product in the market. Another marketer strategy was by offering a free coupon or trial. PappaRich restaurant, Malaysia, was offering free white coffee using stevia as sweetener for some period. This great approach would allow consumers to self-qualify whether they are interested to opt in or not.
| Methodology|| |
- An electronic search of Science Direct, PubMed, and Google Scholar using the following keywords and research criteria were carried out:
- Nine studies/trials were submitted by the proposer
- The following websites were searched for reviews and reports for additional information: Ministry of Health Malaysia, MIMS, and Micromedex.
| Results|| |
Efficacy and safety
Study on benefit effect of stevia already started for more than a decade. One systemic study was conducted involved of 16 volunteer subjects to assess the effect of stevia on glucose tolerance in normal adult humans. Both treatment and control groups receive 13 dose of dry leaves, stevia 65 mg and 250 mg arabinose, respectively, in 6 h interval. This short-term, 3 days, study found that after overnight, FPG level was significantly lower in stevia group compared to control group. The maximum difference in glucose level was seen after 30 min of stevia ingestion.
Wheeler et al. in 2008 conducted a randomized, double-blind, two-way, cross-over study in healthy males ages 18–45 years old to assess the pharmacokinetic of stevioside, as well as rebaudioside A which is the derivative of S. rebaudiana. Safety profile showed no significant adverse event reported, except ecchymosis at the venipuncture site which is unrelated to both of the stevia extract.
A short-term, paired, cross-over study was conducted by Gregersen et al. in 2004 involved of Type 2 diabetic patients using 1 g of stevioside in the treatment group versus 1 g of maize starch (placebo). Results indicated that supplementation with stevia significantly reduce the postprandial blood glucose by 18 ± 5% (522 ± 64 mmol/L) compared to placebo (638 ± 55 mmol/L) and output of urinary glucose was not affected by stevia. No patient experience of any late hypoglycemia symptoms was observed. However, the author concluded that use of stevia as a treatment for diabetes still needs to be proven.
Other than stevia extract, dried leaves of S. rebaudiana as sweetener can reduce the postprandial blood glucose and decreased the mean blood pressure (BP). A randomized, controlled, cross-over, short-term, double-blind study was conducted recently in Morocco involved of 228 diabetic patients allocated to stevia (n = 114) and control group (n = 114). Stevia group received green tea +4 g stevia leaves versus control group received green tea +10 g of sugar. All antidiabetic medications were withheld prior to the experiment. Results after 120 min showed significant decrease in capillary blood glucose (−35.8%) in stevia group while in control group, the level was increased by +8.1% (P < 0.0001). No side effects such as hypoglycemia and adverse event were observed across the study.
When healthy subjects were preload with stevia, aspartame, and sucrose before lunch, stevia preload reduced the intake of food and significantly the postprandial glucose after 20 min compared to aspartame and sucrose groups.
One study on long-term effect of stevioside conducted by Barriocanal et al. in 2008 revealed different findings. This randomized, double-blind, parallel, placebo-controlled study involved of diabetic patients (30 was Type 2 and 16 was Type 1) as well as thirty patients without diabetes and normal BP. All subjects consumed either stevia 250 mg three times/day or placebo. Conversely, after 3 months, stevioside had shown no pharmacological effect in lower blood glucose or BP as no significant different in glucose level and HbA1c was detected compared to the baseline (HbA1c = 7.1 ± 1.6 to 7.3 ± 1.1 in steviol group vs. 8.2 ± 1.4 to 8.3 ± 1.6 in placebo group). However, no hypoglycemia, weight changes, and serious side effects were observed.
Sixteen weeks trial was conducted by Maki et al. in 2008 regarding the effect of chronic consumption (1000 mg/day), one of the stevia extract which is rebaudioside A in diabetes patients. This randomized, double-blind, placebo-controlled, clinical trial conducted at six research sites in the United States involved of diabetes patients age 18–74 years old with HbA1c ≤9.0% and was diagnosed at least 1 year prior of the study. The results reported no significant difference of HbA1c, fasting glucose level, insulin, and C-peptide reduction found in both arms. Adverse event gastroenteritis and upper respiratory tract infection were seen with no significant difference in both groups. This study revealed that chronic consumption of rebaudioside A was well tolerated with no episode of hypoglycemia.
Induced diabetes rats were fed with stevia leaves powder and polyphenol from stevia extract. In this study, Shivanna et al. in 2013 found that stevia was able to decrease the elevated glucose level by 36% when compared with control group. Stevia has ability to increase insulin sensitivity after 4 weeks of treatment as well as enhance the insulin secretion from the β-cell of pancreatic islets. Apart from antidiabetic properties, this study concluded that polyphenol extract from the stevia leaves might contribute to other beneficial effect as antioxidant and renal protective properties. Acute treatments with stevioside significantly lower the plasma glucose response and eventually, increase the sensitivity of insulin in insulin resistance subject.
Stevia mechanism of action in maintaining euglycemia via glucose absorption effect was studied by Toskulkao et al. They indicated that stevioside (stevia extract) has no effect on inhibition of intestinal glucose absorption. However, that mechanism was mediated by steviol glucuronide (stevioside metabolite) via reduction of intestinal mucosal ATP content. Other finding showed although the treatment group has slightly decreased in glucose absorption, no significant different was seen in treatment and placebo groups after 60 min.
| Risk to the General Population|| |
Based on the WHO report, a global number of patients diagnosed with diabetes were estimated 9% and the number keep increasing since a decade despite various new drugs or technologies introduced in the market. In Malaysia alone, there were 3.2 million cases of diabetes in 2014. Aging population, urbanization, physical inactivity, and sedentary lifestyle act as contributing factors that accelerated the prevalence of diabetes.
Therefore, addition of newer and safer pharmacological agent is needed. Most of the available studies prove that both derivatives mainly stevioside able to inhibit the glucose absorption, increase insulin sensitivity and secretion, as well as slow down the gluconeogenesis process in the liver. Furthermore, no other serious toxicity was reported. In Malaysia, stevia product was advertised extensively in social media and attracted consumers with positive reviews. They came in various oral forms such as liquid, powder, and tablet with different brand. Based on the study findings conducted in other ethnic, stevia was considered safe to be used as sugar substitution in patients with diabetes. No serious adverse events and health risk were reported. However, until now, most of the beneficial results were from the study conducted in short-term. Not many studies conducted to assess the health risk of consuming stevia for long-term effect. Therefore, consumers must be warned to used stevia product cautiously and not exceed the recommended dose as instructed. No definite findings yet regarding dose range, minimum and maximum, to achieve optimal outcome and avoid risk of hypoglycemia.
Future study to determine effect of stevia in our population is needed since ethnicity is one factor that may account for the difference finding. Furthermore, most of the study available involved of experimental animals as subjects. In the future, stevia might be the great alternative not only as sugar substitution but also in the treatment of diabetes if more data on benefit and risk in human are available.
| Recommendations and Conclusion|| |
Although some countries still banned the use of stevia since lack of toxicology profile, it was credited with the various health benefits. The Joint Expert Committee on Food Additives revealed that stevia extracts containing 95% steviol glycosides are safe for human use in the range of 4 mg/kg of body weight/day. Stability of stevia under high temperatures also gives an advantage over other artificial sweeteners such as saccharin when it comes for cooking. For the time being, stevia should not be banned in Malaysia market but only be used as sugar substitution and not as a dietary supplement or treatment in diabetes patients until more data available. However, with various brand and dosage form available in the market, consumers must ensure to select the product that safe and benefit to their health. Insufficient data on stevia safety profile, long-term effect, mechanism of action, and pharmacokinetic as well as mixed findings of research indicated that we urgently need more human research to clear all the uncertainties and clarify the benefit effect of stevia in health.
Financial support and sponsorship
This work was supported by Research Acculturation Grant Scheme: RAGS/1/2014/SKK07/UITM//2. The authors would like to express their gratitude to Ministry of Higher Education and Universiti Teknologi MARA (UiTM), Malaysia for financial support for this research.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ministry of Health Malaysia. Management of Type 2 Diabetes Mellitus. Malaysian Clinical Practice Guideline. 2009. p. 1-129.
Cade WT. Diabetes-related microvascular and macrovascular diseases in the physical therapy setting. Phys Ther 2008;88:1322-35.
Koyama E, Sakai N, Ohori Y, Kitazawa K, Izawa O, Kakegawa K, et al
. Absorption and metabolism of glycosidic sweeteners of stevia mixture and their aglycone, steviol, in rats and humans. Food Chem Toxicol 2003;41:875-83.
Shivanna N, Naika M, Khanum F, Kaul VK. Antioxidant, anti-diabetic and renal protective properties of Stevia rebaudiana. J Diabetes Complications 2013;27:103-13.
Pallarés Á, Carrasco G, Nava Y, Pallarés O, Pérez I, Rifá R, et al
. Effectiveness and safety of Stevia rebaudiana dried leaves as an adjuvant in the short-term treatment of type 2 diabetes: A randomized, controlled, cross-over and double-blinded trial. J Med Plant Herbal Ther Res 2015;3:16-26.
Lemus-Mondaca R, Vega-Gálvez A, Zura-Bravo L, Ah-Hen K. Stevia rebaudiana
Bertoni, source of a high-potency natural sweetener: A comprehensive review on the biochemical, nutritional and functional aspects. Food Chem 2012;132:1121-32.
Gregersen S, Jeppesen PB, Holst JJ, Hermansen K. Antihyperglycemic effects of stevioside in type 2 diabetic subjects. Metabolism 2004;53:73-6.
Lailerd N, Saengsirisuwan V, Sloniger JA, Toskulkao C, Henriksen EJ. Effects of stevioside on glucose transport activity in insulin-sensitive and insulin-resistant rat skeletal muscle. Metabolism 2004;53:101-7.
Curi R, Alvarez M, Bazotte RB, Botion LM, Godoy JL, Bracht A. Effect of Stevia rebaudiana on glucose tolerance in normal adult humans. Braz J Med Biol Res 1986;19:771-4.
Chatsudthipong V, Muanprasat C. Stevioside and related compounds: therapeutic benefits beyond sweetness. Pharmacol Ther 2009;121:41-54.
Toskulkao C, Sutheerawattananon M, Piyachaturawat P. Inhibitory effect of steviol, a metabolite of stevioside, on glucose absorption in everted hamster intestine in vitro
. Toxicol Lett 1995;80:153-9.
Wheeler A, Boileau AC, Winkler PC, Compton JC, Prakash I, Jiang X, et al
. Pharmacokinetics of rebaudioside A and stevioside after single oral doses in healthy men. Food Chem Toxicol 2008;46 Suppl 7:S54-60.
Anton SD, Martin CK, Han H, Coulon S, Cefalu WT, Geiselman P, et al
. Effects of stevia, aspartame, and sucrose on food intake, satiety, and postprandial glucose and insulin levels. Appetite 2010;55:37-43.
Barriocanal LA, Palacios M, Benitez G, Benitez S, Jimenez JT, Jimenez N, et al
. Apparent lack of pharmacological effect of steviol glycosides used as sweeteners in humans. A pilot study of repeated exposures in some normotensive and hypotensive individuals and in Type 1 and Type 2 diabetics. Regul Toxicol Pharmacol 2008;51:37-41.
Maki KC, Curry LL, Reeves MS, Toth PD, McKenney JM, Farmer MV, et al
. Chronic consumption of rebaudioside A, a steviol glycoside, in men and women with type 2 diabetes mellitus. Food Chem Toxicol 2008;46 Suppl 7:S47-53.