Safety evaluation of certain food additives - ipcs inchem

202 STEVIOL GLYCOSIDES (addendum)
in the placebo group and two in the test group. Self-reported adverse reactions were
recorded, and fasting blood samples were taken at the end of the study and
analysed for ALT, aspartate aminotransferase (AST), gamma-glutamyltransferase
(GGT), total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein
(LDL), very low density lipoprotein (VLDL) and triglycerides. No effects of treatment
on ALT, AST or GGT were found. Decreases in the total cholesterol and LDL were
observed in both the stevioside group and the placebo group, which were not
treatment related. No adverse effects were observed (Cavalcante da Silva et al.,
2006). The Committee noted at its sixty-eighth meeting that the product used in this
study did not meet the proposed specification.
A randomized double-blind placebo-controlled parallel group trial was
carried out in 122 subjects with type 2 diabetes mellitus (62 male and 60 female
subjects aged 33–75 years). The study was compliant with ethics guidelines of the
International Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use (ICH). Subjects were allocated into two
groups: one group received 1000 mg rebaudioside A (97.4% rebaudioside A, remaining
content other steviol glycosides) per day, and the other group received a
placebo. All subjects consumed four capsules daily, two with breakfast and two with
the evening meal, for 16 weeks. Based on the mean body weight of the test subjects
at the beginning of the study, the mean rebaudioside A dose was 10.2 mg/kg bw
per day, corresponding to 3.4 mg/kg bw per day expressed as steviol. Vital signs
and adverse events were recorded at each clinic visit, along with changes in the
laboratory assessments. HbA1c was measured in weeks 0 and 16. Two individuals
in the test group withdrew from the study (owing to gastrointestinal haemorrhage
and hyperglycaemia), and four in the placebo group withdrew. The reasons for
withdrawal were not considered to be treatment related. Twenty-seven subjects
receiving the test compound experienced one or more adverse events, compared
with 23 in the placebo group. Four further events in the test group and three in the
placebo group were considered to be severe in intensity. These events included
influenza-like symptoms, gastroenteritis, gastrointestinal haemorrhage (a serious
adverse event) and a cyst in the rebaudioside A group; and gastroenteritis, fracture
and bronchitis in the placebo group. These were considered to be unrelated to
treatment. There was no evidence of any adverse effects of treatment on blood
pressure, serum chemistry and haematology parameters, or urinalysis. HbA1c was
unaffected by treatment. The authors concluded that a daily dose of 1000 mg
rebaudioside A did not cause pharmacological effects in this population of diabetic
subjects and had no effect on diabetic control. The authors stated that they did not
investigate the effects of rebaudioside A on individuals with type 1 diabetes because
the purported mechanism of action for steviol glycosides involves enhanced
secretion of insulin from the pancreas when there is impaired response to glucose
stimulation (Wheeler, 2007a; Carakostas et al., 2008; Maki et al., 2008b).
A randomized double-blind placebo-controlled cross-over trial was carried
out in two subgroups of individuals: 45 healthy subjects with normal glucose
tolerance (28 female, 17 male, BMI 27.3 ± 0.8 kg/m 2 ) and 48 individuals with type
2 diabetes mellitus (13 female, 35 male, BMI 32.2 ± 0.6 kg/m 2 ). Subjects were aged
18–74 years, and mean body weight was 78.7 ± 2.7 kg for subjects with normal