EAL

NNNS: Stevia (stevioside) (2010)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To investigate the effect of steviol glycosides consumption in humans [both diabetics (type 1 and type 2) and non-diabetics with normal or low-normal blood pressure (BP)] in order to comply with the first part (the pharmacological effects of steviol glycosides in humans) of Annex 2 of the 63rd meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA).

Inclusion Criteria:

Group One:
- Type 1 diabetes mellitus
- 20 years to 60 years old
- Diabetes duration of more than five years
- Normotensive or hypertensive under treatment
- Glycated hemoglobin of less than 10%
- BMI between 20kg/m² and 35kg/m²
- Without established renal disease
Group Two:
- Type 2 diabetes mellitus
- 40 years to 70 years old
- Diabetes onset at age greater than 30 years
- Diabetes duration of more than one year and less than 10 years
- Treated with diet or oral anti-diabetic agents
- Normotensive or hypertensive under treatment
- Glycated hemoglobin of less than 10%
- BMI between 25kg/m² and 35kg/m²
- Without established renal disease
Group Three:
- Healthy subjects
- 20 years to 60 years old
- Normal or low-normal BP
- BMI between 20kg/m² and 35kg/m².

Exclusion Criteria:

Enrollment in a clinical trial of drugs within the last three months
Significant cardiovascular, psychological, neurological, renal or endocrine disease (apart from diabetes)
Alcohol or drug abuse
Acute illness
Fasting glucose levels of less than 70mg per dL or more than 200mg per dL
BP of at least 170/110mm Hg on the day of the experiment
Glcyated hemoglobin of at least 10%
Pregnancy
Treatment with glucocorticoids
Treatment with insulin except for Group One.

Description of Study Protocol:

Recruitment: Not described
Design: Randomized, double-blind, placebo-controlled, parallel
Blinding used: Double-blind and implied for laboratory measurements.

Intervention

Placebo
Steviol glycoside: Capsules, 250mg TDI, provided by Steviaforma Industrial S.A., Maringa, Brazil; purity at least 92%.

Statistical Analysis

Data are reported as means ±SD
Significance was set at P<0.05 for differences between the active treatment and placebo groups at baseline and between post- and pre-treatments within groups
Student's T-test was used to compare treatment groups at baseline and the paired-samples T-test was used to compare the means of the post- and pre-treatment levels within groups
Power analyses were also conducted to determine whether the samples were large enough to allow for the detection of a clinically significant change between baseline and post-treatment levels within the control and treatment groups. A clinically significant difference was defined based on the range of normal values for each of the parameters considered. The normal ranges were: Systolic BP, 90mm Hg to 120mm Hg; diastolic BP, 60mm Hg to 80mm Hg; glucose, 60mg per dL to 99mg per dL; HbA_1c, 4% to 5.9%. Clincially significant differences were therefore defined as 20mm Hg, 50mg per dL and 1%, respectively.

Data Collection Summary:

Timing of Measurements

Three-month study
Time of year or years not given.

Dependent Variables

Blood pressure: Measured in the clinic using a 90217 Ultralite ABP continuous blood pressure measurement monitor; at the beginning and the end of the study period, 24-hour blood pressure was measured using the same equipment
Laboratory measures: Venous blood drawn between 7:00 A.M. and 9:00 A.M. after an overnight fast; collected at the beginning and the end of the study period for determination of glucose, insulin (for Groups Two and Three), total cholesterol, HDL-cholesterol and LDL-cholesterol, triglycerides, electrolyte and creatin phosphokinase concentrations, renal function (creatinine) and hepatic function (ALT, AST, gammaGT)
Anthropometrics: Measured at the beginning and at the end of the study period; weight, height, BMI and waist circumference
Every two weeks, capillary blood glucose, BP and weight were measured. At these visits, volunteers were asked about adverse events and the capsules were counted to check for compliance.

Independent Variables

Placebo
Steviol glycosides.

Description of Actual Data Sample:

Initial N

86 subjects (45 women, 41 men) were initially enrolled.

Attrition (Final N)

76 subjects (30 with type 2 diabetes, 16 with type 1 diabetes and 30 without diabetes and normal or low-normal BP level
10 volunteers (four in Group One, three in Group Two and three in Group Two) decided to discontinue the study for no specific reason, but not due to side effects.

Age

Mean age was 25.4 years for Group One; 58.2 years for Group Two and 28.1 years for Group Three.

Anthropometrics

Weight, height, BMI and waist circumference were measured at the beginning and at the end of the study period.

Location

Paraguay; specific location not given.

Summary of Results:

Results taken from Tables One through Three

Mean diastolic BP levels changed from 72.6mm Hg to 68.9mm Hg in type 1 diabetics, from 77.3mm Hg to 75.7mm Hg in type 2 diabetics and from 69.9mm Hg to 69.8mm Hg in non-diabetics
Mean systolic BP levels changed from 117.1mm Hg to 115.9mm Hg in type 1 diabetics, from 124.3mm Hg to 120.8mm Hg in type 2 diabetics and from 111.0mm Hg to 113.3mm Hg in non-diabetics
For glucose, mean levels changed from 144.9mg per dL to 155.2mg per dL in type 1 diabetics, from 151.2mg per dL to 133.8mg per dL in type 2 diabetics and from 82.5mg per dL to 82.9mg per dL in non-diabetics
Mean HbA_1c levels changed from 7.1% to 7.3% in type 1 diabetics, from 6.8% to 6.6% in type 2 diabetics and from 5.3% to 5.6% in non-diabetics
No significant changes from baseline were detected within the Placebo Group for BP (systolic and diastolic), glucose and HbA_1c, except for the Type 1 Diabetics Group in the case of mean systolic BP and glucose. Specifically, mean diastolic BP levels changed from 70.7mm Hg to 69.7mm Hg in type 1 diabetics, from 76.7mm Hg to 77.4mm Hg in type 2 diabetics and from 68.8mm Hg to 69.9mm Hg in non-diabetics, while the mean systolic BP levels changed from 108.3mm Hg to 105.7mm Hg in type 1 diabetics, paired T-test P=0.002), and from 124.9 to 125.4mm Hg (Type 2 diabetics), and from 111.7 to 112.2mm Hg (non-diabetics). For glucose, mean levels changed from 219.3 to 298.3mg per dL (Type 1 diabetics, paired T-test value = 0.043), and 131.3 to 118.9mg per dL (Type 2 diabetics) and 82.9 to 82.9mg per dL (non-diabetics), while mean HbA_1c levels changed from 8.2% to 8.3% (Type 1 diabetics), from 6.8% to 6.7% (Type 2 diabetics) and from 5.3% to 5.4% (non-diabetics).

Other Findings

Volunteers' baseline clinical and biochemical characteristics were similar at randomization, except for the Type 1 Diabetics group, where a significant difference between the placebo and steviol glycoside groups was observed for systolic BP and triglycerides
No significant changes from baseline were detected within the steviol glycoside treatment group for BP (systolic and diastolic), glucose and HbA_1c
Similarly, no significant changes from baseline were detected within the placebo group for BP (systolic and diastolic), glucose and HbA_1c except for the Type 1 Diabetics group in the case of mean systolic BP and glucose
A power analyses was conducted post-hoc after no statistically significant changes were observed between baseline and post-treatment in systolic BP, diastolic BP, glucose or Hb1_ac except for the placebo Type 1 diabetics group
All volunteers who completed the study followed the prescribed treatment schedule throughout the three-month period, and the degree of compliance was similar in both groups (steviol glycoside and placebo). Compliance was measured as capsule count.
Steviol glycoside was well tolerated. The types and and incidence of side effects were similar between the steviol glycoside and placebo groups. Shortly after the initiation of treatment, volunteers in both groups (three in the steviol glycoside group and five in the placebo group) experienced adverse effects (abdominal fullness, headache, dizziness, nausea and asthenia), but symptoms disappeared after one week of treatment. No drop-outs were due to side effects.
No significant changes in body weight or biochemical parameters were observed in the two treatment groups.

Author Conclusion:

The authors concluded that consumption of steviol glycosides in humans as a sweetener by normal and diabetic subjects (including those with normal to low-normal blood pressure) is safe and does not produce either hypoglycemica or hypotension.

Funding Source:

Government:

Ministry of Agriculture of Paraguay through the InterAmerican Development Bank

Reviewer Comments:

No limitations cited by authors
This reviewer noted several potential confounding factors that were not discussed by the researchers:
- Large range in BMI for Group 1 [Type 1 Diabetics (normal weight to morbidly obese)] that could influence results (e.g., if effect is dependent on x mg per kg body weight)
- Unexplained difference in duration of diabetes in inclusion criteria between the Type 1 and Type 2 Diabetics
- Post-hoc power analyses
- Large unexplained increase in blood glucose in placebo subjects from baseline to study conclusion.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	???
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	Yes
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	N/A
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	???
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		???
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	No
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	N/A
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	???
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		No
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	No
10.	Is bias due to study's funding or sponsorship unlikely?		???
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	???