DM: FDA-Approved Non-Nutritive Sweeteners (2014)

Citation:

Maki KC, Curry LL, Reeves MS, Toth PD, McKenney JM, Farmer MV, Schwartz SL, Lubin BC, Boileau AC, Dicklin MR, Carakostas MC, Tarka SM. 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-S53.

PubMed ID: 18555575
 
Study Design:
Randomized Controlled Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

To evaluate the effects of 16 weeks of consumption of 1,000mg rebaudioside A (N=60) a steviol glycoside with potential use as a sweetener, compared to placebo (N=62) in men and women (33 to 75 years of age) with type 2 diabetes.

Inclusion Criteria:
  • Men and women (18 to 74 years of age)
  • Provided written informed consent
  • Had type 2 diabetes that was diagnosed at least one year prior to screening; HbA1c of 9.0% o less at screening; and have been treated for at least 12 weeks with stable doses of one to three oral hypoglycemic agents, basal insulin (intermediate or long-acting injections that provide a steady low level of insulin throughout the day and night) or a combination of basal insulin plus one to three oral hypoglycemic agents
  • Body mass index (BMI) between 25 and 45kg/m2
  • Be willing to maintain their habitual diets and physical activity patterns and have no plans to change their smoking habits during the study period
  • Controlled hypertension on a stable dose of medication for at least six weeks.
Exclusion Criteria:
  • Individuals with significant renal, pulmonary, hepatic or biliary disease or a recent history of a cardiovascular event or revascularization procedure or any gastrointestinal condition that could potentially interfere with the absorption of the study product
  • Individuals with poorly controlled hypertension (resting seated systolic blood pressure higher than 160mm Hg or diastolic blood pressure higher than 100mm Hg)
  • Women of childbearing potential who were unwilling to commit to using a medically approved form of contraception or who were pregnant, lactating or planning to be pregnant during the study.
Description of Study Protocol:

Recruitment

Participants were recruited from six different research sites across the United States.

Design

Randomized, placebo-controlled clinical trial.

Blinding Used

Double-blind.

Intervention

  • Subjects randomized to Rebaudioside A (97% purity) or placebo in 250mg capsules provided by Cargill Inc.
  • Subjects took four capsules each day with the first meal of the day and two 250mg capsules with the evening meal to achieve a daily dosage of 1,000mg
  • Subjects visited the clinic four times at four-week intervals during the 16-week treatment period for laboratory assessments
  • Study coordinators contacted the subjects between the clinic visits at four-week intervals beginning two weeks after randomization to reinforce study instructions and answer questions.

Statistical Analysis

  • Statistical analyses were generated using SAS version 9.1.3 service pack 4 (SAS Institute, Cary, NC)
  • All tests of statistical significance were completed at the 5% level, two-tailed
  • Differences between treatment group responses were evaluated in a modified intent to treat population, including all subjects who received at least one dose of study product and provided at least one post-randomization HbA1c value
  • Differences between treatment groups in all outcome variables were assessed by analysis of covariance
  • Differences between treatment groups in the frequencies of adverse events were assessed by Fisher's exact (two-tailed) test, and the differences in clinical laboratory values were evaluated by analysis of covariance.
Data Collection Summary:

Timing of Measurements

Measurements made at baseline and after four, eight, 12 and 16 weeks.

 Dependent Variables 

  • Standard clinical evaluations included serum chemistry, hematology and urinalysis; Medpace Laboratories (Cincinnati, OH) performed all lab tests.
  • HbA1c: Measured by high-performance liquid chromatography
  • Fasting glucose was measured by photometry following a reaction with a hexokinase reagent
  • Fasting insulin and C-peptide were analyzed using electro-chemiluminescence immunoassays
  • Total cholesterol (total-C) and triglycerides were measured by photometry following enzymatic reactions
  • High-density lipoprotein cholesterol (HDL-C) was isolated by a two-step precipitation method and measured by photometry following an enzymatic reaction
  • Low-density lipoprotein cholesterol (LDL-C) concentration in mg per dL was calculated according to the Friedewald equation
  • Blood pressure was measured at each clinic visit using an automated vital signs monitor. Measurements were taken at two minute intervals for 10 minutes while the subject was resting quietly in a seated position.
  • Subjects reported any adverse events that occurred during the study and completed a hypoglycemia diary during the treatment period in which they documented the frequency and severity of hypoglycemic episodes.

Independent Variables

  • Subjects randomized to Rebaudioside A (97% purity) or placebo in 250mg capsules provided by Cargill Inc.
  • Subjects took four capsules each day with the first meal of the day and two 250mg capsules with the evening meal to achieve a daily dosage of 1,000mg
  • Subjects visited the clinic four times at four-week intervals during the 16-week treatment period for laboratory assessments
  • Study coordinators contacted the subjects between the clinic visits at four-week intervals beginning two weeks after randomization to reinforce study instructions and answer questions.
Description of Actual Data Sample:
  • Initial N: 122 (32 male, 28 female Rebaudioside A group; 30 male, 32 female in placebo group)
  • Attrition (final N): 116 (58 in Rebaudioside A group; 58 in the placebo group). Six subjects (two in the Rebaudioside A group and four in the placebo group) did not complete the study. The reasons for discontinuation included:
    • Withdrawal of consent (placebo, N=1)
    • Protocol violation [placebo, N=1 (subject started a weight loss diet)]
    • A work conflict (placebo, N=1)
    • Adverse events [Rebaudioside A, N=2 (gastrointestinal hemorrhage and hyperglycemia); placebo, N=1 (bronchitis)].
  • Age: Mean age 59.1 years in Rebaudioside A group; 61.5 years in placebo group
  • Ethnicity:
    • Rebaudioside A group: 68.3% non-Hispanic White; 21.7%  African American; 8.3% Hispanic
  • Anthropometrics: Mean body mass index (kg/m2) was 33.7 Rebaudioside group, 33.6 placebo group. There were no statistically significant differences between groups at baseline.
  • Location: Six research sites in the U.S.
Summary of Results:

Key Findings

  • Mean ±SE changes in glycosylated hemoglobin levels did not differ significantly between the Rebaudioside A (0.11%±0.06%) and placebo (0.09%±0.05%; P=0.355) groups
  • Changes from baseline for Rebaudioside A and placebo, in fasting glucose (7.5mg±3.7g per dL and 11.2mg±4.5mg per dL), insulin (1.0uU±0.64uU per ml and 3.3uU±1.5uU per ml) and C-peptide (0.13ng±0.09ng per ml and 0.42ng±0.14ng per ml) did not differ significantly
  • Assessments of changes in blood pressure, body weight and fasting lipids indicated no differences by treatment
  • Rebaudioside A was well-tolerated and records of hypoglycemic episodes showed no excess vs. placebo.
Author Conclusion:

The current trial was the first long-term study of Rebaudioside A in persons with type 2 diabetes. It specifically addressed the JEC-FA's request for additional studies involving repeated exposure of steviol glycosides in people with diabetes. These results suggest that chronic intake of 1,000mg per day of Rebaudioside A was well tolerated and did not alter glucose homeostasis or alter blood pressure in men and women with type 2 diabetes.

Funding Source:
Industry:
Cargill
Food Company:
Reviewer Comments:

Study funding and Rebaudioside A provided by Cargill Incorporated.

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? Yes
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? Yes
  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? Yes
  6.6. Were extra or unplanned treatments described? Yes
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  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? Yes
  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? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  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)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  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? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
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? ???