EAL

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

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

"Evaluate the effects of three months of daily consumption of high doses of sucralose in subjects with type 2 diabetes."

Inclusion Criteria:

Type 2 diabetes for at least one year
Thirty-one years to 70 years of age
Managed their diabetes with insulin or an oral hypoglycemic agent, but not both
Had "relatively stable" diabetes
HbA1c≤10%
Familiar with capillary blood glucose monitoring
Familiar with standard diet guidelines for diabetes management
In general good health.

Exclusion Criteria:

None noted.

Description of Study Protocol:

Recruitment

Not described.

Design and Intervention

The study was conducted in three phases:

Six-week screening period

Subject eligibility, baseline glucose homeostasis and general health assessments were determined
On entry to the screening phase, subjects were asked to follow a diet of approximately 14% protein, 30% to 36% fat, 48% to 55% carbohydrates and to monitor their blood glucose concentration at least three times per day, two days per week for the study duration
Two weeks after entering the screening phase, all subjects were given placebo capsules of cellulose and instructed to take one at breakfast and one at dinner for the remaining four weeks of the screening period.

Thirteen-week test period

Subjects were randomized and received two capsules each day of placebo or sucralose (total daily dose=667mg). Compliance to test pills was assessed by capsule count and qualitative measurement of sucralose in the urine every two weeks, beginning two weeks before the test period.

Four-week follow-up period

Subjects were switched back to the two capsule per day placebo regimen.

Blinding

During the test period, both the investigators and the subjects were blind to the capsule contents.

Statistical Analysis

Power analysis: N was selected to achieve at least 90% power to detect a 0.6 treatment group difference in HbA1c.

Statistical analysis was done on an intent-to-treat basis:

Analysis of variance using repeated-measures, with group, type of diabetes therapy, study center and visit as factors, was used to assess treatment difference in change from baseline in HbAlc, fasting plasma glucose and fasting serum C-peptide during the test period
Chi-square test used to assess changes in diabetes medication dosages
Fisher extact test was used to determine treatment group differences for adverse events; hematology, blood chemistry and urinalysis laboratory parameters, physical and ECG examination data
T-test was used to determine differences for vital signs.

Data Collection Summary:

Timing of Measurements

Biochemical

Baseline (at the end of the four-week placebo-blind run-in period)
At least every two weeks during the test phase and with adverse events or changes in medications
Every other week during the follow-up phase.

Dependent Variables

Glycemic control (measured by HbA1c, fasting plasma glucose, fasting serum C-peptide, diabetes medications)
Safety (measured by reports of adverse events; hematology, blood chemistry and urinalysis parameters; vital signs and physical and ECG examination data).

Independent Variables

Sucralose.

Description of Actual Data Sample:

Initial N: 136 (67 in treatment group, 69 in control group)
Attrition (final N): 128 subjects completed; four subjects in each group discontinued after randomization to the test phase (not as a result of an adverse event)
Demographic and diabetes background

No significant differences between groups in age, weight, BMI, duration of diabetes, age at onset of diabetes, sex or race
Subjects were, on average, obese (baseline BMI 32±0.7 and 32±0.9 for experimental and control groups, respectively)
About half of the subjects in both groups took an oral hypoglycemic agent (type and dose was similarly distributed among the groups), while the other half took insulin.

Summary of Results:

Demography and Diabetes Background

Statistic	Control Group	Treatment Group	Statistical Significance of Group Difference
Age (y)	58.0±1.05	57.2±1.03	NS
BMI Men Women	31.6±0.91 30.1±5.2 34.9±10.1	31.6±0.69 31.0±5.5 32.7±5.8	NS NS NS
Duration of diabetes (y)	10.17±0.93	9.34±0.84	NS
Age at onset (y)	48.5±1.15	48.6±1.18	NS
Sex Men Women	46 (67%) 23 (33%)	42 (63%) 25 (37%)	NS
Race White (%) Black (%) Asian (%) Hispanic (%) Other (%)	57 (83%) 4 (6%) 2 (3%) 5 (7%) 1 (1%)	51 (76%) 9 (13%) 3 (5%) 4 (6%) 0 (0%)	NS
Diabetes treatment Insulin Oral hypoglycemic agents	33 (48%) 36 (52%)	31 (46%) 36 (54%)	NS

Treatment Compliance

More than 96% in both groups were compliant based on capsule counts and results of qualitative assays for sucralose in collected urine samples
Calculated daily sucralose intake was 7.5±0.2mg per kg.

Glycemic control

HbA1c

NS difference between groups at baseline, at any visit, in estimated change over time
In both groups, there was a general downward trend
Compared with baseline, mean HbAlc levels for the treatment group were significantly decreased at two, eight, 10 and 13 weeks of treatment and at two and four weeks after treatment cessation
Overall HbA1c change for the experimental group was statistically decreased from baseline (P=0.10).

Fasting plasma glucose

Four weeks after treatment cessation, there was a statistically significant difference between the groups in change from baseline; -0.64mmol/L and a +0.40mmol/L changed for the sucralose and control groups, respectively (P=0.2)
Lower mean fasting plasma glucose concentration for the sucralose group was statistically different, relative to its own baseline concentration (P=0.3).

Fasting serum c-peptide: NS
No other statistically significant findings were noted.

Author Conclusion:

"...no effect of sucralose, at intakes of 667 mg/day, on any measure of glucose control... there were no trends that might suggest an adverse effect on blood glucose control."
"Adverse event data showed that subjects tolerated the high dose of sucralose used in this study as well as they tolerated the cellulose placebo."
"In sum, sucralose-sweetened foods and beverages may be useful tools in the dietary management of individuals with or at risk of diabetes..."

Funding Source:

Not-for-profit

Foundation associated with industry:

Reviewer Comments:

This was an extremely well designed, well executed study.

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
	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
	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
	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
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
	1.	Was the research question clearly stated?	Yes
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.1.	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
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
	1.3.	Were the target population and setting specified?	Yes
	2.	Was the selection of study subjects/patients free from bias?	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
	2.1.	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
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	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
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
	3.	Were study groups comparable?	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)	No
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	No
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	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
	3.3.	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
	3.4.	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
	3.5.	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
	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?	No
4.	Was method of handling withdrawals described?		No
	4.1.	Were follow-up methods described and the same for all groups?	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
	4.2.	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
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	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
	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.	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
	5.1.	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.)	???
	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.)	???
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	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
	5.4.	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
	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.	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
	6.1.	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
	6.2.	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
	6.3.	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
	6.4.	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
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments 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?	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
	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.	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
	7.1.	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
	7.2.	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
	7.3.	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
	7.4.	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
	7.5.	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
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	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.	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
	8.1.	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
	8.2.	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
	8.3.	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
	8.4.	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
	8.5.	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
	8.6.	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
	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.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
	10.	Is bias due to study's funding or sponsorship unlikely?	No
10.	Is bias due to study's funding or sponsorship unlikely?		No
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes