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Scientific studies

Glucose Homeostasis Study

Grotz VL, Henry RR, McGill JB, et al. J Am Diet Assoc. 2003; 103(12):1607-1612.

This double-blind, randomized, placebo-controlled, parallel-group, multicenter study evaluated the effects of high daily doses of sucralose in patients with type 2 diabetes over a period of 3 months.

Introduction 
Patients with diabetes often use no calorie sweeteners to reduce their sugar intake. While clinical studies have demonstrated that sucralose does not affect blood glucose or insulin levels in normal non-diabetic animals and humans, studies in patients with diabetes are limited.

The purpose of this study was to evaluate the effects of high daily doses of sucralose in patients with type 2 diabetes over a period of 3 months.

Methodology
This double-blind, randomized, placebo-controlled, parallel-group, multicentre study enrolled patients based on the following criteria:

  • Diagnosis of type 2 diabetes at least 1 year prior
  • 31 to 70 years of age
  • Management of diabetes with either insulin or an oral hypoglycemic agent, but not both
  • Relatively stable diabetes with HbA1c of <10
  • Familiarity with blood glucose monitoring and standard dietary guidelines for diabetes management
  • General good health

The study was conducted in 3 phases:

•  6-week screening phase – patients were asked to follow a standard diet (approximately 14% protein, 30% to 36% fat, and 48% to 55% carbohydrate), and to monitor their blood glucose levels at least 3 times per day, 2 days per week, for the duration of the study. Two weeks after entering this phase, patients received placebo capsules for 4 weeks (patients were blinded to the nature of the capsules), and at the end of this period, baseline measurements were taken for:

  • HbA1c
  • Fasting plasma glucose (FPG)
  • Fasting serum C-peptide
  • Insulin/oral hypoglycemic agent dosage level

•13-week test phase – patients were randomized to receive 2 capsules daily of either sucralose (667 mg/day) or placebo, to be taken at breakfast and dinner time for 13 weeks.

  • HbA1c, FPG, and fasting serum C-peptide levels were assessed every 2 weeks
  • Adverse events and changes in medications were recorded

 

•  4-week follow-up phase – while still blind to the treatment regimen, all patients were switched back to placebo. During this time:

  • Blood glucose control was evaluated, as in the test phase
  • Adverse events and changes in medications were recorded
  • Physical examinations and hematology, blood chemistry, and urinalysis assessments were performed at the conclusion of follow-up

Results
Of the 136 patients enrolled in the test phase of the study, 67 received sucralose and 69 received placebo; 4 patients in each treatment group discontinued after randomization, none due to an adverse event. Baseline patient demographics were comparable between the 2 groups. Overall, patients were obese, and in each treatment group approximately half took oral hypoglycemia agents. The remainder of patients took insulin. 

No statistically significant differences were observed between treatment groups with regard to changes in HbA1c, FPG or fasting serum C-peptide levels.

  • There were no statistically significant differences between groups in HbA1c at baseline, at any visit (P=0.23 to 0.93), or in the overall estimated change over time (ANOVA using repeated measures; P=0.57)
  • FPG levels were comparable at baseline, at all individual test visits, and over the course of the study (P=0.89)
  • Fasting serum C-peptide levels were comparable at baseline, at each test visit, and in the overall estimated change over time (P=0.29)

 

Safety
The safety of sucralose was comparable to placebo:

  • There were no significant differences between groups in the type, number, or severity of adverse events reported
  • No patients withdrew due to an adverse event
  • No adverse events were documented as a possible or definite result of sucralose
  • No clinically meaningful difference between groups in changes in concomitant medications or any other safety measures were reported

Conclusion

  • Despite consumption of significant doses, approximately 3 times the maximum estimated daily intake of 2.4 mg/kg/day, sucralose did not affect any measure of glucose control evaluated in this study, nor was a trend toward loss of blood glucose control observed
  • These findings are consistent with the results of studies in non-diabetic animal and human subjects, suggesting that patients who are not obese, or whose diabetes is managed by diet alone, would respond similarly to sucralose consumption



The authors conclude that foods and beverages sweetened with sucralose may be beneficial for the dietary management of patients who have, or are at risk for, diabetes.

 

 

Glycemic Effect Study

Mezitis NHE, Maggio CA, Koch P, et al. Diabetes Care. 1996; 19(9):1004-1005.

This randomized, double-blind, placebo-controlled, crossover study was designed to assess the effect of a single oral high dose of sucralose on short-term glycemic control in patients with insulin-dependent diabetes mellitus (T1DM) or non-insulin-dependent diabetes mellitus (T2DM).

Introduction 
Consumption of sucralose, a high-intensity sweetener that is synthesized from sucrose but appears to be metabolically inert, is expected to be high among patients with diabetes, who often use no calorie sweeteners to reduce their sugar intake. Sucralose has been shown to not affect blood glucose or insulin levels in normal laboratory animals and human volunteers.

The purpose of this study was to assess the effect of a single oral high dose of sucralose on short-term glycemic control in patients with insulin-dependent diabetes mellitus (T1DM) or non-insulin-dependent diabetes mellitus (T2DM).

Methodology
This randomized, double-blind, placebo-controlled, crossover study was divided into 3 phases:

  • Screening phase – patient fasting blood glucose levels were evaluated at 3 clinic visits over a period of 2 to 6 weeks. Standard physical examinations, clinical chemistry, blood and urine analyses were also performed
  • Test phase – patients received 1,000 mg of sucralose or placebo 30 minutes after their usual dose of insulin or sulfonylurea, followed immediately by consumption of a standardized 360-kcal liquid breakfast. Tests were conducted approximately one week apart
    1. In each test, blood samples for plasma glucose and serum C-peptide were collected for evaluation at 5 and 40 minutes before test substance administration and at 30, 60, 90, 120, 180, and 240 minutes after consumption of the breakfast. The primary end point was change in area under the curve for glucose, while change in area under the curve for C-peptide was the secondary end point. Area under the curve was estimated from the -5 minute before test substance administration data point and beyond
  • Follow-up evaluation phase – took place approximately 1 week after the test phase for repeat physical examinations, including any intercurrent illnesses or adverse events that may have occurred following the final test visit

Subjects were asked to maintain generally consistent dietary habits throughout the study and to monitor and record preprandial capillary glucose levels 3 times/day, 3 days/week during the screening and test phases.

Inclusion criteria were:

  • Established and adequately controlled diabetes (diagnosis at least 1 year prior; HbA1c to be 10% or less; repeat fasting capillary glucose <175 mg/dL on 2 consecutive screening visits and on the first test visit)
  • 19 to 65 years of age and 41 to 65 years of age, for T1DM and T2DM patients, respectively
  • C-peptide level <0.3 nmol/L and >0.6 nmol/L, 15 minutes following a 1-mg glucagon challenge, for T1DM and T2DM patients, respectively

Results
A total of 27 patients enrolled in the study and 26 patients completed all phases, including 13 patients with T1DM and 13 patients with T2DM.

Key findings
Sucralose did not significantly affect plasma glucose or C-peptide levels (P>0.05).

  • In patients with T1DM:
    1. Mean glucose area under the curve was 11.9 mmol/L (±3.3) for placebo versus 10.3 mmol/L (±3.6) for sucralose
    2. C-peptide area under the curve was 0.03 nmol/L (±0.03) for placebo and 0.15 nmol/L (±0.07) for sucralose
  • In patients with T2DM:
    1. Mean glucose area under the curve was 5.2 mmol/L (±1.9) for placebo versus 5.7 mmol/L (±1.7) for sucralose
    2. Mean C-peptide area under the curve was 1.65 nmol/L (±0.15) for placebo and 1.86 nmol/L (±0.22) for sucralose

Three patients with T1DM experienced 1 episode of symptomatic hypoglycemia at 1.5 to 4 hours after the initiation of blood draws following sucralose administration during the first meal test. One of these episodes resulted in study withdrawal.

No meaningful changes in physical examination findings, clinical laboratory parameters, intercurrent illnesses or concomitant medications, including insulin or sulfonylurea, were observed in any patient during the study.

Conclusions

  • High doses of sucralose did not significantly affect glycemic control in patients with T1DM or T2DM
  • The 3 episodes of symptomatic hypoglycemia reported in this study were not considered related to sucralose consumption:
    1. Hypoglycemia is fairly common among patients with T1DM, especially in subjects such as these who were required by the study protocol to maintain relatively good glycemic control
    2. The events occurred after nonusual morning fasting and concomitant blood draws, and symptoms subsided after the patients were allowed to eat
    3. 2 of the 3 patients entered the test procedures with very low (2.5 and 1.8 mmol/L, respectively) FPG levels following their morning insulin administration, which likely increased the potential for symptomatic hypoglycemia as procedures progressed (a minimum baseline FPG level was not required for participation)
    4. A similar number of patients experienced nonsymptomatic hypoglycemia during their placebo tests (3 with T1DM and 2 with T2DM), based on a plasma glucose level of <3.6 mmol/L (nonsymptomatic hypoglycemia was not recorded as an adverse event during the study)

The authors conclude that sucralose does not adversely affect short-term blood glucose control in patients with T1DM or T2DM.

 

America On the Move®* Family Study

This study investigated whether excessive weight gain could be prevented in overweight children who participated in a fun, family-based, child-oriented program, Families on the Move! (FOM) that encouraged all family members to make 2 small, healthy lifestyle changes. FOM is based on the U.S. national weight-gain prevention initiative, America On the Move®*.

Title: Effectiveness of Families on the Move! A Family-Based Approach for Preventing Excessive Weight Gain in Children 


SJ Rodearmel, EdD, VL Grotz, PhD, LA Goldsmith, PhD VMD, SM Smith, BS, LG Ogden, PhD, HR Wyatt, MD, JR Moran, MD and JO Hill, PhD. 

Center for Human Nutrition, University of Colorado Health Sciences Center, Denver, CO, United States and Medical & Nutritional Affairs, McNeil Nutritionals LLC, Fort Washington, PA, United States.

Background
Physical inactivity and high-fat and high-sugar diets have been suggested to contribute to the increase in overweight children. While there is agreement about the urgent need to address this issue, there are few proven effective preventative strategies.

Objective
To investigate whether excessive weight gain could be prevented in overweight (OW) children who participated in a fun, family-based, child-oriented program, Families on the Move! (FOM) that encouraged all family members to make 2 small, healthy lifestyle changes. FOM is based on the U.S. national weight-gain prevention initiative, America On the Move®*.

Design/Methods
Families with at least 1 OW child (7-14 yrs, 85th% BMI for age) were randomly assigned to the FOM or self-monitor (SM) group. FOM families (n=111) set individual and family-specific goals for making 2 changes: (1) increase physical activity by 2,000 steps/day; (2) eliminate 100 kcals/day from their diets with an emphasis on replacing dietary sugars with SPLENDA® No Calorie Sweetener or beverages made with SPLENDA® Brand Sweetener (sucralose). SM families (n=105) were asked to maintain and monitor their usual physical activity and food intake. Both groups measured physical activity using step counters and completed a sweets frequency survey and food diaries to record dietary intake.

Results
On average, both FOM and SM OW children showed decreases in mean % BMI over 6 months. However, significantly fewer FOM children gained % BMI compared to SM children (32.6% vs 47.2%, P=0.044). Thus, participation in the FOM program was significantly more effective in reducing the number of OW children who gained weight in excess of that attributable to normal growth.

Conclusions
Families on the Move!, a family-based weight-gain prevention program that includes small lifestyle changes consisting of increased physical activity and reduced caloric intake with emphasis on replacing dietary sugars with SPLENDA® No Calorie Sweetener, holds promise as an easily usable tool for preventing excessive weight gain in OW children.

Funded by McNeil Nutritionals, LLC and NIH grant DK42549. 
*The third-party trademarks used herein are trademarks of their respective owners.

 

An Overview of the Safety of Sucralose

Grotz VL, Munroe IC. Regulatory Toxicology and Pharmocology. 2009;55:1-5.

Sucralose is a non-nutritive sweetener used in a broad range of foods and beverages and in the retail SPLENDA® Sweetener Products, composed of sucralose and common food ingredients. A review of the extensive body of evidence that supports the safety of sucralose is provided. The results of an independent review of a recent study investigating the safety of a sucralose-mixture retail product, SPLENDA® No Calorie Sweetener, Granulated are also discussed. The collective evidence supports the conclusion that the ingredient, sucralose, is safe for use in food and that the sucralose-mixture product, SPLENDA® No Calorie Sweetener, Granulated is also safe for its intended use.

 

Dental Considerations in Sucralose Use

Mandel ID, Grotz VL. J Clin Dentistry. 2002;13(3):116-118.

Introduction
Dental caries is commonly mediated by oral bacteria that digest fermentable carbohydrates, such as sucrose, glucose, and fructose, resulting in high acid production and altered plaque pH. This causes microscopic demineralization of tooth enamel, with the formation of subsurface carious lesions. With further mineral loss, bacteria penetrate the tooth and cause cavities. Streptococcus mutans is the prime cariogenic organism in this process, and has a special relationship with sucrose, which helps S mutans adhere to the tooth, giving it an advantage over competing organisms.

This central relationship of sucrose to caries initiation is the major reason for interest in sucrose substitutes, like sucralose, which might be hypo- or non-acidogenic (acid-forming).

This review paper covers the research on the lack of effect observed with sucralose on the initiation and progression of dental caries. The most important of these studies were of three types:

  • In vitro studies of the effect of sucralose on bacterial metabolism
  • In vivo animal studies of the effect of sucralose in foods and in solution
  • In vivo human studies of the effect of sucralose in common beverages including water, tea, and coffee

In vitro studies 
In a study of the effects of sucralose on metabolism in 10 strains of oral bacteria including S mutans, investigators found:

  • Sucralose did not support bacterial growth or acid production, providing strong support that sucralose is not cariogenic in vitro

In vivo animal studies 
A study of sucralose in rats examined the effects of sucralose on coronal (crown) and root caries. A standard, highly cariogenic diet containing various concentrations of sucrose was compared to the same diet, but with varying concentrations of sucralose, substituting for the sucrose.

  • Rats fed the sucralose diet developed significantly fewer dental caries than rats fed the sucrose diet
  • Sucralose-fed rats also had 10- to 20-fold lower levels of S mutans

When the rats were de-salivated to eliminate the potential protective dental factors in saliva, the incidence (total number) of coronal caries was comparable in the sucrose and sucralose groups, however:

  • Coronal caries severity was much lower in the sucralose group
  • Root caries developed at a high rate in the sucrose group, but did not develop in the sucralose group

Coronal caries can be expected simply from the presence of the high starch conditions of the diet employed. Therefore, the lack of significant differences in total incidence of coronal caries is not indicative of sucralose cariogenicity, whereas the absence of root caries and the much lower severity of coronal caries indicate that sucralose is not cariogenic in rats.

In a similar study, de-salivated rats receiving essential nutrition by gastric lavage were given water with sucrose and fructose or sucralose, bypassing the oral cavity.

  • Sucrose and fructose resulted in extensive dental decay
  • Sucralose resulted in no dental decay

Additionally, when rats were given a cariogenic diet supplemented by a variety of sweetener solutions:

  • Sucrose solutions significantly increased the caries scores
  • Sucralose solutions had no additional effects
  • The combination of fluoride in the non-sugar solutions neither enhanced nor interfered with the caries scores, indicating no negative interaction of sucralose and fluoride

Human studies 
The dental effects of sucralose have been evaluated in 3 studies in humans using the widely used in situ plaque pH model methodology. One study compared the effects of 4 aqueous rinses: sucrose (common table sugar), sucralose (SPLENDA® Brand Sweetener) alone, sucralose with maltodextrin (SPLENDA® No Calorie Sweetener, Granulated), and sucralose with maltodextrin plus dextrose (SPLENDA® No Calorie Sweetener, Packets).

  • Sucralose alone did not decrease pH values from baseline, and was therefore considered noncariogenic by the investigators
    • Sucrose (sugar) resulted in the greatest decrease in pH from baseline
    • Both sucralose with maltodextrin and sucralose with maltodextrin plus dextrose decreased pH, but significantly less than sucrose

Similar results have been observed in 2 other studies, where sugar and sucralose alone, or in combination with the other ingredients present in the retail products, were added to hot coffee or iced tea.

  • In either coffee or tea, sucralose had no statistically significant effect on dental plaque pH compared to baseline
  • Sucrose resulted in the greatest decrease in plaque pH (more acidic). Sucralose with either maltodextrin or maltodextrin plus dextrose increased plaque acidity to a lesser degree than sucrose

Conclusion

  • The studies reviewed in this article demonstrate that sucralose does not promote dental caries and fulfills the FDA criteria for non-cariogenicity
  • Foods sweetened with SPLENDA® Brand Sweetener (sucralose) may be non-cariogenic or have significantly less cariogenicity than foods sweetened with sucrose, depending on the other ingredients in the food
  • Both SPLENDA® No Calorie Sweetener, Packets and SPLENDA® No Calorie Sweetener, Granulated, are significantly less acidogenic than sugar and, when used to replace sugar, may help in the dietary management of dental caries

The authors conclude that consumption of foods containing sucralose may help maintain oral health.

 

Sucralose: A Scientific and Safety Review

Sucralose (SPLENDA® Brand Sweetener) was discovered in 1976, and for the next 20 years was subjected to one of the most extensive and thorough safety testing programs ever conducted on a food additive.

In 1990, the safety of sucralose was confirmed by the Food and Agricultural Organization (FAO)/World Health Organization (WHO)/Joint Expert Committee on Food Additives (JECFA).

Canada was the first country to market sucralose under the SPLENDA® Brand. Today, sucralose is permitted for use in more than 80 countries and is used in more than 4,000 foods and beverages worldwide. Data from Sucralose Studies show that SPLENDA® Brand Sweetener (sucralose) can be used safely by all populations, including people with diabetes, women who are pregnant or nursing, and children.