Bernadene MagnusonHow to evaluate clinical and scientific studies on non-caloric sweeteners

How to evaluate clinical and scientific studies on non-caloric

sweeteners

Bernadene Magnuson, PhD, FATS

University of Toronto, Canada

Introduction

• Hundreds of studies and reports have

been published on non-caloric

sweeteners. Yet, is still controversial

topic!

Regulatory agencies approve safety-

Introduction

• Yet, many websites

and articles claim

that sweeteners are

associated with a

wide variety of

potential adverse

effects and should be

avoided.

Introduction• How can we determine what to

believe?

• How can we explain the different

opinions?

• What advice to give patients, family,

friends?

Outline

• Overview of approaches to evaluation of

studies

– Preclinical studies, clinical studies, reviews

• Examples

– Sweeteners and weight loss/gain?

– Aspartame and cancer?

• Conclusions

Critical points to consider

• What type of study and how conducted? – Will discuss in detail in next slides

• Was the study/report published in peer-reviewed literature? – Recent conference presentation on soft

drinks and obesity widely publicized but never published

– reports on websites and media not reviewed by scientists

• What are the credentials of the author(s)?

What type of study?

Preclinical studies• Animal or

“in vitro” using cells, enzymes

Clinical studies • Humans

are the subjects

Secondary Reports• Literature

reviews• Meta-

analyses• Opinions

Methods for assessing reliability of scientific reports

• Toxicology studies

– ToxR tool (Schneider et al., 2009, Toxicology Letters)

• Clinical studies

– Institute for Clinical Systems Improvement( ICSI)

2003

– American Dietetic Association – Evidence Analysis

Assessing preclinical studies• If using cells or cell material (enyzmes),

consider:

– Are simplified, isolated systems

– Effect of digestion and absorption?

• I.e. Aspartame is completely digested to amino

acids and methanol, which is rapidly metabolized

to CO2;

• Direct addition of aspartame to cells? – never

occurs in human

– Concentration – how compares to amount

from diet?

– Response of cells – is effect within the

normal range?

– What is the control treatment?

Assessing preclinical studies• If using animals, consider:

– Dose• given orally? added to diet? Number of

doses?– Diet

• defined composition? nutritionally adequate?

• stability and consistency?– Animals

• background historical incidence of disease• health of animals

– Methods • Appropriate protocols?

Interpretation of results• Evidence of dose response?

– If at high dose only, due to inflammation or metabolic overload?

– Is dose relevant to human exposures?

• Increase over historical controls?

• Is tumor type relevant to humans?

– i.e. forestomach tumors

• Is mechanism relevant to humans?

– i.e. formaldehyde and nasal tumors in rats

• ToxRTool - to assess the reliability of toxicological

data. Schneider et al., 2009, available online

Clinical studies - primary•randomized, controlled trial (RCT)A•cohort studyB•nonrandomized trial with concurrent or historical controls

•case-control study•study of sensitivity and specificity of a diagnostic test

•population-based descriptive study

C•cross-sectional study•case series•case report

DICSI Evidence Grading System

Secondary Reports - clinical studies• meta-analysis • systematic review• decision analysis• cost-effectiveness

analysis

M• consensus statement • consensus report• narrative review

R

• medical opinionX ICSI Evidence Grading System

Primary Study Considerations• Were inclusion/exclusion criteria clearly stated? Adhered

to?

• Any question of bias introduced in the study ?

• Does report show statistically significant but clinically

insignificant effect? Or lack power? Too small sample size?

• Are the results generalizable to other populations?

• Any traits of a poorly-designed study? Examples:

– treatment and control groups different at baseline,

– low compliance with the intervention,

– important outcomes not measured,

– inappropriate statistics for study design. (www.icsi.com)

Secondary Report Considerations

• Was search for primary studies comprehensive and current?

Were clear criteria given for inclusion/exclusion of studies?

• Was quality of the articles assessed and reported?

• If a meta-analysis was done, was homogeneity assessed?

• If no meta-analysis was done, did the authors state why

not? Was there at least a narrative synthesis of primary

studies?

• Are studies in review generalizable to target population?

• Are conclusions valid (i.e., based on primary evidence)?

(www.icsi.com)

Do non-caloric sweeteners promote weight loss? Or gain?

? ?

Preclinical studies• Body weight changes in rats fed non-caloric

sweeteners

– Aspartame-either have no difference or reduced body

weight (and reduced food intake) compared to controls.

– Saccharin –increased weight gain (Swithers et al.,

2009); due to increased food intake.

• Effect on appetite or section of gastrointestinal

peptides

– No effect of sweetener (aspartame, acesulfame K or

sucralose) on appetite or section of gastrointestinal

peptides that regulate appetite in rats or humans

(Steinert et al., 2011) ;

– in contrast to studies with isolated cells in culture.

Critical review of Clinical Studies• American Dietetic Association, January

2009

• Does aspartame affect appetite or food

intake?• Evidence Analysis method used to evaluate each

study, based on ICSI guidelines.• 19 studies in adults ; 14 randomized controlled; 4

nonrandomized; 1 short term.

• Conclusion: “There is good

evidence that aspartame does not

affect appetite or food intake in

adults.”• Grade 1 = good evidence to support conclusion.

Epidemiological studiesExamine relationship between reported use of sweeteners and weight gain. Need to control for confounding variables.

Example - Fowler et al. (2008) - Reported use of sweeteners associate with obesity. Number of methodological concerns – main issue is that data collection taken over 2 phases (1979-1982) and (1984-1988).

Aspartame was not approved for food until (1981) and beverages in 1983! Thus inferences made against Aspartame are invalid!

Do non-caloric sweeteners promote weight loss? Or gain?

Conclusion: Well-conducted clinical studies have shown that weight loss and weight maintenance is more successful with use of non-caloric sweeteners.

• Preclinical studies• Cells and bacteria studies have shown aspartame does NOT cause mutations

• 16 chronic animal studies: multiple species

– 14 found no evidence of carcinogenic or promoting effects of aspartame

– Only studies reporting positive results by Soffritti et al.

• Detailed review of protocol and data of Soffritti by numerous experts:

EFSA; FDA; Health Canada; US National Toxicology Program;

International expert panel (Crit Rev Toxicology, 2007)

• All conclude that:

– Are serious flaws in methodology and interpretation in Soffritti study

– “there is no credible evidence that aspartame is carcinogenic”

– “no need to revise previously established ADI”

Does aspartame cause cancer?

Author Type of study (N) Consumption of Aspartame

Conclusions

Olney (1996)

US SEER brain tumor data from 9 locations

Not measured Incidence increased after aspartame on market

Gurney (1997)

56 brain tumor cases94 controls

Dietary recall - Personal interview

No association

Hardell (2001)

30 brain tumor cases45 controls

Recall of low calorie soft drinks.

No association

Bunin (2005)

315 children - brain tumor, 315 controls

Food frequency completed by mothers of children

No association between consumption during pregnancy and risk

Lim (2006) from NCI

Prospective study 473,984 subjects, 5 yr Hematopoietic cancers and Brain cancers

Food frequency questionnaires

No associations between hematopeoitic or brain cancers and aspartame consumption

Gallus (2007)

Case control; various cancers (8976 cases, 7028 controls)

Food frequency questionnaires

No association between cancer and sweetener

Bosetti (2009)

Case control; various cancers (1010 cases, 2107 controls)

Food frequency questionnaires

No association between cancer and sweetener

Epidemiological Studies

– Most preclinical studies

• aspartame does NOT cause cancer.

• few positive studies - serious flaws.

– Epidemiological studies

• if measured consumption – all find no association

Conclusion: Aspartame does not cause

cancer.

Does aspartame cause cancer?

EFSA review of Aspartame

• At the request of the European Commission, EFSA

has reviewed the safety of aspartame 4 times since

first approved. Most recent – Feb 2011.

• Each time concluded - no need to conduct further

studies, or to alter Acceptable Daily Intake (ADI).

• May 2011 – announced will review again in 2012 as

part of the systematic re-evaluation of all authorized

food additives in the European Union.

Conclusions1. Critical review of primary studies is

required to identify weaknesses or

limitations. Several published guidelines

for conducting reviews are available.

2. The overall weight of evidence from well-

conducted studies supports the use of

approved non-caloric sweeteners.

THANK YOU!

QUESTIONS?

b.magnuson@utoronto.ca

Extra slides

American Dietetic Association Guidelines

Type of Question Preferred Study Designs  

(in Order of Preference)

Diagnosis questions Sensitivity & specificity of diagnostic test  Cross-sectional study

Etiology, causation, or harm questions Prospective cohort

 Case control study  Cross-sectional study

Therapy and prevention questions Randomized controlled trial  Nonrandomized trial

Natural history and prognosis questions

Cohort study

Clinical study - Appetite

Anton et al., 2010. tested effect of preloads containing

stevia, aspartame, or sucrose on food intake, satiety,

and postprandial glucose and insulin levels.

• Design: 19 healthy lean and 12 obese individuals

– Preload, given before lunch and dinner; food intake

measured.

– Hunger and satiety levels reported before and after

meals, and every hour.

• Results: Despite caloric difference in preloads , did

not compensate by eating more at meals

Self- reported hunger and satiety levels did not differ.

Clinical study - MaintenanceBlackburn et al., 1997:- longest RCT (aspartame & weight control)- Design - N = 163 obese women- 2 groups: aspartame or no aspartame- Followed identical low energy weight-loss

diets for 19 weeks (ADA diet 1000 kcal +/- 200 kcal/day)

- 200 mins walking every week)- 1 year maintenance 1500 kcal +/- 300

kcal/day- 2 year follow-up

Blackburn trialResults- Over the 2 year follow-up, the aspartame

group only regained 2.6 of the 10kg lost during the weight loss period.

The non-aspartame (sucrose) groups regained more

than double that (5.4kg).

Conclusion: “participation in a weight-control programme that included the use of aspartame facilitated long-term maintenance of a reduced body weight”.Blackburn et al. AJCN 1997, 65: 409-18.

Secondary review of literature• American Dietetic Association, January

2009

• Does aspartame affect appetite or food

intake?

• Evidence Analysis method used to evaluate each

study

• Only 2 studies in children ; 1 randomized

controlled; 1 nonrandomized.

• Conclusion: “Limited evidence indicates that

aspartame consumption does not affect appetite

or food intake in children.

• Grade III = limited evidence to support conclusion