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Urge to World Health Organization – Please leave natural sweeteners alone !!

On 14th January, 2020, WHO declared that they did not find any clear evidence for human to human transmission of novel coronavirus.  After that, they actively discouraged any action against the spread of the virus and downplayed the risk. WHO also extolled Chinese President Xi Jinping’s ‘very rare leadership’ and China’s ‘transparency’in the pandemic scenario. We helplessly watched the epic goof up and rampage of the ensuing pandemic.

They successfully maintained their creed of obfuscation when they published a report – “Health effects of the use of non-sugar sweeteners - A systematic review and meta-analysis” on 12th April, 2022 followed by publication of “Use of Non-Sugar Sweeteners – WHO Guideline”

Stevia became a collateral casualty through their report – unjustifiably and viciously.

In this publication, they presented a systematic review and Meta analysis of published results of Randomized Clinical Trials (RCTs) and Prospective Observational Studies. On the basis of their own review, they came up with the following postulate –

“The recommendation is based on the findings of a systematic review of the available evidence which suggests that use of NSS does not confer any long-term benefit in reducing body fat in adults or children. Results of the review also suggest that there may be potential undesirable effects from long-term use of NSS, such as an increased risk of type 2 diabetes, cardiovascular diseases, and mortality in adults.”

This weird theory drew flack from almost all the stakeholders in the NSS domain. We have been working with a specific NSS, Steviol glycosides for a lover two decades. Steviol glycosides, being a plant derived natural sweetener, have several advantages over synthetic high intensity sweeteners. To our utter surprise, we observed that, in the said study, WHO merged steviol glycosides with all the other synthetic NSS.

We need to dig deeper !!

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Click on the image to download the original report

The infamous 14th January, 2020 Tweet by WHO

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Let us analyze the methodology adopted by WHO in this study, to understand the underlying fallacies. According to the report, they searched databases like MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) for published reports on Randomized Clinical Trials (RCTs), nonrandomized controlled trials, prospective cohort studies, case–control studies and cross-sectional studies with Non Sugar Sweeteners (NSS). Final selection of studies for review and Meta-analysis is appended below.

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They excluded studies conducted on diabetic or pre-diabetic population and they did not include sugar alcohols or modified sugars. They only included studies that compared NSS consumption with no or lower doses of NSS consumption.

The health outcomes of interest for adults and children were identified by the WHO NutritionGuidance Expert Advisory Group (NUGAG) Subgroup on Diet and Health as:

  1. Measures of adiposity (e.g. body weight, body mass index [BMI], overweight/obesity, fat andlean mass);

  2. Type 2 diabetes and pre-diabetes (incidence and intermediate markers of glycaemic control);

  3. Cardiovascular diseases (incidence and intermediate markers, such as blood pressure andlipids);

  4. Cancer;

  5. Dental caries;

  6. Chronic kidney disease;

  7. Eating behaviour (e.g. appetite, satiety, energy intake);

  8. Sweet preference (e.g. subjective measures, sugars intake);

  9. Neuro-cognition;

  10. Mood and behaviour

  11. Asthma and allergies (for children only).

In addition to the above, they included all-cause mortality; cause-specific mortality related to cardio-vasculardiseases and cancer; and pregnancy and birth outcomes for pregnant women, including gestational diabetes, birthweight and gestation-related outcomes.

On the basis of their review, they came up the following observations on the effect of higher intake of Non Sugar Sweeteners –

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The authors inferred “32% increase in risk of cardiovascular event”. We feel, this observations like this need a little more clarification. We need to know the following very clearly –

  1. What was the pooled sample size for the NSS user and Control group?

  2. How many of them died of cardiovascular events or exposed to increased risk?

 

Let us consider a hypothetical situation. Suppose, the effect of NSS was assessed on a total population of 10,000; divided into two groups of 5,000 each. In this hypothetical study, one group consumed an NSS, the other group received placebo. Now, after the completion of the study, the authors found that 10 persons died of cardiovascular events (due to natural causes) in the control group, whereas 13 people died due to the same reason in the NSS user group. Let us consider that the three extra casualties in the user group was indeed due to NSS adverse effects.

Now we can present the data in two ways –

  1. Out of 5,000, 3 persons were susceptible to NSS adverse effects. The percentage of NSS related casualties was 0.0006%

  2.  In the control group, the percentage of casualties were 10 and the NSS group the casualties were 13. So, there is a 30% increased risk of dying due to due to NSS use.

 

Both are equally true, aren’t they? But, which is the correct representation?  We need to know about the method of data interpretation is used in the study. 

Let us dig even deeper !!

On the basis of their report and guidelines, we are supposed to believe that stevia, when used as a sweetener in recommended quantities can cause all the harm to the user.

 

Let us examine the stevia related scientific studies they considered for the report. In those 370 papers considered by them for the meta-analysis, there were 11 papers on Stevia (on the basis of their list of references). We searched for full texts/abstracts of those papers and our findings are presented below.

Results were not accessible for 2 papers. 2 papers showed non fulfilment of the hypothesis (negative outcome – often very minor) and 7 papers demonstrated distinct positive outcome.

Now let us tabulate the observations of the WHO group vis-a-vis the observations reported in the original papers.

Now, can you find any correlation between the observations of the original authors and the inferences of the WHO "systematic" study ?

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NO CORRELATION !!

We do not wish to declare their methodology is faulty, but I have serious doubt about validity of application of the methodology. The variables and the parameters are too diverse for a meaningful meta-analysis. Thus, the WHO group has unintentionally ended up demonizing several perfectly OK sweetener options through a well intentioned study.

Problems and pitfalls with Meta-analyses:

 

Newton wrote in a letter to Oldenburg in 1676: "For it is not number of experiment, but weight to be regarded; where one will do, what need of many?" And Rutherford once pointed out that when you needed statistics to make your results significant, you would be better off doing a better experiment. Meta-analyses are often used to recover something from poorly designed studies, studies of insufficient statistical power, studies that give erratic results, and those resulting in apparent contradictions. Occasionally, meta-analysis does give worthwhile results, but all too often it is subject to methodological criticisms.Several problems arise in meta-analysis:

 

  • Regressions are often non-linear;

  • Effects are often multivariate rather than univariate;

  • Coverage can be restricted; bad studies may be included

  • The data summarized may not be homogeneous 

  • Grouping different causal factors may lead to meaningless estimates of effects; and the theory-directed approach may obscure discrepancies.

 

Meta-analysis may not be the one best method for studying the diversity of fields for which it has been used. Pooling studies that shouldn’t be combined is one of the most common flaws you’ll see in meta-analyses. A common criticism of meta-analysis is that researchers combine different kinds of studies (apples and oranges) in the same analysis. The argument is that the summary effect will ignore possibly important differences across studies.

The study and its observations reminded me

about an old scientific joke-

 

A scientist was experimenting on a cockroach…..

He pulled out legs of a cockroach one by one, let it free on the table and tapped hard on the table to scare the poor creature...

The scientist noted down the result - Cockroaches can run when one or two legs are pulled out. They can barely walk when three or four legs are pulled out. With only one remaining leg, they can just crawl. When all legs are pulled out, they become insensitive to sound and do not run or walk or crawl.

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In our opinion, clubbing together all the NSS of divergent origin, pharmacology and mode of action was not a good idea. Moreover, in the study, all the different NSS were not represented equally. The number of variables and sources of variations is too high for a meaningful meta-analysis. The result actually mimicked the following conclusion –

10 persons took an apple a day and there was no adverse effect.

200 persons took a rotten fruit every day and 70 of them became sick

So out of 210 people, 70 persons or 30% of the population become sick when they ate a fruit every day.

Hence a person has 30% chance of getting sick if they consume any fruit.

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It is really a pity to watch such an ill-advised application of a research tool and coming up with irrational results.

Selection issues:

 

Within the report, the authors reported the following -

 

“Eight trials that could not be included in the meta-analyses reported no significant effect of NSS on intermediate markers of diabetes…….

 

……..Five RCTs that could not be included in meta-analyses reported no effect of NSS on intermediate cardiovascular disease markers……

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……….In a replacement analysis from the Harvard Pooling Project of Diet and Coronary Disease that could not be included in the meta-analysis, replacing SSBs with beverages containing NSS was associated with a 12% reduction in risk of coronary events…….”

 

The observations of these rejected studies are in direct disagreement with the postulate of the report and recommendations. Though, these exclusions may not be deliberate. But, keeping in view the total number of studies considered (370), these exclusions may have significant effect on the final inferences.

Importance of Risks vs Benefits Analysis:

 

The risk-benefit analysis (RBA) of active ingredients used in foods plays a pivotal role in determining their safety, efficacy, and overall impact on public health.It is important to remember that no ingredient is without risk. However, RBA can help to ensure that the benefits of an ingredient outweigh its risks for the majority of users. It involves assessing the probability and severity of adverse effects alongside the expected lifestyle and therapeutic benefits. The primary goal is to ensure that the benefits of aningredient outweigh its risks and justify its use.

The benefits of aningredient are multifaceted and include its intended beneficial effects, such as improving the palatability, alleviating food related health issues, preventing or curing lifestyle diseases, or improving long term consumer outcomes. Additionally, ingredients may offer societal benefits, such as reducing healthcare costs, increasing productivity, or enhancing public health.

Approval of Steviol glycoside as a sweetener is the result of several risk benefit analysis done by several independent regulatory organizations, some of which are listed in the box. Please click on the links provided here to access the original documents

In all the above studies, it was proved that the health risk due to steviol glycosides (if any) outweighs it possible risks. These studies formed the basis of approval of steviol glycosides as a safe non-sugar sweetener by all major regulatory agencies.

 

Existing/potential users of every specific food ingredient/additives should have complete access to the unbiased risk benefit analysis of the same. Demonizing a perfectly safe sweetener through merging it with sweeteners with different biochemistry is a disservice to the user community and it is a constraint for making informed choice by the consumer. 

The guideline drew global flack:

Response from International Sweeteners Association

 

To develop this draft guideline, WHO considered evidence on the health effects of low/no calorie sweeteners that were reviewed in 2022 in a systematic way and meta-analysed by Rios-Leyvraz and Montez. However, the results of the WHO meta-analyses of randomised controlled trials (RCTs) do not support the draft recommendation suggesting that “non-sugar sweeteners not be used as a means of achieving weight control or reducing risk of non-communicable diseases (conditional recommendation)”. Also, important data from a large battery of clinical trials confirming beneficial short-term effects of low/no calorie sweeteners use in place of sugars on post-prandial glycaemia and dental health were not considered in formulating the recommendation……..

……….in the WHO meta-analysis of RCTs, the gold standard in nutrition and clinical research, Rios-Leyvraz & Montez showed that low/no calorie sweeteners’ use results in reductions in sugars and calorie intakes and in modest but significant weight loss in adults. It is therefore surprising that the benefit of using low/no calorie sweeteners as a way to reduce excess sugars and calories intake, and in turn, to assist in weight management, is not acknowledged in the WHO recommendation suggesting against using non-sugar sweeteners for weight control……..

 

………..The draft guideline states that assessing the health effects of non-sugar sweeteners on individuals with pre-existing diabetes was beyond the scope of this guideline, and therefore this recommendation possibly is not relevant for individuals with diabetes. However, low/no calorie sweeteners are a useful dietary aid for people with diabetes who need to manage their carbohydrate and sugars intake and missing to consider the needs of patients living with diabetes, consisting approximately 10% of the global population, is an important shortcoming of this draft guideline. In fact, the WHO recommendation suggesting not to use non-sugar sweeteners as a means for weight control might even be confusing to people living with diabetes, especially when diabetes and nutrition-related organisations support the use of low/no calorie sweeteners for diabetes management……..

………Based on very low quality evidence, the draft WHO guideline points to “potential undesirable effects from long-term use in the form of increased risk of type 2 diabetes, cardiovascular diseases, and mortality in adults. Limited evidence suggests potential undesirable effects in the form of increased risk of preterm birth with NSS use during pregnancy.” However, this statement is based solely on very low to low evidence from observational studies, which are at risk of residual confounding and reverse causality, as acknowledged in this guideline. Importantly, and contrary to observational findings, results from meta-analyses of RCTs, including in the recent WHO study, confirm that low/no calorie sweeteners have no adverse impact on cardiometabolic risk factors, including glucose and insulin levels, blood lipids and blood pressure. In fact, a recent systematic review of RCTs found potential cardiometabolic health benefits when low/no calorie sweetened beverages are used to replace sugars.

The draft recommendation on use of non-sugar sweeteners is a conditional (weak) recommendation. Conditional recommendations are those recommendations for which the WHO guideline development group is uncertain that the desirable consequences of implementing the recommendation outweigh the undesirable consequences or when the anticipated net benefits are small. This decision was based on the assessment of the available evidence as overall low certainty in the recent WHO systematic review that supported today’s draft guideline. However, this study examined only a fraction of the available literature and missed to assess strong evidence from RCTs examining the impact of low/no calorie sweeteners on postprandial glycaemia and in tooth mineralisation.

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Response from Calorie Control Council –

The conditional recommendation contained in the Guideline, which states, “WHO suggests that non-sugar sweeteners not be used as a means of achieving weight control or reducing the risk of noncommunicable diseases (conditional recommendation), contradicts the world’s most highly regarded health and regulatory agencies which validate and prove low- and no-calorie sweeteners assist in weight management, reduced calorie and sugar intake, and the management of blood glucose levels.

Recommendations from highly regarded global authorities such as the WHO should not be based primarily on prospective data with “low evidence of certainty” and should meet a threshold higher than “conditional”. Formulating recommendations that are not supported by strong scientific evidence is inappropriate and could unnecessarily deter the public from personal choice and potentially beneficial dietary options. Obesity and other non-communicable diseases are multifactorial conditions, with various approaches and tools available to address them. Consumers want and need safe and effective options and, along with exercise and a balanced diet, low- and no-calorie sweeteners are critical tools that can help consumers achieve their dietary and weight management goals….

……..The new WHO guidelines advising against using these sweeteners for weight management and reducing disease risk totally miss the point of why people use these ingredients. Non-sugar sweeteners are safe, documented by numerous studies leading to approval by government health agencies around the world. They provide a way for people to enjoy sweetened foods and beverages with less sugar and fewer calories. Extensive research has shown they can help reduce calorie intake and promote weight loss when they replace calories from sugar in food. They also help lower added sugar, a dietary goal in many countries around the globe to reduce disease risk.
 

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Response from CEO of Splendra-

 

The guidance from the WHO is (with a "low certainty" of evidence and a "conditional" recommendation, which means they were less than certain of the outcome of using their guidance; and without including any persons with prediabetes and diabetes in their consideration, which represents nearly 50% of the American population) that they do not recommend the long-term use of non-sugar sweeteners to achieve weight loss or to avoid non-communicable disease. That is the totality of the WHO guidance. I disagree with this guidance. The WHO does say that in the short-term using low- and no-calorie sweeteners have a benefit on weight loss.

That's it folks. With a low confidence level, that is the guidance. Now compare that to the headlines by the WHO, CNN, NY Post, and others.

Our own review:

 

We did a keyword search with “stevia”+”clinical trial” in Pubmed-National Library of Medicine, which fetched 41 results.

The search result is available here........ 

 

We do not believe to torture data to get a confession which we like. We only selected 30 studies out of those 41 results on the basis of availability of clear quantitative data. The highlights of the studies are tabulated in the linked page. Now we would like to request reader to go through the major observations of the studies and form his/her own impression.

 

 

Our own review indicated that the concerns raised by WHO is not applicable to Stevia. Stevia did not exhibit most of the health concerns postulated by WHO in any of these studies.

 

We believe, it is now time to strongly vocalize our disagreement to the WHO narrative and prevent them to sensationalize a report using public media, before going for a multi-institution peer review of their finding. We should also collectively bring the inherent misjudgement in the WHO report to our policy makers to avoid any knee-jerk reaction from them.  

Comments (1)

Invité
30 mai

Very Impressive..

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