A weight-control efficacy pyramid

The high-profit potential globally for weight-control products makes snake-oil claims inevitable. However, some cognisant manufacturers are becoming aware of the longer-term advantages of directly relevant, well-controlled clinical trials. Mark J Tallon, PhD, cuts through the scientific fact and fiction to uncover the future for this segment

Can the next generation of ingredients provide a sustainable base for the post-ephedrine quagmire?
Millions of adults eating modern Western diets are now defined as obese, and the teenage population is not far behind, according to recent reports by the US Centers for Disease Control. But as consumers become increasingly hesitant to purchase over-hyped products, and with the Food and Drug Administration and Federal Trade Commission tightening their grips on the industry, can the next generation of ingredients provide a sustainable base for the post-ephedrine quagmire?

As a scientist I always ask, show me the data, when it comes to products that claim to influence weight loss. The evidence for such products ranges from extensive to zero. To build back consumer confidence, we need to begin separating those proven products from those lacking data. Although innovation drives the industry, the core ingredients should be scientifically effective and, if needed, supported by the newer products requiring a little more data to move up what I like to call the efficacy pyramid.

The 'high point' segment
The 'high point' of the efficacy pyramid would consist of those products backed by toxicological, in vitro and in vivo human-controlled trials. The nutrients would typically include 7-Keto DHEA, CLA and EGCG. However, even members of the high point of the efficacy pyramid have not had clear sailing of late, with some studies suggesting the benefits may not be as great as we once thought. The following provides an update on these gold-standard weight-loss ingredients, and others, and their current status in the weight-control category.

7-Keto DHEA
Thermogenesis — the production of heat relative to the production of ATP energy — is one mechanism by which the body expends calories, leading to a deficit and subsequent weight loss. A metabolite of DHEA commercially known as 7-Keto DHEA has a weight-management effectiveness based on raising metabolic thermogenesis by optimising 7-Keto levels.

In a randomised, double-blind, placebo-controlled, eight-week study, 100mg 7-Keto was given to 23 obese subjects, or a placebo, twice a day (both groups were on a calorie-restricted diet and moderately exercised). The results demonstrated significant decreases in body weight (2.88kg vs 0.97kg) and in body fat (1.8 per cent vs 0.28 per cent) compared to the placebo group.1

In a follow-up study with the same parameters, 100mg 7-Keto was given to 35 obese subjects, or a placebo, twice a day (both groups were on a calorie-restricted diet and moderately exercised). The results demonstrated significant decreases in weight (2.15kg vs 0.72kg) and in hip circumference (3.78cm vs 2.07cm) compared to the placebo group, and also effectively reversed the decline in resting metabolic rates, which often decrease during restrictive dieting.2

Conjugated linoleic acid (CLA) is a polyunsaturated, conjugated fatty acid that is found primarily in meat and dairy products. Most manufacturers convert linoleic acid from safflowers into CLA. However, processing and the resultant composition of CLA are of critical importance regarding effective weight management. Many studies show efficacy only when specific isomers are used.

The height of CLA's fortunes came with the 2004 publication of a year-long double-blind, placebo-controlled trial on CLA's effects on body-fat mass and lean body mass. The study was notable for its length as well as its results — subjects receiving CLA in triacylglycerol and free fatty-acid forms experienced 8.7 per cent and 6.9 per cent reductions, respectively, in mean body-fat mass compared to the placebo group. The free fatty-acid group also came in with 1.8 per cent greater lean body mass than the placebo group.3

A follow-up trial by the same researchers in a cohort of 134 of the 157 participants who completed the year-long trial had all subjects taking 3.4g/day CLA in triglyceride form. Results of this year-long follow-up were as follows: the initial placebo group lost 1.6kg body weight and 1.7kg body-fat mass over the course of the year, while the CLA groups had no changes. Still, given that most dieters yo-yo from initial weight loss to eventual weight regain, the finding that the group that had lost weight in the initial year trial did not gain it back counted as a victory.4

One of the recent studies causing some consumer questions about CLA's long-term efficacy was carried out in Denmark in 2006.5 The aim of the study was to assess the effect of one-year supplementation with CLA (3.4g/day) on body weight and body-fat regain in moderately obese people. One hundred and twenty-two obese healthy subjects underwent an eight-week dietary run-in with energy restriction (3300-4200kJ/day). A total of 101 subjects who lost greater than eight per cent of their initial body weight were subsequently randomly assigned to a one-year, double-blind CLA (3.4g/day) or placebo (olive oil) supplementation regime in combination with a modest hypocaloric diet of 1250kJ/day. After one year, no significant difference in body-weight or body-fat regain was observed between the treatments. These authors concluded 3.4g/day CLA supplementation for one year does not prevent weight- or fat-mass regain in a healthy obese population.5Cognis, a manufacturer of the Tonalin brand of CLA, commented, "The crash diet preceding the CLA supplementation negated CLA's benefits, and those not taking CLA after the diet regained 20 per cent more body fat." It may, therefore, be more of an issue of weight maintenance than enhancing weight loss. So can we improve the action of CLA to further enhance weight loss?

Recent evidence from Seoul National University in Korea suggests such a possibility.6 Many studies have reported that CLA could be produced by starter-culture bacteria, but the effects of the bacteria were not investigated even with the known influence on lipid profiles and fat loss. Researchers investigated the anti-obesity effect of Lactobacillus rhamnosus PL60, a human-originated bacterial strain that produces t10, c12-conjugated linoleic acid, on diet-induced obese mice. After eight weeks of feeding, L. rhamnosus PL60 reduced body weight without reducing energy intake.6 Results showed that the amount of conjugated linoleic acid produced by L. rhamnosus PL60 was enough to produce an anti-obesity effect by the stimulation of thermogenic proteins. Given the approval of many bacterial and CLA forms as GRAS, this may be an application for the functional-foods markets.

EGCG (epigallocatechin gallate)
Green tea, a product made from the leaf and bud of the plant Camellia sinensis, is the second-most consumed beverage in the world, well ahead of coffee, beer, wine and carbonated soft drinks. Originating in China, tea has gained the world's taste in the past 2,000 years. The chemical composition of green tea is complex. Of all the actives within green tea, flavonols constitute the most interesting group of components, particularly one group, catechins. Of the catechins, epigallocatechin gallate (EGCG) represents approximately 59 per cent of the total. Multiple mechanisms have been suggested as EGCG's weight-regulation effect, including inhibition of leptin (a hormone that regulates energy intake and energy expenditure, including appetite and metabolism), glucose regulation and enhanced fat oxidation.7,8

Green tea has been a huge success in 2006, in part due to research, and more recently the marketing might of Enviga, a new Coca-Cola/Nestlé product. In 2005, both an animal study and a double-blind, placebo-controlled human trial demonstrated EGCG's ability to abolish obesity via a direct influence on adipose tissue.9,10 In the human trial, a 12-week study on 35 healthy Japanese men, the group drinking oolong tea containing 690mg catechins per day experienced significantly lower body weight, body-mass index, waist circumference, body-fat mass and subcutaneous-fat area compared to placebo.10

However, after many years of study some methodological flaws relating to green-tea study design have been re-examined. Although the vast majority of data is supportive of EGCG's effectiveness, the latest human trial found no significant treatment effects on indices of body composition, including visceral or subcutaneous abdominal fat. Teavigo appeared to increase fat oxidation during exercise, but not significantly. Researchers believed confounding reasons for the lack of fat loss could be an insufficient intake of EGCG (300mg/day in this trial) or excessive effects of the exercise programme that accompanied the supplementation. Further work is still warranted.11

The 'BLT' segment
This segment of the efficacy pyramid is the middle of three layers and comprises those studies that have some clinical efficacy, but little long-term and/or safety trials. These often are popular ingredients and offer some clinical work and innovation, while larger trials are under way to provide consistency in effectiveness when combined as a functional food. Although some manufacturers quote many studies on their websites and marketing materials indicate a single-ingredient effect, a closer look sometimes shows combination products and/or poor study design.

Oat and palm oils
One of the newest categories to develop within the weight-loss market is that of oat and/or palm-oil extracts. The mechanism is based on appetite control and feelings of fullness. The branded ingredient Fabuless (once called Olibra, and also offered in a consumer product called Slimthru) is taking advantage of functional oils for weight loss, and is currently the market leader with its patent-protected combination of palm and oat oils (both naturally occurring dietary lipids). Fabuless has been clinically shown to create and maintain a feeling of satiety by slowing absorption, although this is only presented as a series of relatively short-duration studies on macronutrient intakes and energy ranging from four to 36 hours.12,13,14

In one study, 50 subjects from the University of Ulster were given, seven days apart, a 200g portion of yoghurt containing 15g fat, which varied in quantity of Olibra fat (0, 2, 4, 6g) at 09:00 hours. At 13:00 hours, subjects were given ad libitum access to a range of foods. Amounts of food consumed were measured by covert pre- and post-consumption weighing of individual serving dishes.14

Relative to the control yoghurt, mean energy, protein and carbohydrate intakes were progressively reduced with increasing doses of Olibra fat. Energy and macronutrient intakes for the remainder of each study day and over the following 24 hours were significantly lower after all dose levels compared to the control. The result suggests that Olibra fat reduced the effect of overeating during an ad libitum lunch meal and subsequent food intake up to 36 hours post-consumption.

However, in the most recent study, the same research group — using a similar design and 5g Olibra, but over a 22-day period — found in contrast to earlier studies no evidence of a short- or medium-term effect of the Olibra emulsion on food intake or appetite.15 The researchers noted that this confounding result could be owing to numerous factors influencing eating behaviour, and/or the different study design used in the present study.

Hydroxycitric acid (HCA) extracted from Garcinia cambogia has found a strong presence in the sports-nutrition category as an effective weight/fat-loss ingredient. Its action is suggested to be related to an inhibition of lipogenesis in white adipose. Concerns regarding changes in LDL/HDL will likely be re-ignited with the release of some animal data in 2007.16 However, studies showing positive and negative results have been sullied due to the incorporation of calcium into many products, which may influence HCA bioavailability and effectiveness.

One published study shows it controls appetite distinctly by increasing the activity of genes involved with carbohydrate and fat metabolism, as well as appetite control.17

A 2005 study presented at the FASEB Experimental Biology conference delineated how Super CitriMax reduces levels of neuropeptide Y in the hypothalamic tissue of animals; neuropeptide Y is known to increase appetite.

In another study, researchers from Maastricht University, the Netherlands, conducted a double-blind, placebo-controlled, randomised, cross-over design on 10 sedentary, lean, male subjects following one of two feeding protocols: a glycogen-depletion exercise test and a three-day high-fat diet (F/CHO/P, 60/25/15 per cent energy), or a seven-day high-carbohydrate diet (F/CHO/P, 85/10 per cent energy; overfeeding). During overfeeding, they ingested 500mg HCA or placebo three times per day. Body weight increased during overfeeding in both groups (HCA: 2.9+/-0.2kg, placebo: 2.8+/-0.2kg).

The results showed nonprotein oxidation and net-fat synthesis tended to be lower with HCA compared to PLA, indicating lower lipogenesis.18 The authors concluded that an experimental condition resulting in lipogenesis in humans was created and that treatment with HCA during overfeeding with carbohydrates may reduce lipogenesis.

An interesting combination study found effective and safe reduction of body weight and body-mass index with HCA, but even greater results were found with HCA combined with niacin-bound chromium and a standardised Gymnema sylvestre extract in moderately obese subjects.19

Of note in the post-ephedra world — one with a new adverse-events reporting law on the books — is a 2004 published study showing HCA to be safe at doses 25 times greater than currently recommended.20 It is also notable that a 2006 FTC sweep of weight-loss products making false and misleading claims did not include any HCA ingredients.

Bitter orange (Citrus aurantium)
Following the withdrawal of ephedrine from the dietary marketplace, suppliers and manufacturers have scanned the globe in search of safe and effective alternative weight-loss ingredients. Sales of products containing Citrus aurantium for weight loss have increased dramatically as it has been shown to have a similar molecular structure, as well as exhibit similar thermogenic effects to that of ephedrine but in a less-active manner on the central nervous system.21,22

Although synephrine is speculated to be the active constituent in bitter orange, recent studies have characterised — and mischaracterised — the specific isomers within the ingredient. The type of synephrine found in bitter-orange peel is p-synephrine (para-synephrine), not m-synephrine. Synephrine is considered a nonselective beta-3 agonist, which affects body weight and fat mass and also breaks down fats.23,24

The main issue preventing Citrus aurantium from escaping the same scrutiny as ephedra is a lack of definitive safety and efficacy data; the published studies that do exist all too often look at bitter orange in combination with other ingredients such as caffeine and ephedra, so it is difficult to come to a clear conclusion of its overall benefits.

Three recent studies bear further scrutiny. In 2005, researchers found no significant difference on blood pressure between a single 450mg capsule (standardised to 27mg synephrine) of a commercially available bitter-orange extract and placebo.25

In 2006, different researchers using the same commercial product — but two capsules, the recommended dose on the label, instead of one as in the previous study — did indeed find a significant difference between the bitter-orange product and placebo on blood pressure.26

The third study, published in 2005, compared cardiovascular effects of single doses of Advantra Z brand Citrus aurantium; Xenadrine EFX, which contains C. aurantium and other ingredients, with placebo. Compared with placebo, Xenadrine EFX, but not Advantra Z, increased blood pressure and heart rate. However, the authors concluded that the effects were not likely caused by C. aurantium alone, because an eight-fold higher dose of synephrine in the Advantra Z product had no effect on blood pressure, meaning the changes were likely attributable to caffeine and other stimulants in the multi-component formulation.27

As concluded in a 2006 review, "While some evidence is promising, we conclude that larger and more rigorous clinical trials are necessary to draw adequate conclusions regarding the safety and efficacy of C. aurantium and synephrine alkaloids for promoting weight loss."28

Phaseolamin vulgaris
Extracted from the white kidney bean is a non-stimulant weight-control measure that works by neutralising the digestive enzyme alpha amylase before it can convert starch from carbohydrate-heavy foods into glucose and then fat. It essentially allows the carbohydrates to pass through the gastrointestinal system undigested. Studies also show it can decrease the absorption of glucose from a full meal.

Although studies performed on the so-called Phase 2 ingredient have generally been small and not all have been published, results show good tolerability with minimal side effects — which is clearly an issue with many other weight-control products.29 Also, results have demonstrated only moderate effects.

In one recent randomised, double-blind, placebo-controlled study, 27 subjects received either 1,500mg Phase 2 or placebo twice daily with meals for eight weeks. The treatment group lost an average of 3.79 pounds compared with the placebo group, which lost an average of 1.65 pounds. Triglyceride levels showed a more marked effect, dropping an average 26.3mg/dL, more than three times more than the placebo group.30

A GRAS-ready version of Phase 2, called StarchLite, has recently been marketed for integration in a variety of foods and beverages, including baked goods, cereals, frozen foods, packaged meals, pasta, pizza crust, soups and confectionery.

Sensory evaluations showed that StarchLite has no negative effect on the taste or texture of foods.

The 'feeder' segment
The final segment of this theoretical pyramid is that driven by both novelty and consumer dismay at the failings of other products to live up to their claims. This segment should not be underestimated in its ability to draw consumer revenue, and it provides the industry with a substantial base for new growth. These nutrients may go on to become widely recognized as effective, safe and efficacious, but for today limited human data is available.

Svetol (green-coffee extract)
Svetol is a branded product, an extract sourced solely from robusta beans, which contain a specific ratio of 5-caffeoylquinic acid and others caffeoylquinic acid isomers. Svetol is suggested to help control weight by regulating blood-glucose levels, and to inhibit the activity of glucose-6-phosphatase, which releases glucose stored in the liver (meaning glucose is instead drawn from deposits in adipose tissue, stimulating weight loss).

The first toxicology data on Svetol was obtained in 2002, and in 2006 a study was published on Svetol's ability to induce weight loss.31

This study was conducted on 50 overweight volunteers (BMI > 25). They were randomised into placebo and Svetol groups, and given a low-calorie diet. Each volunteer took 200mg Svetol or placebo twice a day with the main meal. After 60 days, a significant reduction in weight (4.97kg) was observed in the Svetol group compared to the control group. Moreover, muscle-to-fat-mass ratio was increased significantly in the Svetol group compared to control group, demonstrating that Svetol is able to exacerbate the effect of a bland, low-caloric diet in the overweight group.

Fucoxanthin is a seaweed-sourced carotenoid brought to market following trials in Japan showing it may increase metabolic thermogenesis.32 Brown seaweed is often used as a flavour component in Asian soups and salads, and contains a compound that appears in animal studies to promote weight loss by reducing the accumulation of fat.

Researchers from the Division of Life Sciences, Hokkaido University, Japan, say they have found that fucoxanthin shows anti-obesity effects with a new molecular mechanism. Mitochondrial uncoupling protein 1 (UCP1) is usually expressed only in brown adipose tissue (BAT). However, there is little BAT in adult humans.33 Therefore, UCP1 expression in tissues other than BAT would be expected to reduce abdominal fat. In 2006 these researchers demonstrated a reduction of abdominal white adipose tissue (WAT) in rats and mice by feeding lipids from edible seaweed, Undaria pinnatifida, compared to a control group.33

Because undaria is composed primarily of glycolipids and the carotenoid fucoxanthin, researchers assessed both to try to isolate the ingredient that activated the thermogenic proteins (UCP1). The fucoxanthin-fed mice showed a significant decrease in WAT and UCP1, while there was no difference in WAT weight and little expression of UCP1 in the glycolipids-fed mice. This result indicates that fucoxanthin upregulates the expression of UCP1 in WAT, which may contribute to reducing WAT weight.

Aralox (Aralia mandshurica and Engelhardtia chrysolepis)
Mushrooms may be becoming more common within the dietary-ingredients market. One such example is the recently released, patented brand of Aralia mandshurica and Engelhardtia chrysolepis, known as Aralox. The proposed mechanism of Aralox on weight loss is the inhibiting hormone sensitive lipase (HSL) and perilipin, both key to the storage of fat.34

In 2006, the phytochemically standardised supplement Aralox, containing triterpene saponins, aralosides and dihydroquercetins, was assessed for its effects on body-fat loss, lipolytic activity, plasma triglycerides (TGs) and adipocytes perilipins, in 32 obese volunteers on restricted-calorie diets for 15 weeks.34 Subjects were randomised to Aralox or placebo, and took 300mg of either three times a day before meals. Daily dietary intake was restricted to 1700kcal — half carbohydrates, 25 per cent from protein and 25 per cent from fat. Food record analyses, body composition, blood and adipose biopsy samples were assessed on admission and after the trials were completed.

Aralox resulted in an average weight loss of 4.3kg in the Aralox group vs 0.7kg for placebo. The average total body weight in Aralox group was reduced from 94.4kg to 90.1kg, while weight in the placebo group was reduced from 94.2kg to 93.7kg. The body-weight reduction correlated with the reduction of body-fat mass, indicating that 95 per cent of the body-weight lost in the Aralox group was due to body-fat loss and not lean tissue.

The results also indicated that patients who received Aralox significantly reduced the content of perilipins protein and increased HSL activity in adipocytes. Plasma fatty-acid levels were also increased in the Aralox group. No significant change of these markers were observed in the placebo group. No side effects were reported.

Caralluma fimbriata (green-coffee extract)
The final ingredient, Caralluma fimbriata, is one of more than an estimated 45,000 plant species inhabiting semi-arid areas across India. In the Kolli hills of South India, C. fimbriata is an edible vegetable used daily. In the semi-arid regions of western India, it is known as a famine food, appetite suppressant and a thirst quencher. The green follicles are eaten, boiled and salted.

A trial conducted at the Western Geriatric Research Institute, Louisiana (US), showed a significant weight reduction compared to placebo when 500mg was given for four weeks. This paper is still awaiting peer-review publication. C. fimbriata has now achieved GRAS status and has a series of safety, pharmacokinetic and in vitro studies under way.

Efficacy, the demand driver
The industry already has a selection of efficacious products, and handfuls more that I have only briefly touched upon ... and some I couldn't, such as cycloxanthin, prickle pear cactus, Cissus quandrangularis and Lagerstroemia spp.

The current flood of ingredients is directed toward appetite suppression, with the buzz of 2007 focusing on resistant starch due to its food applications. Similar attention is also becoming more apparent for weight loss and proteins.

Food makers are into ingredients that increase satiety, compared with the supplement world's fixation on stimulants
Among food companies, the buzz word is 'satiety' — the feeling of fullness between meals. From prebiotic fibres to whey protein, food manufacturers are more interested in ingredients that increase satiety, compared with the supplement world's fixation of stimulants like caffeine.

With further research to show which ingredients are and are not effective, and with a supporting consumer-education campaign based on real evidence and not spin, the entire industry can enjoy a successful future.

Mark J Tallon, PhD, is chief science officer of OxygeniX, a London-based consultancy firm specialising in claims substantiation, product development and technical writing.
Dr Tallon is also co-founder of Cr-Technologies, a raw-ingredients supplier.
Respond: [email protected]

Select Suppliers: Ingredients that aid in slimming

Berkem Labs: Svetol is the first green coffee-bean extract drawn on natural coffee benefits.

BioSerae: NeOpuntia is derived from the Opuntia ficus-indica cactus using a chemical- and solvent-free process. The fibre source works in a similar way to chitosan by binding fat in the gut.

Century Foods: Manufacturer of meal replacements, supplements and dairy proteins under private label and contract-manufacturing agreements.

Cognis: Tonalin-brand conjugated linoleic acid (CLA) is the GRAS-certified category leader.

DSM: Teavigo brand green-tea EGCG is GRAS and can be included in beverages, bars, cereals and supplements. Fabuless is designed for dairy applications; its structure and composition also delivers beneficial textural properties such as improved mouthfeel.

Ecuadorian Rainforest: Botanicals supplier selection of more than 1,000 herbs includes Hoodia gordonii, cha de bugre and green coffee bean.

Gencor Pacific Group: Slimaluma brand Caralluma fimbriata extract is for supplements, an edible succulent used for appetite suppression.

Humanetics Corp: 7-Keto DHEA plays an important role in up-regulating key thermogenic enzymes in the body, thereby enhancing resting metabolic rate.

Integrity Nutraceuticals International: Besides its flagship Cinnulin PF for blood-sugar issues, Integrity offers Razberi-K, a ketone unique to red raspberries, marketed for the potential to decrease body fat by inhibiting absorption of dietary fat and increasing norepinephrine-induced lipolysis. Integrity also offers iFAS50(3), composed of three fatty-acid synthase inhibitors: green tea, tuber fleeceflower and parasitic loranthus.

InterHealth: Super CitriMax is GRAS affirmed for the functional-foods and beverage weight-control markets. It is soluble, tasteless, odourless and colourless in solution.

Lipid Nutrition: PinnoThin is derived from the long-chain polyunsaturated fatty acid pinolenic acid, which comes from the seeds of the Korean pine nut tree, Pinus koraiensis. The ingredient won the Frost & Sullivan award for product innovation in 2006.

Lonza: CarniPure brand L-carnitine plays an essential role in human energy production. Its brand satisfies all relevant food and pharmaceutical standards, and is kosher certified and GRAS.

National Bioscience: Aralox is the company's recently released, patented brand of Aralia mandshurica and Engelhardtia chrysolepi.

National Starch: Hi-maize 5-in-1 Fiber contains fewer calories than flour, is well tolerated, promotes digestive health, helps to balance energy following a meal and helps maintain healthy blood-sugar levels.

Nutratech: The exclusive distributor of Avantra-Z brand of Citrus aurantium, patented to stimulate thermogenesis, reduce weight, increase ratio of lean-muscle mass to total body mass, improve athletic performance and suppress appetite.

Orafti: Beneo is made up of inulin, a prebiotic fibre with a neutral taste, and mildly sweet oligofructose. Useful for inducing satiety, Beneo is mostly used in food products and comes as either a white powder or a clear solution in water.

Pharmachem: Phase 2 starch neutraliser and its food-ready GRAS counterpart, StarchLite, are standardised white-bean extracts to induce carbohydrate malabsorption to aid in weight loss and reduced glucose levels in diabetics.

Sabinsa: Forslean is a standardised extract from the roots of the Coleus forskohlii plant, the only known plant source of forskolin. It was the winner of the 2001 NutrAward for best new product of the year.

Sigma Tau: L-carnitine may contribute to optimal fat oxidation, thereby promoting weight loss, decreasing body-mass index as well as body-fat content.

Stella Labs: Cha de burgre is derived from the leaves, fruit and bark of the Cordia salicifolia tree, native to Brazil, and is suitable for weight loss as an appetite suppressant.

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