Botanical Agents for the Treatment of Obesity, Lipid Abnormalities, and Metabolic Syndrome

By Bridget S. Bongaard, MD, FACP, Dr. Bongaard is a Fellow in Integrative Medicine at the University of Arizona, Program in Integrative Medicine, in Tucson; she reports no consultant, stockholder, speaker's bureau, research, or other financial relationships to this field of study.

It is estimated that more than one billion adults worldwide are overweight.1 More than 60% of all Americans are now obese, and 47 million people have the metabolic syndrome (increased waist-to-hip ratio, hyperglycemia, insulin resistance, hypertension, and dyslipidemia). In underdeveloped countries, the incidence of obesity is also rising as they experience the same phenomenon of a continuous decrease in energy expenditure from physical activity and an increase in caloric intake.

Complicating the problem is that attempts at weight loss are rarely successful, and compliance with exercise or other weight-management programs is notoriously poor, indicating a need for safe and effective therapeutic options.2 Even a modest 5% loss of body weight significantly decreases the risk of developing diabetes and cardiovascular disease.3

Obesity is tightly linked to major public health problems such as: Type 2 diabetes, dyslipidemias, hypertension, sleep apnea, and an increased inflammatory milieu in the body, which may contribute to the development of cancers. The incidence of osteoarthritis secondary to degeneration of weight-bearing joints increases with the progression of obesity as well. These conditions lead to substantial complications and suffering, as well as to strain on respective national health care budgets.

Definition of Obesity

Healthy normal body weight for a person is defined clinically as having a measured body mass index (BMI) of 18.5-24.9 kg/m2. Currently, 34% of the U.S. population is overweight with a BMI of 25-29.9 kg/m2, while 31% is obese at a BMI of > 30 kg/m2.2 Morbid obesity is defined as having a BMI > 40 kg/m2. A child is defined as being severely obese if his or her BMI meets or exceeds the 99th percentile for age,2 as the usual definition of BMI/morbid obesity is not relevant for children between ages 2 and 19.

Pathophysiology of Obesity

The location of the obesity is just as important as the determination of total weight, as central obesity (located around the waist area) is much more deleterious than fat deposits on the hips or upper arms. This central deposition of fat is associated with insulin resistance, which then leads to postprandial hyperinsulinemia, elevated blood glucose levels, and the eventual development of Type 2 diabetes. The insulin-resistant, hyperinsulinemic state also creates dyslipidemia due to abnormal lipase activity leading to the development of elevated serum free fatty acids and subsequent oxidative changes of LDL, with reduction in the production of the cardioprotective HDL component. The oxidation of LDL to a small dense lipoprotein particle is known to induce atherogenic cardiovascular changes. Obesity contributes to oxidative stress throughout the body. Oxidative stress in accumulated fat is one of the underlying causes of dysregulation of adipocytokines and development of metabolic syndrome.4

Botanically Based Agents for Treatment of Obesity-induced Risk Factors

Hoodia gordonii, a centrally acting anorectic agent

Though widely used in the nutraceutical market for appetite suppression, clinical trial research on Hoodia gordonii is not available to date. Most of the existing research details the mechanism of action of this succulent plant native to sub-Saharan Africa's Kalahari Desert. It is used traditionally by the San, an indigenous tribe, for appetite suppression to reduce hunger in times of famine.

Research indicates that the active ingredient in hoodia is a sterol glycoside called P57, which acts on receptors deep within the brain. When injected into rats' third ventricle a 40-60% reduction in 24-hour food intake is noted.5 This was suspected to occur in response to changes in ATP governing mechanisms, as it was found that the ATP levels increased by 50-150% in the hypothalamic nuclei following administration of hoodia. The hypothalamus plays a critical role in running the body's homeostatic mechanism of thirst and temperature, as well as appetite, hence hoodia's anorectic effect.

Recommendations regarding the use of hoodia for the treatment of overweight and obesity must wait until sound clinical trials have been performed. To date, no published randomized controlled studies employing hoodia for weight loss exist; there are also no adequate guidelines for assessing a possible effective dose, inadequate understanding of how P57 affects other medications, and no research assessing potential side effects from usage in humans.

Phaseolus vulgaris extract, a starch neutralizer

Overconsumption of rapidly absorbed carbohydrates is frequently associated with obesity. Starch blockers could promote weight loss by inhibiting or retarding the degradation of ingested complex carbohydrates. The mechanism behind potential weight loss with use of the extract appears to be inhibition of a-amylase. With the reduced activity of a-amylase, the splitting of complex carbohydrates into simple absorbable sugars is decreased, thereby reducing the availability of carbohydrate-derived calories. By delaying the absorption of the carbohydrates in the upper gastrointestinal tract and shifting it to the colon, there is a decrease in the postprandial insulin response, which in turn leads to lesser fat accumulation.1

Two well-performed clinical studies exist assessing the use of white bean extract (Phaseolus vulgaris). The first study by Udani et al utilized a cohort of 27 subjects with a BMI of 30-43 kg/m2, taking 1,500 mg of white bean extract (Phase 2™) in the setting of a 100-200 g complex carbohydrate-restricted diet over eight weeks.3 The randomized, double-blind, placebo-controlled study excluded subjects with eating, endocrine, gastrointestinal, neuralgic, cardiac, renal, hepatic, or substance abuse disorders. The primary outcome measurements were weight loss and triglyceride levels. Secondary outcomes of percentage body fat, energy level, appetite control, hunger, HbA1c, total cholesterol, and change in waist and hip measurements were also examined.

The group utilizing Phase 2 lost an average of 3.79 lbs, while the placebo group averaged a 1.65 lbs weight loss, a statistically significant difference. Triglyceride levels showed a positive reduction in the active vs. control group, decreasing on average by 26.3 mg/dL. No adverse events were noted. The study was limited by small sample size, but provides a framework upon which future research can take place. The study is important in that it suggests that 1,500 mg of P. vulgaris extract taken after two daily carbohydrate-rich meals could not only prevent the absorption of digested complex carbohydrate calories and promote weight loss, but also potentially reduce cardiovascular morbidity by significantly decreasing the hypertriglyceridemia present in the obese cohort.

The second study from Celleno et al again was a randomized, double-blinded, placebo-controlled study looking at the impact of a dietary supplement containing 445 mg of P. vulgaris extract (Phase 2) in a 30-day trial of 60 overweight volunteers whose weight had been stable for six months.1 The study cohort followed a carbohydrate-rich 2,000-2,200 calorie diet. Outcome measurements of body weight, BMI, fat mass, adipose tissue thickness, waist/hip/thigh circumferences, and lean body mass were examined.

The group receiving the Phase 2 compound had much greater loss of body weight (-2.93 kg), fat mass (-2.4 kg), adipose tissue thickness (-4.2 mm), and decreased waist, hip, and thigh circumference with a barely significant loss in lean body mass (P < 0.05) over the 30-day period. Again, no adverse effects were noted during the trial. One observation made by the study authors was that scale weight loss may not reflect reduction of specific fat compartments. Results of the study showed that body fat, rather than lean body mass, was reduced. BMI is known to relate closely to fat mass more than scale weight alone, and in this study's subjects BMI was reduced from 25.9 ± 2.0 kg/m2 to 24.9 ± 1.9 kg/m2.

Cissus quadrangularis, reducing obesity-induced oxidative stress

This medicinal and culinary succulent native to India and Africa has been used for centuries by traditional Ayurvedic healers to treat bone fractures, stomach ailments, and digestive problems, as well as ear and eye diseases. It is also an edible vegetable naturally containing high amounts of vitamin C, vitamin A, and calcium. Phytochemical analysis revealed high contents of anabolic steroidal substances as well.4 The effects of anabolic steroids on physical performance are unclear. Well controlled, double-blind studies have rendered conflicting results. Almost all studies have failed to show a beneficial effect on maximal oxygen consumption or endurance capacity.

As increasing obesity places the individual at progressive risk for oxidative stress and sequelae of cardiovascular disease, Type 2 diabetes, and inflammatory state-mediated diseases, it appears imperative that antioxidant therapy be utilized to stabilize the tissues against the oxidative stress. These compounds are abundant in fruits and vegetables, but also are present in Cissus quadrangularis.

A recent study examined the effect of C. quadrangularis on obesity, obesity-induced oxidative stress, and treatment of the metabolic syndrome. Oben et al performed a double-blind, placebo-controlled investigation of the antioxidant and weight-loss properties of two compounds containing C. quadrangularis.4 The methodology utilized both a pure standardized extract preparation of 300 mg of C. quadrangularis (CQR-300) taken once a day, and a formulated product (CORE 1,028 mg daily) containing C. quadrangularis 7.5 mg, ChromeMate® (niacin-bound chromium concentrate) 0.15 mg, green tea extract (40% polyphenols, 22% EGCG, 40% caffeine) 100 mg, selenium 0.06 mg, soy albumin 50 mg, vitamin B6 50 mg, vitamin B12 0.05 mg, and folic acid 0.04 mg. The participants were 168 overweight individuals with BMIs ranging from 25 kg/m2 to 48.7 kg/m2 (weight 70.6-142 kg).

Patients were randomized to five study arms of 6-8 weeks duration, utilizing placebo with a 2,100 kcal diet, and the two separate compounds with and without dietary restriction. Anthropomorphic measurements and blood sampling for analysis of plasma thiobarbituric acid reactive substances (TBARS) formation (measuring lipid peroxidation) and carbonyls (marker for oxidative injury), and the ability to scavenge free radicals were ascertained in all groups. Measurements of lipid profile, fasting plasma glucose, plasma serotonin levels, and plasma creatinine were evaluated simultaneously.

High plasma concentration of TBARS and carbonyl compounds were present in study participants, and were significantly reduced after treatment. CORE formula elicited the larger response compared to CQR-300. There was also a significant reduction of weight and BMI in the obese patients. In the CORE group there was an 8.5% change in weight and a reduction in BMI from 37 kg/m2 to 33 kg/m2. This was comparable to observed weight loss using orlistat for six months or one year and sibutramine for one year. A substantial increase in HDL (from 38 mg/dL to 55 mg/dL) and decrease in LDL (from 116 mg/dL to 78 mg/dL) were also noted. An increase in serotonin was found and was believed to have a positive effect on mood. It is possible this serotonergic impact could help reduce binge-eating behaviors, but further study is needed. An increase in creatinine concentrations was identified and paralleled an increase in lean muscle mass, and likely a reduction in total body fat. Serum glucose levels were also reduced. As there was a significant improvement in the lipid profiles, blood sugar, and serotonin profiles of the participants, and an increase in antioxidant and free radical scavenging properties, it was suggested that CQR-300 as well as CORE could have applications as potential treatment for metabolic as well as other physiological complications in which there is an increase in oxidative stress.

Conclusion

The research on the botanical preparations discussed in this article utilized small patient samples, thus the results may not be generalizable; however, they do seem to point to the possibility of using white bean extract and the cissus products for weight loss and reduction of linked disease morbidity. More studies are clearly warranted.

Recommendation

Over the counter weight-loss agents should be analyzed carefully before purchase and consumption. Inherent quality issues may arise from efforts to protect species such as hoodia, and may lead to the substitution of other phytochemicals or the dilution of the purported active compound, limiting any potential therapeutic effectiveness. Adequate research may not be available, such as in the case of hoodia, to determine potentially effective dose, duration of treatment, contraindications, or side effect profile. A wide variety of weight loss compounds are available over the counter, and they can be expensive as well as ineffective.

Prescribed pharmacologic agents are readily available for the treatment of obesity. Serotoninergic agents, noradrenergic agents, and lipase inhibitors, while effective, are expensive, and can have serious side effects such as valvular heart disease, hypertension, seizures, sexual dysfunction, and fecal incontinence, all for a minimal amount of weight loss.5 It is hoped that quality research continues to illuminate and expand the possible safe alternatives currently available to tackle the obesity epidemic in the United States and globally.

References

1. Celleno L, et al. A dietary supplement containing standardized Phaseolus vulgaris extract influences body composition of overweight men and women. Int J Med Sci 2007;4:45-52.

2. Zoler ML. Morbid obesity affects more than 1% of American teens. Internal Medicine News May 15, 2007:14.

3. Udani J, et al. Blocking carbohydrate absorption and weight loss: A clinical trial using Phase 2 brand proprietary fractionated white bean extract. Altern Med Rev 2004;9:63-99.

4. Oben JE, et al. The effect of Cissus quadrangularis (CQR-300) and a Cissus formulation (CORE) on obesity and obesity-induced oxidative stress. Lipids Health Dis 2007;6:4.

5. MacLean DB, Luo LG. Increased ATP content/production in the hypothalamus may be a signal for energy-sensing of satiety: Studies of the anorectic mechanism of a plant steroidal glycoside. Brain Res 2004;1020:1-11.