Conceptual and methodologic challenges of assessing the short-term efficacy of Guggulu in obesity: data emergent from a naturalistic clinical trial.AD Bhatt, DG Dalal, SJ Shah, BA Joshi, MN Gajjar, RA Vaidya, AB Vaidya, DS Antarkar
Swami Prakashananda Ayurveda Research Centre, Juhu, Bombay.
An open comparative trial was conducted in 58 adult obese patients (Body Mass Index > or = 25 kg/square metre). Group I (n = 27), non-drug, was advised diet (1200-1600 cals) and a brisk walk for 30 minutes. Group II, in addition, received Guggulu (Medohar) 1.5-3 gms/day for 30 days. Mean difference in weight loss between Guggulu and non-drug group was 0.32 kg (ns) on day 15 and 0.58 kg on day 30 (ns). The mean weight reduction in patients (> 90 kgs) was 1.92 kg (ns) and 2.25 kg (ns) higher in Guggulu group. All patients weighing > 90 kg lost weight in Guggulu group whilst 3 in non-drug group did not lose weight. Guggulu was tolerated well. The data from this pilot study suggest a synergistic diet-Guggulu interaction over 30 days in patients weighing > 90 kgs which needs to be confirmed in a large placebo controlled study.
Keywords: Adult, Comparative Study, Female, Human, Male, Medicine, Ayurvedic, Middle Age, Obesity, drug therapy,Pilot Projects, Plant Extracts, therapeutic use,Plants, Medicinal, Statistics, Nonparametric, Treatment Outcome,
Obesity is an important health hazard and a known risk factor for several diseases. In the US 26% adults are significantly overweight. In India too, obesity is emerging as a problem. The standard management of obesity is based on a very- low-calorie (800) diet (VLCD), diverse forms of exercise and attempts at behavioural modification. However, VLCD is quite difficult to comply with on long term basis and therefore patients find it difficult to maintain the reduced level of weight.
A large, long term intervention study carried over 4 years has shown that the anti-obesity drugs are necessary to initiate and maintain the weight loss. The study used an anorexiant, which has a variety of central nervous and other side effects.
In the Western literature, the acceptable goal of weight loss is 450 to 900 gms/week. Even a moderate caloric restriction diet (18-20 cals/ideal Body Weight) and standard exercise (300 cals thrice a week) advised to patients (Body Mass Index (BMI) m +/- SEM 33.4 +/- 2.2 kg/sq.m.) resulted in a weight loss of 1.1 - 1.4 kg in 2 weeks and 2.7 - 3.0 kg in 4 weeks.
With the current “back to nature” thrust, many obese patients also look for some help from the alternative systems like Ayurveda. Guggulu has been cited in Charaka, Sushruta and is also reported to be widely used as MEDOHAR for reduction of Medafat. Guggulu has been studied in hyperlipidemia,,, but there is a scarcity of properly designed studies in obesity.
Satyavati et al used Guggulu 2 gms/kg/day in oil fed rabbits. There was a significant difference in weight of 0.05 kg at 3 weeks between the treated and the control groups. Kotiyai et al tried Guggulu in a dose of 1.5 gms/day and compared it with placebo capsules of oil. However, there was no record of BMI. The weight of patients was around 70-71 kg. No diet or exercise was advised. A weight loss of 0.64 kg at wk 4,0.74 kg at wb 8 and 0.93 kg at wk 12 was seen in Guggulu group and 0.13, 0.43 and 1.41 kg in placebo group respectively.
Kuppurajan et al used Guggulu 6 gms/day in 20% overweight patients. Again there was no record of BMI and the weight loss was not significant. They also noticed mild gastrointestinal upsets in 17.5% of patients.
Upadhyaya et al used a high dose of Guggulu 12-16 gms/day in patients with an average weight of 69 kg. There was a significant weight loss of 1.01 kg in 4 weeks and 1.75 kg in 8 weeks. Kulkarni reported an average weight loss of 2.2 - 2.4 kg with “Triphala guggul”.
Some of the above studies have certain methodologic lacunae. The selection of patient groups is not well defined and in absence of BMI data it is difficult to judge the extent of obesity. There are wide variations in Guggulu dose and there is no mention of the concurrent dietary or exercise advice or their effect on weight loss.
In view of this, we decided to study the short-term effects of Guggulu, along with diet and exercise in properly selected obese patients.
The study was planned as an open and a naturalistic trial in adult patients attending the Obesity Clinic of Bharatiya Vidya Bhavan's Swami Prakashananda Ayurveda Research Centre.
The main criterion of selection was Body Mass Index (BMI), which was calculated as a ratio of weight in kg and square of height in meters. Patients with BMI > 25 kg/square meters and who had uncomplicated obesity were selected.
Patients, currently receiving drugs, which are likely to influence weight e.g. diuretics, anti-diabetics, appetite - suppressants, steroids, NSAIDs or those taking drugs used to manage a primary cause of obesity, e.g., thyroxine, were excluded. For ethical reasons, pregnant patients and those who had severe systemic conditions e.g. cardiac, renal, hepatic requiring aggressive treatment of obesity were also excluded.
The selected patients were divided in 2 groups.
Group 1 or the Non-drug group received only advice regarding diet and exercise. Group II or the drug group was advised diet, exercise and a standard dose of Guggulu. For both groups, the diet was 12001600 cats with instructions on what foods to eat and avoid. The standard advice for exercise was an every day brisk walk for 30 minutes. In the group II, Guggulu formulation ‘Medohar’ was used as 2-4 tabs (250 mg) 3 times a day (total dose 1.5 - 3 gms/day). The patients were asked to chew the tablets for proper absorption.
Follow up weight and clinical examinations were carried out on day 15 and 30. Compliance to diet, exercise and drug intake was also checked.
The statistical analysis of change in weight was done for the whole group as well as for patients with a weight > 90 kg. Both parametric Student's ‘t’ test and non-parametric Wilcoxon's signed rank sum test were used.
[Table - 1] shows the demography and the baseline and follow-up number (n) of the patients. Both groups were comparable in all parameters including mean BMI and basal weight.
[Table - 2] shows a comparison of the reduction in weight. All drug group patients showed directionally a better weight loss on day 15 and day 30. The mean difference in the weight loss was 0.32 kg on day 15 and 0.58 kg on day 30. However, the change was not significant by Student's T test or Wilcoxon's test.
Guggulu group was much higher. The mean difference between the two groups was 1.92 kg on day 15 and was 2.25 kg on day 30. Although the differences were not significant statistically, detailed analysis showed that in the drug group all the patients lost weight while in the non-drug group 2 patients gained weight and 1 did not lose weight. There were no significant clinical side effects. The short-term compliance to non-drug measures was satisfactory. ?
The study showed that the short-term goal of weight loss of 450-900 gms per week (or 900-1.8 gms in 15 days) could be achieved in both groups. However, the mean weight loss in drug group was better by 0.32 kg on day 15 and 0.58 kg on day 30. The difference in weight reduction between the groups was statistically non-significant. In patients with a higher baseline body weight (>90 kg), the weight loss was much higher in the drug group; the mean difference being 1.92 at kg at day 15 and 2.25 kg at 30. The trend was non-significant as the number of patients in each group was small. Analysis of weight loss in individual patients (weight > 90 kg) showed that in non-drug group 2 patients (day 15) gained weight and 1 patient (day 30) did not lose weight; whilst in the drug group all patients lost weight on both follow up days. The overall mean weight loss at day 30 in non-drug group of 2.39 kg and in Guggulu group of 2.97 kg was higher as compared to the weight loss reported by Katiyal's group of 0.64 kg with guggulu in a dose of 1.5 gms/day and that reported by Upadhyayall et al of 1.01 kg with a very high dose of guggulu of 12-16 gms/day.
These differences highlight the complexity of clinical drug research in metabolic problems like obesity and the non-availability of a standardise approach for evaluation of natural products. Clinical trial design of a modern synthetic drug is based on preclinical pharmacodynamic studies in several animal species, and early clinical studies in healthy volunteers and patients, which provide data on dose effect tolerability relationship. For a natural or an Ayurvedic product, such data are not readily available, hence a close scrutiny of available animal and human studies is essential before embarking on exploring clinical activity of a natural product. One can also learn from the use experience of senior vaidyas about clinical usage and dosages, etc. One also has to consider the variables, which can modify the drug response in the disease under study. After this, a pilot study would be desirable to evaluate the interaction between drug and non-drug measures and to assess the different aspects of drug dose, duration, effect, side effect etc.
Our pilot study was based on the available modern and ayurvedic literature. Salyavati's animal study suggested that after 3 weeks, Guggulu in a dose of 2 gm/kg showed significant weight loss. A human dose of Guggulu extrapolated from this animal study would be 0.2 gms/kg, i.e. about 10 gms for a person with 50 kg body weight. However, animal-man correlation for drug-dose, is not absolute. This dose of guggulu is widely used in ayurvedic practice for treatment of arthritis. Upadhyaya et al. had used Guggulu in this dose range. As non-drug measures are known to cause weight loss, we expected that requirement of Guggulu, in a patient already on dietary and exercise measures would be lower than in the above studies where non-drug measures were not advised, Besides, at higher doses the compliance would be affected due to gastrointestinal side effects and an increase in number and frequency of tablets.
The current study did provide early useful information on non-drug (diet exercise) and drug interaction and also confirmed that a period of 15-30 days would be necessary to judge the effects of this interaction. As non-drug measures provided acceptable weight loss, in both the groups; and the difference of weight loss in patients > 90 kg weight was much higher in Guggulu group, it may be advisable to focus on this group of patients and conduct well-controlled clinical studies to confirm the results of the current pilot study.
[Table - 1], [Table - 2]