A Randomised Placebo Controlled Trial of Herbal Medicine (Sugaradik) in the Treatment of Type 2 Diabetes

Transcription

1 142 Alternative Medicine A Randomised Controlled Trial of Herbal Medicine (Sugaradik) in the Treatment of Type 2 Diabetes R.P. Agrawal, Professor, Shekhar Goyal, Jr. Research Fellow, Amit Chopra, Research Scientist, Shreyans Jain, Research Scientist, Vivek Agarwal, Jr. Research Fellow, Mahesh Pal Khatri, Sr. Registrar Diabetes Care & Research Centre, S.P. Medical College, Bikaner. Geeta Watal, Associate Professor Development Division, Department of Chemistry, University of Allahabad, Allahabad. Abstract Introduction: To evaluate the safety and effectiveness of polyherbal powder (Sugaradik) in achieving glycaemic control in newly diagnosed type 2 diabetics. Methods: It was a randomised double blind placebo controlled study. Eighty newly diagnosed patients of type 2 diabetes were selected after meeting inclusion and exclusion criteria. Patients were randomly divided into two groups. One group received drug and other group received placebo bearing a distinctive code number. Anthropometric parameters and HbA 1 c were performed initially as well as after three months of treatment period. Fasting blood sugar and blood pressure were recorded weekly. Student s t test was applied as statistical tool. Results: After three months of treatment of polyherbal powder (Sugaradik) there was a significant improvement in systolic blood pressure (136.05±3.30 to ±1.51 mmhg) and fasting blood sugar (233.03±8.81 to ±4.96 mg/dl; p less than 0.001). There was a significant reduction in HbA 1 c (8.39±0.30 to 6.37±0.10 percent; p less than 0.001). No adverse effects were observed in this trial. Conclusion: Polyherbal preparation of ten classic herbs appears to be effective in controlling glycemia. Sugaradik seems to be a safe drug and an effective oral agent in the management of type 2 diabetes. Keywords herbal medicine, sugaradik, type 2 diabetes Introduction Since time immemorable, diabetes has been treated with plant medicines. About six hundred plants, mentioned in ayurveda and Hindu literature like Charak Sanhita, Madhav Nidan and Astang Sanghrah are supposed to have anti diabetic and antioxidant properties. It is believed that herbal plants or their pharmaceutical products display little toxicity and few side effects as compared to synthesized chemical medicines. The use of traditional herbs is getting popularity in western societies; however, research is needed to be carried out regarding physiological actions, mechanism, efficiency and safety of herbal remedies. Address for correspondence: Dr R.P. Agrawal, 2, Adarsh Colony, Bikaner , Rajasthan, India. drrpagrawal@yahoo.co.in

2 143 Herbal medicine attracted attention of various workers in the management of diabetes. Many antidiabetic products of herbal origin are now available in the market. Hence, this study was planned to evaluate effect of this polyherbal preparation Sugaradik on clinical and biochemical parameters of diabetes. Methods Design of study: Randomised double blind placebo controlled study. Selection of patients: The present study was carried out on eighty newly diagnosed patients of type 2 diabetes attending primary care medical outpatient department. Patients were ranging from 35 yrs to 75 yrs. All patients, participated voluntarily, were duly informed about possible side effects of drugs and written informed consent was taken. The recruitment period was two months. The approval was taken before hand from Ethics committee, S.P.Medical College, Bikaner. The whole research plan followed guidelines of the declaration of Helsinki. Inclusion criteria: Subject with a diagnosis of type 2 diabetes mellitus, according to American Diabetes Association guidelines. Fasting blood sugar > 126 but < 250 mg/dl. Written consent showing willingness to participate in the study. Exclusion criteria: Patients taking any oral hypoglycaemic agent, insulin, lipid lowering drugs, anti hypertensive agents/ weight reducing drugs. Subjects suffering from liver disease, arthritis, pulmonary tuberculosis, malabsorption, or alcoholism. Subjects with any diabetic complications whether neuropathy, nephropathy or retinopathy. Patients meeting inclusion criteria were stabilized by standard diet and excersise for one month. The randomly selected patients were given a code number to avoid chance of bias. All patients were randomised into two groups: Group I these patients were given usual treatment i.e. diet, exercise along with powder A one teaspoonful (four gm) twice a day before breakfast and evening meal for continuous three months duration. Group II the same treatment plan as followed by patient of group-i except powder-b instead of powder-a was given and this group served as control (Fig. 1). The method employed for randomization was stratified. Random allocation sequence was generated by random table. The powder provided to the patients of both the groups were given in identical packs bearing a distinctive code number. Depending on the specific code number the patients received either powder A or powder B similar flavoring and coloring was made to conceal the difference between powder A and powder B. Patient s visits were scheduled weekly and a pack of 250 Group I (n=40) Newly Onset Diabetic Subjects (n=100) Randomised Selection (n=80) One month stabilization period (FHS mg/dl) Group II (n=40) Clinical Examination: HbA1c Blood Sugar (weekly), BML, Waist-Hip Ratio Diet, Exercise + Powder A Completed 38 (2 discontinued due to poor glycemic control) Fig. 1 Flow chart of the study 3 months duration Completed 36 (1 discontinued due to loose motion, 1 for headache and other 2 due to increased blood sugar > 250) Clinical Examination HbA1c Blood Sugar (weekly), BML, Waist-Hip Ratio Decoding Statistical Analysis Diet, Exercise + Powder B

3 144 gm powder was provided on each visit. On weekly visits patients compliance was checked by weighing the provided pack. Clinical examination and blood sugar were performed weekly and HbA 1 c was repeated after three months. Waist hip ratio and body mass index were examined weekly. Patients were examined for: Waist Circumference body circumference measured midway between iliac crest and lowest rib Blood pressure By sphygmomanometer in resting supine position after five min rest for three times. (Diamond Regular Ltd., Pune, India) Fasting Blood Sugar By glucose oxidase method with Stat Fax (Ark Diagnostic Pvt. Ltd., Bangalore, India) HbA 1 c By DS5 Drew Scientific machine (ion exchange chromatography). (Drew Scientific Ltd., Cumbria, LA144QR, UK) At the end of three months all the results were collected and decoded by statistician. After decoding, it was recorded that patients of group I (n = 38) taking powder A received drug Sugaradik whereas patients of group II (n = 36) consuming powder B received placebo. Safety profile: Blood urea, Serum bilirubin, SGOT, SGPT, Serum creatinine. Statistical analysis The data was assessed by using SPSS version (SPSS South Asia Pvt. Ltd., Bangalore, India). Numerical variables were reported as mean ± SE. Inter group comparisons for numerical variables were performed using t test. P value < 0.05 was considered significant. Results At the beginning of study, the demographic and clinical profiles of both the groups (drug and placebo) were studied for different variables and no significant difference was found in baseline characteristics (Table 1). Parameters Table 1 Baseline characteristics of study groups Group I (n = 38) Group II (n = 36) Mean ± SE Mean ± SE Age (yrs) 52.79± ± NS Sex (M:F) 24:14 22: BMI 24.48± ± NS Waist / Hip Ratio 0.96± ± NS Pulse 80.08± ± NS t p Blood Pressure (mmhg) Glycaemic Control Renal Function LFT Systolic ± ± NS Diastolic 86.21± ± NS FBS(mg/dl) ± ± NS HbA 1 c(%) 8.39± ± NS B. urea (mg/dl) 28.80± ± NS S. Creatinine (mg/dl) 0.97± ± NS S. Bilirubin (mg/dl) 0.76± ± NS SGOT (IU/L) 24.50± ± NS SGPT (IU/L) 25.29± ± NS

4 145 Parameters Table 2 Comparative effect of poly herbal powder (Sugaradik) and placebo drug on different parameters Baseline After 3 months t p Baseline After 3 months t p BMI 24.48± ± NS 25.17± ± NS W/H Ratio 0.96± ± ± ± NS Pulse 80.08± ± NS 81.00± ± NS BP Systolic ± ± < ± ± NS Diastolic 86.21± ± < ± ± NS FBS ± ± < ± ± <0.001 HbA 1 c 8.39± ± < ± ± <0.001 The mean BMI increased from 24.48±0.64 to 25.44±0.62 in treatment group. Systolic blood pressure improved from ±3.30 to ±1.51 mmhg which was significant at (p<0.02) levels after treatment with Sugaradik. The mean fasting blood sugar and HbA 1 c improved from ±8.81 mg/dl and 8.39±0.30 % to ±4.96 mg/dl and 6.37±0.10 % respectively (p<0.001) in the treatment group (Figs. 2, 3 and Table 2). On the other hand, fasting blood sugar increased from ±5.81 mg/dl to ±4.73 mg/dl (p<0.001) while Fig. 2 Comparison of fasting blood sugar in treatment and placebo groups Fig. 3 Comparison of HbA 1 c in treatment and placebo groups month 12 months HbA 1 c increased from 8.90±0.14 to 11.43±0.19% (p<0.001) in placebo group (Table 2). In both the groups, during three months duration there were no noticeable side effects (Table 3, 4). Discussion Type 2 diabetes is a progressive disease, characterized by a slow but steady deterioration of beta cell function. It is well recognized that attaining good glycaemic control in type 2 diabetes is not always adequate and many require some alternative approach. This difficulty has been an impetus to explore the effectiveness of a herbal product

5 146 Renal Function LFT Parameters Table 3 Comparison of side effect profiles in drug and placebo 0 month 3 months p 0 month 3 months B urea (mg/dl) 28.80± ±1.44 NS 29.33± ±1.03 NS S. Creatinine (mg/dl) 0.97± ±0.04 NS 0.99± ±0.03 NS S. Bilirubin 0.76± ±0.19 NS 0.70± ±0.07 NS SGOT (IU/L) 24.50± ±1.01 NS 25.15± ±1.35 NS SGPT (IU/L) 25.29± ±2.86 NS 24.07± ±1.02 NS p Side Effect Table 4 Side effect profile of poly herbal powder (Sugaradik) (N = 38) Poor Glycaemic Control 2 Vomiting 0 Loss of appetite 0 Burning epigastrium 0 Liver dysfunction 0 Renal dysfunction 0 Sugaradik and thus the current study was undertaken to evaluate the safety and efficacy of this herbal product in newly diagnosed type 2 diabetes patients. During three months, mean Fasting Blood Sugar (FBS) and HbA 1 c values improved significantly (p<0.001) in the treatment group while the same parameters showed worsening of glycaemic control in placebo group. Although our results are not comparable with earlier studies due to non-availability of similar studies in the literature, various ingredients of this compound have been shown to exert positive effect on glycaemic control by various workers. Improvement in glucose tolerance in diabetes with Vijayasar and Syzigiun cumini was demonstrated 1. The glucose lowering effect of Momordica charantia was studied on glucose and insulin concentration administration of fresh bitter gourd juice cause a significant reduction in plasma glucose level and improved response n of oral glucose load 2. The extract of Momordica charantia has been shown to have insulin like activity. Hypoglycaemic effect of Momordica Charantia extract in streptozocin diabetic mice has been studied 3. Momordica charantia, Pterocarpus marsupium (not included in sugaradik powder) and Trigonella foenum greacum have been reported to be beneficial for treating type 2 diabetes 4. Similar results were also observed in other studies 5,6,7. Hypoglycaemic potential of some of the ingredients of Sugaradik may be responsible for significant fall in fasting blood sugar and HbA 1 c. When both normoglycaemic and alloxan-induced hyperglycaemic rats were treated with oil of Azadirachta indica, a significant fall in blood glucose appeared. This lowering of blood glucose may be attributed to many mechanisms including increased release of insulin and increased peripheral glucose utilization 8. Seed of Trigonella foenum graecum, containing 4- hydroxyisoleucine, has been demonstrated to possess insulinotropic and antidiabetic properties in a glucose dependent manner 9. Similarly Gymnema sylvestris leaves, containing gymnemic acid IV have antisweet antihyperglycaemic properties 10. In a study, significant increase in blood sugar, total lipids, triglycerides and total cholesterol was observed in alloxan-induced diabetic rats 11. Administration of seed powder of Trigonella foenum graecum and sodium-orthovandate showed potential hypoglycaemic effect along with amelioration of altered lipid metabolism. A poly herbal formulation, containing ten medicinal plants including five used in Sugaradik, was studied for its antihyperglycaemic, antiperoxidative and antihyperlipidemic activity. Reduction in blood glucose level and tissue lipids was found significant 12.

6 147 Hypoglycaemic effect of syzigium cumini seed on alloxan-induced diabetic rats was observed in a study 13. Trigonella foenum graecum extract, an important ingredient, has been shown to have effect on cholesterol and blood sugar 14. It has been shown to cause hypoglycaemic effect on normal and diabetic rats also 15. The safety and effectiveness of Inolter (Herbal product) containing Momordica charantia, Trigonella foenum graecum, Shilajeet, Gymnema sylvestre and Eugenia jambolena was evaluated. It was reported that the mean fasting blood sugar, HbA 1 c along with lipid profile improved significantly after treatment 16. A double blind study indicated Hyponidd (herbal formulation ingredients including Vijaysar (Pterocarpus marsupium), Gurmar (Gymneme sylvestre), Jambu Beej (Syzigium cumine), Amla (Emblica officianale), Haldi (Curcuma longa), Neem (Melia azadirachta), Trivang Bhasma and Shilajeet) as a safe drug and an effective oral agent in the management of asymptomatic and oligo symptomatic freshly detected type 2 diabetic patients 17. Researchers underwent a study to evaluate and synthesize the evidence on the effect of Ayurvedic therapies for diabetes mellitus. A systematic review of trials were assessed and botanical therapy was found by far the most commonly studied Ayurvedic treatment 18. In all, 993 titles in Western computerized databases and 318 titles identified by hand-searching journals in India were examined, yielding 54 articles reporting the results of 62 studies. The moststudied herbs were Gymnema sylvestre, Cassia indica, Trigonella foenum graecum, and Eugenia jambolana. A number of herbal formula were tested but Ayush-82 (Herbal formulation ingredients are Amer Bija (Magnifere indica Linn seed); Jambu Bija (Eugena jamolana seed); Karvellaka Bija (M.charantia Linn seed); and Gudmar (Gymnema sylvestre wood). Shudh Shilajeet) and D-400 (Herbal formulation ingredients are Gymnema sylvestre, Eugenia jambolana, Tinospora cordifolia, Pterocarpus marsupium, Momordica charantia, Ocimum sanctum, Shilajeet) were most often studied. Italian herbalists frequently suggested herbal remedies like Gymnema, Psyllium, Fenugreek, Bilberry, Garlic, Chinese ginseng, Dandelion, Burdock, Prickly pear cactus, and Bitter melon for glycaemic control 19. Among dietary supplements were biotin, vanadium, chromium, vitamin B6, vitamin C, vitamin E, zinc, selenium, alpha-lipoic acid, and fructooligosaccharides (by 685 herbalists) which were found efficacious in reducing glycemia. Many kinds of natural products, such as terpenoids, alkaloids, flavonoids, phenolics and some others have shown antidiabetic potential. Particularly schulzeines A, B, and C, radicamines A and B, 2,5-immino- 1,2,5-trideoxy L-glucitol, beta-homofuconojirimycin, myrciacitrin IV, dehydrotrametenolic acid, corosolic acid (Glucosol), 4-(alpha-rhamnopyranosyl) ellagic acid and 1,2,3,4,6-pentagalloylglucose have shown significant antidiabetic activities (20). The beneficial impact of Sugaradik may be because of individual or combined effect of its components. Protection, stimulation and regeneration of α-cells, decreasing insulin resistance by reducing adiposity, increased peripheral glucose utilization, antioxidant effect by inhibiting oxidative stress may be possible mechanisms involved. Conclusion Although no such study of polyherbal formulation containing the same ten ingredients is available, the results obtained are in accordance with the earlier studies using polyherbs with some of these components. It appears that Sugaradik is a safe and efficacious oral medicine and seems to be useful in controlling glycemia, in newly diagnosed diabetic subjects. Although more thorough safety testing trials are needed in future. Reference 1. Bose Nath S. Effect of Vijayasar and Jamun seed in madhumeha. Sachitra Ayurvedha, 64: Leatherdale B.A. Improvement in glucose tolerance due to Momordica charantia (Karela). Ind Med J., 146: Karunanayake E.H., Jeevathayaparan S., Tennekoon K.H. Effect of Momordica charantia fruit juice on streptozotocin induced diabetes in rats. J Ethnopharmacol (Switz), ; Saxena A., Vikram N.K. Role of selected Indian plants in management of type 2 diabetes: a review. J Altern Complement Med., ; Shanmugasundaram E.R., Gopinath K.L., Radha Shanmugasudaram K., Rajendran V.M. Possible regeneration of the islets of Langerhans in streptozotocin-diabetic rats given Gymnema sylvestre leaf extracts. J Ethnopharmacol, ; 1990.

7 Cakici I., Hurmoglu C., Tunctan B et al Hypoglycaemic effect of Momordica charantia extracts in normoglycaemic or cyproheptadine induced hyperglycaemic mice. J Ethnopharmacol (Ireland), ; Ng TB, Wong C.M., Li W.W. et al Insulin like molecules in Momordica charantia seeds. J Ethanopharmacol, : Dixit V.P., Sinha R., Tank R. Effect of neem seed oil on the blood glucose concentration of normal and alloxan diabetic rats. J Ethnopharmacol, 95-98: Sauvaire Y., Petit, Broca C. et al 4- hydroxyisoleucine: a novel amino acid potentiator of insulin secretion. Diabetes, : Kimura I. Medical benefits of using natural compounds and their derivatives having multiple pharmacological actions. Yakugaku Zasshi, : Yadav U.C., Moorthy K., Baquer N.Z. Effects of sodium orthovanadate and Trigonella foenum graecum seeds on hepatic and renal lipogenic enzymes and lipid profile during alloxan diabetes. J Bioscience., 81-91: Saravanan R., Pari L. Antihyperlipidemic and antiperoxidative effect of diasulin, a polyherbal formulation in alloxan inducded hyperglucemic rats. BMC comp alt med., 5-14: Prince P.S., Kamalakkannan N., Menon V.P. Antidiabetic and antihyperlipidaemic effect of alcoholic Syzigium cumini seeds in alloxan induced diabetic albino rats. J. Ethnopharmacol, : Nadkarni K.M. Trigonella foenum graeceum. Indian Material Medica, ; Ali L., Azad Khan A.K., Hassan Z. et al. Characterization of the hypoglycemic effects of Trigonella foenum graecum seed. Planta Med (Germany), ; Agrawal RP, Sharma Aradhana, Dua AS et al - A Randomized Controlled Trial of Inolter (Herbal Product) in the Treatment of Type 2 Diabetes. JAPI, ; Chalkhore S., Pendsey S. Role of Herbal formulation (Hyponidd) in freshly detected type 2 diabetes mellitus (A Double-blind Control Study). The Asian Journal of Diabetology, 39-42; Shekelle P.G., Hardy M., Morton S.C. et al. Are Ayurvedic herbs for diabetes effective? J Fam Pract, ; Cicero A.F., Derosa G., Gaddi A. What do herbalists suggest to diabetic patients in order to improve glycemic control? Evaluation of scientific evidence and potential risks. Acta Diabetol, 91-98; Jung M., Park M., Lee Hc et al. Antidiabetic agents from medicinal plants. Curr Med Chem, ;2006.