This article was downloaded by: [Universite Laval] On: 03 October 2014, At: 07:01 Publisher: Routledge Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
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Efficacy and Safety of the Dietary Supplement DBCare® in Patients With Type 2 Diabetes Mellitus and Inadequate Glycemic Control Pnina Rotman-Pikielny MD e
a b
b
d
, Rosane Ness-Abramof MD , Gideon Charach MD , Alexander c
Roitman MD , Rivka Zissin MD & Yair Levy MD
a
a
Department of Medicine E , Meir Medical Center , Kfar Saba , Israel
b
Endocrine Unit, Meir Medical Center , Kfar Saba , Israel
c
Diagnostic Imaging, Meir Medical Center , Kfar Saba , Israel
d
Internal Medicine C, Tel Aviv Sorasky Medical Center, affiliated with the Sackler Faculty of Medicine, Tel Aviv Universit , Tel Aviv , ISRAEL e
Diabetes Clinic, Clalit Health Services , Herzliya South , ISRAEL Published online: 17 Feb 2014.
To cite this article: Pnina Rotman-Pikielny MD , Rosane Ness-Abramof MD , Gideon Charach MD , Alexander Roitman MD , Rivka Zissin MD & Yair Levy MD (2014) Efficacy and Safety of the Dietary Supplement DBCare® in Patients With Type 2 Diabetes Mellitus and Inadequate Glycemic Control, Journal of the American College of Nutrition, 33:1, 55-62, DOI: 10.1080/07315724.2014.870008 To link to this article: http://dx.doi.org/10.1080/07315724.2014.870008
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Original Research
Efficacy and Safety of the Dietary Supplement DBCare in Patients With Type 2 Diabetes Mellitus and Inadequate Glycemic Control R
Pnina Rotman-Pikielny, MD, Rosane Ness-Abramof, MD, Gideon Charach, MD, Alexander Roitman, MD, Rivka Zissin, MD, Yair Levy, MD Department of Medicine E (P.R.-P., Y.L.), and Endocrine Unit (P.R.-P., R.N.-A.), Diagnostic Imaging (R.Z.), Meir Medical Center, Kfar Saba, Israel, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, ISRAEL; Internal Medicine C, Tel Aviv Sorasky Medical Center, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, ISRAEL (G.C.); Diabetes Clinic, Clalit Health Services, Herzliya South, ISRAEL (A.R.)
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Key words: Ayurvedic medicine, diabetes mellitus, herbal medicine, oral hypoglycemic treatment R (Ace Continental Exports Inc., London, UK) is a traditional Indian herbal food supplement Aims: DBCare marketed as an antidiabetes remedy. This study evaluated the efficacy and safety of DBCare in patients with inadequately controlled type 2 diabetes mellitus (T2DM) despite oral hypoglycemic treatment. Methods: A 12-week randomized double-blind placebo-controlled trial was conducted. Patients with T2DM on oral hypoglycemic agents with HbA1C > 7.0% were randomized to receive DBCare or placebo tablets. Results: Thirty-five patients (20 male/15 female; mean age 61.2 ± 7.6 years), with a mean baseline HbA1C of 7.9% ± 0.6%, received DBCare (N = 18) or placebo (N = 17). During the study period, HbA1C declined R group and 0.2% ± 0.8% in the placebo group (p = 0.806). No significant changes 0.4 ± 0.7% in the DBCare occurred in fasting plasma glucose, lipid profile, or homeostasis model assessment throughout the study or in body mass index, waist circumference, or blood pressure values. Hypoglycemic episodes (glucose < 70 mg/dL) were more frequent in the treatment group (7 vs 1, p = 0.043), necessitating a decrease in other hypoglycemic medications in 2 patients. DBCare was generally well tolerated, with mild side effects that were not different from those of the placebo group. Conclusions: This preliminary study did not demonstrate that DBCare was efficacious in improving glycemic control in inadequately controlled patients with T2DM on oral hypoglycemics. A trend toward improved glycemic control was noted in the DBCare group, which correlates with more frequent hypoglycemic episodes. Further studies are needed to elucidate DBCare’s hypoglycemic effect in patients with T2DM in general and in specific clinical settings, such as HbA1C ≥ 8%, short (≤10-year) duration of diabetes, or young age in particular.
INTRODUCTION
medications [4–6]. Uncontrolled diabetes can cause microvascular and macrovascular complications, increasing population morbidity and mortality, as well as health care costs [7]. Hence, the search for the ideal hypoglycemic medication is increasing worldwide. The remedial properties of herbal substances generate avid interest in the Western world and they are used by up to a third of patients with DM [8]. Although some Ayurvedic medications demonstrate hypoglycemic properties, due to a lack of large, well-designed and conducted studies, no definite conclusions
Despite the variety of pharmacological options available for treating type 2 diabetes mellitus (T2DM), the results regarding diabetes control are unsatisfactory and about half of the patients do not reach treatment goals of glycated hemoglobin level (HbA1C) < 7% [1–3]. The reasons for the failure to control T2DM are multifaceted, including the natural history of the disease; lifestyle issues; side effects of the medications, such as hypoglycemia and weight gain; and the short-lived effectiveness of
Address correspondence to: Dr. Pnina Rotman-Pikielny, Department of Medicine E, Meir Medical Center, 59 Tchernihovsky St., Kfar Saba, ISRAEL 44281. E-mail: [email protected] Trial Registration: Clinicaltrials.gov Identifier NCT0056004
R Disclosures: Dhanvantary Herbochem Pvt Ltd. Inc. (Mira Road Thane, Maharashtra, India) and Ace Continental Exports Inc. (London) supplied placebo and DBCare tablets and sponsored a research grant that included a research assistant throughout the study and all lab work expenses. The companies did not have access to the medical data or any involvement in the data analysis or preparation of the manuscript.
Journal of the American College of Nutrition, Vol. 33, No. 1, 55–62 (2014) C American College of Nutrition Published by Taylor & Francis Group, LLC 55
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R Effect of DBCare on Type 2 Diabetes Mellitus
have been drawn regarding their beneficial hypoglycemic effect [9–13]. R is a traditional food supplement composed of 11 DBCare herbal ingredients that is marketed in India and accessible electronically from all over the world as a natural antidiabetes remedy. A recent Google search under DBCare yielded 29,700 results. Although it is very popular in India and has been used for many decades, we could not determine the origin of the specific 11-ingredient combination. Nine of DBCare’s components demonstrated hypoglycemic properties in anecdotal animal and human studies [14–29] and 8 ingredients had an antioxidant effect in animal models [29–35]. To the best of our knowledge, no prospective study has evaluated the efficacy and safety of the 11-ingredient combination in patients with T2DM. Our hypothesis was that using DBCare in uncontrolled diabetes patients would cause a 1% A1C reduction with a commensurate 30 mg/dL reduction in fasting blood sugar. Our secondary endpoint was a 10% reduction in total and low-density lipoprotein cholesterol. We also checked the safety profile of DBCare by monitoring clinical side effects and biochemical parameters, including liver and kidney function tests and white blood cell count. We report here the results of the first prospective, randomized, placebo-controlled study that evaluated the efficacy and safety of DBCare tablets in patients with inadequately controlled T2DM despite oral hypoglycemic treatment.
MATERIALS AND METHODS Study Design A prospective, 12-week, randomized double-blind placebocontrolled trial was conducted in a single secondary referral hospital in Israel. Patients were recruited from the Diabetes Clinic of Clalit Health Services in south Herzliya and by advertisements in local and national newspapers. Eligible patients had T2DM, were ≥ 18 years of age, were on oral hypoglycemic agents, and had an HbA1C level > 7.0%. Screening included a short medical history and recent (within 3 months) lab tests of serum electrolytes, fasting blood glucose, HbA1C level, kidney and liver function tests, lipid profile, and blood count. Detailed inclusion and exclusion criteria are provided below. Randomization was performed by the Pharmacy Department of the institution. Among 80 patients screened over 8 months, 41 met the entry criteria and were randomized to receive DBCare (2 tablets 3 times daily) or placebo and complete the first study visit (Fig. 1). Six patients, 4 from the DBCare group and 2 from the placebo group were excluded after that visit, all due to HbA1C levels below the allowable limits of the study (≤7%). The remaining 35 patients were included in the analyses and comprised the study group. The 12-week study included 4 outpatient visits: at time 0 (study initiation) and at weeks 1, 4, and 12 (study completion). At the initial visit, clinical assessment included a complete medical history, including duration of
80 patients were screened for the study 39 patients were excluded before randomization
41 patients were randomized 4 patients were excluded due to violation of protocol matters
DBCare® N=18
2 patients were excluded due to violation of protocol matters Placebo N=17
1 patient withdrew
2 patients withdrew
DBCare® completed N=17
Placebo completed N=15
Fig. 1. Recruitment and randomization of study participants.
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diabetes, target organ damage, list and dosage of all medications, number of hypoglycemic episodes in the last 6 months, as well as evidence of comorbidities such as hyperlidemia, ischemic heart disease, hypertension, stroke, etc. Physical examination and 12lead electrocardiogram were conducted, body weight and height were measured, and serum electrolytes, fasting plasma glucose (FPG), kidney and liver function tests, lipid profile, blood count, fasting insulin, and HbA1C level were analyzed. The clinical assessment at each subsequent visit included a medical interview focusing on compliance and adverse effects, measurement of vital signs, and blood tests including serum electrolytes, FPG, kidney and liver function tests, lipid profile, and blood count. A 1-week follow-up visit was included to detect a possible rapid impact of the investigated supplement on blood glucose and liver or kidney functions. At the end of the study, the medical interview included each patient’s conjecture regarding the nature of the study medication and its disclosure. On this visit, at the completion of the 12-week treatment period, in addition to serum electrolytes, FPG, kidney and liver function tests, lipid profile, and blood count, the biochemical workup included repeated measurement of fasting insulin and HbA1C levels. Patients were instructed to monitor their glucose levels at home at least 3 times a day, before meals, and when hypoglycemic symptoms or any unusual symptoms occurred. Those measurements were reviewed by the investigators at each visit. When hypoglycemia (FPG ≤ 70 mg/dL) or hyperglycemia (FPG ≥ 200 mg/dL) was documented, the concomitant oral hypoglycemic medications were modified according to clinical judgment, in order to maintain safe glucose levels. DBCare dose was not modified in any patient throughout the study. The study was approved by the Ethical Committee of the Medical Center. All patients provided written informed consent.
Patients Our aim was to study DBCare in adult patients with uncontrolled diabetes (HbA1C level above 7.0%) despite stable oral medical therapy. Due to safety reasons, we limited study enrollment to patients without significant target organ damage. Eligibility criteria included the following: 1. adult (≥18 years old), nonpregnant patients with T2DM (according to American Diabetes Association criteria); 2. on oral antidiabetes regimen; 3. stable antidiabetes regimen for at least 3 months prior to study initiation; 4. HbA1C level 7.0%–10%. Exclusion criteria were as follows: 1. patients < 18 years old or pregnant women; 2. patients with type 1 DM; 3. HbA1C level < 7.0%;
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
4. insulin therapy or a change in the medical treatment of diabetes during the previous 3 months; 5. abnormal liver function with elevated alanine aminotransferase or aspartate aminotransferase equal to or greater than twice above normal level; 6. abnormal kidney function tests with creatinine ≥ 2 mg/dL; 7. clinical evidence of active ischemic heart disease or congestive heart failure based on the patient’s report, physical examination, and electrocardiogram test (creatine phosphokinase blood level and echocardiogram were not performed during the study); 8. inability to comply with the study requirements regarding adherence to medication consumption and the follow-up visit schedule.
Treatment The ingredients and dry weight composition of DBCare tablets are listed in Table 1. Single-batch DBCare tablets and indistinguishable placebo tablets containing 0.5 g lactose only were manufactured by Dhanvantary Herbochem Pvt Ltd. Inc. (Mira Road Thane, Maharashtra, India) and supplied by Ace Continental Exports Inc. (London). Patients were instructed to take 2 tablets 3 times daily with lukewarm water after meals and to reduce consumption of fried foods to a minimum. All study patients were instructed to follow this dietary regimen per manufacturer’s instructions, in order to maximize the treatment effect and promote a healthy lifestyle.
Outcome Variables The primary outcome of the study was the change in HbA1C in the study group compared to the control group during the study period. Secondary outcome included the change in FPG from baseline throughout the study duration. Table 1. Composition of DBCare Tablets Ingredient Ayurvedic (Botanical) Names Karela (Mormordica charanpia or charantia) Mamejava (Enicostemma littorale) Jambubeej (Eugenia jambolana) Kariyatu (Swertia chirata or Andrographis panculata) Methi (Tragonella foenum) Neempan (Melia azabirachta or Azadirachta indicasome) Gudmaar (Gymnema sylvestre) Amla (Emblica officinalis) Galo (Tinospora cordifolia) Kadu (Picrorhiza kurroa) Haldi (Curcuma longa)
Weight (mg) (Total 500 mg)
% Dry Weight
150
30
50
10
50 40
10 8
40 30
6 8
30 30 30 30 20
6 6 6 6 4
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R Effect of DBCare on Type 2 Diabetes Mellitus
Variables evaluating efficacy were HbA1C, FPG, the homeostasis model assessment (HOMA) for insulin resistance (IR) and insulin secretion (β-cell), and lipid profile. Variables evaluating safety included clinical side effects, liver function tests, kidney function tests, and white blood cell count.
Withdrawals
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Study withdrawal criteria were (1) hypoglycemia or hyperglycemia necessitating hospitalization; (2) safety concerns, as judged by the investigators; (3) poor compliance with study instructions—that is, medication consumption schedule as per self-report or follow-up visit schedule (compliance was assessed by the investigator, only one missed visit was allowed); or (4) patient request.
Laboratory Analyses All labs were obtained between 0700 and 0900 after an overnight fast and analyzed in the central lab of the medical center. HbA1C (normal range 4.8%–6.0%) plasma level was deterR mined immunoturbidometrically using Cobas INTEGRA 700 (Roche Diagnostics, Mannheim, Germany). Insulin levels (normal range 5–25 mU/L) were assayed using chemiluminescent R 2000, Siemens Healthcare Diimmunometric assay (Immulite agnostics, Deerfield, IL). The HOMA for IR and insulin secretion (β-cell) were calculated according to the following equations [36]: HOMA IR = fasting insulin (μU/mL) ×fasting glucose (mg/dL)/405 HOMA β-cell = 20 × fasting insulin (μU/mL) /fasting glucose (mg/dL) × 0.0555 − 3.5
Statistical Analysis The sample size was calculated based on assumptions of an absolute difference of 0.5% in HbA1C between the 2 groups at the end of trial and standard deviation of 0.5%. Using these estimates, a sample size of 22 per group would be required to yield a statistical power of 90% and a sample size of 17 per group would yield a statistical power of 80%. Although parameters were distributed normally (ShapiroWilk test), analysis was performed using both parametric and nonparametric tests. Tables 2 and 3 show the results of parametric tests. Continuous parameters are expressed as mean ± SD and categorical parameters are expressed as numbers and percentages. Comparison between DBCare- and placebo-treated groups was performed using chi-square analysis for categorical variables and 2-tailed t test for continuous variables (as well as the Mann-Whitney nonparametric test). The changes in all variables from initiation to end of study were analyzed for each group
58
Table 2. Clinical and Metabolic Data of the Study Subjects at Baseline Clinical Parameter Age (years)a Gender (male/female)b BMI (kg/m2)a Waist circumference (cm)a Duration of diabetes (years)a Treated with metforminb Dyslipidemiab Hypertensionb Ischemic heart diseaseb Systolic blood pressure (mmHg)a Diastolic blood pressure (mmHg)a FPG (mg/dL)a HbA1C (%)a Fasting insulin (μU/ml)a HOMA-IRa HOMA-β a
DBCare Group Placebo Group N = 18 N = 17 p Value 61.8 ± 7.1 8/10 (44/56) 27.1 ± 4.3 95.4 ± 8.5 11.3 ± 7.8
60.6 ± 8.4 12/5 (71/29) 29.8 ± 4.0 100.5 ± 11 8.9 ± 7.1
0.637 0.176 0.067 0.130 0.357
17 (94.4) 17 (94.4) 12 (66.7) 3 (16.7) 146.3 ± 28.2
16 (94.1) 14 (82.3) 13 (76.5) 5 (29.4) 148.5 ± 20.5
1.000 0.322 0.711 0.433 0.800
78.3 ± 12.1
83.1 ± 18.0
0.361
± ± ± ± ±
0.186 0.324 0.431 0.618 0.130
150.0 7.8 13.1 5.4 69.0
± ± ± ± ±
42.0 0.5 11.7 5.6 67
171.2 8.0 10.5 4.6 41.4
50.7 0.7 6.2 3.5 26.1
BMI = body mass index, FPG = fasting plasma glucose, HOMA-IR = homeostasis model assessment for insulin resistance, HOMA-β = homeostasis model assessment for insulin secretion. a Data are given as mean ± SD. b Data are given as number (%).
(the placebo and active treatment groups) using paired t test (as well as the Wilcoxon nonparametric test). Changes between the 2 groups over time were analyzed using a general linear model with repeated measures. Correlations between parameters were analyzed using Pearson’s correlation and Spearman’s correlation. The statistical significance was set to 0.05 and the statistical analyses were performed using SPSS for Windows, version 18.0 (SPSS Inc., Chicago, IL).
RESULTS Thirty-five patients (20 male/15 female; mean age 61.2 ± 7.6 years), with a mean baseline HbA1C of 7.9% ± 0.6%, were randomized to receive either DBCare (N = 18) or placebo (N = 17). Baseline clinical and biochemical characteristics of both groups were similar in all parameters (Table 2). The patients were overweight (mean body mass index [BMI] = 28.4 ± 4.3 kg/m2), with hypertension and dyslipidemia in 71% and 89%, respectively. They were diagnosed with diabetes for an average of 10.1 ± 7.5 years and treated with a mean of 1.8 ± 0.7 medications each (metformin 94%; insulin secretagogues 66%). Mean changes from baseline to week 12 in clinical and metabolic parameters are shown in Table 3. As demonstrated, baseline HbA1C in the DBCare group (7.8% ± 0.5%) decreased significantly during the study period, by 0.4% ± 0.7% (p = 0.033), whereas no significant
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Table 3. Metabolic Parameters Before and After 12 Weeks of Treatmenta DBCare Group (N = 18) Parameter
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BMI (kg/m2) Waist circumference (cm) FPG (mg/dL) Fasting insulin (μU/ml) HbA1C (%) HOMA-IR HOMA-β Triglycerides (mg/dL) T cholesterol (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL)
Baseline 27.1 95.1 153.6 13.1 7.8 5.7 57.4 210.5 175.1 42.1 85.4
± ± ± ± ± ± ± ± ± ± ±
Final
4.4 8.6 39.1 12.1 0.5 5.9 45.9 161.0 41.9 13.7 21.2
27.0 94.4 142.6 15.3 7.4 6.1 72.4 164.9 165.1 42.6 81.8
± ± ± ± ± ± ± ± ± ± ±
Placebo Group (N = 17) Change
4.2 8.1 27.7 16.4 0.7 7.4 58.5 109.9 31.7 10.4 19.4
−0.1 −0.7 −11.1 2.2 −0.4 0.4 15.0 −45.6 −10.1 0.5 −3.6
± ± ± ± ± ± ± ± ± ± ±
0.4 2.4 29.1 5.4 0.7∗ 2.2 48.2 106.6 20.7 6.0 15.8
Baseline 29.7 101.3 169.1 10.7 8.0 4.7 41.7 209.7 161.7 44.5 90.3
± ± ± ± ± ± ± ± ± ± ±
4.3 11.3 49.0 6.5 0.7 3.7 26.0 120.5 35.0 15.0 29.1
Final
Change
± ± ± ± ± ± ± ± ± ± ±
−0.2 ± 0.9 0.17 ± 4.9 −11.5 ± 45.5 1.5 ± 5.7 −0.2 ± 0.8 0.0 ± 0.9 16.0 ± 31.4 −13.2 ± 72.8 13.5 ± 26.7 −0.5 ± 9.6 6.5 ± 25.1
29.5 101.2 157.6 12.2 7.8 4.6 57.6 196.5 175.2 44.0 96.8
4.5 8.2 38.4 7.5 0.8 2.8 45.0 100.2 21.3 9.1 17.3
BMI = body mass index, FPG = fasting plasma glucose, HOMA-IR = homeostasis model assessment for insulin resistance, HOMA-β = homeostasis model assessment for insulin secretion, HDL-C = high-density lipoprotein cholesterol, LDL-C = low-density lipoprotein cholesterol. a Data are given as mean ± SD. ∗ p = 0.033 based on paired t test.
change was found in the placebo group. There was no difference in HbA1C between the DBCare and placebo groups (p = 0.806, Mann-Whitney test) at the end of the study. FPG did not change significantly from week 0 to 12 in either group. However, hypoglycemia (FPG ≤ 70 mg/dL) was significantly more common in the DBCare group (7 patients vs 1 in the control group, p = 0.043). Consequently, the dosage of other hypoglycemic agents was decreased in 2 patients in the DBCare group and in one patient in the placebo group. An increase in hypoglycemic medications occurred in 2 patients, one in each group (Table 4). No hypoglycemic or hyperglycemic episodes necessitating hospitalization occurred during the study. Subgroup analyses of patients with T2DM of ≤ 10 years duration revealed HbA1C reduction of 0.33% ± 0.67% (p = 0.034) at week 12 vs baseline. A 0.63% ± 0.65% (p = 0.009) decrease in HbA1C was noted for patients with BMI > 30 kg/m2. Significant HbA1C and glucose reductions at the end of the Table 4. Incidence of Adverse Events During 12 Weeks of Treatment Variable Hypoglycemic events∗ Increased dosage of hypoglycemic medications Decreased dosage of hypoglycemic medications Flatulence Nausea Abdominal pain Diarrhea Patients with side effects Total number of side effects Patients’ conjecture regarding treatment correct/incorrect ∗
DBCare N = 18 (%)
Placebo N = 17 (%)
7 (39) 1 (6)
1 (6) 1 (6)
2 (11)
1 (6)
1 (6) 0 (0) 1 (6) 1 (6) 5 (28) 7 (39) 8/4 (67/33)
2 (12) 1 (5) 0 (0) 1 (5) 4 (24) 6 (35) 7/3 (70/30)
p = 0.043; hypoglycemia was defined as fasting plasma glucose ≤ 70 mg/dL.
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study (0.57% ± 0.44%, p = 0.0001, and 12.6 ± 21.4 mg/dL, p = 0.045, respectively) were also noted in patients younger than 60 years of age. Although triglycerides (TG) level decreased 45.6 ± 106 mg/dL in the study group and only 13.2 ± 72.8 mg/dL in the placebo group (Table 3), these differences were not statistically significant (p = 0.133 and p = 0.561, respectively). Other metabolic parameters including BMI, waist circumference, systolic and diastolic blood pressure, and cholesterol profile did not differ at the end of the study compared to baseline. Poor metabolic parameters at the beginning of the study were found to correlate positively with glucose reduction during the study, initial FPG (r = 0.67, p = 0.005), initial HbA1C (r = 0.55, p = 0.028 for), and initial HOMA IR (r = 0.59, p = 0.02). No study drug-related abnormality was detected in kidney and liver function tests and in the hematologic parameters monitored. About a third of each group had side effects, mainly gastrointestinal (Table 4). Three patients withdrew from the study, one from the treatment group (due to a renal colic episode and the patient’s concern that it might have been related to the study drug) and 2 from the placebo group (one due to nausea and abdominal discomfort and the other due to difficulty in complying with the follow-up visit schedule).
DISCUSSION In this randomized, double-blind placebo-controlled trial, we have shown that DBCare treatment was not effective in improving glycemic control in patients with inadequately controlled T2DM on oral treatment. We demonstrated a small reduction in HbA1C of 0.4% from a baseline of 7.8% ± 0.5% (p = 0.033). However, this did not fulfill our primary outcome goals and was not different from the 0.2% HbA1C reduction seen in the placebo group. In concert with these results, FPG level, as well
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as HOMA-IR and HOMA-β, were not decreased after 3 months compared to baseline. Additionally, DBCare-treated patients had significantly more episodes of symptomatic hypoglycemia (39% vs 6%), which led to a reduction in antihyperglycemic medications in 11%, than did placebo-treated patients. Taken together, these results indicate that it is plausible that DBCare has a beneficial effect on glucose metabolism that could not be conclusively demonstrated in the current study. This lack of effect has several possible explanations. Most important among these is the relatively low baseline HbA1C, because pharmacotherapy is more effective with higher baseline HbA1C values [4]. Second, our patients were relatively old (mean age 61.2 ± 7.7 years) with a long duration of disease (mean 10.1 ± 7.5 years) and hence had fewer β-cell reserves. A subanalysis showed that patients ≤ 60 years of age had a 4fold greater HbA1C reduction in response to treatment compared to older patients. The beneficial effect of DBCare on glycemic control was accentuated in younger (≤60 years) and heavier patients (BMI > 30 kg/m2) and in patients with less than 10year disease duration. To the best of our knowledge this is the first randomized double-blind placebo-controlled trial that investigated the glucose-lowering effect of this 11-ingredient Ayurvedic compound. Previous reports supported the hypoglycemic effect of some of its components. The fruit juice produced from the plant Mormordica charantia (karela, also known as bitter melon), which is the dominant component in DBCare, improved glucose control in subjects with T2DM and increased the number of insulin-positive β cells in the pancreas of streptozotocindiabetic rats [14,16]. However, a recent 3-month double-blind placebo-controlled trial did not document a glucose-lowering effect of Mormordica charantia [15]. Neem (Azadirachta indica), a tree grown throughout India, was shown to have a significant glucose-lowering effect in alloxan-treated rats and in patients with T2DM [24,25]. In addition, extracts from the Gymnema sylvestre vine (Gudmaar) improved glucose control in patients with T2DM on oral treatment in an uncontrolled 18-month study [20], and powdered seeds of Trigonella foenum graceum (also known as methi or fenugreek) improved HOMA-IR and insulin excursions in a randomized double-blind placebo-controlled in patients with T2DM [17,18]. A recent meta-analysis found that Trigonella foenum graceum had a significant glucose-lowering effect, reducing FPG and A1C by 66 mg/dl and 1.15%, respectively [19]. Mormordica charantia, which comprises 30% of each DBCare tablet, is proposed to enhance insulin release and action and increase glucose uptake by peripheral tissues, possibly by activation of the α- and γ -perixosome proliferator-activated receptors [11,37]. The glucose-lowering effect of Gymnema sylvestre possibly results from an increased number and function of βcells [22] and that of Trigonella foenum from improved insulin resistance and inhibition of gastric motility and carbohydrate absorption [11,17].
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The herbal mixture Pancreas Tonic, which shares 5 of its 10 ingredients with DBCare, was previously investigated in a 3-month placebo-controlled trial in patients with uncontrolled T2DM [38]. In that study, patients with entry HbA1C of 10.9% ± 1.0% had a statistically significant decline in HbA1C, whereas patients with lower HbA1C at baseline did not improve throughout the study. Of note, the patients in that study were younger than ours (mean age 47.4 years), with a different ethnic background (the majority were Hispanic) and a shorter duration of disease (mean 4.3 years). A recent Cochrane database review on Ayurvedic treatments for diabetes mellitus concluded that Pancreas Tonic did not show a clear hypoglycemic effect [13]. DBCare-treated patients showed a 45.6 mg/dL drop in TG levels with no effect on other lipid parameters (p = 0.133). Previously, Ahmed et al. demonstrated a hypotrigliceridemic effect in diabetic rats treated with Mormordica charantia [39]. Gupta et al. showed such an effect in diabetic patients treated with Trigonella foenum graceum [18] and Babu and Srinivasan observed a significant TG reduction in Curcuma longa–fed diabetic rats [40]. This hypotrigliceridemic effect is not consistent throughout the literature and was not seen in our study population either. Other traditional cardiometabolic risk factors, such as BMI, waist circumference, and lipid profile, did not show significant changes during the 3-month DBCare treatment, although such benefits have been attributed to some of its components [9,12]. Several components of DBCare such as Momordica charantia, Trigonella foenum, and Gymnema sylvestre have demonstrated an antioxidant effect [29–35], which might ameliorate increased oxidative stress in the diabetic patient and improve target organ damage [29]. The current study was short term, did not detect oxidative stress–related parameters, and did not address target organ damage. With regard to safety, DBCare was well tolerated except for minor hypoglycemic episodes. Side effects included mild gastrointestinal discomfort, with no biochemical changes suggesting end-organ effects at the present dose regimen. This study had a few limitations. The study design did not include a run-in period; therefore, 6 of 41 recruited patients (14.6%) were not eligible for the study after the first visit, primarily due to A1C ≤ 7%. Additionally, due to safety considerations the study design did not enforce a fixed dose regimen of hypoglycemic medications other than DBCare among the patients, leading to an imbalance between the groups. The randomization process did not match the patients according to any specific parameter, leading to small between-group differences in baseline parameters. In summary, this preliminary randomized double-blind placebo-controlled trial showed that DBCare treatment was not effective in improving glycemic control in patients with inadequately controlled T2DM despite oral hypoglycemic treatment, although a trend toward a hypoglycemic effect was noticed, because A1C levels decreased during the study period and more
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frequent hypoglycemic episodes were documented. DBCare was well tolerated without significant side effects. Larger-scale studies are needed with a selected patient population that might derive maximum benefit from this herbal supplement. According to our study results, this population might include younger patients ( 8%. Two recent meta-analyses on herbal treatments for diabetes mellitus urged the need for high-quality large-scale studies that will elucidate the effect of the herbs on glycemic control [13,15]. Although our study provides new information on the hypoglycemic effect of DBCare, we would like to support this proposition.
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ACKNOWLEDGMENTS The authors thank Lior Sudri, RN, for her help in conducting the study, and Faye Schreiber, MS, for her careful review of the manuscript
Author Contributions Pnina Rotman-Pikielny: design and conduct of the study, data collection and analysis, data interpretation, and manuscript writing. Rosane Ness-Abramof: design and conduct of the study, data collection, and interpretation. Gideon Charach: design and conduct of the study. Alexander Roitman: design and conduct of the study. Rivka Zissin: data interpretation and manuscript writing. Yair Levy: design and conduct of the study.
REFERENCES 1. American Diabetes Association: Standards of medical care in diabetes—2010. Diabetes Care 33(Supp. 1):S11–S61, 2010. 2. DeFronzo RA, Goodman AM: The multicenter Metformin Study Group. Efficacy of metformin in patients with non-insulindependent diabetes mellitus. N Engl J Med 333:541–549, 1995. 3. Dodd HA, Colby MS, Boye KS: Treatment approach and HbA1c control among US adults with type 2 diabetes: NHANES 1999– 2004. Curr Med Res Opin 25:1605–1613, 2009. 4. Baron A, Neumann C, and the PROTECT study group: PROTECT (Precose Resolution of Optimal Titration to Enhance Current Therapies) interim results: a large multi center study of patients with type II diabetes. Clin Ther 19:282–285, 1997. 5. Kogan AJ: Overcoming obstacles to effective care of type 2 diabetes. Am J Manag Care 15:255–262, 2009. 6. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al.: Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355:2427–2443, 2006. 7. UK Prospective Diabetes Study Group: Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853, 1993. 8. Ryan EA, Pick ME, Marceau C: Use of alternative medicines in diabetes mellitus. Diabet Med 18:242–245, 2001.
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9. Kar A, Choudhary BK, Bandyopadhyay NG: Comparative evaluation of hypoglycaemic activity of some Indian medicinal plants in alloxan diabetic rats. J Ethnopharmacol 84:105–108, 2003. 10. Prabhakar PK, Doble M: A target based therapeutic approach towards diabetes mellitus using medicinal plants. Curr Diabetes Rev 4:291–308, 2008. 11. Saxena A, Kishore Vikram N: Role of selected Indian plants in management of type 2 diabetes: a review. J Altern Complement Med 10:369–378, 2004. 12. Yeh GY, Eisenberg DM, Kaptchuk TJ, Phillips RS: Systematic review of herbs and dietary supplements for glycemic control in diabetes. Diabetes Care 26:1277–1294, 2003. 13. Sridharan K, Mohan R, Ramaratnam S, Panneerselvam D: Ayurvedic treatments for diabetes mellitus. Cochrane Database Syst Rev 12: Art.No. CD008288, 2011. DOI: 10.1002/14651858. CD008288.pub2. 14. Ahmed I, Adeghate E, Sharma AK, Pallot DJ, Singh J: Effects of Momordica charantia fruit juice on islet morphology in the pancreas of the streptozotocin-diabetic rats. Diabetes Res Clin Pract 40:145– 151, 1998. 15. Dans AM, Villarruz MV, Jimeno CA, Javelosa MA, Chua J, Bautista R: The effect of Mormordica charanthia capsule preparation on glycemic control in type 2 diabetes mellitus needs further studies. J Clin Epidemiol 60:554–559, 2007. 16. Welihinda J, Karunanayake EH, Sheriff MH, Jayasinghe KS: Effect of Mormordica charantia on the glucose tolerance in maturity onset diabetes. J Ethnopharmacol 17:277–282, 1986. 17. Ali L, Azad Khan AK, Hassan Z, Mosihuzzaman M, Nahar N, Nasreen T, Nur-e-Alam M, Rokeya B: Characterization of the hypoglycemic effects of Trigonella foenum graecum seed. Planta Med 61:358–360, 1995. 18. Gupta A, Gupta R, Lal B: Effect of Trigonella foenum graceum (fenugreek) seeds on glycemic control and insulin resistance in type 2 diabetes mellitus: a double blind controlled study. J Assoc Physicians India 49:1057–1061, 2001. 19. Suksomboon N, Poolsup N, Boonkaew S, Suthisisang CC: Metaanalysis of the effect of herbal supplement on glycemic control in type 2 diabetes. J Ethnopharmacol 137:1328–1333, 2011. 20. Baskaran K, Kizar Ahamath B, Radha Shanmugasundaram K, Shanmugasundaram ER: Antidiabetic effect of a leaf extract from Gymnema sylvestra (Gudmaar) in non-insulin-dependent diabetes mellitus patients. J Ethnopharmacol 30:295–300, 1990. 21. Tominaga M, Kimura M, Sugiyama K, Abe T, Igarashi K, Igarashi M, Eguchi H, Sekikawa A, Ogawa A, Manaka H: Effects of seishin-renshi-in and Gymnema sylvestre on insulin resistance in streptozotocin-induced diabetic rats. Diabetes Res Clin Pract 29:11– 17, 1995. 22. Al-Romaiyan A, King AJ, Persaud SJ, Jones PM: A novel extract of Gymnema sylvestre improves glucose tolerance in vivo and stimulates insulin secretion and synthesis in vitro. Phytother Res 2012. DOI: 10.1002/ptr.4815. 23. Dixit VP, Sinha R, Tank R: Effect of Neem seed oil on the blood glucose concentration of normal and allaxon diabetic rats. J Ethnopharmacol 17:95–98, 1986. 24. Gupta S, Kataria M, Gupta PK, Murganandan S, Yashroy RC: Protective role of extracts of neem seeds in diabetes caused by streptozotocin in rates. J Ethnopharmacol 90:185–189, 2004.
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Downloaded by [Universite Laval] at 07:01 03 October 2014
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25. Murty KS, Rao DK: A preliminary study on hypoglycemic and antihyperglycemic effects of Azadirachta indica. Indian J Pharmacol 10:247–250, 1978. 26. Upadhyay UM, Goyal RK: Efficacy of Enicostemma littorale in type 2 diabetic patients. Phytother Res 18:233–235, 2004. 27. Srinivasan M, Padmanabhan M, Stanely Maisen Prince S: Effect of aqueous Enicostemma littorale Blume extract on key carbohydrate metabolic enzymes, lipid peroxides and antioxidants in alloxaninduced diabetic rats. J Pharm Pharmacol 57:497–503, 2005. 28. Madhu Bala Bajpai, Asthana RK, Sharma NK, Chatterjee SK, Mukherjee SK: Hypoglycemic effect of swerchirin from the hexane fraction of swertia chirayita. Planta Med 57:102–104, 1991. 29. Sabu MC, Kuttan R: Anti-diabetic activity of medicinal plants and its relationship with their antioxidant property. J Ethnopharmacol 81:155–160, 2002. 30. Ravi K, Ramchandran B, Subramanian S: Protective effect of Eugenia jambolana seed kernel on tissue antioxidants in streptozotocininduced diabetic rats. Biol Pharm Bull 27:1212–1217, 2004. 31. Sathishsekar D, Subramanian S: Antioxidant properties of Momordica charantia (bitter gourd) seeds on streptozotocin induced diabetic rats. Asia Pacific J Clin Nutr 14:153–158, 2005. 32. Anuradha CV, Ravikumar P: Restoration on tissue antioxidants by fenugreek seeds (Trigonella foenum graecum) in alloxan-diabetic rats. Indian J Physiol Pharmacol 45:408–420, 2001. 33. Prince PS, Kamalakkannan N, Menon VP: Restoration of antioxidants by ethanolic Tinospora cordifolia in alloxan-induced diabetic Wistar rats. Acta Pol Pharm 61:283–287, 2004.
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34. Sithisarn P, Supabphol R, Gritsanapan W: Antioxidant activity of Siamese neem tree (VP1209). J Ethnopharmacol 99:109–112, 2005. 35. Rastogi R, Srivastava AK, Rastogi AK: Long term effect of aflatoxin B(1) on lipid peroxidation in rat liver and kidney: effect of picroliv and silymarin. Phytotherapy Research 15:307–310, 2001. 36. Matthews D, Hosker J, Rudenski A, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentration in man. Diabetologia 28:412–419, 1985. 37. Hsia SH, Bazargan M, Davidson MB: Effect of pancreas tonic (an ayurvedic herbal supplement) in type 2 diabetes mellitus. Metabolism 53:1166–1173, 2004. 38. Leung L, Birtwhistle R, Kotecha J, Hannah S, Cuthbertson S: Anti-diabetic and hypoglycaemic effects of Mormordica charantia (bitter melon): a mini review. Br J Nutr 102:1703–1708, 2009. 39. Ahmed I, Lakhari MS, Gillett M, John A, Raza H: Hypotrigliceridemic and hypocholesterolemic effects of anti-diabetic Mormordica charantia (karela) fruit extract in streptozotocin-induced diabetic rats. Diabetes Res Clin Pract 51:155–161, 2001. 40. Babu PS, Srinivasan K: Hypolipidemic action of curcumin, the active principale of turmeric (Curcuma longa) in STZ induced diabetic rats. Mol Cell Biochem 166:169–175, 1997.
Received January 26, 2012; revision accepted May 30, 2013.
VOL. 33, NO. 1
Journal of the American College of Nutrition Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/uacn20
Efficacy and Safety of the Dietary Supplement DBCare® in Patients With Type 2 Diabetes Mellitus and Inadequate Glycemic Control Pnina Rotman-Pikielny MD e
a b
b
d
, Rosane Ness-Abramof MD , Gideon Charach MD , Alexander c
Roitman MD , Rivka Zissin MD & Yair Levy MD
a
a
Department of Medicine E , Meir Medical Center , Kfar Saba , Israel
b
Endocrine Unit, Meir Medical Center , Kfar Saba , Israel
c
Diagnostic Imaging, Meir Medical Center , Kfar Saba , Israel
d
Internal Medicine C, Tel Aviv Sorasky Medical Center, affiliated with the Sackler Faculty of Medicine, Tel Aviv Universit , Tel Aviv , ISRAEL e
Diabetes Clinic, Clalit Health Services , Herzliya South , ISRAEL Published online: 17 Feb 2014.
To cite this article: Pnina Rotman-Pikielny MD , Rosane Ness-Abramof MD , Gideon Charach MD , Alexander Roitman MD , Rivka Zissin MD & Yair Levy MD (2014) Efficacy and Safety of the Dietary Supplement DBCare® in Patients With Type 2 Diabetes Mellitus and Inadequate Glycemic Control, Journal of the American College of Nutrition, 33:1, 55-62, DOI: 10.1080/07315724.2014.870008 To link to this article: http://dx.doi.org/10.1080/07315724.2014.870008
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Original Research
Efficacy and Safety of the Dietary Supplement DBCare in Patients With Type 2 Diabetes Mellitus and Inadequate Glycemic Control R
Pnina Rotman-Pikielny, MD, Rosane Ness-Abramof, MD, Gideon Charach, MD, Alexander Roitman, MD, Rivka Zissin, MD, Yair Levy, MD Department of Medicine E (P.R.-P., Y.L.), and Endocrine Unit (P.R.-P., R.N.-A.), Diagnostic Imaging (R.Z.), Meir Medical Center, Kfar Saba, Israel, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, ISRAEL; Internal Medicine C, Tel Aviv Sorasky Medical Center, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, ISRAEL (G.C.); Diabetes Clinic, Clalit Health Services, Herzliya South, ISRAEL (A.R.)
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Key words: Ayurvedic medicine, diabetes mellitus, herbal medicine, oral hypoglycemic treatment R (Ace Continental Exports Inc., London, UK) is a traditional Indian herbal food supplement Aims: DBCare marketed as an antidiabetes remedy. This study evaluated the efficacy and safety of DBCare in patients with inadequately controlled type 2 diabetes mellitus (T2DM) despite oral hypoglycemic treatment. Methods: A 12-week randomized double-blind placebo-controlled trial was conducted. Patients with T2DM on oral hypoglycemic agents with HbA1C > 7.0% were randomized to receive DBCare or placebo tablets. Results: Thirty-five patients (20 male/15 female; mean age 61.2 ± 7.6 years), with a mean baseline HbA1C of 7.9% ± 0.6%, received DBCare (N = 18) or placebo (N = 17). During the study period, HbA1C declined R group and 0.2% ± 0.8% in the placebo group (p = 0.806). No significant changes 0.4 ± 0.7% in the DBCare occurred in fasting plasma glucose, lipid profile, or homeostasis model assessment throughout the study or in body mass index, waist circumference, or blood pressure values. Hypoglycemic episodes (glucose < 70 mg/dL) were more frequent in the treatment group (7 vs 1, p = 0.043), necessitating a decrease in other hypoglycemic medications in 2 patients. DBCare was generally well tolerated, with mild side effects that were not different from those of the placebo group. Conclusions: This preliminary study did not demonstrate that DBCare was efficacious in improving glycemic control in inadequately controlled patients with T2DM on oral hypoglycemics. A trend toward improved glycemic control was noted in the DBCare group, which correlates with more frequent hypoglycemic episodes. Further studies are needed to elucidate DBCare’s hypoglycemic effect in patients with T2DM in general and in specific clinical settings, such as HbA1C ≥ 8%, short (≤10-year) duration of diabetes, or young age in particular.
INTRODUCTION
medications [4–6]. Uncontrolled diabetes can cause microvascular and macrovascular complications, increasing population morbidity and mortality, as well as health care costs [7]. Hence, the search for the ideal hypoglycemic medication is increasing worldwide. The remedial properties of herbal substances generate avid interest in the Western world and they are used by up to a third of patients with DM [8]. Although some Ayurvedic medications demonstrate hypoglycemic properties, due to a lack of large, well-designed and conducted studies, no definite conclusions
Despite the variety of pharmacological options available for treating type 2 diabetes mellitus (T2DM), the results regarding diabetes control are unsatisfactory and about half of the patients do not reach treatment goals of glycated hemoglobin level (HbA1C) < 7% [1–3]. The reasons for the failure to control T2DM are multifaceted, including the natural history of the disease; lifestyle issues; side effects of the medications, such as hypoglycemia and weight gain; and the short-lived effectiveness of
Address correspondence to: Dr. Pnina Rotman-Pikielny, Department of Medicine E, Meir Medical Center, 59 Tchernihovsky St., Kfar Saba, ISRAEL 44281. E-mail: [email protected] Trial Registration: Clinicaltrials.gov Identifier NCT0056004
R Disclosures: Dhanvantary Herbochem Pvt Ltd. Inc. (Mira Road Thane, Maharashtra, India) and Ace Continental Exports Inc. (London) supplied placebo and DBCare tablets and sponsored a research grant that included a research assistant throughout the study and all lab work expenses. The companies did not have access to the medical data or any involvement in the data analysis or preparation of the manuscript.
Journal of the American College of Nutrition, Vol. 33, No. 1, 55–62 (2014) C American College of Nutrition Published by Taylor & Francis Group, LLC 55
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R Effect of DBCare on Type 2 Diabetes Mellitus
have been drawn regarding their beneficial hypoglycemic effect [9–13]. R is a traditional food supplement composed of 11 DBCare herbal ingredients that is marketed in India and accessible electronically from all over the world as a natural antidiabetes remedy. A recent Google search under DBCare yielded 29,700 results. Although it is very popular in India and has been used for many decades, we could not determine the origin of the specific 11-ingredient combination. Nine of DBCare’s components demonstrated hypoglycemic properties in anecdotal animal and human studies [14–29] and 8 ingredients had an antioxidant effect in animal models [29–35]. To the best of our knowledge, no prospective study has evaluated the efficacy and safety of the 11-ingredient combination in patients with T2DM. Our hypothesis was that using DBCare in uncontrolled diabetes patients would cause a 1% A1C reduction with a commensurate 30 mg/dL reduction in fasting blood sugar. Our secondary endpoint was a 10% reduction in total and low-density lipoprotein cholesterol. We also checked the safety profile of DBCare by monitoring clinical side effects and biochemical parameters, including liver and kidney function tests and white blood cell count. We report here the results of the first prospective, randomized, placebo-controlled study that evaluated the efficacy and safety of DBCare tablets in patients with inadequately controlled T2DM despite oral hypoglycemic treatment.
MATERIALS AND METHODS Study Design A prospective, 12-week, randomized double-blind placebocontrolled trial was conducted in a single secondary referral hospital in Israel. Patients were recruited from the Diabetes Clinic of Clalit Health Services in south Herzliya and by advertisements in local and national newspapers. Eligible patients had T2DM, were ≥ 18 years of age, were on oral hypoglycemic agents, and had an HbA1C level > 7.0%. Screening included a short medical history and recent (within 3 months) lab tests of serum electrolytes, fasting blood glucose, HbA1C level, kidney and liver function tests, lipid profile, and blood count. Detailed inclusion and exclusion criteria are provided below. Randomization was performed by the Pharmacy Department of the institution. Among 80 patients screened over 8 months, 41 met the entry criteria and were randomized to receive DBCare (2 tablets 3 times daily) or placebo and complete the first study visit (Fig. 1). Six patients, 4 from the DBCare group and 2 from the placebo group were excluded after that visit, all due to HbA1C levels below the allowable limits of the study (≤7%). The remaining 35 patients were included in the analyses and comprised the study group. The 12-week study included 4 outpatient visits: at time 0 (study initiation) and at weeks 1, 4, and 12 (study completion). At the initial visit, clinical assessment included a complete medical history, including duration of
80 patients were screened for the study 39 patients were excluded before randomization
41 patients were randomized 4 patients were excluded due to violation of protocol matters
DBCare® N=18
2 patients were excluded due to violation of protocol matters Placebo N=17
1 patient withdrew
2 patients withdrew
DBCare® completed N=17
Placebo completed N=15
Fig. 1. Recruitment and randomization of study participants.
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diabetes, target organ damage, list and dosage of all medications, number of hypoglycemic episodes in the last 6 months, as well as evidence of comorbidities such as hyperlidemia, ischemic heart disease, hypertension, stroke, etc. Physical examination and 12lead electrocardiogram were conducted, body weight and height were measured, and serum electrolytes, fasting plasma glucose (FPG), kidney and liver function tests, lipid profile, blood count, fasting insulin, and HbA1C level were analyzed. The clinical assessment at each subsequent visit included a medical interview focusing on compliance and adverse effects, measurement of vital signs, and blood tests including serum electrolytes, FPG, kidney and liver function tests, lipid profile, and blood count. A 1-week follow-up visit was included to detect a possible rapid impact of the investigated supplement on blood glucose and liver or kidney functions. At the end of the study, the medical interview included each patient’s conjecture regarding the nature of the study medication and its disclosure. On this visit, at the completion of the 12-week treatment period, in addition to serum electrolytes, FPG, kidney and liver function tests, lipid profile, and blood count, the biochemical workup included repeated measurement of fasting insulin and HbA1C levels. Patients were instructed to monitor their glucose levels at home at least 3 times a day, before meals, and when hypoglycemic symptoms or any unusual symptoms occurred. Those measurements were reviewed by the investigators at each visit. When hypoglycemia (FPG ≤ 70 mg/dL) or hyperglycemia (FPG ≥ 200 mg/dL) was documented, the concomitant oral hypoglycemic medications were modified according to clinical judgment, in order to maintain safe glucose levels. DBCare dose was not modified in any patient throughout the study. The study was approved by the Ethical Committee of the Medical Center. All patients provided written informed consent.
Patients Our aim was to study DBCare in adult patients with uncontrolled diabetes (HbA1C level above 7.0%) despite stable oral medical therapy. Due to safety reasons, we limited study enrollment to patients without significant target organ damage. Eligibility criteria included the following: 1. adult (≥18 years old), nonpregnant patients with T2DM (according to American Diabetes Association criteria); 2. on oral antidiabetes regimen; 3. stable antidiabetes regimen for at least 3 months prior to study initiation; 4. HbA1C level 7.0%–10%. Exclusion criteria were as follows: 1. patients < 18 years old or pregnant women; 2. patients with type 1 DM; 3. HbA1C level < 7.0%;
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
4. insulin therapy or a change in the medical treatment of diabetes during the previous 3 months; 5. abnormal liver function with elevated alanine aminotransferase or aspartate aminotransferase equal to or greater than twice above normal level; 6. abnormal kidney function tests with creatinine ≥ 2 mg/dL; 7. clinical evidence of active ischemic heart disease or congestive heart failure based on the patient’s report, physical examination, and electrocardiogram test (creatine phosphokinase blood level and echocardiogram were not performed during the study); 8. inability to comply with the study requirements regarding adherence to medication consumption and the follow-up visit schedule.
Treatment The ingredients and dry weight composition of DBCare tablets are listed in Table 1. Single-batch DBCare tablets and indistinguishable placebo tablets containing 0.5 g lactose only were manufactured by Dhanvantary Herbochem Pvt Ltd. Inc. (Mira Road Thane, Maharashtra, India) and supplied by Ace Continental Exports Inc. (London). Patients were instructed to take 2 tablets 3 times daily with lukewarm water after meals and to reduce consumption of fried foods to a minimum. All study patients were instructed to follow this dietary regimen per manufacturer’s instructions, in order to maximize the treatment effect and promote a healthy lifestyle.
Outcome Variables The primary outcome of the study was the change in HbA1C in the study group compared to the control group during the study period. Secondary outcome included the change in FPG from baseline throughout the study duration. Table 1. Composition of DBCare Tablets Ingredient Ayurvedic (Botanical) Names Karela (Mormordica charanpia or charantia) Mamejava (Enicostemma littorale) Jambubeej (Eugenia jambolana) Kariyatu (Swertia chirata or Andrographis panculata) Methi (Tragonella foenum) Neempan (Melia azabirachta or Azadirachta indicasome) Gudmaar (Gymnema sylvestre) Amla (Emblica officinalis) Galo (Tinospora cordifolia) Kadu (Picrorhiza kurroa) Haldi (Curcuma longa)
Weight (mg) (Total 500 mg)
% Dry Weight
150
30
50
10
50 40
10 8
40 30
6 8
30 30 30 30 20
6 6 6 6 4
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R Effect of DBCare on Type 2 Diabetes Mellitus
Variables evaluating efficacy were HbA1C, FPG, the homeostasis model assessment (HOMA) for insulin resistance (IR) and insulin secretion (β-cell), and lipid profile. Variables evaluating safety included clinical side effects, liver function tests, kidney function tests, and white blood cell count.
Withdrawals
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Study withdrawal criteria were (1) hypoglycemia or hyperglycemia necessitating hospitalization; (2) safety concerns, as judged by the investigators; (3) poor compliance with study instructions—that is, medication consumption schedule as per self-report or follow-up visit schedule (compliance was assessed by the investigator, only one missed visit was allowed); or (4) patient request.
Laboratory Analyses All labs were obtained between 0700 and 0900 after an overnight fast and analyzed in the central lab of the medical center. HbA1C (normal range 4.8%–6.0%) plasma level was deterR mined immunoturbidometrically using Cobas INTEGRA 700 (Roche Diagnostics, Mannheim, Germany). Insulin levels (normal range 5–25 mU/L) were assayed using chemiluminescent R 2000, Siemens Healthcare Diimmunometric assay (Immulite agnostics, Deerfield, IL). The HOMA for IR and insulin secretion (β-cell) were calculated according to the following equations [36]: HOMA IR = fasting insulin (μU/mL) ×fasting glucose (mg/dL)/405 HOMA β-cell = 20 × fasting insulin (μU/mL) /fasting glucose (mg/dL) × 0.0555 − 3.5
Statistical Analysis The sample size was calculated based on assumptions of an absolute difference of 0.5% in HbA1C between the 2 groups at the end of trial and standard deviation of 0.5%. Using these estimates, a sample size of 22 per group would be required to yield a statistical power of 90% and a sample size of 17 per group would yield a statistical power of 80%. Although parameters were distributed normally (ShapiroWilk test), analysis was performed using both parametric and nonparametric tests. Tables 2 and 3 show the results of parametric tests. Continuous parameters are expressed as mean ± SD and categorical parameters are expressed as numbers and percentages. Comparison between DBCare- and placebo-treated groups was performed using chi-square analysis for categorical variables and 2-tailed t test for continuous variables (as well as the Mann-Whitney nonparametric test). The changes in all variables from initiation to end of study were analyzed for each group
58
Table 2. Clinical and Metabolic Data of the Study Subjects at Baseline Clinical Parameter Age (years)a Gender (male/female)b BMI (kg/m2)a Waist circumference (cm)a Duration of diabetes (years)a Treated with metforminb Dyslipidemiab Hypertensionb Ischemic heart diseaseb Systolic blood pressure (mmHg)a Diastolic blood pressure (mmHg)a FPG (mg/dL)a HbA1C (%)a Fasting insulin (μU/ml)a HOMA-IRa HOMA-β a
DBCare Group Placebo Group N = 18 N = 17 p Value 61.8 ± 7.1 8/10 (44/56) 27.1 ± 4.3 95.4 ± 8.5 11.3 ± 7.8
60.6 ± 8.4 12/5 (71/29) 29.8 ± 4.0 100.5 ± 11 8.9 ± 7.1
0.637 0.176 0.067 0.130 0.357
17 (94.4) 17 (94.4) 12 (66.7) 3 (16.7) 146.3 ± 28.2
16 (94.1) 14 (82.3) 13 (76.5) 5 (29.4) 148.5 ± 20.5
1.000 0.322 0.711 0.433 0.800
78.3 ± 12.1
83.1 ± 18.0
0.361
± ± ± ± ±
0.186 0.324 0.431 0.618 0.130
150.0 7.8 13.1 5.4 69.0
± ± ± ± ±
42.0 0.5 11.7 5.6 67
171.2 8.0 10.5 4.6 41.4
50.7 0.7 6.2 3.5 26.1
BMI = body mass index, FPG = fasting plasma glucose, HOMA-IR = homeostasis model assessment for insulin resistance, HOMA-β = homeostasis model assessment for insulin secretion. a Data are given as mean ± SD. b Data are given as number (%).
(the placebo and active treatment groups) using paired t test (as well as the Wilcoxon nonparametric test). Changes between the 2 groups over time were analyzed using a general linear model with repeated measures. Correlations between parameters were analyzed using Pearson’s correlation and Spearman’s correlation. The statistical significance was set to 0.05 and the statistical analyses were performed using SPSS for Windows, version 18.0 (SPSS Inc., Chicago, IL).
RESULTS Thirty-five patients (20 male/15 female; mean age 61.2 ± 7.6 years), with a mean baseline HbA1C of 7.9% ± 0.6%, were randomized to receive either DBCare (N = 18) or placebo (N = 17). Baseline clinical and biochemical characteristics of both groups were similar in all parameters (Table 2). The patients were overweight (mean body mass index [BMI] = 28.4 ± 4.3 kg/m2), with hypertension and dyslipidemia in 71% and 89%, respectively. They were diagnosed with diabetes for an average of 10.1 ± 7.5 years and treated with a mean of 1.8 ± 0.7 medications each (metformin 94%; insulin secretagogues 66%). Mean changes from baseline to week 12 in clinical and metabolic parameters are shown in Table 3. As demonstrated, baseline HbA1C in the DBCare group (7.8% ± 0.5%) decreased significantly during the study period, by 0.4% ± 0.7% (p = 0.033), whereas no significant
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Table 3. Metabolic Parameters Before and After 12 Weeks of Treatmenta DBCare Group (N = 18) Parameter
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BMI (kg/m2) Waist circumference (cm) FPG (mg/dL) Fasting insulin (μU/ml) HbA1C (%) HOMA-IR HOMA-β Triglycerides (mg/dL) T cholesterol (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL)
Baseline 27.1 95.1 153.6 13.1 7.8 5.7 57.4 210.5 175.1 42.1 85.4
± ± ± ± ± ± ± ± ± ± ±
Final
4.4 8.6 39.1 12.1 0.5 5.9 45.9 161.0 41.9 13.7 21.2
27.0 94.4 142.6 15.3 7.4 6.1 72.4 164.9 165.1 42.6 81.8
± ± ± ± ± ± ± ± ± ± ±
Placebo Group (N = 17) Change
4.2 8.1 27.7 16.4 0.7 7.4 58.5 109.9 31.7 10.4 19.4
−0.1 −0.7 −11.1 2.2 −0.4 0.4 15.0 −45.6 −10.1 0.5 −3.6
± ± ± ± ± ± ± ± ± ± ±
0.4 2.4 29.1 5.4 0.7∗ 2.2 48.2 106.6 20.7 6.0 15.8
Baseline 29.7 101.3 169.1 10.7 8.0 4.7 41.7 209.7 161.7 44.5 90.3
± ± ± ± ± ± ± ± ± ± ±
4.3 11.3 49.0 6.5 0.7 3.7 26.0 120.5 35.0 15.0 29.1
Final
Change
± ± ± ± ± ± ± ± ± ± ±
−0.2 ± 0.9 0.17 ± 4.9 −11.5 ± 45.5 1.5 ± 5.7 −0.2 ± 0.8 0.0 ± 0.9 16.0 ± 31.4 −13.2 ± 72.8 13.5 ± 26.7 −0.5 ± 9.6 6.5 ± 25.1
29.5 101.2 157.6 12.2 7.8 4.6 57.6 196.5 175.2 44.0 96.8
4.5 8.2 38.4 7.5 0.8 2.8 45.0 100.2 21.3 9.1 17.3
BMI = body mass index, FPG = fasting plasma glucose, HOMA-IR = homeostasis model assessment for insulin resistance, HOMA-β = homeostasis model assessment for insulin secretion, HDL-C = high-density lipoprotein cholesterol, LDL-C = low-density lipoprotein cholesterol. a Data are given as mean ± SD. ∗ p = 0.033 based on paired t test.
change was found in the placebo group. There was no difference in HbA1C between the DBCare and placebo groups (p = 0.806, Mann-Whitney test) at the end of the study. FPG did not change significantly from week 0 to 12 in either group. However, hypoglycemia (FPG ≤ 70 mg/dL) was significantly more common in the DBCare group (7 patients vs 1 in the control group, p = 0.043). Consequently, the dosage of other hypoglycemic agents was decreased in 2 patients in the DBCare group and in one patient in the placebo group. An increase in hypoglycemic medications occurred in 2 patients, one in each group (Table 4). No hypoglycemic or hyperglycemic episodes necessitating hospitalization occurred during the study. Subgroup analyses of patients with T2DM of ≤ 10 years duration revealed HbA1C reduction of 0.33% ± 0.67% (p = 0.034) at week 12 vs baseline. A 0.63% ± 0.65% (p = 0.009) decrease in HbA1C was noted for patients with BMI > 30 kg/m2. Significant HbA1C and glucose reductions at the end of the Table 4. Incidence of Adverse Events During 12 Weeks of Treatment Variable Hypoglycemic events∗ Increased dosage of hypoglycemic medications Decreased dosage of hypoglycemic medications Flatulence Nausea Abdominal pain Diarrhea Patients with side effects Total number of side effects Patients’ conjecture regarding treatment correct/incorrect ∗
DBCare N = 18 (%)
Placebo N = 17 (%)
7 (39) 1 (6)
1 (6) 1 (6)
2 (11)
1 (6)
1 (6) 0 (0) 1 (6) 1 (6) 5 (28) 7 (39) 8/4 (67/33)
2 (12) 1 (5) 0 (0) 1 (5) 4 (24) 6 (35) 7/3 (70/30)
p = 0.043; hypoglycemia was defined as fasting plasma glucose ≤ 70 mg/dL.
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study (0.57% ± 0.44%, p = 0.0001, and 12.6 ± 21.4 mg/dL, p = 0.045, respectively) were also noted in patients younger than 60 years of age. Although triglycerides (TG) level decreased 45.6 ± 106 mg/dL in the study group and only 13.2 ± 72.8 mg/dL in the placebo group (Table 3), these differences were not statistically significant (p = 0.133 and p = 0.561, respectively). Other metabolic parameters including BMI, waist circumference, systolic and diastolic blood pressure, and cholesterol profile did not differ at the end of the study compared to baseline. Poor metabolic parameters at the beginning of the study were found to correlate positively with glucose reduction during the study, initial FPG (r = 0.67, p = 0.005), initial HbA1C (r = 0.55, p = 0.028 for), and initial HOMA IR (r = 0.59, p = 0.02). No study drug-related abnormality was detected in kidney and liver function tests and in the hematologic parameters monitored. About a third of each group had side effects, mainly gastrointestinal (Table 4). Three patients withdrew from the study, one from the treatment group (due to a renal colic episode and the patient’s concern that it might have been related to the study drug) and 2 from the placebo group (one due to nausea and abdominal discomfort and the other due to difficulty in complying with the follow-up visit schedule).
DISCUSSION In this randomized, double-blind placebo-controlled trial, we have shown that DBCare treatment was not effective in improving glycemic control in patients with inadequately controlled T2DM on oral treatment. We demonstrated a small reduction in HbA1C of 0.4% from a baseline of 7.8% ± 0.5% (p = 0.033). However, this did not fulfill our primary outcome goals and was not different from the 0.2% HbA1C reduction seen in the placebo group. In concert with these results, FPG level, as well
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as HOMA-IR and HOMA-β, were not decreased after 3 months compared to baseline. Additionally, DBCare-treated patients had significantly more episodes of symptomatic hypoglycemia (39% vs 6%), which led to a reduction in antihyperglycemic medications in 11%, than did placebo-treated patients. Taken together, these results indicate that it is plausible that DBCare has a beneficial effect on glucose metabolism that could not be conclusively demonstrated in the current study. This lack of effect has several possible explanations. Most important among these is the relatively low baseline HbA1C, because pharmacotherapy is more effective with higher baseline HbA1C values [4]. Second, our patients were relatively old (mean age 61.2 ± 7.7 years) with a long duration of disease (mean 10.1 ± 7.5 years) and hence had fewer β-cell reserves. A subanalysis showed that patients ≤ 60 years of age had a 4fold greater HbA1C reduction in response to treatment compared to older patients. The beneficial effect of DBCare on glycemic control was accentuated in younger (≤60 years) and heavier patients (BMI > 30 kg/m2) and in patients with less than 10year disease duration. To the best of our knowledge this is the first randomized double-blind placebo-controlled trial that investigated the glucose-lowering effect of this 11-ingredient Ayurvedic compound. Previous reports supported the hypoglycemic effect of some of its components. The fruit juice produced from the plant Mormordica charantia (karela, also known as bitter melon), which is the dominant component in DBCare, improved glucose control in subjects with T2DM and increased the number of insulin-positive β cells in the pancreas of streptozotocindiabetic rats [14,16]. However, a recent 3-month double-blind placebo-controlled trial did not document a glucose-lowering effect of Mormordica charantia [15]. Neem (Azadirachta indica), a tree grown throughout India, was shown to have a significant glucose-lowering effect in alloxan-treated rats and in patients with T2DM [24,25]. In addition, extracts from the Gymnema sylvestre vine (Gudmaar) improved glucose control in patients with T2DM on oral treatment in an uncontrolled 18-month study [20], and powdered seeds of Trigonella foenum graceum (also known as methi or fenugreek) improved HOMA-IR and insulin excursions in a randomized double-blind placebo-controlled in patients with T2DM [17,18]. A recent meta-analysis found that Trigonella foenum graceum had a significant glucose-lowering effect, reducing FPG and A1C by 66 mg/dl and 1.15%, respectively [19]. Mormordica charantia, which comprises 30% of each DBCare tablet, is proposed to enhance insulin release and action and increase glucose uptake by peripheral tissues, possibly by activation of the α- and γ -perixosome proliferator-activated receptors [11,37]. The glucose-lowering effect of Gymnema sylvestre possibly results from an increased number and function of βcells [22] and that of Trigonella foenum from improved insulin resistance and inhibition of gastric motility and carbohydrate absorption [11,17].
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The herbal mixture Pancreas Tonic, which shares 5 of its 10 ingredients with DBCare, was previously investigated in a 3-month placebo-controlled trial in patients with uncontrolled T2DM [38]. In that study, patients with entry HbA1C of 10.9% ± 1.0% had a statistically significant decline in HbA1C, whereas patients with lower HbA1C at baseline did not improve throughout the study. Of note, the patients in that study were younger than ours (mean age 47.4 years), with a different ethnic background (the majority were Hispanic) and a shorter duration of disease (mean 4.3 years). A recent Cochrane database review on Ayurvedic treatments for diabetes mellitus concluded that Pancreas Tonic did not show a clear hypoglycemic effect [13]. DBCare-treated patients showed a 45.6 mg/dL drop in TG levels with no effect on other lipid parameters (p = 0.133). Previously, Ahmed et al. demonstrated a hypotrigliceridemic effect in diabetic rats treated with Mormordica charantia [39]. Gupta et al. showed such an effect in diabetic patients treated with Trigonella foenum graceum [18] and Babu and Srinivasan observed a significant TG reduction in Curcuma longa–fed diabetic rats [40]. This hypotrigliceridemic effect is not consistent throughout the literature and was not seen in our study population either. Other traditional cardiometabolic risk factors, such as BMI, waist circumference, and lipid profile, did not show significant changes during the 3-month DBCare treatment, although such benefits have been attributed to some of its components [9,12]. Several components of DBCare such as Momordica charantia, Trigonella foenum, and Gymnema sylvestre have demonstrated an antioxidant effect [29–35], which might ameliorate increased oxidative stress in the diabetic patient and improve target organ damage [29]. The current study was short term, did not detect oxidative stress–related parameters, and did not address target organ damage. With regard to safety, DBCare was well tolerated except for minor hypoglycemic episodes. Side effects included mild gastrointestinal discomfort, with no biochemical changes suggesting end-organ effects at the present dose regimen. This study had a few limitations. The study design did not include a run-in period; therefore, 6 of 41 recruited patients (14.6%) were not eligible for the study after the first visit, primarily due to A1C ≤ 7%. Additionally, due to safety considerations the study design did not enforce a fixed dose regimen of hypoglycemic medications other than DBCare among the patients, leading to an imbalance between the groups. The randomization process did not match the patients according to any specific parameter, leading to small between-group differences in baseline parameters. In summary, this preliminary randomized double-blind placebo-controlled trial showed that DBCare treatment was not effective in improving glycemic control in patients with inadequately controlled T2DM despite oral hypoglycemic treatment, although a trend toward a hypoglycemic effect was noticed, because A1C levels decreased during the study period and more
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frequent hypoglycemic episodes were documented. DBCare was well tolerated without significant side effects. Larger-scale studies are needed with a selected patient population that might derive maximum benefit from this herbal supplement. According to our study results, this population might include younger patients ( 8%. Two recent meta-analyses on herbal treatments for diabetes mellitus urged the need for high-quality large-scale studies that will elucidate the effect of the herbs on glycemic control [13,15]. Although our study provides new information on the hypoglycemic effect of DBCare, we would like to support this proposition.
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ACKNOWLEDGMENTS The authors thank Lior Sudri, RN, for her help in conducting the study, and Faye Schreiber, MS, for her careful review of the manuscript
Author Contributions Pnina Rotman-Pikielny: design and conduct of the study, data collection and analysis, data interpretation, and manuscript writing. Rosane Ness-Abramof: design and conduct of the study, data collection, and interpretation. Gideon Charach: design and conduct of the study. Alexander Roitman: design and conduct of the study. Rivka Zissin: data interpretation and manuscript writing. Yair Levy: design and conduct of the study.
REFERENCES 1. American Diabetes Association: Standards of medical care in diabetes—2010. Diabetes Care 33(Supp. 1):S11–S61, 2010. 2. DeFronzo RA, Goodman AM: The multicenter Metformin Study Group. Efficacy of metformin in patients with non-insulindependent diabetes mellitus. N Engl J Med 333:541–549, 1995. 3. Dodd HA, Colby MS, Boye KS: Treatment approach and HbA1c control among US adults with type 2 diabetes: NHANES 1999– 2004. Curr Med Res Opin 25:1605–1613, 2009. 4. Baron A, Neumann C, and the PROTECT study group: PROTECT (Precose Resolution of Optimal Titration to Enhance Current Therapies) interim results: a large multi center study of patients with type II diabetes. Clin Ther 19:282–285, 1997. 5. Kogan AJ: Overcoming obstacles to effective care of type 2 diabetes. Am J Manag Care 15:255–262, 2009. 6. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al.: Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 355:2427–2443, 2006. 7. UK Prospective Diabetes Study Group: Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853, 1993. 8. Ryan EA, Pick ME, Marceau C: Use of alternative medicines in diabetes mellitus. Diabet Med 18:242–245, 2001.
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9. Kar A, Choudhary BK, Bandyopadhyay NG: Comparative evaluation of hypoglycaemic activity of some Indian medicinal plants in alloxan diabetic rats. J Ethnopharmacol 84:105–108, 2003. 10. Prabhakar PK, Doble M: A target based therapeutic approach towards diabetes mellitus using medicinal plants. Curr Diabetes Rev 4:291–308, 2008. 11. Saxena A, Kishore Vikram N: Role of selected Indian plants in management of type 2 diabetes: a review. J Altern Complement Med 10:369–378, 2004. 12. Yeh GY, Eisenberg DM, Kaptchuk TJ, Phillips RS: Systematic review of herbs and dietary supplements for glycemic control in diabetes. Diabetes Care 26:1277–1294, 2003. 13. Sridharan K, Mohan R, Ramaratnam S, Panneerselvam D: Ayurvedic treatments for diabetes mellitus. Cochrane Database Syst Rev 12: Art.No. CD008288, 2011. DOI: 10.1002/14651858. CD008288.pub2. 14. Ahmed I, Adeghate E, Sharma AK, Pallot DJ, Singh J: Effects of Momordica charantia fruit juice on islet morphology in the pancreas of the streptozotocin-diabetic rats. Diabetes Res Clin Pract 40:145– 151, 1998. 15. Dans AM, Villarruz MV, Jimeno CA, Javelosa MA, Chua J, Bautista R: The effect of Mormordica charanthia capsule preparation on glycemic control in type 2 diabetes mellitus needs further studies. J Clin Epidemiol 60:554–559, 2007. 16. Welihinda J, Karunanayake EH, Sheriff MH, Jayasinghe KS: Effect of Mormordica charantia on the glucose tolerance in maturity onset diabetes. J Ethnopharmacol 17:277–282, 1986. 17. Ali L, Azad Khan AK, Hassan Z, Mosihuzzaman M, Nahar N, Nasreen T, Nur-e-Alam M, Rokeya B: Characterization of the hypoglycemic effects of Trigonella foenum graecum seed. Planta Med 61:358–360, 1995. 18. Gupta A, Gupta R, Lal B: Effect of Trigonella foenum graceum (fenugreek) seeds on glycemic control and insulin resistance in type 2 diabetes mellitus: a double blind controlled study. J Assoc Physicians India 49:1057–1061, 2001. 19. Suksomboon N, Poolsup N, Boonkaew S, Suthisisang CC: Metaanalysis of the effect of herbal supplement on glycemic control in type 2 diabetes. J Ethnopharmacol 137:1328–1333, 2011. 20. Baskaran K, Kizar Ahamath B, Radha Shanmugasundaram K, Shanmugasundaram ER: Antidiabetic effect of a leaf extract from Gymnema sylvestra (Gudmaar) in non-insulin-dependent diabetes mellitus patients. J Ethnopharmacol 30:295–300, 1990. 21. Tominaga M, Kimura M, Sugiyama K, Abe T, Igarashi K, Igarashi M, Eguchi H, Sekikawa A, Ogawa A, Manaka H: Effects of seishin-renshi-in and Gymnema sylvestre on insulin resistance in streptozotocin-induced diabetic rats. Diabetes Res Clin Pract 29:11– 17, 1995. 22. Al-Romaiyan A, King AJ, Persaud SJ, Jones PM: A novel extract of Gymnema sylvestre improves glucose tolerance in vivo and stimulates insulin secretion and synthesis in vitro. Phytother Res 2012. DOI: 10.1002/ptr.4815. 23. Dixit VP, Sinha R, Tank R: Effect of Neem seed oil on the blood glucose concentration of normal and allaxon diabetic rats. J Ethnopharmacol 17:95–98, 1986. 24. Gupta S, Kataria M, Gupta PK, Murganandan S, Yashroy RC: Protective role of extracts of neem seeds in diabetes caused by streptozotocin in rates. J Ethnopharmacol 90:185–189, 2004.
61
Downloaded by [Universite Laval] at 07:01 03 October 2014
R Effect of DBCare on Type 2 Diabetes Mellitus
25. Murty KS, Rao DK: A preliminary study on hypoglycemic and antihyperglycemic effects of Azadirachta indica. Indian J Pharmacol 10:247–250, 1978. 26. Upadhyay UM, Goyal RK: Efficacy of Enicostemma littorale in type 2 diabetic patients. Phytother Res 18:233–235, 2004. 27. Srinivasan M, Padmanabhan M, Stanely Maisen Prince S: Effect of aqueous Enicostemma littorale Blume extract on key carbohydrate metabolic enzymes, lipid peroxides and antioxidants in alloxaninduced diabetic rats. J Pharm Pharmacol 57:497–503, 2005. 28. Madhu Bala Bajpai, Asthana RK, Sharma NK, Chatterjee SK, Mukherjee SK: Hypoglycemic effect of swerchirin from the hexane fraction of swertia chirayita. Planta Med 57:102–104, 1991. 29. Sabu MC, Kuttan R: Anti-diabetic activity of medicinal plants and its relationship with their antioxidant property. J Ethnopharmacol 81:155–160, 2002. 30. Ravi K, Ramchandran B, Subramanian S: Protective effect of Eugenia jambolana seed kernel on tissue antioxidants in streptozotocininduced diabetic rats. Biol Pharm Bull 27:1212–1217, 2004. 31. Sathishsekar D, Subramanian S: Antioxidant properties of Momordica charantia (bitter gourd) seeds on streptozotocin induced diabetic rats. Asia Pacific J Clin Nutr 14:153–158, 2005. 32. Anuradha CV, Ravikumar P: Restoration on tissue antioxidants by fenugreek seeds (Trigonella foenum graecum) in alloxan-diabetic rats. Indian J Physiol Pharmacol 45:408–420, 2001. 33. Prince PS, Kamalakkannan N, Menon VP: Restoration of antioxidants by ethanolic Tinospora cordifolia in alloxan-induced diabetic Wistar rats. Acta Pol Pharm 61:283–287, 2004.
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34. Sithisarn P, Supabphol R, Gritsanapan W: Antioxidant activity of Siamese neem tree (VP1209). J Ethnopharmacol 99:109–112, 2005. 35. Rastogi R, Srivastava AK, Rastogi AK: Long term effect of aflatoxin B(1) on lipid peroxidation in rat liver and kidney: effect of picroliv and silymarin. Phytotherapy Research 15:307–310, 2001. 36. Matthews D, Hosker J, Rudenski A, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentration in man. Diabetologia 28:412–419, 1985. 37. Hsia SH, Bazargan M, Davidson MB: Effect of pancreas tonic (an ayurvedic herbal supplement) in type 2 diabetes mellitus. Metabolism 53:1166–1173, 2004. 38. Leung L, Birtwhistle R, Kotecha J, Hannah S, Cuthbertson S: Anti-diabetic and hypoglycaemic effects of Mormordica charantia (bitter melon): a mini review. Br J Nutr 102:1703–1708, 2009. 39. Ahmed I, Lakhari MS, Gillett M, John A, Raza H: Hypotrigliceridemic and hypocholesterolemic effects of anti-diabetic Mormordica charantia (karela) fruit extract in streptozotocin-induced diabetic rats. Diabetes Res Clin Pract 51:155–161, 2001. 40. Babu PS, Srinivasan K: Hypolipidemic action of curcumin, the active principale of turmeric (Curcuma longa) in STZ induced diabetic rats. Mol Cell Biochem 166:169–175, 1997.
Received January 26, 2012; revision accepted May 30, 2013.
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