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The Antiseptic 2004; 101(11), 487-494 Evaluation of the clinical efficacy and safety of Diabecon in NIDDM 1 Dr. K.R. Kohli1, MD, Dr. Rangesh Paramesh2, MD(Ay) Professor & Head, Dr. Sanjay Tamoli, MD (Scholar), Department of Kayachikitsa and Panchkarma, R.A. Podar Medical College, Worli, Mumbai, India 2 Medical Advisor, R&D Center, The Himalaya Drug Company, Bangalore, India [*Corresponding author] ABSTRACT ABBREVIATIONS: Despite understanding the BSL : Blood sugar level etiopathogenesis of NIDDM, there is an COX : Cyclo-oxygenase alarming rise in the insulin-resistant CRF : Case report form cases and failure of OHAs. Early CVA : Cerebral vascular accident FBSL : Fasting blood sugar level diagnosis and control of NIDDM is important in order to reduce the risk of IDDM : Insulin-dependent diabetes mellitus : Lipopolysaccharide later complications. Various herbs have LPS NIDDM : Noninsulin-dependent diabetes mellitus been found beneficial in the NO : Nitric oxide management of NIDDM and are gaining OHA : Oral hypoglycemic agent considerable recognition in the PG : Prostaglandin management of NIDDM worldwide. The PPBSL : Postprandial blood sugar level present study was planned to evaluate the clinical efficacy and safety of Diabecon as a monotherapy and also as an adjunct with other OHAs, in the management of NIDDM. This was a prospective, open, non-randomized, phase III clinical trial. A total of 50 patients of either sex, between 30-60 years of age, in whom the diagnosis of NIDDM was confirmed, and who were willing to give informed consent were included in the study. Insulin-dependent diabetes mellitus patients and NIDDM patients with acute complications of diabetes, pregnant and lactating women, patients with concomitant severe illness necessitating other medications, patients with severe hypertension, history of severe unstable angina, myocardial infarction, CVAs, renal failure, and those patients, who were not willing to give informed consent were excluded from the study. All enrolled patients were categorized into 2 groups. The 1st group included 25 freshly diagnosed cases of NIDDM who were not consuming any OHA, while the 2nd group included 25 patients of NIDDM, who were already consuming some OHAs. Patients from the both the groups were advised to consume 2 tablets of Diabecon, twice daily, for 3 months. In all the patients, BSL was assessed at the time of enrollment and thereafter every month, for 3 months. All the patients had to undergo biochemical laboratory investigations. The improvement in the NIDDM symptoms were rated using a predefined symptom score scale ranging from 0-3. The predefined primary efficacy end points were PPBSL control and reduction in the dose of other OHAs. The predefined secondary safety endpoints were reduced incidence of adverse reactions and overall compliance to the drug therapy. All the patients were followed up for 3 months (during the treatment period). All adverse events reported or observed by patients were recorded with information about severity, date of onset, duration and action taken regarding the study drug. Statistical analysis was done according to intention-to-treat principles. This study observed a significant reduction in the FBSL and PPBSL in the newly diagnosed patients of NIDDM and a highly significant reduction in FBSL in those patients who consumed Diabecon along with other OHAs. Similarly, there was significant improvement in general symptoms, in both the groups after treatment with Diabecon, after a month. There were no clinically significant changes in the hematological and biochemical parameters. There were no clinically significant adverse reactions and overall compliance to the treatment was excellent. Therefore, it may be concluded that Diabecon is clinically effective and safe in the management of NIDDM, as a monotherapy in newly diagnosed patients and as an adjunct in patients on conventional OHAs. INTRODUCTION Despite understanding the etiopathogenesis of NIDDM, there is an alarming rise in the insulin-resistant cases and failure of OHAs. The past 2 decades have seen an explosive global increase in the number of people diagnosed as NIDDM. In India, it is estimated that 19.4 million individuals are affected by NIDDM, which is likely to go up to 57.2 million by the year 2025. India leads the world today with the largest number of diabetics in any given country. In the 1970s, the prevalence of diabetes among urban Indians was reported to be 2.1 per cent and this has now risen to 12.1 per cent. Moreover, there is an equally large pool of individuals with impaired glucose tolerance (IGT), many of who will eventually develop NIDDM in the coming future.1 Diabetes can affect almost every physiological system in the body and the chronic hyperglycemia of diabetes is associated with long-term dysfunction, damage and failure of various organs (eyes, kidneys, nerves, heart and blood vessels). Individuals with undiagnosed NIDDM are also at higher risk for cardiovascular disease, coronary artery disease and peripheral vascular disease as compared with non-diabetics. They also have a greater likelihood of having dyslipidemia, hypertension and obesity. Early diagnosis and control of NIDDM is important in order to reduce the risk of later complications, which includes cardiovascular events, visual loss, renal failure and limb amputations.2 Various herbs have been found beneficial in the management of NIDDM and are gaining considerable recognition in the management of NIDDM worldwide.3 The analysis of available data indicates that the use of herbs is increasing during the last several years.4,5 Recently, guidelines for investigation of herbs have been developed and herbal extracts have been clinically studied in detail for their pharmacodynamic and pharmacotherapeutic properties.6 Diabecon is a polyherbal formulation which contains extracts of Balsamodendron mukul, Gymnema sylvestre, Pterocarpus marsupium, Glycyrrhiza glabra, Casearia esculenta, Eugenia jambolana, Asparagus racemosus, Boerhaavia diffusa, Sphaeranthus indicus, Tinospora cordifolia, Swertia chirata, Tribulus terrestris, Phyllanthus amarus, Gmelina arborea, Gossypium herbaceum, Berberis aristate, Aloe vera, Shilajeet and powders of Momordica charantia, Piper nigrum, Ocimum sanctum, Abutilon indicum, Curcuma longa, Rumex maritimus, Vidangadi lauham, Abhraka bhasma, Pravala bhasma, Vanga bhasma, Akika pishtia, Shingraf, Yashada bhasma and Trikatu. The present study was planned to evaluate the clinical efficacy and safety of Diabecon as monotherapy and also as an adjunct with other OHAs in the management of NIDDM. Study aim The present study was planned to evaluate the clinical efficacy and safety (long- and shortterm) of Diabecon as monotherapy and as an adjunct with other OHAs in the management of NIDDM. Study design This was a prospective, open, non-randomized, phase III clinical trial conducted at the out patient department of M.A. Podar Hospital, Mumbai, India. MATERIALS AND METHODS Inclusion criteria A total of 50 patients of either sex, between 30-60 years of age in whom the diagnosis of NIDDM was confirmed, and who were willing to give informed consent were included in the study. The WHO diagnosis criteria (1980) was considered for diagnosis of NIDDM (For newly diagnosed patients: FBSL >120 mg% and after 2 hours of consuming 75 grams of glucose: >180 mg%). Exclusion criteria Insulin-dependent diabetes mellitus patients and NIDDM patients with acute complications of diabetes were excluded form the trial. Pregnant and lactating women, patients with concomitant severe illness necessitating other medications, patients with severe hypertension, history of severe unstable angina, myocardial infarction, CVAs, renal failure, and those patients, who were not willing to give informed consent were also excluded from the study. Study procedure All the enrolled patients were categorized into 2 groups. The 1st group included 25 freshly diagnosed cases of NIDDM who were not consuming any OHA, while the 2nd group included 25 patients of NIDDM who were already consuming some OHAs. Patients from the both groups were advised to consume 2 tablets of Diabecon, twice daily, for 3 months. Patients with mild to moderate NIDDM were advised to consume 2 tablets of Diabecon before breakfast followed by another 2 tablets before lunch, while patients with severe NIDDM were advised to consume an additional 2 tablets before dinner. In all the patients, BSL was done at the time of enrollment and thereafter every month, for 3 months. All patients were investigated for urine (routine and microscopic), hemogram, total leucocyte count, differential leucocyte count, serum creatinine, blood urea, serum albumin, serum globulin and lipid profile. The improvement in the NIDDM symptoms was assessed using a predefined symptom score scale from 0 to 3 (0=absent, 1=mild, 2=moderate and 3=severe). Primary and secondary endpoints The predefined primary efficacy end points were PPBSL control and reduction in the dose of other OHAs. The PPBSL control was graded as: excellent : upto 130 mg%, good : upto 150 mg%, fair : upto 180 mg%, poor : upto 250 mg% and treatment failure : >250 mg%. The predefined secondary safety endpoints were reduced incidence of adverse reactions and overall compliance to the drug therapy. Follow-up and assessment All patients were followed up for 3 months (during the treatment period) and at each followup visit, the patient’s response to the study drug was recorded in a structured CRF. The subjective symptomatic relief and changes in the symptom score scale for each symptom were recorded during each follow-up visit. Adverse events All adverse events reported or observed by patients were recorded with information about the severity, date of onset, duration and action taken regarding the study drug. Relation of adverse events to study medication was predefined as “Unrelated” (a reaction that does not follow a reasonable temporal sequence from the time of administration of the drug), “Possible” (follows a known response pattern to the suspected drug, but could have been produced by the patient’s clinical state or other modes of therapy administered to the patient), and “Probable” (follows a known response pattern to the suspected drug that could not be reasonably explained by the known characteristics of the patient’s clinical state). Patients were allowed to voluntarily withdraw from the study, if they had experienced serious discomfort during the study or sustained serious clinical events requiring specific treatment. For patients withdrawing from the study, efforts were made to ascertain the reason for dropout. Non-compliance (defined as failure to take less than 80% of the medication) was not regarded as treatment failure, and reasons for non-compliance were noted. Statistical analysis Statistical analysis was done according to intention-to-treat principles. The changes in various parameters from baseline values and the values after 1st, 2nd and 3rd month were analyzed by “Paired “t” Test”. The minimum level of significance was fixed at 95% confidence limit and a 2-sided p value of <0.05 was considered as significant. RESULTS There was a significant reduction in the FBSL in the newly diagnosed patients of NIDDM from 170 ± 40.47 mg% to 161.51 ± 52.13 mg%. Similarly, there was a significant reduction in the PPBSL from 247.66 ± 70.65mg% to 223.13 ± 79.22 mg% (Figure 1). In those patients who consumed Diabecon along with OHAs, there was highly significant reduction in FBSL from 174.69 ± 55.77 mg% to 148.66 ± 35.49 mg%, after a month and there was further reduction to 145.40 ± 39.43 mg%, at the end of the study. In eleven (22%) patients the dose of other OHAs was reduced to 50% (Figure 2). There was a significant improvement in the general symptoms of NIDDM (Tables 1 and 2) such as polyuria (Figure 3), generalized weakness (Figure 4) and there was an improvement in the appetite (Figure 5). The study also observed a reduction in leg cramps and burning sensation in hands and soles (Figure 6) in both the groups after a month of treatment with Diabecon. There were no clinically significant changes in the hematological and biochemical parameters. There were no clinically significant adverse reactions, either reported Figure 1: Reduction in blood sugar level in newly diagnosed patients of NIDDM on treatment with Diabecon alone by patients, or observed by the investigators and the overall compliance to the treatment was excellent. DISCUSSION This study observed a significant reduction in the FBSL and PPBSL in the newly diagnosed patients of NIDDM and a highly significant reduction in FBSL and PPBSL also in those patients who consumed Diabecon along with OHAs. Similarly, there was significant improvement in general symptoms, in both the groups after treatment with Diabecon, after a month. These beneficial effects of Diabecon in NIDDM might be due to the synergistic action of its ingredients, which are well documented. Figure 2: Reduction in blood sugar level in patients consuming conventional OHAs on treatment with Diabecon Table 1: Symptomatic improvement in NIDDM patients treated with Diabecon alone Symptom Baseline 1st month 2nd month 3rd month Polyuria Weakness Loss of appetite Burning sensation in hands and soles Mean S.D. SEM t value p value p value summary Mean S.D. S.E.M. t value p value p value summary Mean S.D. S.E.M. t value p value p value summary Mean S.D. S.E.M. t value p value p value summary 1.63 1.25 2.04 1.25 0.40 0.79 1.09 1.06 1.04 0.84 0.13 4.43 <0.001 Highly significant 1.00 0.69 0.11 8.45 <0.001 Highly significant 0.22 0.61 0.10 1.70 >0.1 0.90 0.92 0.18 3.88 <0.001 Highly significant 0.68 0.56 0.15 8.45 <0.001 Highly significant 0.04 0.21 0.15 2.34 <0.05 0.59 0.66 0.19 5.50 <0.001 Highly significant 0.45 0.59 0.19 9.31 <0.001 Highly significant 0.04 0.21 0.15 2.34 <0.05 Not significant Significant Significant 0.95 0.89 0.11 1.21 >0.1 0.81 0.73 0.18 1.5 <0.05 0.68 0.77 0.24 1.67 <0.05 Not significant Significant Significant Table 2: Symptomatic improvement with Diabecon treatment in NIDDM patients consuming conventional OHAs Symptom Baseline 1st month 2nd month 3rd month Mean 1.40 0.81 0.59 0.59 S.D. 1.06 0.66 0.50 0.50 S.E.M. 0.10 0.11 0.11 Polyuria t value 5.35 6.95 6.95 p value <0.001 <0.001 <0.001 p value Highly Highly Highly significant summary significant significant Mean 1.86 1.04 0.5 0.40 S.D. 0.88 0.72 0.59 0.59 S.E.M. 0.13 0.16 0.18 Weakness t value 6.15 8.04 7.97 p value <0.001 <0.001 <0.001 p value Highly Highly Highly significant summary significant significant Mean 0.90 0.54 0.36 0.31 S.D. 1.15 0.73 0.78 0.64 S.E.M. 0.10 0.17 0.16 Loss of t value 3.46 3.19 3.48 appetite p value <0.01 <0.01 <0.01 p value Significant Significant Significant summary Mean 0.86 0.54 0.40 0.31 S.D. 1.08 0.91 0.59 0.47 Burning S.E.M. 0.13 0.12 0.15 sensation in t value 2.30 3.57 3.46 hands and p value <0.005 <0.01 <0.01 soles p value Significant Significant Significant summary Curcuminoids from Curcuma longa have an ameliorating influence on diabetic nephropathy, possibly by their ability to lower blood cholesterol levels. Analysis of documented data on enzymuria, albuminuria, activity on renal ATPases and fatty acid composition of renal membranes in diabetic condition indicate that curcuminoids significantly arrest the progression of diabetic nephropathy.7 Figure 3: Improvement in the symptom score of polyuria in the NIDDM patients with Diabecon treatment The active ingredients of Gymnema sylvestre are the gymnemic acids and Gymnema sylvestre has been studied extensively for its beneficial action in diabetes mellitus.8 Gymnema sylvestre appears to correct the metabolic derangements in diabetic liver, kidney and muscle and reverses the hepatic pathological changes during the hyperglycemic phase by controlling hyperglycemia. Results from studies show that extracts of Gymnema sylvestre exert a stimulatory effect on insulin release by increasing the cellular permeability. In one study, the extract of Gymnema sylvestre was found to suppress the elevation of blood glucose level by inhibiting glucose absorption in the 9 intestine. Some studies have also shown that Gymnema sylvestre helps in the regeneration or revitalization of residual beta cells in NIDDM and IDDM patients, resulting in enhancement of 10-12 endogenous insulin, which is supported by the raised insulin levels in the Figure 4: Improvement in the symptom score of weakness in the NIDDM patients with Diabecon treatment serum after Gymnema sylvestre supplementation. In one experimental study, the administration of Gymnema sylvestre regulated the BSL in alloxan diabetic rabbits. It has also been documented that Gymnema sylvestre not only produces blood glucose homeostasis but also increases the activity of enzymes, affording better utilization of glucose by insulin dependent pathways (it controls the levels of Figure 5: Improvement in the symptom score of loss of appetite in the phosphorylase, NIDDM patients with Diabecon treatment gluconeogenic enzymes and sorbitol dehydrogenase). It was also observed that Gymnema sylvestre increases the uptake and incorporation of glucose into glycogen and proteins (hepatic, renal and muscular).13 The active ingredient of Pterocarpus marsupium is epicatechin and several studies have documented the antihyperglycemic activity of Pterocarpus marsupium.14,15 In one study, which assessed the effect of administration of Pterocarpus marsupium on the glycogen content, there was a decrease in BSL by 38% and 60% on 15th and 30th day and there was decrease in the hepatic and renal weight. Similarly, the renal glycogen content increased by 10-fold, while the hepatic and skeletal muscle glycogen content decreased by 75% and 68%. Pterocarpus marsupium also renormalized the activities of hexokinase, glucokinase and phosphofructokinase.16 Pterocarpus marsupium also has been shown to exhibit alphaglucosidase inhibitory activity comparable to that of metformin.17,18 Epicatechin increases the cAMP content of the islets, which is associated with the increased insulin release, conversion of proinsulin to insulin and cathepsin B activity.19 In one study, the administration of Eugenia jambolana significantly decreased the levels of blood glucose, blood urea, and cholesterol, with increased glucose tolerance and the levels of total proteins and liver glycogen. It also decreased the activities of glutamate oxaloacetate transaminase and glutamate pyruvate transaminase and the Figure 6: Improvement in the symptom score of burning soles in the hypoglycemic efficacy NIDDM patients with Diabecon treatment was comparable to glibenclamide.20 Amelioration of experimental diabetic neuropathy and gastropathy following oral administration of Eugenia jambolana has also been documented.21 In another study, administration of Eugenia jambolana resulted in the enhancement in serum insulin levels in normoglycemic and diabetic rats and the incubation of isolated islets of langerhans with Eugenia jambolana was found to stimulate insulin secretion in normal and diabetic animals, accompanied by the inhibition of hepatic and renal insulinase activity.22 In one study, the effects of daily oral administration of Boerhaavia diffusa was investigated; and a significant decrease in blood glucose with significant increase in plasma insulin levels were observed in normal and diabetic rats. Treatment with Boerhaavia diffusa resulted in a significant reduction of glycosylated hemoglobin and an increase in the total hemoglobin level. Boerhaavia diffusa has been shown to exert influence on the activities of the hepatic enzymes (hexokinase, glucose-6-phosphatase and fructose-1, 6-bisphosphatase); as hexokinase activity is significantly increased and activities of glucose-6-phosphatase, fructose-1, 6-bisphosphatase are significantly decreased in diabetic rats. Boerhaavia diffusa also improved the oral glucose tolerance test and the effect was more prominent when compared to glibenclamide.23 Significant inhibition of gluconeogenesis by Tribulus terrestris, along with the reduction in the levels of plasma triglycerides have been documented.24,25 The antihyperglycemic activity of the extracts of Aloe vera have been extensively documented and the hypoglycemic effect of Aloe vera might be mediated through the stimulation of synthesis and/or release of insulin from the beta cells of langerhans.26,27 Piperine, the active alkaloid of Piper nigrum has been evaluated for its glucose regulatory efficacy and daily oral administration for 15 days lowered blood glucose concentrations and hepatic glucose-6-phospatase enzyme activity.28 Various studies have elucidated the antihyperglycemic potential of Ocimum sanctum. Ocimum sanctum renormalizes the glycogen content in various tissues and in a study, administration of Ocimum sanctum was found to bring about a significant reduction in FBSL, uronic acid, total amino acids, total cholesterol, triglycerides, phospholipids and total lipids. There was also a significant reduction in the hepatic total cholesterol, triglycerides and total lipids and a similar significant reduction in the renal total lipids. There was a significant reduction in the total cholesterol content in cardiac tissue and of phospholipids.29-31 Oxidative stress has a critical role to play in the initiation of hyperglycemia; and it is also responsible for tissue damage and vascular endothelial dysfunction, leading to the diabetic complications. Many of the herbs used in Diabecon act as powerful antioxidants. The antioxidant activity of Glycyrrhiza glabra, Eugenia jambolana, Curcuma longa, Casearia esculenta, Asparagus racemosus, Tinospora cordifolia, Boerhaavia aristata, Phyllanthus amarus, Swertia chirata, Aloe vera and Curcuma longa has a contributory role in the antihyperglycemic activity of Diabecon.32-35 As observed in various studies, Diabecon helps in improving the glycogen stores in the liver and prevents the oxidative damage of beta cells by increasing the islet cell superoxide dismutase activity. Diabecon stimulates insulin secretion by stimulating cell membrane permeability, and also helps in the regeneration and revitalization of islet cells. Diabecon also enhances the peripheral utilization of glucose. By exerting effective control over hyperglycemia, Diabecon thus prevents complications due to uncontrolled hyperglycemia. In one study, Diabecon attenuated the progression of diabetic nephropathy and also improved diabetic retinopathy.36 In another study, Diabecon resolved retinal and vitreal hemorrhages, with subsequent prevention of the same and also enhanced the absorption of hard and soft exudates by its anti-inflammatory properties. In a clinical study, Diabecon caused the retardation of microaneurysmal and proliferative changes in the retina.37 CONCLUSION Despite understanding the etiopathogenesis of NIDDM, there is an alarming rise in the insulin resistant cases and failure of OHAs. Early diagnosis and control of NIDDM is important in order to reduce the risk of later complications. Various herbs have been found beneficial in the management of NIDDM and are gaining considerable recognition in the management of NIDDM worldwide. The present study was planned to evaluate the clinical efficacy and safety of Diabecon as a monotherapy and also as an adjunct with other OHAs in the management of NIDDM. This study observed significant reduction in the FBSL and PPBSL in the newly diagnosed patients of NIDDM and a highly significant reduction FBSL in those patients who consumed Diabecon along with OHAs. Similarly, there was a significant improvement in general symptoms in both the groups, after treatment with Diabecon, after a month. There were also no clinically significant changes in the hematological and biochemical parameters. There were no clinically significant adverse reactions, either reported by patients, or observed by the investigators and the overall compliance to the treatment was excellent. Diabecon helps in improving the hepatic glycogen stores and prevents the oxidative damage of beta cells by increasing the islet cell superoxide dismutase activity. Diabecon stimulates insulin secretion and also helps in the regeneration and revitalization of islet cells. Diabecon also enhances the peripheral utilization of glucose. 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