Plantabetics Dietary supplement for dietetic treatment of diabetes mellitus type 2

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1 Plantabetics Dietary supplement for dietetic treatment of diabetes mellitus type 2 Clinical study on efficacy and safety of Plantabetics according to GCP guidelines Protokoll ID : Trial register number: PMS/110519/PB/DM CTRI/2011/11/ [Registered on: 25/11/2011] - Trial Registered Prospectively An exploratory study on efficacy and safety of Plantabetics on diabetic type 2 patients in highly advanced stage. Objective: The objective of this study was to determine the efficacy and safety of Plantabetics, a herbal formulation for dietetic treatment of diabetes mellitus type 2. It contains extracts of grape seed, Indian gooseberry, turmeric and fenugreek seeds. The patients were in advanced stage and were on treatment with a combination of metformin and sulfonylurea. Introduction Theoretical background Oral hypoglycemic agents (OHAs) are prescribed to achieve glycaemic control in diabetes Typ 2 patients. Two of the widely used OHAs are metformin and sulfonylureas, the former increases insulin sensitivity and the later increase insulin secretion from beta cells. Patients recruited in this study were receiving a combination of both since they were in advanced stage and one component alone was not effective. The main goal of the oral hypoglycemic agents is to reduce high blood sugar level. Maintaining a normal blood sugar level is the primary objective of diabetes treatment. However, blood sugar lowering agents fail to maintain normal blood sugar level of diabetes type 2 patients in long run. As the disease progresses, it becomes increasingly difficult to achieve the targeted glycaemic control with OHAs alone, and at advanced stage insulin injection becomes necessary. Diabetes type 2 is a multiple metabolic disorder, including disorder of sugar and fat metabolisms, disorder in endogenous enzyme production and disorder of endocrine function. In current therapeutic approach for diabetes type 2 only sugar metabolism disorder is treated with OHAs but others disorders are not taken care of. Hence, modern therapy of diabetes type 2 is unable to control the progress of diabetes permanently.

2 We postulate, that high oxidative stress mediated ß-cell necrosis is likely to be the most important reason for uncontrolled diabetes. Further, immune mediated ß-cell destruction is the principal cause of Diabetes type 1 and it may also play a role in etiology of diabetes type 2. Role of Plantabetics in Diabetes Control Plantabetics contains 110 mg fenugreek (Trigonella foenum-graecum) extract, 90 mg Indian gooseberry (Emblica officinalis) extract, 80 mg turmeric (Curcuma longa) extract and 80 mg grape seed (Vitis vinifera) extract (total 360 mg extracts) filled in cellulose capsule. The ingredients of Plantabetics are selected on the basis of following pharmacological properties: Tannins of Indian gooseberry and proanthocyanidins of grape seeds have been reported to induce endogenous antioxidant production and improve antioxidant status in rat's heart and pancreas. These chemical constituents might have a similar effect on pancreatic islets of human. The enzyme induction can possibly increase the level of endogenous anti-oxidant enzymes in pancreas thereby reducing oxidative stress so that reduction of ß cell mass due to free radical attack can be diminished. As mentioned before, reduction of ß cell mass and resulting insulin deficiency is one of the main reasons of progressive deterioration of diabetic condition. Polyphenols of turmeric have antioxidant as well as anti-inflammatory properties, which may be helpful in reducing the inflammation in pancreas caused by ß cell death. This may in turn facilitate the generation of new ß cells. Fenugreek contains immune regulatory polysaccharides. Immune imbalance may also be a cause of ß cell death in diabetes type 2, as it is in the case of diabetes type 1. Together the above four ingredients of Plantabetics may possibly offer a complete therapy for diabetes type 2. In patients who are in advanced stage of diabetes, beta cell destruction might have progressed to large extent and insulin production might have reached to a very low level. In those patients Plantabetics might help to generate new beta cells and finally contribute to maintain a stable normal blood sugar level. When administrated together with hypoglycemic drugs, Plantabetics may offer gradual reduction of symptoms offering full treatment for the multiple etiologies of type 2 Diabetes. Research design and method A exploratory clinical study under GCP compliance was designed to test the effect of plantabetics. Plantabetics does not contain any blood sugar lowering plant extract like Gymnema sylvestre, Eugenia jambolana or bitter melon. Hence it was anticipated, that if Plantabetics is able to improve blood sugar level in type 2 diabetic patients, who were in highly advanced stage, then this improvement in blood sugar level must be due to the actions of the Plantabetics ingredients described in points 1-3. The efficacy and safety of this product

3 has been demonstrated by a pilot clinical study according to GCP guidelines. The study was conducted in India (Mumbai) and the trial was registered in national trial register according to WHO instruction. An independent ethics committee approved the study. Diabetes Patients aged between years in highly advance stage were recruited. The patients included in the study were required to have fasting blood glucose value between 140 and 200 mg/dl, HbA1c value between 7.5 % and 12 % and were not using any herbal product except the investigational product. They were under treatment with metformin and sulphonyl urea combination since at least last 6 months before participation in the study without improvement in fasting blood sugar level or HbA1C value since last 3 months. Patients were instructed to take one Plantabetics capsule twice daily, together with their prescribed antidiabetic medicines. They were asked not to change their normal eating habit and life style throughout the study period. Duration of the study was 84 days. The primary efficacy endpoints were HbA1C value and fasting blood glucose. Secondary efficacy endpoints were postprandial blood sugar (PPBS), plasma triglyceride, HDL and LDL values. Efficacy and safety variables were measured every 21 days interval except HbA1C and PPBS which were measured on 0 (starting point), 42 and 84 days. Blood analysis was conducted in certified clinical laboratory in Mumbai. Result In total 40 patients were recruited and 35 completed the study. Out of them 23 patients (65.71%) showed marked improvement in all efficacy parameters whereas 12 (34.29%) did not show any improvement. This was expected, because the study population was in advance stage of diabetes, not responding to the current therapy. Table 1 Analysis of mean change in efficacy parameters in subgroups from Baseline to end of treatment done by paired t-test (N=35) Responders (n=23) Non responders (n=12) Parameters Baseline EoT p Baseline EoT P HbA1c (%) 8.76 (0.82) 7.50 (0.94) p< (1.27) (1.80) 0.04 FBS (mg/dl) (28.19) (35.58) p< (42.84) (48.63) 0.62 PPBS (mg/dl) (54.63) (74.43) p< (91.34) (70.40) 0.83 HDL (mg/dl) (12.01) (9.93) (13.52) (17.74) 0.67 LDL (mg/dl) (42.20) (32.20) (39.83) (32.58) 0.39

4 Serum cholesterol (mg/dl) (50.35) (36.86) (48.07) (52.50) 0.52 Serum Triglycerides (mg/dl) (92.15) (77.37) (108.89) (47.94) 0.84 BMI (kg/m 2 ) (4.91) (4.67) (2.55) (2.24) 0.80 Abbreviation: EoT: End of treatment; FBS: Fasting blood sugar; HbA1c: Glycosylated hemoglobin; HDL: High density lipoprotein; LDL: Low density lipoprotein; PPBS: Post prandial blood sugar; SD: Standard deviation. Average changes in primary Efficacy parameters are presented in Table 2 and in fig 1-3. Table 2: Average values of primary efficacy parameters Efficacy parameter Day 0 Day 42 Day 84 HbA1c (%) FBS (mg/dl) PPBS (mg/dl) Figure 1: Change in average HbA1C value in 12 weeks (responder group) Figure 2: Change in average fasting blood sugar value in responder group in 12 weeks (responder subgroup)

5 Responders Figure Mean change in PPBS from Baseline to end of treatment (Responder subgroup) 262, ,1 188 Responders 0 PPBS_0 PPBS_42 PPBS_84 Discussion Average fasting blood sugar value in responder group came down from 160 mg/dl to 119 mg/dl in 3 months. Similarly, average value of HbA1C was reduced from 8.76% to 7.5% in the above-mentioned period. Above improvements in efficacy values are considered to be highly significant, as evident by statistically significant p value (<0,001). Zänker et.al published a study on the treatment of diabetes type 2 patients with Momordica charantia extract for 6 months [1]. Daily dose of Momordica charantia extract in this study was 2 kapsules each of 500 mg, taken along with on-going therapy. Momordica charantia is a natural blood sugar lowering agent. Above study reported a reduction of average fasting blood sugar level from 162 mg/dl to 119 mg/dl, whereas HbA1C average value was reduced from 6.8 to 6.3% and relative reduction in HbA1C was reported to be (6.8% 6.3% =) 0.5 %. Plantabetics does not contain any blood sugar lowring agent, yet it could reduce HbA1C from 8.76 % to 7.5%. A 1.2% relative reduction of HbA1C in 3 months, which considered to be highly significant. This reduction in HbA1C can probably attributed to the induction of

6 endogen antioxidant enzymes by constituents of Plantabetics leading to regeneration of new beta cells and thereby production of more active insulin. The FBS values in some patients came down below 90 mg/dl (see figure 1), so that they needed reduction in anti-diabetic medicines in order to avoid hypoglycemic episode. One patient actually suffered from hypoglycemia and consulted the investigating physician, who reduced the dose of sulphonylurea to stabilize the condition Fig. 1: Patients with blood sugar level less than 90 mg/dl at the end of study Fasting blood sugar (FBS) in mg/dl Duration of treatment in days i Non-responders Patients were instructed to take IP along with anti-diabetic medicines, hence a possible drug interaction of metformin with herbal constituents cannot be ruled out. Natural constituents like flavonoids and tannins are known to reduce bioavailability of metformin. The nonresponder group was on a dose of sulphonylurea medication that probably could marginally release some insulin in the blood, may be because limited numbers of beta cells were available. An abrupt ceasing of medication (metformin) due to drug interaction caused worsening of the condition and increase in the values of diabetes parameters. This can be the reason of not responding to the treatment by certain individuals. The responder group on the other hand was on a does of sulphonyl urea that probably could release a good amount of Insulin in the blood. Drug interaction might have affected the diabetes parameter values but only temporarily not to worsen the diabetes parameter values. Bioavailability of a metformin given under fasting conditions is approximately 40 to 60% (Metformin information leaflet). Plasma concentration of metformin reaches a maximum in 2.26±0.72 h after intake. Hence, a time gap of at least 2 hours should be maintained between Plantabetics and any other medicine including OHAs to avoid drug interaction.

7 Safety of Plantabetics There was only one drug related adverse event in responder group where the test person felt uneasiness after taking his dose of Plantabetics near the end of study. The person was admitted to the hospital according to GCP rule for check-up. The cause of uneasiness was found to be hypoglycemia (low blood sugar value). The dose of diabetes medicine was reduced by the attending medical in-charge and the symptoms were abolished. Conclusion Type 2 Diabetes needs multiple therapeutic approaches to cope with multiple disorders. Modern medicine treats only one aspect, control of blood sugar level. The innovative product Plantabetics is a complementary treatment for disorders not addressed by current therapy and helps to achieve a successful and durable control of diabetes type 2. A statistically significant reduction was observed in HbA1c (p=0.04) and a notable reduction was observed in FBS, PPBS and serum triglyceride from Baseline to End of study in total study population. In the subgroup analysis, Plantabetics showed a significant efficacy in responder group. Number of responders was almost twice to number of non-responders (23 vs. 12 respectively). In the responder subgroup, there was a statistically significant reduction from Baseline to end of treatment in HbA1c, FBS and PPBS with p< Plantabetics was very good tolerated by all study participants. The only adverse effect noted was under sugar symptoms, when reduction of diabetes medicine dose was necessary. Thus, it was in fact an indication for improvement in diabetic condition. 1) Zänker KS, Gottschalk G, Hans S., Sicherheits- und Wirksamkeitsstudie mit einem Extrakt aus Momordica charantia bei Patienten mit Typ-2-Diabetes, Z. Phytother 2003; 24: