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Table of Contents
BASIC RESEARCH
Year : 2018  |  Volume : 8  |  Issue : 9  |  Page : 446-455

Add-on therapy of herbal formulation rich in standardized fenugreek seed extract in type 2 diabetes mellitus patients with insulin therapy: An efficacy and safety study


1 Department of Scientific Affairs, Indus Biotech Private Limited, 1, Rahul Residency, Off Salunke Vihar Road, Kondhwa, Pune - 411048, India
2 Ruby Hall Clinic, 40, Sassoon Road, Pune 411001, India
3 Tulip, Opp. Camp Education Society's High School, Camp, Pune-411001, India

Date of Submission02-Jul-2018
Date of Decision01-Aug-2018
Date of Acceptance05-Sep-2018
Date of Web Publication27-Sep-2018

Correspondence Address:
Amit Kandhare
Department of Scientific Affairs, Indus Biotech Private Limited, Rahul Residency, Off Salunke Vihar Road, Kondhwa, Pune - 411 048, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2221-1691.242288

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  Abstract 

Objective: To assess the safety and efficacy of herbal formulation rich in standardized fenugreek seed extract (IND-2) add-on therapy in type 2 diabetes mellitus (T2DM) patients who were on insulin treatment in prospective, single arm, open-label, uncontrolled, multicentre trial. Methods: T2DM patients (n=30) with aged 18-80 years who were stabilized on insulin treatment with fasting blood sugar (FBS) level between 100-140 mg/dL received IND-2 capsules (700 mg, thrice a day) for 16 weeks. The primary endpoints were an assessment of FBS at week 2, 4, 6, 8, 12 and 16. Secondary end-points include post-prandial blood sugar level, glycosylated Hb (HbA1c), reduction in the dose of insulin and number of hypoglycemic attacks, and improvement in lipid profile at various weeks. Safety and adverse events (AEs) were also assessed during the study. Results: Study was completed in twenty T2DM patients, and there was no significant reduction in FBS and post-prandial blood sugar level after addon therapy of IND-2. However, add-on therapy of IND-2 significantly reduced (P<0.01) the HbA1c values, requirements of insulin and hypoglycemic events as compared with baseline. Total cholesterol, high-density lipoproteins-cholesterol, and low-density lipoprotein-cholesterol levels were significantly increased (P<0.01) after IND-2 add-on therapy. Body weight and safety outcomes did not differ significantly in IND-2 add-on therapy group at week 16. Additionally, add-on therapy of IND-2 did not produce any serious adverse events. Conclusions: The results of present investigation suggest that add-on therapy of IND-2 with insulin in T2DM patients improves glycaemic control through a decrease in levels of HbA1c and number of insulin doses needed per day without an increase in body weight and risk of hypoglycemia. Thus, IND-2 may provide a safe and well-tolerated add-on therapy option for the management of T2DM.

Keywords: Add-on therapy, Dietary supplement, Glycaemic control, HbA1c, Standardized fenugreek seed extract, Type 2 diabetes


How to cite this article:
Kandhare A, Phadke U, Mane A, Thakurdesai P, Bhaskaran S. Add-on therapy of herbal formulation rich in standardized fenugreek seed extract in type 2 diabetes mellitus patients with insulin therapy: An efficacy and safety study. Asian Pac J Trop Biomed 2018;8:446-55

How to cite this URL:
Kandhare A, Phadke U, Mane A, Thakurdesai P, Bhaskaran S. Add-on therapy of herbal formulation rich in standardized fenugreek seed extract in type 2 diabetes mellitus patients with insulin therapy: An efficacy and safety study. Asian Pac J Trop Biomed [serial online] 2018 [cited 2018 Dec 13];8:446-55. Available from: http://www.apjtb.org/text.asp?2018/8/9/446/242288

Foundation project: This work was funded by Indus Biotech Pvt. Ltd., Pune.



  1. Introduction Top


Type 2 diabetes mellitus (T2DM) is a complex, chronic progressive disease which is most common amongst the various forms of diabetes. It is manifested by hyperglycemia, disturbance in the metabolism of carbohydrate, fat, and protein which could be the result from deficiency secretion of insulin or its actions[1]. It is a long-term metabolic disorder which is associated with multiple comorbidities as well as microvascular and macrovascular complications such as retinopathy, nephropathy, neuropathy, cardiomyopathy[2],[3]. Numerous epidemiological studies have suggested that obesity, insulin resistance, hyperlipidemia, hypertension, and smoking are the risk factors associated with T2DM[4],[5]. The prevalence of T2DM is fast-growing worldwide and now become a major public health problem. The projected prevalence of T2DM is predicted to affect more than 350 million people by 2025 worldwide[6],[7]. It also produces significant economic burdens, and in a developing country like India, the cost of illness for diabetic care is estimated at USD 336[8].

Due to a progressive increase in the costs of treatment, the intensive lifestyle modifications have been suggested as a treatment alternative to decrease the risk for diabetes development[9],[10]. However, it is difficult to achieve a targeted glycaemic control with lifestyle modification alone. Hence, a strategic escalation of antidiabetic therapy has suggested by the American Diabetes Association and European Association for the Study of Diabetes[1]. Thus, metformin has been recommended by the American Diabetes Association and European Association for the Study of Diabetes as first-line therapy in combination with lifestyle modifications for patients with T2DM[1]. However, metformin may not be able to effectively control glycaemic goals in the patients with higher baseline glycated hemoglobin (HbA1c) levels. Thus, in such patient management of diabetes needs multiple pharmacological treatments[1],[11].

Dipeptidyl-peptidase-4 inhibitors and sulfonylureas are another optional pharmacological therapies now available[5],[12],[13] that increases insulin secretion by acting on pancreatic β -cells[14]. However, these treatment regimens are associated with decreased β -cell function along with concern for weight management. Thus, adequate control of glycemia is difficult over a long period[15]. Thiazolidinediones (such as pioglitazone, rosiglitazone) is another class of oral antihyperglycemic agents that act by regulating glucose and lipid metabolism via modulation of peroxisome proliferator-activated receptor γ[16]. However, clinical evidence showed the association of use of these agents with myocardial events risk and nephrotoxicity[17].

It has been suggested that the failure in the maintenance of the targeted level of glycated hemoglobin (HbA1c) is a major cause for the worsening nature of T2DM[18],[19]. Thus, the advanced therapy of insulin has been recommended for improvement in glycaemic control[1],[20],[21]. It has been showed that initiation of the insulin therapy in the patients with metformin-alone helps to achieve the glycaemic control with HbA1c reduction[22]. However, additional risk such as weight gained and hypoglycemia need to be considered while management of T2DM using insulin[23]. Furthermore, cost of insulin, unavailability of insulin by the oral route, medication compliance and insulin resistance are the major obstacles in insulin therapy for the management of T2DM. The add-on therapy with insulin may provide sustained glycaemic control along as well as a decrease in the frequency of use of insulin[24],[25]. Therefore, interest in add-on therapies to insulin is increasing amongst diabetic patients.

Herbal medicine can be considered as an efficacious and safe treatment alternative for the fulfillment of the unmet medical need as an “add-on therapy” along with insulin in the long-term management of T2DM[26],[27],[28]. A wide range of phytoconstituents isolated from herbal origin can act by multiple mechanisms including stimulation of insulin production, increase on insulin sensitivity, reduction in HbA1c, modulation of insulin action, reduction of carbohydrate absorption amongst others[28]. The traditional Indian and Chinese medicines have documented an array of such medications for the T2DM treatment with proven clinical safety and efficacy[29]. Camellia sinences, Emblica officinalis, Gymnema sylvestre, Linum usitatissimum, Salacia reticulata, Tribulus terrestris, etc. are few amongst them which showed clinical efficacy and safety in the management of T2DM[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40].

Trigonella foenum–graecum Linn. (Fabaceae) (fenugreek) has ancient traditional uses in the treatment of diabetes. Fenugreek possesses a broad spectrum of pharmacological and therapeutic properties including anti-hyperlipidemic, antidiabetic, anticancer, anti-arthritic, antioxidant, antimicrobial, antinociceptive and anti-inflammatory potential[41],[42],[43],[44],[45],[46],[47]. Fenugreek plays a vital role in the prevention of heart, liver, kidney and spleen diseases[48],[49],[50],[51],[52],[53]. Several investigators have reported the hypocholesterolemic and anti-diabetic potential of defatted fenugreek seed[43],[54]. Studies carried out by various researchers have reported the anti-diabetic potential of fenugreek in an array of animal models[41],[42],[55] as well as in human subjects[43],[54]. These effects are related to the presence of constituents such as alkaloid (Trigonelline) and amino acid (2S,3R,4S, 4-hydroxyisoleucine (4-HI))[56],[57],[58],[59]. In this view, the herbal formulation (IND-2) has been developed which is rich in standardized fenugreek seed extract. Previously, the researcher also showed the beneficial effect of herbal formulation rich in standardized fenugreek seed extract in the management of T2DM patients inadequately controlled with a sulphonylurea[60]. However, to our knowledge, add-on therapy of herbal formulation rich in standardized fenugreek seed extract (IND-2) for its the efficacy and safety have not been evaluated in a patient with T2DM who were stabilized on insulin treatment. Hence, present investigation aimed to assess the safety and efficacy of IND-2 add-on therapy in T2DM patients on insulin treatment in prospective, single arm, open-label, uncontrolled, multicentre study.


  2. Materials and methods Top


2.1. Study design and protocol

The study was designed as a prospective, open-label, single arm, uncontrolled, multicentre study to assess the safety and efficacy of herbal formulation rich in standardized fenugreek seed extract (IND-2) [Table 1] 700 mg, thrice a day as add-on therapy in T2DM patients who were stabilized on insulin treatment. All patients received 3 capsules of IND-2 per day, one in the morning (preferably at 7 am), one in the afternoon (preferably at 3 pm), and one at night (preferably at 11 pm). The capsules were administered one hour before of taking the food or two hours after taking the food. The dose of IND-2 was to be adjusted only when the blood sugar level < 80 mg/dL or 20% less than the previous value. Patients who complained about hypoglycemic attacks were discontinued from the study.
Table 1: Composition of IND-2.

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The study comprised a screening and enrolment period namely week (-2) (visits 1) and week 0 i.e. baseline (visit 2), during which patients continued background medication consisting of a stable dose of insulin, and a treatment period, during which patients received 700 mg thrice a day as add-on therapy of IND-2 added to background medication for 16 weeks. Total eight study visits occurred viz., week 2 (visits 3), week 4 (visit 4), week 6 (visit 5), week 8 (visit 6), week 12 (visit 7) and week 16 (visit 8, i.e., treatment end) [Figure 1].
Figure 1: Study design.
E: Enrolment; EOT: End of treatment; IOT: Initiation of treatment; V: Visit.


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2.2. Inclusion and exclusion

Eligible patients were: (1) male or female subject aged 18-80 years, (2) T2DM (Non-insulin dependent) patients who were stabilized on insulin treatment, (3) fasting blood sugar (FBS) level between 100 mg/dL and 140 mg/dL including both (100 mg/dL and 140 mg/dL), (4) difference between two blood sugar level readings (Visit 1 and Visit 2) should not be more than 30 mg/dL, (5) written informed consent from the subject, (6) stabilized at the same dose of insulin for a minimum period of 8 weeks, (7) no participation in any other clinical studies during last 60 days.

Exclusion criteria were subjects with conditions such as (1) severe renal insufficiency defined by a creatinine value above 1.5 mg/dL, (2) severe hepatic insufficiency defined by an SGOT (serum glutamic oxaloacetic transaminase) or SGPT (serum glutamic pyruvic transaminase) value equal or higher than the threefold normal values of the respective laboratory safety value, (3) pregnant, willing to get pregnant or nursing women, (4) participation in a clinical trial during the 60 days before the present trial, (5) simultaneous participation in another clinical trial, (6) cardiovascular disorder.

2.3. Withdrawal criteria

The participation in a clinical trial by the subjects may be terminated at any time under the following conditions:

  • At the discretion of the investigator: subjects can be withdrawn on the discretion of the investigator at any time during the trial if the possibility of any impairment of the subjects’ health cannot be excluded.
  • At the subject’s request: the subject can withdraw himself from the trial without any reason.
  • If an adverse event (AE) occurs: if a subject is withdrawn due to an AE, this should be followed up until it has resulted in a stabilized medical condition (recovered, recovered with residual damage, death).
  • Patients who did not get performed their laboratory testing within 7 days from the end of treatment visit
  • If patients failed to come within 7 days of the scheduled follow-up visit
  • If patients become pregnant during the study
  • If the major protocol violation occurred by the patients: like missing two consecutive visits, not taking medication for 1 week, etc.


2.4. Compliance with ethics

All patients provided written and informed consent. The study protocol was approved by the institutional review board of each center (The protocol No. IBHM02/2002). The study was conducted in compliance with the Declaration of Helsinki and the International Conference on Harmonization Guideline for Good Clinical Practice guidelines as defined by the International Conference on Harmonization.

2.5. Compliance with treatment

Patients were encouraged not to skip scheduled medication intake or reduce dosages on their own. Lapses observed during visits were documented on the appropriate page of the Case Report Form. Investigators evaluated treatment compliance by measuring unused medication in the subject medication box. If more than 20% of the total prescribed medication was not consumed by the patient during every 2 weeks, the patient was termed as noncompliant and was excluded from the trial.

2.6. Study endpoints

The effect of IND-2 (700 mg, thrice a day) on FBS compared with baseline (week 0) was the primary efficacy endpoint. Whereas, the effects of IND-2 on post-prandial blood sugar level (PPBS) and glycosylated Hb (HbA1c), to check the feasibility of reduction in the dose of insulin and number of hypoglycemic attacks after addition of IND-2 and to assess improvement in lipid profile [i.e., triglycerides, high-density lipoproteins-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), total cholesterol (TC), and LDL-C to HDL-C ratio] as compared with the baseline were the secondary efficacy endpoints. Assessment of FBS, PPBS, HbA1c, insulin dose and hypoglycemic attacks were done on all visits (Week 0, 2, 4, 6, 8, 12 and 16). The lipid profile was assessed on alternate visits (Week 0, 8 and 16).

2.7. Safety parameters

The following safety parameters were investigated to assess the safety of IND-2:

  • The clinical safely was evaluated on all visits by vital signs, ECG recordings, and any AEs which may be spontaneously reported and observed directly.
  • The following vital signs were considered for a measure of clinical safety variable:
  • The temperature of the body ( ° F)
  • Respiratory rate (breath/minute)
  • Systolic blood pressure (mmHg)
  • Diastolic blood pressure (mmHg)
  • Heart rate (beats/minute)


The laboratory safety was evaluated by determining the following parameters at the initiation of treatment (week 0), and after 8 and 16 weeks: Haemoglobin (Hb), white blood cell (WBC): total and differential count, red blood cell (RBC) count, platelet count, mean corpuscular volume (MCV), mean corpuscular haemoglobin concentration (MCHC), erythrocyte sedimentation rate (ESR), total bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase(ALT), lactic dehydrogenase (LDH), serum proteins, urinalysis, blood urea nitrogen (BUN) and creatinine.

2.8. Blood sampling and measurements

Blood samples were collected after fasting condition of at least 10 h. Then samples of blood were processed and analyzed in one central laboratory. Samples were handled according to laboratory routines, and the laboratory variables were analyzed according to routine assay techniques at the laboratory.

2.9. Statistical analysis

A total of 30 participants were recruited with an assumption of a 20 percent dropout rate. Being a pilot study, no statistical method was applied to decide the sample size. Results are represented as mean ± standard deviation (SD). Mean values of various diabetic markers (FBS and PPBS levels, number of hypoglycemic attacks since the last visit, amount of insulin required) and HbA1c at each visit were compared with baseline. The secondary efficacy parameters, i.e., various lipid markers (TC, LDL-C, HDL-C, triglycerides, the ratio of LDL-C and HDL-C), AEs (haematology and biochemistry) and vital parameters at V6 as well as at V8 were compared with baseline and analyzed using a paired t-test. The P<0.05 was considered statistically significant. The SPSS version 16.0 software used for statistical analysis.


  3. Results Top


3.1. Patient recruitment, demographics and baseline characteristics

Total 60 subjects were screened, and 30 (male = 16 and female 14) were recruited in the trial. Ten subjects were withdrawn from the trial at various stages. The lost of follow-up [4/10 (40%)], and AE [4/10 (40%)] were the most common reasons for treatment discontinuation. Two subjects discontinued due to lack of compliance and inclusion violation. Thus, 20 subjects were considered for the study and received treatment with IND-2 add-on therapy. [Figure 2] depicted the patient recruitment and selection process.
Figure 2: Patient disposition.

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The demographics and baseline characteristics of the subjects were represented in [Table 2]. At the baseline of the study, mean age was 52 years, HbA1c was 6.19%, BMI was 27.31 kg/m2, FBS levels was 121.71 mg/dL, and PPBS levels was 193.560 mg/dL.
Table 2: Demographic data (n = 20).

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3.2. Treatment compliance

After each visit, the unused capsules were counted from which the treatment compliance was determined on a study population of 20. If more than 20% of the total prescribed medication was not consumed by the patient during every 2 weeks, the patient was termed as noncompliant and was excluded from the trial. The mean treatment compliance was > 98%, which was deemed acceptable.

3.3. Effects of IND-2 add-on therapy on glucose regulation

There was no statistically significant reduction in FBS and PPBS level at week 2, 4, 6, 8, 12 and 16 after add-on therapy of IND-2 when compared with baseline (week 0) [Figure 3]. However, addon therapy of IND-2 with insulin showed a significant decrease (P<0.01) in HbA1c at week 8 compared with the baseline [Figure 4]A. Additionally, requirements of insulin (in terms of units consumed per day) at week 2, 6, 8, 12 and 16 were also significantly less (P<0.001, P<0.01, P<0.01, P<0.01 and P<0.01, respectively) after add-on therapy of IND-2 as compared with from baseline [Figure 4]B. Furthermore, reductions in hypoglycemic events after add-on therapy of IND-2 at week 2, 6 and 12 were also significantly reduced (P<0.01, P<0.01 and P<0.05, respectively) as compared with baseline [Figure 4]C.
Figure 3: Effect of add-on therapy of IND-2 on FBS and PPBS over 16 weeks. Values are shown as the mean ± standard deviation. Data were analyzed by paired “t” test.

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Figure 4: Effect of add-on therapy of IND-2 on the HbA1c level (A), insulin dose (B) and hypoglycemic events (C) over 16 weeks.
Values are shown as the mean ± standard deviation. Data were analyzed by paired “t” test, *P<0.05, **P<0.01 and ***P<0.001 as compared with baseline (week 0). HbA1c: Glycated hemoglobin.


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3.4. Effects of IND-2 add-on therapy on lipid profile

LDL and TC showed a slight but significant increase (P<0.01 and P<0.05) at week 8 in the IND-2 add-on treatment group as compared with the baseline. At 16 weeks of treatment, LDL, HDL, and TC were also significantly increased (P<0.01) as compared with the baseline. However, triglyceride levels and LDL: HDL ratio did not differ significantly at week 8 and 16 when compared with the baseline [Table 3].
Table 3: Effect of add-on therapy of IND-2 on efficacy variables of lipid profile.

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3.5. Effects of IND-2 on safety outcomes

At week 16, there was no significant difference in body weight, plasma AST, ALT, protein, and creatinine in add-on therapy with IND-2 as compared with baseline [Table 4]. However, treatment with IND-2 showed significantly decreased (P<0.05) in ALP, bilirubin, and significantly increased (P<0.05) in a BUN at week 8 as compared with the baseline but these differences did not continue till week 16 and remain non-significant as compared with the baseline [Table 4].
Table 4: Effect of add-on therapy of IND-2 on safety parameters.

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The levels of Hb, hematocrit, MCHC, RBC, WBC, eosinophils, neutrophils, lymphocytes, and monocytes did not differ significantly in IND-2 add-on therapy at week 8 and week 16 as compared with the baseline. However, add-on therapy of IND-2 for 8 weeks resulted in a significantly increase (P<0.01) in MCV and platelets levels when compared with baseline, but these changes were discontinued till week 16 and remain non-significant when compared with baseline. Similarly, the respiratory rate was decreased significantly (P<0.05) at week 8 and remained non-significant at week 16 in IND-2 add-on therapy group as compared with the baseline [Table 4].

3.6. AEs

Overall AEs and the most common AEs are summarized in [Table 5] and [Table 6]. Add-on therapy of IND-2 did not produce any serious AEs during the clinical study. Total 99 AEs were documented in the study out of which 5 adverse events were graded as severe which includes a cough (2), dyspnoea (1), diarrhea (1), and gastritis (1). Seventeen events were considered as ‘related’ to the test drug, and 4 subjects were discontinued from the trial due to adverse events.
Table 5: Summary of adverse events experienced by a number of patients at least once.

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Table 6: Absolute frequency of adverse events.

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Taken individually, absolute frequency of adverse events such as increase in ESR, gastritis/epigastric pain and diarrhea were the first three most commonly observed adverse events. In terms of patients experiencing the adverse events, the same adverse events were most commonly observed. Mean values of some laboratory tests were altered after 8 weeks and returned to normal after 16 weeks. There were no deaths, or serious medical event reported in during this clinical study.


  4. Discussion Top


T2DM is a chronic, complex heterogeneous condition resulted from impairment of insulin secretion from β cells of the pancreas, insulin action, or insulin resistance in the peripheral tissues. In the last few decades, the prevalence of T2DM increases significantly which makes it one of the most critical growing health issues worldwide. Therefore, the guidance of the American Association of Clinical Endocrinologists recommended the various treatment regimen including dipeptidyl peptidase-4 inhibitors (such as sitagliptin), thiazolidinediones, sulfonylureas, and insulin[61],[62]. However, these agents are also associated with substantially clinical side effects including a risk of hypoglycemia, increased body weight, lactic acidosis, the risk of myocardial events, etc[1]. Hence, many investigators have employed various add-on therapies from the natural origin for the treatment of T2DM[4],[63]. In the present investigation, we have also assessed the safety and efficacy of IND-2 add-on therapy in T2DM patients who were on insulin treatment. The outcomes of the present investigation showed that addition of IND-2 (700 mg, thrice a daily) with insulin treatment for 16 weeks significantly improved the amount of insulin required per day along with significant decrease in of the numbers of hypoglycemic attacks without any serious adverse events.

Numerous clinical evidence suggests that control over FBS and PPBS level are essential outcomes in the management of T2DM and reflected as the gold standard for overall glycaemic control[64],[65]. However, FBS level determination over time course trend failed to provide the detailed information of diabetes status and is also non-satisfactory[66]. Hence, according to the American Diabetes Association, glycated hemoglobin (HbA1c, with a cut-point ≥6.5%) has been recommended over FBS (≥7.0 mmol/L) for diabetes detection[20]. Furthermore, HbA1c provides an insight about the individual average levels of blood glucose over the last two to three months. Thus, HbA1c is considered as a reliable indicator of chronic glycemia and reflected the risk of various chronic diabetes complications such as retinopathy, neuropathy, nephropathy, etc. Hence, currently, HbA1c is widely used as an essential test for chronic management of diabetes. In the present investigation, we have also determined the effect of add-on therapy of IND-2 on HbA1c and result show that it significantly decreased HbA1c levels over 8 weeks. Fenugreek (Trigonella foenum–graecum), E. officinalis, G. sylvestre, S. reticulata, and C. sinensis were reported to reduce the HbA1clevel in clinical and preclinical studies[30],[31],[32],[33],[34],[35],[36],[67]. Additionally, the presence of 4-HI in standardized fenugreek seed extract may be responsible for the reduction in HbA1c level in T2DM patients and the findings of the previous investigator also support this notion[56],[57],[58],[59].

The management of T2DM many time needs the combination of oral antidiabetic therapies including sulfonylureas, DDP-4 inhibitors. However, these therapies are substantially limited by its side effects[1]. Hence, many T2DM patients eventually moved to insulin therapy for maintaining better glycaemic control. Although insulin is the most effective treatment available for the management of blood glucose levels, it is still also associated with side effects such as weight gain and risk of hypoglycaemia[1],[23]. Therefore, in such patients, there is a need for add-on therapy with more viable and safe option. In the present investigation, we have implicated IND-2 as an add-on therapy along with insulin for the management of T2DM. The finding showed that IND-2 with insulin decreased (27% reduction) the number of insulin dose needed per day as compared with baseline. The observed beneficial effects of IND-2 on top of insulin are anticipated from its complementary mechanism of action. This action of IND-2 may depend on the amount of glucose present which caused the secretion of insulin. This mechanism of action of IND-2 is further supported by the decrease in the number of hypoglycemic events over 16 weeks. Whereas, sulfonylurea has a limitation where it caused continuous stimulation of insulin secretion, even with decreasing level of glucose which results in hypoglycemia[1]. Thus, clinically IND-2 can be considered as a potential add-on therapeutic agent with insulin for T2DM management, with a decrease in hypoglycemia risk and a decrease in the number of insulin doses needed per day.

Further, we have also investigated the effect of IND-2 on lipids profile which showed that a moderate but significant increase in total, HDL and LDL cholesterol over 16 weeks. It has been well documented that elevated level of cholesterol associated with risk for CHD (coronary heart disease) and atherosclerosis[68]. However, a recent clinical study also reported that vildagliptin add-on therapy with insulin improves control on glycemia with an increase in the risk of hyperlipidemia[69]. In the present investigation, documented increase in lipid profile might be a secondary effect resulting from decreased HbA1c levels.

According to the ADA/EASD guidelines, the treatment approach for T2DM therapy should be based on patient-centric which should consider various aspects including the need for treatment, preference of patient and values[1]. Although ADA/EASD recommends insulin as effective treatment for the management of T2DM, weight gain is a common side effect associated with it. Thus, weight control during the treatment of diabetes is an important consideration for the T2DM management therapy. In the present study, body weight in add-on therapy of IND-2 with insulin did not differ significantly despite significant improvement in HbA1c which can be considered an advantage of IND-2 along with insulin treatment.

Traditional medicines are considered to be relatively safe option with low side-effects, but their efficacy is found relatively low as compared with Western medicines. Hence, many times the high dose was usually needed to attend the optimal therapeutic efficacy. Thus, their toxicity cannot be neglected in the view of their therapeutic applications[70]. The common adverse event associated with herbal supplementation includes complications related to gastrointestinal tracts such as nausea, vomiting, diarrhea, and constipation[71]. Also, herb-drug interaction related to pharmacokinetics and pharmacodynamics properties needs to be considered during their administration. In the present investigation, add-on therapy of IND-2 with insulin was well tolerated. There was no any serious AEs were reported during the trial. Among the reported AEs, the majority of the events were mild and not related to the IND-2 add-on therapy. However, discontinuation of 4 subjects from the trial due to adverse events is a significant finding. The previous investigator also reported similar kind of cause which lead to treatment discontinuation[72],[73]. Increased ESR is reported in a maximum number of patients and tops the list of the number of absolute adverse events. Though, the rise in ESR was reported as not related to drugs, there is a need for further studies with a large number of patient population to confirm the effect of IND-2 on ESR. All the events, which were related to the drug were gastrointestinal tract events. Six significant abnormalities in laboratory parameters were observed which were present during week 8 and not continued till week 16.

Recent year various researchers have investigated the effect of polyherbal formulation on HbA1c levels[74],[75]. Administration of polyherbal formulation that contains Gymnema sylvestre extract in T2DM for 3 months showed significant improvement in HbA1c levels and antioxidant enzyme activities[74]. Furthermore, a polyherbal formulation containing standardized extracts of Trigonella foenu–graecum and Emblica officinalis also showed a decrease in HbA1c, FBS and PPBS in the T2DM patient with uncontrolled blood sugar despite a sulfonylurea and metformin stable dose[65]. These studies suggested that Trigonella foenum–graecum, Gymnema sylvestre, and Emblica officinalis were most widely implemented herbs for preparation of polyherbal formulations in the management of diabetes. Additionally, safety and efficacy of Trigonella foenum–graecum as an anti-diabetic medication have also been well established clinically[76],[77]. Thus, results of current investigation along with findings of earlier researchers both substantially provide the potential of this polyherbal formulation (IND-2) as a safe and well-tolerated add-on treatment option for the T2DM management in the patients with insulin treatment.

The present investigation has certain limitations. The primary limitation of this study is a single-arm study without placebo-control. Hence, study with placebo-control will be required to assess comparative efficacy of IND-2 in T2DM subjects. Secondly, the sample size of the present investigation is relatively too small, and the study duration is also too short which provides only short-term effects. Hence, analysis of long-term effect with larger sample size remains to be evaluated. Lastly, in this study, we have not evaluated the parameters which give an insight to the possible mechanism of action of IND-2 such as serum insulin level, molecular markers in blood, level of antioxidants in blood, etc.

The findings of present investigation suggest that add-on therapy of IND-2 (herbal formulation rich in standardized fenugreek seed extract) with insulin in T2DM patients improved glycaemic control through a decrease in levels of glycated hemoglobin and number of insulin doses needed per day without a change in blood sugar, body weight and risk of hypoglycemia. Thus, IND-2 may provide a safe and well-tolerated add-on therapy option for the management of T2DM.

Conflict of interest statement

Amit Kandhare and Prasad Thakurdesai are the full-time employees of Indus Biotech Pvt. Ltd., Pune.

Acknowledgments

The authors gratefully acknowledge the support of all the investigators and medical staff at the participating centers. The authors would also like to acknowledge Hanul Medizin Pvt. Ltd., Pune, India for clinical research services. This work was funded by Indus Biotech Pvt. Ltd., Pune.

 
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