Efficacy and safety of add on therapy of bromocriptine with metformin in Indian patients with type 2 diabetes mellitus: A randomized open labeled phase IV clinical trial,Arijit Ghosh1, Nilanjan Sengupta2, Pranab Sahana2, Debasis Giri2, Parama Sengupta1, Nina Das1, : Indian Journal of Pharmacology

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RESEARCH ARTICLE	[Download PDF]

Year : 2014 \| Volume : 46 \| Issue : 1 \| Page : 24--28

Efficacy and safety of add on therapy of bromocriptine with metformin in Indian patients with type 2 diabetes mellitus: A randomized open labeled phase IV clinical trial

Arijit Ghosh¹, Nilanjan Sengupta², Pranab Sahana², Debasis Giri², Parama Sengupta¹, Nina Das¹,
¹ Department of Pharmacology, Nilratan Sircar Medical College, Kolkata, West Bengal, India
² Department of Endocrinology, Nilratan Sircar Medical College, Kolkata, West Bengal, India

Correspondence Address:
Arijit Ghosh
Department of Pharmacology, Nilratan Sircar Medical College, Kolkata, West Bengal
India

Abstract

Objective: To compare the effectiveness and safety of add on therapy of bromocriptine with metformin in type 2 diabetes mellitus (DM) patients. Material and Methods: Adult type 2 DM patients fulfilling the inclusion criteria were randomized in three groups. Group A received metformin (1000 mg/ day), while group B patients were treated with metformin (1000 mg/day) plus bromocriptine (0.8 mg/day) and group C received metformin (1000 mg/day) plus bromocriptine (1.6 mg/day) for 12 weeks. Fasting plasma glucose (FPG), postprandial plasma glucose (PPPG), and body weight were measured at week 4, 8, and 12 visits and glycosylated hemoglobin (HbA _1C ) at week 12 visit. Results: Metformin alone and in combination with bromocriptine in escalating dose (0.8 mg/day and 1.6 mg/day) significantly (P < 0.05) decreased FPG and PPPG levels at weeks 4, 8, and 12 compared with pretreatment values. HbA _1C level in all three treatment groups significantly (P < 0.05) decreased at week 12 as compared with pretreatment baseline value. HbA _1C level in groups B and C significantly (P < 0.05) decreased as compared with group A at week 12 . Addition of bromocriptine to metformin also significantly (P < 0.05) decreased FPG and PPPG levels in a dose-dependent manner as compared with metformin alone. Intergroup analysis did not show any statistically significant change in weight of study subjects at different intervals. Conclusion: The combination of bromocriptine with metformin significantly decreased FPG, PPPG, and HbA _1C compared with metformin alone in type 2 DM patients in a dose-dependent manner.

How to cite this article:
Ghosh A, Sengupta N, Sahana P, Giri D, Sengupta P, Das N. Efficacy and safety of add on therapy of bromocriptine with metformin in Indian patients with type 2 diabetes mellitus: A randomized open labeled phase IV clinical trial.Indian J Pharmacol 2014;46:24-28

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Ghosh A, Sengupta N, Sahana P, Giri D, Sengupta P, Das N. Efficacy and safety of add on therapy of bromocriptine with metformin in Indian patients with type 2 diabetes mellitus: A randomized open labeled phase IV clinical trial. Indian J Pharmacol [serial online] 2014 [cited 2023 Mar 21 ];46:24-28
Available from: https://www.ijp-online.com/text.asp?2014/46/1/24/125160

Full Text

Introduction

Diabetes mellitus (DM) is characterized by chronic hyperglycemia and disturbances of carbohydrate, fat, and protein metabolism occurs due to deficiency of insulin (type 1) or insensitivity of the target tissues to insulin (type 2). [1]

Several oral antidiabetic agents (ADAs) like metformin, sulfonylureas, meglitinides and Dipeptidyl peptidase 4 (DPP 4) inhibitors are currently available. Some of them increase the insulin secretion from pancreas, while others increase peripheral utilization of glucose by increasing the sensitivity of peripheral tissues to utilize glucose. Oral therapy for type 2 DM, when used appropriately, can safely assist patients to achieve glycemic target in the short term to medium term. Issues of safety and tolerability, notably change in weight, often limit the optimal application of antidiabetic drugs such as metformin and thiazolidinediones. [2] Therefore, there is need for novel oral ADAs with different mechanisms of action from existing oral ADAs. Bromocriptine mesylate quick release formulation has been approved by Food and Drug Administration in May 2009 for the treatment of type 2 DM in adults as an adjunct to diet and exercise to improve glycemic control. [3],[4] Treatment with dopamine agonist bromocriptine has been proposed as a mean to improve glucose and energy metabolism through activation of central nervous system (CNS) dopaminergic pathways responsible for metabolic control. This mechanism of action of bromocriptine tends to address hither to unexplored pathophysiology of hyperglycemia in type 2 DM. The pharmacological activity of bromocriptine occurs mainly through activation of D 2 receptors and inhibition of D 1 receptors in the CNS. [5]

Current treatment guidelines recommend metformin as the first agent to be added to diet and lifestyle changes for the majority of patients. Metformin monotherapy is capable of lowering glycosylated hemoglobin (HbA 1C ) significantly and is generally well-tolerated with lower risk of hypoglycemia. [6] A study conducted by Ramteke et al., [2] has showed bromocriptine is an effective and safe ADA which can be employed as monotherapy or in conjunction with metformin to achieve and maintain optimal glycemic control in Indian population. Against this backdrop, the present study was planned to compare effectiveness and safety of add on therapy of bromocriptine with metformin in Indian patients with type 2 DM.

Material and Methods

It was a prospective, randomized, open-labeled phase IV clinical trial. The study was approved by the institutional ethics committee and conducted according to the Indian Council of Medical Research guidelines for Biomedical Research on Human Subjects, 2006, and the Declaration of Helsinki. Subjects were recruited in the diabetes outpatient department under the department of endocrinology of a tertiary care teaching hospital and the study was conducted between May and October 2012. The study was registered under Clinical Trials Registry-India (Registration Number-CTRI/2012/05/002659).

Based on an effect size of one, standard deviation of one, significance level α of 0.05 and power of the study as 80%, the target number of "evaluable" subjects was 20 per group. The sample size was calculated by using primer of biostatistics software (version 5.0). Considering a 20% drop out rate, this translated to a target recruitment of 25 subjects in each group.

Adults of either gender, aged between 18 and 60 and newly diagnosed cases (as per ADA guidelines) [7] of type 2 DM with HbA 1C ≥ 6.5 and ≤ 10, were included in the study. Pregnant or lactating women, patients with FPG > 250 mg/dL, PPPG > 350 mg/dL, comorbid cardiovascular, renal and psychiatric complications, coadministration of drugs that were likely to interact with bromocriptine or metformin were excluded.

Patients, who fulfilled the selection criteria, were randomly allocated in three different treatment groups. Randomization was done by computer-generated randomization number. Patients in group A received metformin sustained release (SR) tablet (Lupin Diabetes Care Ltd., Mumbai, Maharashtra, India) 500 mg twice a day after food. Group B was treated with metformin 500 mg SR tablet twice a day after food plus bromocriptine mesylate (0.8 mg) quick release tablet(Lupin diabetes care Ltd., Mumbai, Maharastra, India) after breakfast. Group C was treated with metformin 500 mg SR tablet twice a day after food and bromocriptine (0.8 mg) quick release tablet after breakfast for first 7 days and thereafter continued to take two tablets for further treatment period. Compliance was assessed by pill count method at each follow-up visit and at the end of the study.

Clinical (body weight) and biochemical (FPG, PPPG) evaluation was done at baseline (day 0) and at subsequent follow-up visits on weeks 4, 8, and 12. HbA 1C estimation was done at baseline and at the end of treatment (12 th week).

Patients with worsening clinical conditions or rising plasma glucose level were withdrawn prematurely from the study. All patients were advised to stop smoking and consumption of alcohol during the study period. Patients were monitored continuously throughout the study for any adverse event (AE). Causality analysis of AE was done as per the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) criteria. (8)

Statistical Analysis

Data were analyzed as per modified intention to treat (ITT) basis. Subjects reporting for at least one post-baseline follow-up visit were analyzed. All patients who were randomized were considered for safety analysis. Data were analyzed by repeated measures analysis of variance (ANOVA) and paired t test for intragroup comparison and by ANOVA for intergroup comparison. Post hoc analysis was done by Tukey's honestly significant difference (HSD) test. Categorical data in baseline demographic profile (gender) were analyzed by chi-square test. P value < 0.05 was considered to be statistically significant.

Results

Out of 80 patients screened, 74 were enrolled in the study. Out of 74 patients, 23 were treated with metformin 1000 mg/day (group A), 25 were treated with metformin 1000 mg/day and bromocriptine 0.8 mg/day (group B) and 26 were treated with metformin 1000 mg/day and bromocriptine 1.6 mg/day (group C). Out of 74 patients, 71 completed the study and 3 patients were lost to follow-up [Figure 1]. The mean age of patients was 48.1, 52.6, and 49.3 years in the groups A, B, and C, respectively. {Figure 1}

There was no statistically significant difference in the baseline HbA 1C , FPG and PPPG levels [Table 1]. HbA 1C level significantly decreased in all three treatment groups at week 12 from their respective baseline values(P < 0.05). Metformin alone and in combination with bromocriptine in escalating dose (0.8 mg/day and 1.6 mg/day) significantly (P < 0.05) decreased FPG and PPPG levels at weeks 4, 8, and 12 compared with pretreatment values.{Table 1}

Intergroup analysis of data show at every interval (weeks 4, 8, and 12) add on therapy of bromocriptine with metformin compared with metformin alone significantly (P < 0.05) decreased FPG and PPPG levels in a dose-dependent manner [Figure 2] and [Figure 3]. At week 12, HbA 1C level in groups B and C significantly decreased compared with group A [Figure 4]. Intergroup analysis did not show any statistically significant change in weight of study subjects at different intervals.{Figure 2}{Figure 3}{Figure 4}

Safety analysis was carried out as per ITT analysis. All patients who were randomized were considered for safety analysis. Total nine patients developed AEs. The most common AEs are nausea and vomiting. None of the patients in group A reported any AE. Three patients (12%) in group B reported nausea and vomiting. Six patients (23%) in group C reported dizziness and vomiting. These AEs were noted during initiation of therapy and they were mild to moderate in nature. These lasted for about 2 weeks. Two patients (8%) in group B and three patients (12%) in group C were withdrawn from the study due to AEs. Causality analysis showed that they were in the "possible" category. Causality analysis of AE was done as per the WHO-UMC criteria. (8)

Discussion

Despite availability of several oral ADAs, pharmacotherapy of type 2 DM is far from satisfactory. Hence, there is always need for newer therapeutic targets and newer drugs. Bromocriptine is a dopamine type 2 (D 2 )-receptor agonist that has been approved for the treatment of type 2 DM. Based on animal and human studies, timed bromocriptine administration within 2 h of awakening is believed to augment low hypothalamic dopamine levels and inhibit excessive sympathetic tone within the CNS. This results in decrease in plasma glucose levels due to suppression of hepatic glucose production. [9]

Data from our study suggest metformin alone and in combination with bromocriptine in escalating dose (0.8 mg and 1.6 mg/day) significantly decreased FPG and PPPG levels at weeks 4, 8, and 12 compared with their respective baseline values. HbA 1C level in all three treatment groups significantly decreased at week 12 from their respective baseline value. Add on therapy of bromocriptine with metformin compared to metformin alone significantly decreased FPG and PPPG levels in a dose-dependent manner. At week 12, HbA 1C level in groups B and C significantly decreased compared with group A. There was no statistically significant change in weight from baseline in any of the study groups suggesting weight neutrality of bromocriptine. However, the duration of present study was only 12 weeks.

There are few clinical trials evaluated efficacy and safety of bromocriptine in type 2 DM. In a small study of 12 nondiabetic obese hyperinsulinemic (≥20 μU/mL) subjects, bromocriptine (1.6 mg/day for 2 weeks) reduced the fasting and postprandial (standardized meals) glucose levels without change in body weight. [9],[10] In all studies, bromocriptine was administered in the morning within 2 h of awaking. These studies included: 24-week monotherapy trial [11] , two 24-week add-on to sulfonylurea trials [12] and 52-week add-on to various oral ADAs trial. [13] Results of these studies consistently demonstrated a placebo-subtracted decline in HbA 1C of 0.5%-0.7%. Efficacy data also are available from a large 52-week randomized, double-blind, placebo-controlled trial in which bromocriptine was added to therapy in poorly controlled (HbA 1C > 7.5%) type 2 diabetic patients who were taking one to two oral ADAs. [14] In type 2 diabetic subjects who completed 24 weeks of treatment and who took ≥80% of their medication, the placebo-subtracted decrease in HbA 1C ranged from 0.6% to 0.9% and was consistent in subjects failing any oral ADA, or their combinations. [10],[14],[15] Data from our study are also in agreement with these studies.

Safety analysis of our studies shows incidence nausea, vomiting, and dizziness in few patients on bromocriptine. These AEs were mild to moderate in nature. Although 8% patients in group B and 12% patients in group C necessitate drug withdrawal, there was no reported case of serious life-threatening AE.

Conclusion

The results of this randomized, open-labeled phase IV clinical trial showed that add on therapy of bromocriptine with metformin is more effective compared with metformin alone in a dose-dependent manner. This add-on therapy is also safe.

Acknowledgment

The authors would like to thank Lupin Diabetes Care Ltd, Mumbai, Maharashtra, India for providing gift samples of study medications.

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