Bromocriptine mesylate: Food and Drug Administration approved new approach in therapy of non-insulin dependant diabetes mellitus with poor glycemic control

Abstract

Food and Drug Administration (FDA) approved bromocriptine mesylate, a quick release formulation, 0.8 mg tablets, as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Bromocriptine products were previously approved by the FDA for the treatment of pituitary tumors and Parkinson's disease. Bromocriptine is thought to act on circadian neuronal activities within the hypothalamus to reset abnormally elevated hypothalamic drive for increased plasma glucose, triglyceride, and free fatty acid levels in fasting and postprandial states in insulin-resistant patients. Adverse events most commonly reported in clinical trials of bromocriptine included nausea, fatigue, vomiting, headache, and dizziness. These events lasted a median of 14 days and were more likely to occur during initial titration of the drug. Due to novel mechanism of action, single daily dose, and lower incidence of stroke, myocardial infarction and vascular events, bromocriptine may act as landmark in treatment of type 2 diabetes.

Bromocriptine mesylate is a dopamine D2 receptor agonist. Food and Drug Administration (FDA) approved a quick release formulation of bromocriptine , 0.8 mg tablets, by trade name Cycloset [produced by VeroScience, LLC, Tiverton, Rhode Island, USA. (marketed with S2 Therapeutics, Inc. of Bristol, Tenn. UK .)] as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus on May 5, 2009. Bromocriptine is the first drug that had been used for years for other indications and now approved for the treatment of type 2 diabetes. Bromocriptine products were previously approved by the FDA for the treatment of pituitary tumors and Parkinson's disease.[1]

Available evidence suggests that bromocriptine can reverse many of the metabolic alterations associated with insulin resistance and obesity by resetting central hypothalamic circadian organization of monoamine neuronal activities.[2] Additionally, dopamine agonist treatment reduces ventromedial, arcuate and paraventricular hypothalamic drive for increased hepatic glucose production, lipid synthesis and mobilization, and insulin resistance.[3,4]

Bromocriptine may be used as monotherapy or as adjunctive therapy to sulfonylurea, metformin/sulfonylurea, and single or dual oral hypoglycemic agent therapies; use with insulin has not been studied. Bromocriptine had been previously used as monotherapy in a few clinical trials. Pijl et al.[5] used bromocriptine quick release formulation in patients having mean fasting plasma glucose 192 ±13 mg/dl and hemoglobin 1 Ac (Hb1Ac) level 8.7 ± 0.13%. In recent clinical trial, where the bromocriptine was used in low dose of 0.8–4.8 mg/day as monotherapy or combination therapy, baseline HbA1c was 7.0% with a mean baseline fasting plasma glucose of 142 mg/dl.[6]

Bromocriptine is a centrally-acting dopamine D₂ receptor agonist. When administered as a single timed morning dose, bromocriptine is thought to act on circadian neuronal activities within the hypothalamus to reset abnormally elevated hypothalamic drive for increased plasma glucose, triglyceride, and free fatty acid levels in fasting and postprandial states in insulin-resistant patients.[2–4] This can be explained as among representative species of all the major vertebrate classes of animals, the development of obesity and its accompanying insulin resistance has certain adaptive advantages. This adaptation improves survival in times of seasonal famine.[7] Many vertebrate species develop obesity and insulin resistance in preparation for hibernation, migration or during over-wintering periods when food availability is extremely low.[8] Extensive experimental evidence indicates that circadian neuroendocrine rhythms play a pivotal role in the development of seasonal changes in body fat stores and insulin sensitivity. Specifically, temporal changes in the interaction of two distinct circadian neural circadian oscillations, mediated in part by dopaminergic and serotonergic neurotransmitter activity, have been shown to regulate the dramatic seasonal alterations in body weight and body composition that are characteristic of all vertebrate classes from teleosts to mammals.[7] Additional data obtained in pigs and rats suggest that similar mechanisms may play a role in the development of nonseasonal (e.g., aging-related) obesity and insulin resistance.[8,9] Bromocriptine mesylate, an ergot derivative, is a sympatholytic dopamine D2 receptor agonist that can exert inhibitory effects on serotonin turnover in the central nervous system.[10] Available evidence suggests that bromocriptine can reverse many of the metabolic alterations associated with insulin resistance and obesity by resetting central (hypothalamic) circadian organization of monoamine neuronal activities.[2]

Bromocriptine is the first diabetes drug to be approved under the FDA's new guidelines requiring clinical trials to demonstrate no increased cardiovascular risk. In a 52-week, double-blind, placebo-controlled safety trial (n = 3000), treatment with bromocriptine did not increase the risk for a composite of myocardial infarction, stroke, hospitalization for unstable angina, congestive heart failure, and revascularization surgery (hazard ratio, 0.58; 95% confidence interval, 0.35–0.96).[6] For patients newly diagnosed with type 2 diabetes or those who cannot adequately control their blood sugar with currently available medications, bromocriptine provides a complete new approach to treat diabetes. Patients with type 2 diabetes are at high-risk for cardiovascular events, so it is important that bromocriptine has been demonstrated not to increase the risk of cardiovascular events such as heart attacks, and may actually have the potential to lower this risk.[11]

The recommended starting dose of bromocriptine is 0.8 mg daily and is increased in 0.8 mg increments weekly until the target range (1.6–4.8 mg) or until maximal tolerance in this dose range is reached. The maximum tolerated dose for glycemic control in type 2 diabetes is 4.8 mg.[6] The usual therapy of bromocriptine in Parkinson's disease started with 1.25 mg once in the night, gradually increased as needed up to 5–10 mg thrice daily.[12] Recommended doses of bromocriptine for treatment of hyperprolactinemia are in the range of 2.5–10 mg/day.[12] Doses for treatment of diabetes mellitus should be administered once daily within 2 hours of waking in the morning and with food to reduce the risk for gastrointestinal tract adverse effects such as nausea.[6] Adverse events most commonly reported in clinical trials of bromocriptine included nausea, fatigue, vomiting, headache, and dizziness. These events lasted a median of 14 days and were more likely to occur during initial titration of the drug. None of the reports of nausea or vomiting were described as serious. In a 52-week safety clinical trial, bromocritpine mesylate was used at a dosage of 0.8–4.8 mg/day; incidence of nausea was 32.2 % and that of fatigue, vomiting, headache, and dizziness were 13.9, 8.1, 11.4, and 14.8%, respectively. No dyskinesia was observed in this clinical trial.[6] The FDA warns that bromocriptine can cause orthostatic hypotension and syncope, particularly on initiation of therapy and dose escalation. Caution is advised when treating patients who are receiving antihypertensive therapy; vital signs of orthostatic hypotension should be evaluated at baseline and periodically thereafter.[6]

Bromocriptine is contraindicated in i) patients with known hypersensitivity to bromocriptine, ergot-related drugs, or any of the excipients, ii) syncopal migraine as it potentiates the risk for syncope in these patients, and iii) nursing mothers as it may inhibit lactation.[6]

Bromocriptine shows the following drug interactions. i) As highly bound to serum proteins, may increase the unbound fraction of other concomitantly used highly protein-bound therapies like salicylates, sulfonamides, chloramphenicol, and probenecid, which may alter their effectiveness and risk for side effects. ii) Concomitant use of dopamine receptor antagonists, such as neuroleptics like phenothiazines, butyrophenones, thioxanthenes, or metoclopramide, may diminish the effectiveness of bromocriptine and bromocriptine may diminish the effectiveness of these other therapies. Bromocriptine is extensively metabolized by the liver via CYP3A4. Therefore, potent inhibitors or inducers of CYP3A4 may increase or reduce the circulating levels of bromocriptine, respectively. Use caution when co-administering drugs that are strong inhibitors, inducers, or substrates of CYP3A4.[6]

Most commonly reported signs and symptoms associated with acute overdose of bromcriptine are nausea, vomiting, constipation, diaphoresis, dizziness, pallor, severe hypotension, malaise, confusion, lethargy, drowsiness, delusions, hallucinations, and repetitive yawning. The lethal dose has not been established. Treatment of overdose consists of removal of the drug by emesis (if conscious), gastric lavage, activated charcoal, or saline catharsis. Careful supervision and recording of fluid intake and output is essential. Hypotension should be treated by placing the patient in the Trendelenburg position and administering intravenous fluids. If satisfactory relief of hypotension cannot be achieved by using the above measures to their fullest extent, vasopressors should be considered.[6]

There are a very few clinical studies on the effect of bromocriptine on glycemic control, but bromocriptine had shown beneficial effects in patients of type 2 diabetes as well as in dyslipidemia. Kamath et al. (1997)[13] observed significant beneficial effect of quick release formulation of bromocriptine on hyperglycemia and dyslipidemia in obese nondiabetic hyperinsulinemic women. Cincotta et al. (1999)[14] observed significant improvement in glycemiccontrol and serum lipid profile with bromocriptine, when given daily for 6 months.Pijl et al. (2000)[5] observed significant improvement in glycemic control as well as reduction in levels of both fasting and postprandial (pp) glucose and no change in weight. Aminorroaya et al., (2004)[15] in a study, administered bromocriptine 2.5 mg daily for 3 months and observed that there was a significant decrease in fasting plasma glucose level, HbA1c level and no change in body weight or body mass index (BMI).

Bromocriptine may prove to be a landmark in the treatment of non-insulin dependent diabetes mellitus. As it takes care of both dyslipidemia as well as glycemic control, it will be beneficial in obese patients. Further, in clinical trials, if it is found to reduce the body weight in obese diabetics, it may be the preferred drug in obese diabetic patients who do not respond to usual oral antidiabetic drugs. Novel mechanism of action, single daily dose, and lower incidence of stroke, myocardial infarction, and vascular events are the points in favor of use of bromocriptine in treatment of type 2 diabetes.