Bromocriptine

Bromocriptine is a well-known treatment for patients with Parkinson’s disease, hyperprolactinemia or acromegaly. However, since 2009 a bromocriptine quick release variant has been approved in the USA for the treatment of type 2 diabetes mellitus, as an adjunct to diet and exercise. In obese patients with type 2 diabetes mellitus, bromocriptine has been shown to induce positive metabolic effects such as improving glycaemic control and serum lipid profile. In addition, bromocriptine may have a positive effect on body weight, blood pressure and cardiovascular events in patients with type 2 diabetes mellitus.

Mechanism of action

Dopaminergic signalling is a part of the pathways in the central nervous system that control metabolism. Drug with anti-dopaminergic effects, (e.g. antipsychotic drug such as olanzapine, clozapine) induce negative metabolic effects (insulin resistance and dyslipidemia) and weight gain in formerly healthy subjects. Conversely, bromocriptine treatment contributes to a favourable metabolic profile. The exact working mechanism of bromocriptine still has to be elucidated, but there are several theories considering its mechanism of action.

Bromocriptine differs from other anti-diabetes medication in that it presumably exerts its effects through the central nervous system. Bromocriptine is a centrally acting sympathicolytic dopamine 2 receptor agonist with inhibitory effects on serotonin and noradrenalin levels in the ventromedial hypothalamus. The ventromedial hypothalamus is involved in whole body energy metabolism via the sympathetic nervous system. Increased sympathetic activity has negative metabolic effects reflecting insulin resistance, such as increased free fatty acid levels and increased glucose levels. In addition, an increased sympathetic activity can induce cardiovascular effects such as an increased risk at hypertension and cardiovascular diseases.

Evolutionary, an increased body weight and insulin resistance are thought to be protective during winter months or times of famine. The insulin resistant or glucose intolerant state ensures glucose supply to the central nervous system by increasing hepatic glucose output, sparing peripheral glucose utilisation and increasing basal lipolytic activity for peripheral use. In times of abundance of food, animals are able to revert back to an insulin sensitive or glucose tolerant condition. These seasonal changes in body weight and insulin resistance are due to changes in hypothalamic neuroendocrine rhythms[1]. During the insulin resistant or glucose intolerant state, serotonin and noradrenalin levels in the ventromedial hypothalamus are increased. Daily systemic or intracerebroventricular administration of bromocriptine was shown to reverse this seasonal insulin resistant state in animals, presumably by reducing the hypothalamic ventromedial noradrenergic and serotonergic activity. A similar change in these neuroendocrine rhythms is thought to play a role in the non-seasonal development of obesity in humans. The metabolic modifications, which are protective in times of fasting or famine (e.g. insulin resistance, increased hepatic glucose output and increased lipolysis), contribute to the hyperglycaemia and dyslipidaemia state in patients with type 2 diabetes.

In patients with type 2 diabetes mellitus, the dopamine levels are thought to be lower in the morning as compared to healthy volunteers, leading to increased sympathetic activity. Bromocriptine has sympatholytic effects which could diminish the increased sympathetic tone in humans with obesity and diabetes mellitus type 2 and thereby counteract the adverse effects described. The bromocriptine quick release variant is usually administered in the morning to compensate for this morning dip. This timed administration of bromocriptine augments these low hypothalamic dopamine levels and thereby inhibits the excessive sympathetic tonus within the central nervous system. Though bromocriptine is thought to influence the circadian neuroendocrine rhythms and decrease the sympathetic tonus, the exact working mechanism of bromocriptine and the reason why administration results in an improved metabolic profile in humans is still unknown.

Pharmacokinetics

Figure 1. Molecule structure of bromocriptine quick release.
Figure 1. Molecule structure of bromocriptine quick release.
Bromocriptine quick release[2] (Cycloset®, figure 1) is administered once daily within 2 hours of awakening. The starting dose of bromocriptine quick release is 0.8 mg/day and can be weekly increased to a maximum of 4.8 mg/day. When administered orally, approximately 65-95% is absorbed within 30 minutes. On an empty stomach, the peak plasma concentration is reached in about 53-60 minutes. In order to reduce potential gastro-intestinal side effects, it is recommended to take the bromocriptine quick release in combination with food. The maximum plasma concentration in a fed state will be reached within 90-120 minutes because the absorption is delayed by the food. The bioavailability is increased under fed conditions. After absorption, approximately 7% of the ingested dose will reach the systemic circulation due to an extensive first-pass effect in the liver. Bromocriptine is metabolised by cytochrome P450, especially CYP3A4, and approximately 16-30 metabolites are formed. The biologic activity of these metabolites is still largely unknown. Bromocriptine is mainly excreted via the biliary route, approximately 2-6% is excreted via the kidneys. Bromocriptine has an elimination half-life of 6 hours, independent of the consumption of a (high-fat) meal.

Side effects

Adverse reactions reported in controlled clinical trials in ≥ 5% of patients and more than in the placebo treated group included nausea, fatigue, dizziness, vomiting, and headache. Nausea, the main side effect, occurs in approximately 32% of the patients versus 8% in the placebo group. Furthermore, fatigue occurred in approximately 14% of the patients. Dizziness occurred in 15% of the patients, vomiting in 8% and headache in 11% of the patients. Most side effects occur mainly during the initial titration phase and are transient, lasting around 14 days.

Efficacy of bromocriptine quick release

Metabolic effects

Bromocriptine can be used as monotherapy or in combination with oral glucose lowering medication. The metabolic effects of combining bromocriptine administration with insulin has not yet been studied. Several randomized controlled trials (mostly combining bromocriptine with other oral glucose lowering medication) show a significant reduction in several metabolic parameters such as a 0.4-0.7% reduction in HbA1c[3][4][5], but also lower fasting plasma glucose values and post meal glucose. In one trial comparing metformin, bromocriptine, and bromocriptine combined with metformin, metformin monotherapy was superior to bromocriptine monotherapy in terms of fasting plasma glucose and HbA1c. However, combination therapy of metformin and bromocriptine resulted in a significant further decrease in HbA1c levels. One trial combined metformin (1000mg/day) and bromocriptine (0.8 mg/day or 1.6 mg/day) and evaluated HbA1c levels after 12 weeks. Baseline HbA1c was 7.9%; metformin reduced HbA1c by 0.3%, metformin and bromocriptine 0.8 mg/day reduced HbA1c by 0.9% and metformin and bromocriptine 1.6 mg/day reduced HbA1c values by 1.3%. In another trial, bromocriptine 2.4 mg/day reduced HbA1c values after 12 weeks by 0.46%, metformin 500mg twice/day reduced HbA1c by 0.63% and the combination of metformin 500mg twice/day and bromocriptine 1.6mg/day reduced HbA1c by 0.74%. Addition of bromocriptine to sulphonylurea reduced HbA1c values by approximately 0.55%. The effects of bromocriptine on free fatty acids and triglycerides are inconsistent.

Effects on weight

The results on weight after treatment with bromocriptine are likewise inconsistent. However, the use of bromocriptine is not associated with weight gain.

Cardiovascular effects

Apart from metabolic improvements, several trials show that bromocriptine quick release reduces blood pressure and suggest a reduction cardiovascular adverse events in patients with type 2 diabetes (event rate: 1.8-1.9% in the bromocriptine treated group vs 3.2%) .

Conclusion

There is a wide variety in the treatment effects of bromocriptine in different trials. Up until now, a formal meta-analysis considering the effects of bromocriptine on metabolic profile and cardiovascular risk is lacking. Bromocriptine seems to have (at best) modest beneficial effects in type 2 diabetes patients on HbA1c; the data on cardiovascular effects are insufficient to draw any firm conclusions. There is still an essential gap in our knowledge about the working mechanism, combination therapies and efficacy and long term safety. Future research is needed to address these questions.

References

  1. ^ Cincotta AH, Schiller BC, Landry RJ, Herbert SJ, Miers WR, Meier AH. Circadian neuroendocrine role in age-related changes in body fat stores and insulin sensitivity of the male Sprague- Dawley rat. Chronobiol Int 1993;10:244-58

  2. ^ SPC cycloset, //www.accessdata.fda.gov/drugsatfda_docs/label/2009/020866lbl.pdf

  3. ^ Vinik AI, Cincotta AH, Scranton RE, Bohannon N, Ezrokhi M, Gaziano JM. Effect of bromocriptine-QR on glycemic control in subjects with uncontrolled hyperglycemia on one or two oral anti-diabetes agents. Endocr Pract. 2012;931-43. 10.4158/EP12187.OR

  4. ^ Cincotta AH, Meier AH, Cincotta Jr M. Bromocriptine improves glycaemic control and serum lipid profile in obese Type 2 diabetic subjects: a new approach in the treatment of diabetes. Expert Opin Investig Drugs 1999;8:1683–1707

  5. ^ 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;46:24-8. doi: 10.4103/0253-7613.125160.

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