Applied Evidence

Bromocriptine: Its place in type 2 diabetes Tx

J Fam Pract. 2011 November;60(11):E1-E5

References

1. Cincotta AH, Meier AH, Cincotta JM. 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.

2. Santarus, Inc. Santarus Licenses Novel Type 2 Diabetes Drug CYCLOSET [press release]. Available at: http://ir.santarus.com/releasedetail.cfm?ReleaseID=505694. Accessed May 9, 2011.

3. Cornell S, Lullo A. Getting to goal for patients with type 2 diabetes: mission possible. Diabetes Trends. 2009;21:2-10.

4. Holt RIG, Barnett AH, Bailey CJ. Bromocriptine: old drug, new formulation, and new indication. Diabet Obes Metab. 2010;12:1048-1057.

5. Dowse G, Zimmet P. The thrifty genotype in non-insulin dependent diabetes. BMJ. 1993;306:532-533.

6. Meier AH, Cincotta A. Circadian rhythms regulate the expression of the thrifty genotype/phenotype. Diabetes Rev. 1996;4:464-487.

7. Luo S, Luo J, Cincotta AH. Association of the antidiabetic effects of bromocriptine with a shift in the daily rhythm of monoamine metabolism within the suprachiasmatic nuclei of the Syrian hamster. Chronobiol Int. 2000;17:155-172.

8. Cincotta AH, Schiller BC, Meier AH. Bromocriptine inhibits the seasonally occurring obesity, hyperinsulinemia, insulin resistance, and impaired glucose tolerance in the Syrian hamster, Mesocricterus auratus. Metabolism. 1991;40:639-644.

9. Cincotta AH, Meier AH, Southern LL. Bromocriptine alters hormone rhythms and lipid metabolism in swine. Ann Nutr Metab. 1989;33:305-314.

10. Cincotta AH, MacEachern TA, Meier AH. Bromocriptine redirects metabolism and prevents seasonal onset of obese hyperinsulinemic state in Syrian hamsters. Am J Physiol. 1993;254:E285-E293.

11. Luo S, Liang Y, Cincotta AH. Intracerebroventricular administration of bromocriptine ameliorates the insulin-resistant/ glucose-intolerant state in hamsters. Neuroendocrinology. 1999;69:160-166.

12. Barnett AH, Chapman C, Gailer K, et al. Effect of bromocriptine on maturity onset diabetes. Postgrad Med J. 1980;56:11-14.

13. Gaziano JM, Cincotta AH, O’Connor CM, et al. Randomized clinical trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes. Diabetes Care. 2010;33:1503-1508.

14. Aminorroaya A, Janghorbani M, Ramezani M, et al. Does bromocriptine improve glycemic control of obese type-2 diabetics? Horm Res. 2004;62:55-59.

15. Pijl H, Ohashi S, Matsuda M, et al. Bromocriptine: a novel approach to the treatment of type 2 diabetes. Diabetes Care. 2000;23:1154-1161.

16. Cycloset (bromocriptine mesylate) [prescribing information]. Tiverton, RI: VeroScience LLC; September 2010.

17. Scranton R, Cincotta A. Bromocriptine-unique formulation of a dopamine agonist for the treatment of type 2 diabetes. Expert Opin Pharmacother. 2010;11:269-279.

18. Maurer G, Schreier E, Delaborde S, et al. Fate and disposition of bromocriptine in animals and man. II: Absorption, elimination, and metabolism. Eur J Drug Metab Pharmacokinet. 1983;8:51-62.

19. Cincotta A, Meier AH. Bromocriptine (Ergoset) reduces body weight and improves glucose tolerance in obese subjects. Diabetes Care. 1996;19:667-670.

There were no differences in the pattern of common adverse events across races or age groups (<65 vs >65 years old). Hypoglycemia occurred infrequently during the 52-week safety trial, with 6.9% of the bromocriptine patients and 5.3% of the placebo patients reporting an event.¹³ In this same safety trial, 1.6% of bromocriptine patients experienced syncope vs 0.7% of placebo-treated patients. CNS effects (somnolence and hypoesthesia) were minimal. Serious adverse events affected 8.5% of bromocriptine patients and 9.6% of placebo-treated patients (hazard ratio=1.02; 96% one-sided confidence interval, 1.27). Fewer people in the bromocriptine group reported a cardiovascular disease endpoint (composite of myocardial infarction, stroke, coronary revascularization, hospitalization for angina, and hospitalization for congestive heart failure) than did those in the placebo group (1.8% vs 3.2%, respectively).^13,16

Postmarketing data link bromocriptine with hallucinations, fibrotic complications, and psychotic disorders. However, these adverse reactions were found with the use of much higher doses (30-140 mg/d) and with other indications for bromocriptine. These reactions have not been reported in clinical trials of bromocriptine used to treat T2D.¹⁶

Drugs to avoid (or use cautiously) with bromocriptine

FAST TRACK

Avoid giving dopamine antagonists or metoclopramide if prescribing bromocriptine.

Because bromocriptine is highly bound to serum proteins, it may increase the unbound fraction of other highly protein-bound drugs (eg, salicylates, sulfonamides, chloramphenicol, probenecid), which could alter their effectiveness or risk for adverse effects. Because bromocriptine is a dopamine receptor agonist, concomitant use of dopamine antagonists such as neuroleptic agents (clozapine, olanzapine) or metoclopramide is not recommended.¹⁶

Combining bromocriptine with ergot-related drugs (eg, migraine therapies) may increase the occurrence of ergot-related adverse effects such as nausea, vomiting, and fatigue, and may diminish effectiveness of migraine therapies. Dosing of the 2 therapies should occur at least 6 hours apart.¹⁶

Bromocriptine is extensively metabolized via CYP3A4. Potent inhibitors of this enzyme (eg, azole antimycotics, HIV protease inhibitors) or inducers (eg, rifampin, carbamazepine, phenytoin, phenobarbital) should be used with caution. Clinical trial data are limited regarding the safety of sumatriptan (5-HT_1B agonist) used concurrently with bromocriptine, so it is prudent to avoid using them together.¹⁶

Not for breastfeeding moms, migraine sufferers

Bromocriptine is contraindicated for patients with syncopal migraine due to an increase in the likelihood of a hypotensive episode. It is also contraindicated for women who are breastfeeding due to its ability to inhibit lactation and to postmarketing reports of stroke in this population. Bromocriptine can lead to hypotension; monitor blood pressure during dose escalation and when a patient is taking antihypertensives.

FAST TRACK

Bromocriptine can lead to hypotension, so blood pressure should be monitored during dose escalation and when a patient is taking an antihypertensive.

Bromocriptine should not be used in patients with severe psychiatric disorders, as it may exacerbate their conditions or diminish the effectiveness of their treatment. Warn patients that somnolence can occur with bromocriptine, particularly during titration. No clinical studies have shown conclusive evidence of macrovascular risk reduction with bromocriptine or any other antidiabetic drug.¹⁶ But neither has bromocriptine increased risk for cardiovascular events.¹³

Putting bromocriptine’s usefulness into perspective

The larger studies of bromocriptine have shown absolute mean reductions in A1c of 0.1% to 0.6% and in fasting glucose of 0 to 10 mg/dL. When compared with placebo, mean A1c and fasting glucose differences were 0.4% to 1.2% and 23 to 38 mg/dL, respectively. While these findings were statistically significant when compared with placebo, they are clinically modest.

Although bromocriptine offers a few advantages, such as no weight gain, low risk of hypoglycemia, and possible beneficial effects on insulin resistance and triglyceride levels, its use should be limited at this time because it is less efficacious than other agents and long-term trials are lacking. Bromocriptine is not currently included in any treatment guidelines for the management of T2D. Cost is also a concern (TABLE). Because the medication is supplied only as 0.8-mg tablets, patients on the maximum dose would need to take 6 tablets once daily.

CORRESPONDENCE
Karen R. Sando, PharmD, CDE, University of Florida, College of Pharmacy, Department of Pharmacotherapy and Translational Research, 101 S. Newell Drive, HPNP Building, Room 3306, Gainesville, FL 32610; ksando@cop.ufl.edu