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New formulation of bromocriptine for diabetes
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Quick-release bromocriptine is a new formulation of bromocriptine mesylate that the FDA approved in May 2009 for the treatment of type 2 diabetes. Bromocriptine is an ergot alkaloid dopamine D2 receptor agonist that has previously been used for the treatment of Parkinson’s disease, acromegaly and hyperprolactinemia.
Although the exact mechanism is not known, the effect of bromocriptine (Cycloset, VeroScience) to improve glycemic control in type 2 diabetes has been hypothesized to be due to adjustments in the neural control of seasonal and diurnal patterns of food intake and nutrient storage.
The recommended dose is 1.6 mg to 4.8 mg once daily with food within 2 hours after waking in the morning. Morning dosing is important because central nervous system dopaminergic activity peaks in the early morning in healthy people and is an attempt to mimic dopaminergic activity and circadian rhythms in healthy, lean people. The product is available in a 0.8-mg tablet, and titration is recommended to reduce gastrointestinal adverse effects, particularly nausea. The recommendation is to begin with 0.8 mg daily and titrate up to 4.8 mg daily as tolerated.
Available data
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The use of bromocriptine for type 2 diabetes has been studied in several trials of varying size and length. I will focus on the larger trials; however, a few very small trials have shown HbA1c reductions of 0.4% to 0.6% with bromocriptine.
The manufacturer studied bromocriptine in four different studies involving patients with type 2 diabetes. One study included 159 overweight patients who were not meeting glycemic goals. Besides diet and exercise, patients received either placebo or bromocriptine for 24 weeks. Mean baseline HbA1c was 9% in the bromocriptine group and 8.8% in the placebo group. After 24 weeks, HbA1c was reduced by 0.1% in the treatment group and increased 0.3% in the placebo group. Weight increased 0.2 kg in the treatment group and 0.5 kg in the placebo group.
The next two 24-week studies had very similar designs and compared the addition of either bromocriptine or placebo to existing sulfonylurea therapy in patients with uncontrolled type 2 diabetes. The first of these studies had 122 patients assigned to bromocriptine and 127 to placebo. The bromocriptine group demonstrated a mean reduction of 0.4% in HbA1c and 3 mg/dL in fasting glucose. The placebo group experienced an increase of 0.3% in HbA1c and 23 mg/dL in fasting glucose. The second study included 122 patients treated with bromocriptine and 123 with placebo. The addition of bromocriptine resulted in an HbA1c reduction of 0.1% and a fasting glucose decrease of 10 mg/dL, on average. The control group had an increase of 0.4% in HbA1c and an increase of 28 mg/dL in fasting glucose. All of these results were statistically significant.
The last manufacturer-reported study, which was also published in a peer-reviewed journal, evaluated the addition of bromocriptine to various other existing diabetes treatments (diet-controlled or up to two antidiabetes medications). Although the primary goal of this study was to evaluate safety, efficacy was also monitored. This was a 52-week, randomized, placebo-controlled trial of more than 3,000 patients. Overall, after 24 weeks, there was no change in HbA1c after the addition of bromocriptine. However, most of the patients in this study were already controlled (HbA1c <7%). A subgroup analysis of those with an HbA1c level of more than 7.5% while on other agents showed some improvement with the addition of bromocriptine (0.5% mean reduction in HbA1c). After 52 weeks, 25% of patients assigned to bromocriptine who originally had an HbA1c of more than 7.5% achieved a level of less than 7%. Meanwhile, 9% of those patients who received placebo obtained an HbA1c of less than 7%.
Lastly, in another 24-week study, bromocriptine titrated up to 4.8 mg per day was assigned to patients either on no other diabetes medication or on a sulfonylurea. In those not on any current treatment, HbA1c was reduced by 0.2% with bromocriptine. In patients already taking a sulfonylurea, HbA1c was reduced by 0.1%. HbA1c increased by 0.3% in those receiving placebo.
Clinical use
Bromocriptine offers a few advantages, such as no weight gain, low risk of hypoglycemia and, possibly, beneficial effects on insulin resistance and triglycerides, but its use should probably be limited at this time. Relative to other agents, it is less efficacious and long-term trials are lacking. Cost is also of concern; because medication is only supplied as 0.8-mg tablets, patients on the maximum dose would have to take six tablets per day.
James R. Taylor, PharmD, CDE, is a clinical associate professor in the department of pharmacy practice at the University of Florida in Gainesville.
For more information:
- Aminorroaya A. Horm Res. 2004;62:55-59.
- Cincotta AH. Expert Opin Investig Drugs. 1999;8:1683-1707.
- Cycloset [package insert]. Research Triangle Park, NC: VeroScience LLC; February 2011.
- Gaziano JM. Diabetes Care. 2010,33:1503-1508.
- Pijl H. Diabetes Care. 2000;23:1154-1161.
Disclosure: Dr. Taylor reports no relevant financial disclosures.