PRACTICE RECOMMENDATIONS
• Reserve bromocriptine for cases in which only a modest reduction in A1c is needed. A
• Advise patients to take bromocriptine in the morning with food to maximize its bioavailability. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
For obese patients with type 2 diabetes (T2D) who do not tolerate other diabetes medications or for patients who need only a minimal reduction in glycosylated hemoglobin (A1c) to reach goal, bromocriptine may be a therapeutic agent to consider. Approved by the US Food and Drug Administration (FDA) in 2009, Cycloset is a quick-release formulation of bromocriptine mesylate, an ergot alkaloid dopamine D2 receptor agonist that has a faster onset of action than the customary formulation, Parlodel, which has been used to treat Parkinson’s disease, acromegaly, and hyperprolactinemia.1 In addition to its modest benefit in improving glycemic control, Cyclocet avoids undesirable side effects such as hypoglycemia and weight gain.
VeroScience, LLC holds the new drug application and related technologies for Cycloset and partnered with Santarus, Inc. and S2 Therapeutics to market it in September 2010.2
Bromocriptine’s likely mechanism of action
Although its exact mechanism of action is unclear, bromocriptine does not stimulate insulin release, reduce hepatic glucose production, increase glucose transporter production, or increase or mimic glucagon-like peptide-1 activity as other T2D agents do.3 Its contribution to glycemic control in T2D has been hypothesized to be due to adjustments in the neural control of seasonal and diurnal patterns of food intake and nutrient storage.4
Early hunter-gatherers and farmers are thought to have benefited from a “thrifty genotype” that favored fat deposition when food was seasonally abundant. With food in western society available year-round and often energy dense in both fat and carbohydrates, this same gene may lead to obesity and noninsulin-dependent diabetes mellitus.5
The hypothesis assumes that circadian rhythm, photo- periodism, and seasonal factors play a role in insulin resistance, hepatic gluconeogenesis, and weight gain. In vertebrates, the neuroendocrine system plays an important role in synchronizing the animal with cyclic environmental changes. The hypothalamic suprachiasmatic nucleus (SCN) is known as the circadian pacemaker that maintains this rhythm. Oscillations in the SCN occur due to external cues such as changes in light or temperature. Circadian dopaminergic and serotonergic activities are likely responsible for modifying such oscillations, and neurotransmitters have been shown to regulate the dramatic seasonal alterations in body weight and body composition of all vertebrate classes.6 Bromocriptine can reverse metabolic alterations associated with insulin resistance and obesity by resetting central (hypothalamic) circadian organization of monoamine neuronal activities.7
Proven anti-T2D effects. When administered systemically or into the cerebral ventricle at first light, bromocriptine prevents or reverses seasonal fattening, insulin resistance, and hyperinsulinemia, and it decreases endogenous (hepatic) glucose production in mammals.8-11 Bromocriptine also decreases both fasting and postprandial triglyceride and free fatty acid levels.1
Clinical trials show modest benefit
Although bromocriptine has been studied since 1980 for its effects on hyperglycemia in T2D,12 trials leading to the approval of the drug for clinical use with T2D have only been completed within the last 15 years. Randomized controlled trials of varying sizes and lasting from 6 to 52 weeks have shown absolute A1c reductions from 0.1% to 0.6%.1,12-16 Compared with placebo, A1c reductions have ranged from 0.4% to 1.2% with monotherapy and in combination with other antidiabetes medications.1,13-16
The manufacturer assessed bromocriptine in 4 studies involving patients with T2D. In all 4 studies, the bromocriptine dose was titrated to a maximum of 4.8 mg/d.16
One study involved 159 overweight subjects who were not meeting glycemic goals.16 Patients received either placebo or bromocriptine for 24 weeks in addition to diet and exercise. Mean baseline A1c was 9.0% in the bromocriptine group and 8.8% in the placebo group. After 24 weeks, A1c was reduced by 0.1% in the treatment group and increased by 0.3% in the placebo group. Mean fasting glucose was 215 mg/dL at baseline in the treatment group and was unchanged after 24 weeks. In the placebo group, fasting glucose increased from 205 to 228 mg/dL during the study. Weight increased by 0.2 kg in the treatment group and by 0.5 kg in the placebo group.
The next two 24-week manufacturer studies used similar designs to compare the addition of either bromocriptine or placebo to existing sulfonylurea therapy in patients with uncontrolled T2D.16 One study assigned 122 patients to bromocriptine and 127 to placebo. The bromocriptine group demonstrated mean reductions of 0.4% in A1c and 3 mg/dL in fasting glucose. In the placebo group, A1c increased by 0.3% and fasting glucose rose by 23 mg/dL.