- ACRONYMS AND DEFINITIONS
- A1C - Hemoglobin A1C
- ADA - American Diabetes Association
- BP - Blood pressure
- GI - Gastrointestinal
- T2DM - Type 2 diabetes
- DRUGS IN CLASS
- Dopamine agonist
- Bromocriptine (Cycloset®)
- MECHANISM OF ACTION
- Bromocriptine
- Bromocriptine is a drug that stimulates dopamine receptors in the brain
- Bromocriptine has been used for years to treat the following conditions:
- Hyperprolactinemia - a condition where a brain tumor secretes excessive amounts of the hormone prolactin
- Acromegaly- a condition where a brain tumor secretes excessive amounts of growth hormone
- Parkinson's disease - a condition where dopamine activity in the brain is diminished
- Cycloset®
- Cycloset® is a unique formulation of bromocriptine
- Cycloset® works quicker and has a shorter duration of action compared to other formulations of bromocriptine
- In 2009, The FDA approved Cycloset® for the treatment of Type 2 diabetes
- Mechanism of action
- The mechanism of action of bromocriptine in diabetes is not completely understood
- Much of the information comes from animal studies
- Animals that hibernate have an internal mechanism that shifts their metabolism from a condition of insulin-sensitivity (feeding season) to a condition of insulin-resistance (hibernation)
- The condition of insulin-resistance promotes more efficient utilization of energy stores during periods of food deprivation
- Studies have found that the shift from insulin-sensitive state to insulin-resistant state is partially mediated by dopamine activity in the brain
- Higher levels of dopamine activity are associated with the insulin-sensitive state
- Diabetics are believed to have an early morning dip in dopamine activity which contributes to their insulin-resistance
- This led researchers to study the effects of bromocriptine (a drug that mimics dopamine) on diabetes [2]
- FDA-APPROVED INDICATIONS
- Type two diabetes - as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
- EFFECTIVENESS
| Cycloset® Monotherapy for 24 weeks in T2DM | ||
|---|---|---|
| Cycloset® 1.6 - 4.8 mg/day (N=80) |
Placebo (N=79) |
|
| HgA1C (average change from baseline) |
-0.10% | +0.3% |
| Cycloset® added to metformin and sulfonylurea for 24 weeks in T2DM | ||
|---|---|---|
| Cycloset® 1.6 - 4.8 mg/day (N=177) |
Placebo (N=90) |
|
| HgA1C (average change from baseline) |
-0.50% | 0.0% |
- Body weight effects
- Cycloset® does not appear to have a significant effect on body weight [1,2,3,6]
- Lipid parameter effects
- In some studies, Cycloset® has been shown to lower triglyceride levels [6]
- Cycloset® does not appear to have a significant effect on other lipid parameters [1]
- Clinical outcome
- No well-done studies have evaluated the effects of Cycloset on clinical outcomes in T2DM
- ADA recommendations
- The ADA 2019 diabetes guidelines do not make any recommendations for Cycloset
- See ADA T2DM treatment recommendations for more
- SIDE EFFECTS
| Side effects of Cycloset in placebo-controlled trials | ||
|---|---|---|
| Side effect | Cycloset 1.6 - 4.8 mg daily (N=80) |
Placebo (N=79) |
| Nausea | 33% | 8% |
| Runny nose (Rhinitis) | 14% | 4% |
| Weakness | 13% | 6% |
| Headache | 13% | 9% |
| Dizziness | 13% | 8% |
| Constipation | 11% | 4% |
| Sinusitis | 10% | 3% |
| Diarrhea | 9% | 5% |
| Upset stomach | 8% | 3% |
| Vision changes | 8% | 1% |
| Vomiting | 6% | 1% |
| Decreased appetite | 5% | 1% |
- Low blood pressure (hypotension)
- Cycloset® has been associated with episodes of low blood pressure
- The risk appears to be greater when the drug is first initiated or when the dose is increased
- In one large randomized trial, 2.2% of patients on Cycloset® reported an episode of low blood pressure compared to 0.8% of patients on placebo
- Low blood pressure when standing (orthostatic hypotension) can be a problem, so patients at risk for hypotension should be careful to make slow postural changes while on Cycloset® [1]
- Low blood sugar (hypoglycemia)
- When used by itself, Cycloset® does not appear to increase the risk of low blood sugars
- When added to other medications that can cause low blood sugars (sulfonylureas, insulin, meglitinides), Cycloset® may increase the risk of low blood sugars [1]
- CONTRAINDICATIONS
- Known hypersensitivity to bromocriptine or ergot-related drugs
- Syncopal migraine
- Lactating patients - bromocriptine inhibits lactation
- Postpartum patients
- PRECAUTIONS
- Kidney disease
- The safety and efficacy of Cycloset® has not been studied in patients with kidney disease
- The kidneys are a minor pathway for the elimination of Cycloset®
- Manufacturer makes no specific dosing recommendations [1]
- Liver disease
- The safety and efficacy of Cycloset® has not been studied in patients with liver disease
- Cycloset® is extensively metabolized by the liver. Significant liver disease would be expected to affect the clearance of Cycloset®
- Manufacturer makes no specific dosing recommendations [1]
- Syncopal migraine
- Bromocriptine may worsen syncopal migraine
- Bromocriptine is contraindicated in patients with a history of syncopal migraine
- Nursing women
- Cycloset® may inhibit lactation
- Impulse control / Compulsive behavior
- Cases of intense and uncontrollable urges related to gambling, sex, and money spending have been reported in patients taking medications with dopaminergic activity including bromocriptine
- Consider dose reductions or stopping Cycloset in patients who experience these urges
- Psychotic disorders
- Cycloset® is a dopamine agonist
- Cycloset® may exacerbate psychosis and/or diminish the effect of antipsychotic medications [1]
- Low blood pressure (hypotension)
- In trials, patients on Cycloset® had a slightly higher incidence of low blood pressure (see low blood pressure above)
- Use with caution in patients with low blood pressure and in those who may be susceptible to orthostatic hypotension (e.g. elderly) [1]
- Somnolence
- Cycloset may cause somnolence. In a 52-week trial, 4.3% of Cycloset-treated patients and 1.3% of placebo-treated patients reported somnolence. Most patients reported resolution of somnolence over time.
- Patients experiencing somnolence should refrain from driving or operating heavy machinery
- Postpartum patients
- Cycloset is contraindicated in postpartum patients. Serious and life-threatening adverse reactions including hypertension, myocardial infarction, seizures, stroke and psychosis have been reported in the postmarketing setting in postpartum women who were administered bromocriptine for inhibition of lactation.
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- CYP3A4 strong inducers and strong inhibitors - Cycloset® is a CYP3A4 sensitive substrate. Strong CYP3A4 inducer and inhibitors may affect blood levels of Cycloset®
- Dopamine receptor antagonists - Cycloset® is a dopamine agonist. It may diminish the effectiveness of dopamine receptor antagonists and vice versa. Commonly used dopamine receptor antagonists include antipsychotics and metoclopramide.
- Dopamine receptor agonists - Cycloset® is a dopamine agonist. It may potentiate the effect of other dopamine agonists. Other dopamine agonists include drugs to treat Parkinson's disease and restless leg syndrome (pramipexole, ropinirole, rotigotine, and carbidopa-levodopa).
- Ergotamine derivatives (Cafergot®, DHE®, Migranal®, etc) - Cycloset® may worsen the side effects of ergotamine derivatives, and it may also reduce their effectiveness. Cycloset® should not be taken within 6 hours of ergotamine derivatives.
- Sympathomimetic drugs (e.g. pseudoephedrine, methylphenidate) - Reports of hypertension and rapid heart rate have been reported in patients taking sympathomimetics with bromocriptine. Do not take Cycloset with sympathomimetics for more than 10 days. [1]
- Triptan migraine medications - Cycloset® can stimulate serotonin receptors in addition to dopamine receptors and therefore may increase the serotonergic effects of triptans. These medications should not be taken together [1,5]
- Metabolism and clearance
- CYP3A4 - sensitive substrate and inhibitor
- P-glycoprotein - substrate and inhibitor
- LONG-TERM SAFETY
- Cycloset® was FDA approved in 2009
- Bromocriptine has been used for years in other conditions and has generally been shown to be safe
- DOSING
- Dosage forms
- 0.8 mg tablet
- Dosing
- Starting: 0.8 mg once daily
- Maintenance: 4.8 mg (6 tablets) once daily
- Max: 4.8 mg once daily
- Increase in increments of 0.8 mg every 7 days
- Nausea may limit maximum dose
- Take in morning within 2 hours of waking
- Take with food to decrease gastrointestinal side effects
- Price
- No generic | One month of therapy > $150
- BIBLIOGRAPHY
- 1 - Cycloset PI
- 2 - PMID 21447659
- 3 - PMID 20332352
- 4 - PMID 18945920
- 5 - PMID 12388668
- 6 - PMID 11139820