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General Information

Cycloset is a quick release formulation of micronized bromocriptine mesylate (bromocriptine-QR). It is a dopamine receptor agonist.

Cycloset is specifically indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Cycloset is supplied as a tablet designed for oral administration. The recommended initial dose of the drug is 1.6 mg to 4.8 mg administered once daily within two hours after waking in the morning. Cycloset should be initiated at one tablet (0.8 mg) and increased by one tablet per week until a maximum daily dose of 6 tablets (4.8 mg) or until the maximal tolerated number of tablets between 2 and 6 per day is reached.

Clinical Results

FDA Approval
The FDA approval of Cyloset was based on the results of four clinical trials; a 24-week monotherapy trial, two 24-week add-on to sulfonylurea trials and a 52-week safety trial. In all four clinical trials, subjects assigned to treatment with Cycloset received an initial dose of 0.8 mg, which was increased by 0.8 mg each week for 6 weeks (4.8 mg/day final dose) if no intolerance occurred or until the maximum tolerated dose > 1.6 mg/day was reached.

Monotherapy Trial
This 24-week, double-blind, placebo-controlled study enrolled 159 overweight adults with type II diabetes and inadequate glycemic control. The trial was designed to evaluate the efficacy and safety of Cycloset as an adjunct to diet and exercise. Of the 80 subjects in the Cycloset group, 69% (N=55) achieved the maximum daily dose of 4.8 mg. Cycloset improved HbA1c and fasting plasma glucose compared to placebo. Mean HbA1c at baseline was 9.0% in the Cycloset group and 8.8% in the placebo group. The 24-week change from baseline was -0.1 in the Cycloset arm and 0.3 in the placebo arm (a -0.4 difference from placebo; p≡0.05). The mean baseline fasting plasma glucose (mg/dl) was 215 in the Cycloset arm and 205 in the placebo arm. At 24 weeks, the adjusted mean change from placebo was -23 (p=0.005). Mean change from baseline in body weight was +0.2 kg in the Cycloset group and +0.5 kg in the placebo group.

Combination Therapy
Study L This 24-week, randomized, double-blind, placebo-controlled trial enrolled 249 subjects with type 2 diabetes and inadequate glycemic control (HbA1c 7.8-12.5%) on sulfonylurea therapy. The study was designed to evaluate the safety and glycemic efficacy of Cycloset when added to stable sulfonylurea therapy versus placebo plus sulfonylurea. The mean baseline HbA1C was 9.3% in the Cycloset arm and 9.4% in the placebo arm. At 24 weeks, the adjusted mean from baseline was -0.4% and 0.3 for Cycloset and placebo, respectively (-0.6 difference; p< 0.001). The baseline FPG was 220 mg/dl in the Cycloset arm and 226 mg/dl in the placebo arm. At 24 weeks, the adjusted mean change from baseline was 3 mg/dl and 23 mg/dl, respectively (-20 difference; p≡0.006). The mean change from baseline in body weight was +0.9 kg in the Cycloset group and +0.5 kg in the placebo group. Study K This 24-week, randomized, double-blind, placebo-controlled trial enrolled 245 subjects with type II diabetes and inadequate glycemic control (HbA1c 7.8-12.5 %) on stable sulfonylurea therapy who were randomized to add-on therapy with either Cycloset or placebo. Of the 122 subjects in the Cycloset group, 91 (75%) achieved the maximum dose of study drug. Mean change from baseline in body weight was +1.4 kg in the Cycloset group and +0.5 kg in the placebo group. The mean baseline HbA1C was 9.3% in the Cycloset arm and 9.4% in the placebo arm. At 24 weeks, the adjusted mean from baseline was -0.1% and 0.4% for Cycloset and placebo, respectively (-0.5 difference; p< 0.001). The baseline FPG was 216 mg/dl in the Cycloset arm and 227 mg/dl in the placebo arm. At 24 weeks, the adjusted mean change from baseline was 10 mg/dl and 28 mg/dl, respectively (-18 difference; p≡0.02).

Cycloset add-on to various oral anti-diabetic agents: 52 week safety trial
This randomized, double-blind, placebo-controlled safety trial enrolled approximately 3,000 subjects with type II diabetes receiving various anti-diabetic therapies (mean baseline HbA1c 8.3%). Approximately 70% of subjects assigned to treatment with Cycloset reached the maximum daily dose of 4.8 mg. Mean baseline HbA1c was 7.0% in both treatment groups. The least-squares mean change in HbA1c from baseline to Week 24 was 0.0% with Cycloset and +0.2% with placebo. Subjects receiving Cycloset, compared to placebo, experienced a significant improvement in HbA1c when used as adjunctive therapy to 1-2 oral antidiabetic medications, including the subgroup of patients treated only with background metformin + sulfonylurea. The mean change in body weight for the glycemic efficacy subgroup from baseline to Week 24 was -0.1 kg with Cycloset and +0.1 kg. The mean change in body weight for the entire study population from baseline to Week 52 was +0.2 kg with Cycloset and +0.1 kg with placebo.

Additional Trials:

Patients with type 2 diabetes and inadequate glycemic control on diet alone were randomized to Cycloset or placebo in a 24-week monotherapy clinical trial. At baseline and study end, plasma samples for insulin and glucose were obtained before and 1 hour, and 2 hours after standardized meals for breakfast, lunch, and dinner. In this trial, once-daily (8am) Cycloset improved postprandial glucose without increasing plasma insulin concentrations.

Patients with type 2 diabetes and inadequate glycemic control on sulfonylurea therapy were randomized to Cycloset or placebo in a 16-week clinical trial. In this trial Cycloset therapy improved insulin-mediated glucose disposal and glucose tolerance and resulted in lower plasma glucose and HbA1c levels.

Ongoing Study Commitments

VeroScience has agreed to a deferred pediatric bioavailability study: To Assess the Safety, Tolerability and Pharmacokinetics of Cycloset in 10 to 16 year old Type 2 Diabetic Subjects
Final Protocol Submission Date: No later than December 31, 2009
Study Completion Date: No later than August 31, 2010
Final Study Report Submission Date: No later than October 31, 2010 Study has been completed.
VeroScience has agreed to a deferred pediatric feasibility study: A Randomized, Double-Blind, Controlled Study To Assess the Use and Effectiveness of Cycloset in Children Aged 10 to 16 With a Diagnosis of Type 2 Diabetes Mellitus
Final Protocol Submission Date: No later than November 30, 2010
Study Completion Date: No later than October 31, 2012
Final Study Report Submission Date: No later than March 31, 2013 Study no longer required to complete
VeroScience has agreed to a deferred clinical efficacy and safety study: A Pivotal, Randomized, Double-Blind, Controlled, Efficacy and Safety Study of the Use of Cycloset for the Treatment of Type 2 Diabetes Mellitus in Children Aged 10- 16 years with a Diagnosis of Type 2 Diabetes Mellitus
Final Protocol Submission Date: No later than August 31, 2013
Study Completion Date: No later than February 28, 2015
Final Study Report Submission Date: No later than July 31, 2015 Submission date has been extended to 2020

Side Effects

Adverse events associated with the use of Cycloset may include, but are not limited to, the following:

Nausea
Dizziness
Fatigue
Headache
Vomiting
Diarrhea
Constipation

Mechanism of Action

Cycloset contains bromocriptine mesylate, a sympatholytic, dopamine D2 receptor agonist. In patients with type 2 diabetes, timed morning administration of Cycloset is associated with increased insulin sensitivity and glucose disposal and reduced fasting and postprandial hyperglycemia throughout the meals of the day without raising plasma insulin levels. Cycloset contains bromocriptine mesylate, a sympatholytic, dopamine D2 receptor agonist. In patients with type 2 diabetes, timed morning administration of Cycloset is associated with increased insulin sensitivity, glucose disposal, reduced fasting, and postprandial hyperglycemia throughout the meals of the day without raising plasma insulin levels.

Literature References

Scranton RE, Gaziano JM, Rutty D, Ezrokhi M, Cincotta A A randomized, double-blind, placebo-controlled trial to assess safety and tolerability during treatment of type 2 diabetes with usual diabetes therapy and either Cycloset or placebo. BMC endocrine disorders 2007 Jun 25;7:3

Aminorroaya A, Janghorbani M, Ramezani M, Haghighi S, Amini M Does bromocriptine improve glycemic control of obese type-2 diabetics? Hormone Research 2004;62(2):55-9

Pijl H, Edo AM Modulation of monoaminergic neural circuits: potential for the treatment of type 2 diabetes mellitus. Treatments in Endocrinology 2002;1(2):71-8

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 Opinion on Investigational Drugs 1999 Oct;8(10):1683-1707

Bindu Chamarthi, Anthony H. Cincotta (2017) Effect of bromocriptine-QR therapy on glycemic control in subjects with type 2 diabetes mellitus whose dysglycemia is inadequately controlled on insulin. Postgraduate Medicine 129:4, pages 446-455.

Bindu Chamarthi, Michael Ezrokhi, Dean Rutty, Anthony H. Cincotta. (2016) Impact of bromocriptine-QR therapy on cardiovascular outcomes in type 2 diabetes mellitus subjects on metformin. Postgraduate Medicine 128:8, pages 761-769.