Michael Ezrokhi

Randomized clinical trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes.

OBJECTIVE Quick-release bromocriptine (bromocriptine-QR), a D2 dopamine receptor agonist, is indicated as a treatment for type 2 diabetes. The Cycloset Safety Trial, a 52-week, randomized, double-blind, multicenter trial, evaluated the overall safety and cardiovascular safety of this novel therapy for type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 3,095 patients with type 2 diabetes were randomized 2:1 to bromocriptine-QR or placebo in conjunction with the patients usual diabetes therapy (diet controlled only or up to two antidiabetes medications, including insulin). The all-cause–safety end point was the occurrence of any serious adverse event (SAE), with a hazard ratio (HR) noninferiority margin of 1.5. In a prespecified analysis, the frequency of cardiovascular disease (CVD) events defined as a composite of myocardial infarction, stroke, coronary revascularization, and hospitalization for angina or congestive heart failure was evaluated using modified intent-to-treat analysis (clinicaltrials.gov, NCT00377676). RESULTS In the bromocriptine-QR group, 176 (8.6%) people reported SAEs compared with 98 (9.6%) in the placebo group (HR 1.02 [96% one-sided CI 1.27]). Fewer people reported a CVD end point in the bromocriptine-QR group versus the placebo group (37 [1.8%] vs. 32 [3.2%], respecively) (HR 0.60 [95% two-sided CI 0.35–0.96]). Nausea was the most commonly reported adverse event in the bromocriptine-QR group. CONCLUSIONS The frequency of SAEs was comparable between the treatment arms. Compared with patients in the placebo arm, fewer patients taking bromocriptine-QR experienced a cardiovascular end point.

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

BackgroundCycloset™ is a quick-release formulation of bromocriptine mesylate, a dopamine agonist, which in animal models of insulin resistance and type 2 diabetes acts centrally to reduce resistance to insulin- mediated suppression of hepatic glucose output and tissue glucose disposal. In such animals, bromocriptine also reduces hepatic triglyceride synthesis and free fatty acid mobilization, manifesting decreases in both plasma triglycerides and free fatty acids. In clinical trials, morning administration of Cycloset™ either as monotherapy or adjunctive therapy to sulfonylurea or insulin reduces HbA1c levels relative to placebo by 0.55–1.2. Cycloset™ therapy also reduces plasma triglycerides and free fatty acid by approximately 25% and 20%, respectively, among those also receiving sulfonylurea therapies. The effects of once-daily morning Cycloset™ therapy on glycemic control and plasma lipids are demonstrable throughout the diurnal portion of the day (7 a.m. to 7 p.m.) across postprandial time points.Methods/Design3,095 individuals were randomized in a 2:1 ratio into a one year trial aimed to assess the safety and efficacy of Cycloset™ compared to placebo among individuals receiving a variety of treatments for type 2 diabetes. Eligibility criteria for this randomized placebo controlled trial included: age 30–80, HbA1c ≤ 10%, diabetes therapeutic regimen consisting of diet or no more than two hypoglycemic agents or insulin with or without one additional oral agent (usual diabetes therapy; UDT). The primary safety endpoint will test the hypothesis that the rate of all-cause serious adverse events after one year of usual diabetes therapy (UDT) plus Cycloset™ is not greater than that for UDT plus placebo by more than an acceptable margin defined as a hazard ratio of 1.5 with a secondary endpoint analysis of the difference in the rate of serious cardiovascular events, (myocardial infarction, stroke, coronary revascularization or hospitalization for or angina or congestive heart failure). Efficacy analyses will evaluate effects of Cycloset™ versus placebo on change from baseline in HbA1c, fasting glucose, body weight, waist circumference, blood pressure and plasma lipids.DiscussionThis study will extend the current data on Cycloset™ safety, tolerability and efficacy in individuals with type 2 diabetes to include its effects in combination with thiazolodinediones, insulin secretagogues, metformin, alpha-glucosidase inhibitors and exogenous insulin regimens.Trial registrationclinical trials.gov NCT00377676

Effect of bromocriptine-QR on glycemic control in subjects with uncontrolled hyperglycemia on one or two oral anti-diabetes agents.

OBJECTIVE To investigate the effect of Bromocriptine-QR on glycemic control in patients with type 2 diabetes whose glycemia is poorly controlled on one or two oral anti-diabetes agents. METHODS Five hundred fifteen Type 2 Diabetes Mellitus (T2DM) subjects (ages 18 to 80 and average body mass index [BMI] of 32.7) with baseline HbA1c ≥ 7.5 and on one or two oral anti-diabetes (OAD) medications (metformin, sulfonylurea, and/or thiazolidinediones) were randomized 2:1 to bromocriptine-QR (1.6 to 4.8 mg/day) or placebo for a 24 week treatment period. Study investigators were allowed to adjust, if necessary, subject anti-diabetes medications during the study to attempt to achieve glycemic control in case of glycemic deterioration. The impact of bromocriptine-QR treatment intervention on glycemic control was assessed in subjects on any one or two OADs (ALL treatment category) (N = 515), or on metformin with or without another OAD (Met/OAD treatment category) (N = 356), or on metformin plus a sulfonylurea (Met/SU treatment category) (N = 245) 1) by examining the between group difference in change from baseline a) concomitant OAD medication changes during the study, and b) HbA1c and 2) by determining the odds of reaching HbA1c of ≤ 7.0% on bromocriptine-QR versus placebo. RESULTS Significantly more patients (approximately 1.5 to 2-fold more; P<.05) intensified concomitant anti-diabetes medication therapy during the study in the placebo versus the bromocriptine-QR arm. In subjects that did not change the intensity of the baseline diabetes therapy (72%), and that were on any one or two OADs (ALL), or on metformin with or without another OAD (Met/OAD), or on metformin plus sulfonylurea (Met/SU), the HbA1c change for bromocriptine-QR versus placebo was -0.47 versus +0.22 (between group delta of -0.69, P<.0001), -0.55 versus +0.26 (between group delta of -0.81, P<.0001) and -0.63 versus +0.20 (between group delta of -0.83, P<.0001) respectively, after 24 weeks on therapy. The odds ratio of reaching HbA1c of ≤ 7.0% was 6.50, 12.03 and 11.45 (P<.0002) for these three groups, respectively. CONCLUSION In T2DM subjects whose hyperglycemia is poorly controlled on one or two oral agents, bromocriptine-QR therapy for 24 weeks can provide significant added improvement in glycemic control relative to adding placebo.

Randomized Clinical Trial Assessing the Efficacy and Safety of Bromocriptine-QR when Added to Ongoing Thiazolidinedione Therapy in Patients with Type 2 Diabetes Mellitus

Aims: To evaluate the glycemic control efficacy and cardio-metabolic safety of bromocriptine- quick release (Bromocriptine-QR) among subjects with type 2 diabetes who were taking a thiazolidinedione (TZD) at baseline. Methods: A subgroup from the Cycloset Safety trial who were taking a TZD at baseline with or without another oral anti-diabetes medication were randomized to receive additional once daily (morning) bromocriptine-QR (1.6 - 4.8 mg/day) or placebo for up to 52 weeks. Glycemic efficacy analyses were based on intent to treat modified (ITTm) and evaluable per protocol (EPP) population using general linear model after adjusting for baseline covariates and stratified by A1C level of <7.5 of ≥7.5. The odds ratio of participants achieving A1C ≤7% were calculated. Similar analyses for safety were performed on weight and hypoglycemia. Results: In this trial 495 subjects were taking a TZD at baseline and 122 also had a baseline A1C of ≥7.5. For subjects with an A1C of ≥7.5, bromocriptine-QR treatment led to significant reduction in A1C (ITTm -0.81%, p=0.001and EPP -0.91%, p=0.002), fasting plasma glucose (ITTm -21.5 mg/dl, p=0.03 and EPP -20.5 mg/dl, p=0.05), and higher frequency achieving an A1C≤7% (32.1% vs. 15.9%, p=0.05) when compared with placebo. For subjects with a baseline A1C of <7.5, subjects randomized to bromocriptine-QR had a greater odds of having an A1C level of ≤7.0 (OR 2.74, 95% CI 1.45, 5.15; p =0.002). Treatment with bromocriptine-QR had no adverse impact on weight or risk of hypoglycemia. Conclusion: Daily morning bromocriptine-QR added to ongoing TZD treatment for uncontrolled type 2 diabetes improved glycemic control and was well tolerated.

Timed Bromocriptine-QR Therapy Reduces Progression of Cardiovascular Disease and Dysglycemia in Subjects with Well-Controlled Type 2 Diabetes Mellitus

Background. Type 2 diabetes (T2DM) patients, including those in good glycemic control, have an increased risk of cardiovascular disease (CVD). Maintaining good glycemic control may reduce long-term CVD risk. However, other risk factors such as elevated vascular sympathetic tone and/or endothelial dysfunction may be stronger potentiators of CVD. This study evaluated the impact of bromocriptine-QR, a sympatholytic dopamine D2 receptor agonist, on progression of metabolic disease and CVD in T2DM subjects in good glycemic control (HbA1c ≤7.0%). Methods. 1834 subjects (1219 bromocriptine-QR; 615 placebo) with baseline HbA1c ≤7.0% derived from the Cycloset Safety Trial (this trial is registered with ClinicalTrials.gov Identifier: NCT00377676), a 12-month, randomized, multicenter, placebo-controlled, double-blind study in T2DM, were evaluated. Treatment impact upon a prespecified composite CVD endpoint (first myocardial infarction, stroke, coronary revascularization, or hospitalization for angina/congestive heart failure) and the odds of losing glycemic control (HbA1c >7.0% after 52 weeks of therapy) were determined. Results. Bromocriptine-QR reduced the CVD endpoint by 48% (intention-to-treat; HR: 0.52 [0.28−0.98]) and 52% (on-treatment analysis; HR: 0.48 [0.24−0.95]). Bromocriptine-QR also reduced the odds of both losing glycemic control (OR: 0.63 (0.47−0.85), p = 0.002) and requiring treatment intensification to maintain HbA1c ≤7.0% (OR: 0.46 (0.31−0.69), p = 0.0002). Conclusions. Bromocriptine-QR therapy slowed the progression of CVD and metabolic disease in T2DM subjects in good glycemic control.

Cycloset (Quick-Release Bromocriptine Mesylate), a Novel Centrally Acting Treatment for Type 2 Diabetes

Young adulthood is a time of change when diabetes control often deteriorates. Prior to 2002, 40% of young people with diabetes in our region did not attend specialist clinics, precipitating the establishment of a purpose-designed transition clinic. This study reviewed the efficacy of the young adult clinic over the last three years. Up to October 2007, ninety-three young people had attended the clinic (51 male, age 21.2(18-24) years, diabetes duration 10.8±0.5 years). Two patients had Type 2 diabetes (on oral hypoglycaemic agents) and 64 (69%) were on multiple daily injections of insulin. Mean HbA1c was 9.3±0.2% with 18 (19%) achieving a target HbA1c <7.5%. Over the study period, 522 clinic appointments were made with 437 (84%) attended, 20 (4%) cancelled by the patient and 65 (12%) not attended. Four patients moved from the area. Among the 89 remaining patients, 74 (83%) attended for annual review in the previous fifteen months, with 69 (78%) undergoing digital retinal screening, 71 (80%) foot surveillance, and 52 (58%) providing a urine sample for microalbuminuria. Among those screened, prevalence of retinopathy (any grade) was 45% and microalbuminuria 10%. Although glycaemic control is sub-optimal for the majority of young adults, the establishment of a transition clinic has improved attendance and resulted in high rates of screening for complications. Determination of microalbuminuria remains problematic, requiring the patient to supply a urine sample and alternative biomarkers may be of benefit in this population. Cycloset (Quick-Release Bromocriptine Mesylate), a Novel Centrally Acting Treatment for Type 2 Diabetes ANTHONY H CINCOTTA, J MICHAEL GAZIANO, MICHAEL EZROKHI , RICHARD E SCRANTON Veroscience, Tiverton, RI, Harvard Medical School, Boston, MA,

Impact of bromocriptine-QR therapy on cardiovascular outcomes in type 2 diabetes mellitus subjects on metformin

ABSTRACT Objectives: Type 2 diabetes mellitus (T2DM) is associated with a substantially increased risk of cardiovascular disease (CVD). Bromocriptine-QR (B-QR), a quick release sympatholytic dopamine D2 receptor agonist, is a FDA-approved therapy for T2DM which may provide CVD risk reduction. Metformin is considered to be an agent with a potential cardioprotective benefit. This large placebo controlled clinical study assessed the impact of B-QR addition to existing metformin therapy on CVD outcomes in T2DM subjects. Methods: 1791 subjects (1208 B-QR; 583 placebo) on metformin ± another anti-diabetes therapy at baseline derived from the Cycloset Safety Trial, a 12-month, randomized, multicenter, placebo-controlled, double-blind study in T2DM, were included in this study. The primary CVD endpoint evaluated was treatment impact on CVD event rate, prespecified as a composite of time to first myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina/congestive heart failure. Impact on glycemic control was evaluated as a secondary analysis. Results: The composite CVD end point occurred in 16/1208 B-QR treated (1.3%) and 18/583 placebo treated (3.1%) subjects resulting in a 55% CVD hazard risk reduction (intention-to-treat, Cox regression analysis; HR: 0.45 [0.23–0.88], p = 0.028). Kaplan-Meier curves demonstrated a significantly lower cumulative incidence rate of the CVD endpoint in the B-QR treatment group (Log-Rank p = 0.017). In subjects with poor glycemic control (HbA1c ≥ 7.5) at baseline, B-QR therapy relative to placebo resulted in a significant mean %HbA1c reduction of −0.59 at week 12 and −0.51 at week 52 respectively (p < 0.001 for both) and a 10 fold higher percent of subjects achieving HbA1c goal of ≤7% by week 52 (B-QR 30%, placebo 3%; p = 0.003). Conclusion: These findings suggest that in T2DM subjects on metformin, BQR therapy may represent an effective strategy for reducing CVD risk. Cycloset Safety Trial registration: ClinicalTrials.gov Identifier: NCT00377676.