the cycloset safety trial study protocol has been previously published in abbreviated form ( 11 ) . eligible patients had type 2 diabetes , as defined by the 2004 american diabetes association guidelines ( 18 ) , were between the ages of 30 and 80 years , had a bmi of < 43 kg / m , and an a1c level 10.0% . exclusion criteria were current chronic ( greater than 10 days ) use of prescription sympathomimetic drugs , ergot alkaloid derivatives , or abortive migraine medications , clinically significant comorbid conditions such as uncontrolled hypertension , new york heart classification ( nyhc ) iii - iv congestive heart failure , renal failure , or cancer ( other than nonmelanoma skin or nonmetastatic prostate cancer ) within the past 5 years . patients with nyhc i - ii congestive heart failure were allowed in the trial as were those with significant cardiovascular disease , including a cardiovascular event prior to 6 months before screening . patients were required to be on a stable antidiabetes regimen consisting of either diet , oral hypoglycemic agents ( no more than two ) , or insulin ( alone or with no more than one oral hypoglycemic agent ) for at least 30 days prior to randomization after a two - week lead - in period . patients were randomized in a 2:1 ratio to their usual antidiabetes regimen plus bromocriptine - qr or placebo taken with their morning meal . during the first 6 weeks of the study , the daily dose of the study drug was titrated up by one tablet ( 0.8 mg ) per day on a weekly basis until a maximal dose of up to six tablets ( 4.8 mg ) per day was achieved or until the patient could not tolerate a higher dose . patients were required to continue their usual antidiabetes regimen during the first 3 months of the study but were allowed to alter the dosages of these medications to optimize blood glucose control as deemed appropriate by the site investigator ( 19 ) . after 3 months , alterations to antidiabetes medications ( elimination or addition of an agent ) were allowed when necessary , but if a medication was added the final regimen was limited to no more than two oral antidiabetes agents , or no more than one antidiabetes agent if taking insulin . during the first 6 weeks of the study , patients were called weekly , had office visits at weeks 3 and 6 , and then visits every 3 months until the study end ( week 52 ) or early termination . patients were contacted 30 days after stopping a study drug to record any adverse events that occurred after cessation . physical exams and laboratory assessments ( blood chemistries , hematology , and urine analyses ) were obtained at baseline , week 24 , and week 52 or study termination . the study protocol was approved by each va hospital institutional review board and a central or academic - affiliated institutional review board for non - va centers . there were two main objectives of the cycloset safety trial : 1 ) assessment of overall safety of bromocriptine - qr by measuring the frequency of serious adverse events ( saes ) among patients taking bromocriptine - qr and placebo , and 2 ) cardiovascular safety assessed by determining the frequency of major cardiovascular events , defined as a composite of first myocardial infarction , stroke , coronary revascularization , or hospitalization for angina or congestive heart failure that occurred after randomization . an independent adverse event adjudication committee ( aeac ) consisting of two cardiologists and an endocrinologist , blinded to treatment assignment and medical dictionary for regulatory activities ( meddra ) coding of events by the study team , made the final sae system organ class ( soc ) classifications and assignment of an sae as a cardiovascular end point . additional safety measures included laboratory measures ( blood chemistries , hematology , and urine analyses ) at weeks 0 , 24 , and 52 of the study and evaluation of electrocardiograms ( ecgs ) at weeks 0 , 24 , 52 or early termination . an analysis of noninferiority tested the hypothesis that usual antidiabetes therapy ( uadt ) plus bromocriptine - qr is not inferior to that of uadt plus placebo in terms of the occurrence of all - cause saes using a one - sided  = 0.05 level . in order to test the primary hypothesis at a one - sided  = 0.05 and with a power of one  = 0.90 when the noninferiority margin is 1.5 , the total number of patients with all - cause saes needed during the study was calculated to be 235 . all randomized patients that took at least one dose of study drug were included in the all - cause sae analysis . saes that occurred on a study drug or within 30 days of stopping a study drug were considered as treatment emergent events . statistical testing between the two groups was conducted using the two - sided 91.9% ci for the rate ratio of all - cause saes because this provides the same confidence boundaries as a one - sided 96% ci . the ci was estimated by the corresponding estimate for the hazard ratio ( hr ) with cox regression analysis with consideration for possible center interaction . the analysis of the composite cardiovascular endpoint used the modified intent - to - treat population of patients receiving at least one dose of a study drug . superiority or noninferiority between bromocriptine - qr and placebo for the composite cvd end point was defined as the upper bound of the two - sided 95% confidence limit being < 0 and < 1.5 , respectively . assuming a cvd composite event rate of 3.4% , this sample size provided a power of 75% to demonstrate cvd noninferiority . upon confirming noninferiority , a sequential superiority analysis of cvd end point based on the cox proportional - hazards regression with two - sided p values analysis of the cvd end point was conducted adjusting for baseline covariates including history of stroke and cardiovascular revascularization and center . changes in laboratory measures were assessed using the wilcoxon rank sum test except for a1c , which was based on a general linear model with baseline and treatment as fixed effects . the significant level was set at p < 0.05 . ( toronto , canada ) using sas software version 8.2 ( cary , nc ) . there were two main objectives of the cycloset safety trial : 1 ) assessment of overall safety of bromocriptine - qr by measuring the frequency of serious adverse events ( saes ) among patients taking bromocriptine - qr and placebo , and 2 ) cardiovascular safety assessed by determining the frequency of major cardiovascular events , defined as a composite of first myocardial infarction , stroke , coronary revascularization , or hospitalization for angina or congestive heart failure that occurred after randomization . an independent adverse event adjudication committee ( aeac ) consisting of two cardiologists and an endocrinologist , blinded to treatment assignment and medical dictionary for regulatory activities ( meddra ) coding of events by the study team , made the final sae system organ class ( soc ) classifications and assignment of an sae as a cardiovascular end point . additional safety measures included laboratory measures ( blood chemistries , hematology , and urine analyses ) at weeks 0 , 24 , and 52 of the study and evaluation of electrocardiograms ( ecgs ) at weeks 0 , 24 , 52 or early termination . an analysis of noninferiority tested the hypothesis that usual antidiabetes therapy ( uadt ) plus bromocriptine - qr is not inferior to that of uadt plus placebo in terms of the occurrence of all - cause saes using a one - sided  = 0.05 level . in order to test the primary hypothesis at a one - sided  = 0.05 and with a power of one  = 0.90 when the noninferiority margin is 1.5 , the total number of patients with all - cause saes needed during the study was calculated to be 235 . all randomized patients that took at least one dose of study drug were included in the all - cause sae analysis . saes that occurred on a study drug or within 30 days of stopping a study drug were considered as treatment emergent events . statistical testing between the two groups was conducted using the two - sided 91.9% ci for the rate ratio of all - cause saes because this provides the same confidence boundaries as a one - sided 96% ci . the ci was estimated by the corresponding estimate for the hazard ratio ( hr ) with cox regression analysis with consideration for possible center interaction . the analysis of the composite cardiovascular endpoint used the modified intent - to - treat population of patients receiving at least one dose of a study drug . superiority or noninferiority between bromocriptine - qr and placebo for the composite cvd end point was defined as the upper bound of the two - sided 95% confidence limit being < 0 and < 1.5 , respectively . assuming a cvd composite event rate of 3.4% , this sample size provided a power of 75% to demonstrate cvd noninferiority . upon confirming noninferiority , a sequential superiority analysis of cvd end point based on the cox proportional - hazards regression with two - sided p values analysis of the cvd end point was conducted adjusting for baseline covariates including history of stroke and cardiovascular revascularization and center . changes in laboratory measures were assessed using the wilcoxon rank sum test except for a1c , which was based on a general linear model with baseline and treatment as fixed effects . the significant level was set at p < 0.05 . ( toronto , canada ) using sas software version 8.2 ( cary , nc ) . a total of 4,074 patients were screened and 879 patients were excluded for not meeting eligibility criteria , withdrawal of consent , or other reasons . of the 3,070 patients that received a study drug , 47% stopped treatment on bromocriptine - qr and the on treatment exposure time was 1,643 person - years and 914 person - years for bromocriptine - qr and placebo , respectively , which represents 77 and 86% of the expected person - time , respectively . additionally , 82% of the study patients had final assessments , which accounts for 91% of the expected person time for this trial ( 2,906 of 3,193 possible total person - years ) ( appendix iv , figure a , available in an online appendix at http://care.diabetesjournals.org/cgi/content/full/dc09-2009/dc1 ) . the study included a diverse population of patients with type 2 diabetes ( table 1 ) with the majority of patients receiving cardioprotective medications . on average for the study population , the baseline a1c , lipid , and blood pressure values indicated reasonably good control of hyperglycemia , dyslipidemia , and hypertension , respectively ; however , the presence of cardiovascular disease was still prevalent . overall , there were no differences in baseline characteristics between the groups that would not be expected by chance . saes occurred among 9.6% of placebo - treated patients versus 8.6% of bromocriptine - qr  treated patients . aside from the cardiac soc class , the frequency of all remaining saes grouped by soc was similar between bromocriptine - qr and placebo . it should be noted that the cardiac soc includes a much broader definition comprising thirty - seven preferred terms ( i.e. , arrhythmia , chest pain , syncope ) as opposed to the prespecified cardiovascular end point . saes by soc and all - cause safety and composite cardiovascular end point * soc as determined by meddra coding of preferred term provided by study investigator . patients may appear in more than one system organ category if they experienced multiple aes belonging to different socs . all saes were adjudicated by an independent aeac . * * the cardiac soc includes 37 different preferred terms such as arrhythmia , myocardial infarction , chest pain , and coronary artery disease ; however the composite cardiovascular end point comprised events that met the prespecified end point criteria set forth by an independent aeac that was blinded to treatment assignment . patients may appear in more than one component of the composite cardiovascular end point if they experienced multiple cardiovascular aes . in the analysis of time to first all - cause sae , the and upper bound of the one - sided confidence limit support noninferiority between bromocriptine - qr and placebo , ( hr 1.02 [ 96% one - sided ci 1.27 ] ) . the treatment effect did not change appreciably with the addition of the baseline covariates of age , duration of diabetes , insulin usage , sex and race . the composite cvd end point occurred in 37 bromocriptine - qr  treated ( 1.8% ) and 32 placebo - treated ( 3.2% ) patients resulting in a 40% cvd relative risk reduction ( hr 0.60 [ 95% two - sided ci 0.370.96 ] ; table 2 ) . the observed cvd risk reduction did not change appreciably with the addition of the baseline covariates of age , baseline a1c level , sex , race , and prior history of stroke or prior history of coronary revascularization . figure 1 shows the kaplan - meier estimates of the proportion of patients by treatment that experienced an event within the composite end point and demonstrates a clear separation in the curves that begins after 3 months of treatment . kaplan - meier curve of the occurrence of the prespecified composite cardiovascular end point among patients randomized to bromocriptine - qr or placebo . the composite cardiovascular end point consisted of the time to first myocardial infarction , stroke , coronary revascularization , hospitalization for unstable angina , or hospitalization for congestive heart failure that occurred after randomization . the hazard ratio of bromocriptine - qr versus placebo for the occurrence of the composite cardiovascular end point was 0.60 ( 95% ci 0.370.96 ) . the effect of treatment was estimated from the unadjusted cox proportional - hazard model that used all the available data . the frequency of deaths that occurred while on a study drug or within 30 days of stopping a study drug was similar between the treatment groups ( 0.19% bromocriptine - qr , 0.20% placebo ) . five patients randomized to bromocriptine - qr and one randomized to placebo died in excess of 30 days after stopping the study drug . adverse events ( aes ) occurred in 89% of bromocriptine - qr  treated and 83% of placebo - treated patients . aes were not commonly reported as severe in either treatment group ( 17% events reported as severe on bromocriptine - qr compared with 14% on placebo ) . more patients discontinued bromocriptine - qr than placebo due to an adverse event ( 24% vs. 11% , respectively ) . the most commonly reported adverse event among patients who discontinued bromocriptine - qr was nausea ( 7.6% bromocriptine - qr vs. 1% placebo ) . the only aes that occurred at a frequency rate of at least 5% and were numerically greater in the bromocriptine - qr arm were nausea , vomiting , dizziness , headache , and diarrhea . nausea was the most common adverse event ( 32.2% bromocriptine - qr vs. 7.6% placebo ) . the majority of the commonly occurring adverse events attributed to bromocriptine - qr occurred during the initial titration phase were dose related and transient in nature ( mean duration of < 14 days ) . after the initial titration phase , commonly occurring adverse events were reported at a frequency similar to that observed in the placebo treated arm . somnolence ( 4.3 bromocriptine - qr vs. 1.3% placebo ) and hypoesthesia ( 1.4 bromocriptine - qr vs. 1.1% placebo ) were the only aes within the nervous system organ class that were reported at a rate of < 5% and 1% and that occurred at a numerically greater frequency among bromocriptine - qr - treated patients . additionally , 15 ( 0.7% ) of patients on bromocriptine - qr and 14 ( 1.4% ) on placebo reported depression or depressed mood , and 13 ( 0.6% ) patients on bromocriptine - qr and 8 ( 0.8% ) on placebo reported anxiety . hypoglycemic aes occurred infrequently , with 6.9% bromocriptine - qr patients reporting an event versus 5.3% in the placebo - treated arm . there were no significant differences between the treatment arms in changes from baseline in hematology or chemistry laboratory values . there were minimal changes from baseline in lipid measures and blood pressure in both groups ( online appendix iv , table b ) . compared with those on placebo , heart rate among patients randomized to bromocriptine - qr decreased 1 bpm from a baseline study population mean heart rate of 68 bpm at week 52 ( p = 0.02 ) . the corrected qt interval decreased , albeit nonsignificantly , from baseline to week 52 among bromocriptine - qr  treated patients by 3.2 ms ( baseline average 418 ms ) and by 1.9 ms for the placebo arm ( baseline average 420 ms ) . there was no difference in the mean change in body weight from baseline to week 52 for either bromocriptine - qr ( + 0.2 kg ) or placebo ( + 0.1 kg ) . the study included a diverse population of patients with type 2 diabetes ( table 1 ) with the majority of patients receiving cardioprotective medications . on average for the study population , the baseline a1c , lipid , and blood pressure values indicated reasonably good control of hyperglycemia , dyslipidemia , and hypertension , respectively ; however , the presence of cardiovascular disease was still prevalent . overall , there were no differences in baseline characteristics between the groups that would not be expected by chance . saes occurred among 9.6% of placebo - treated patients versus 8.6% of bromocriptine - qr  treated patients . aside from the cardiac soc class , the frequency of all remaining saes grouped by soc was similar between bromocriptine - qr and placebo . it should be noted that the cardiac soc includes a much broader definition comprising thirty - seven preferred terms ( i.e. , arrhythmia , chest pain , syncope ) as opposed to the prespecified cardiovascular end point . saes by soc and all - cause safety and composite cardiovascular end point * soc as determined by meddra coding of preferred term provided by study investigator . patients may appear in more than one system organ category if they experienced multiple aes belonging to different socs . * * the cardiac soc includes 37 different preferred terms such as arrhythmia , myocardial infarction , chest pain , and coronary artery disease ; however the composite cardiovascular end point comprised events that met the prespecified end point criteria set forth by an independent aeac that was blinded to treatment assignment . patients may appear in more than one component of the composite cardiovascular end point if they experienced multiple cardiovascular aes . in the analysis of time to first all - cause sae , the and upper bound of the one - sided confidence limit support noninferiority between bromocriptine - qr and placebo , ( hr 1.02 [ 96% one - sided ci 1.27 ] ) . the treatment effect did not change appreciably with the addition of the baseline covariates of age , duration of diabetes , insulin usage , sex and race . the composite cvd end point occurred in 37 bromocriptine - qr  treated ( 1.8% ) and 32 placebo - treated ( 3.2% ) patients resulting in a 40% cvd relative risk reduction ( hr 0.60 [ 95% two - sided ci 0.370.96 ] ; table 2 ) . the observed cvd risk reduction did not change appreciably with the addition of the baseline covariates of age , baseline a1c level , sex , race , and prior history of stroke or prior history of coronary revascularization . figure 1 shows the kaplan - meier estimates of the proportion of patients by treatment that experienced an event within the composite end point and demonstrates a clear separation in the curves that begins after 3 months of treatment . kaplan - meier curve of the occurrence of the prespecified composite cardiovascular end point among patients randomized to bromocriptine - qr or placebo . the composite cardiovascular end point consisted of the time to first myocardial infarction , stroke , coronary revascularization , hospitalization for unstable angina , or hospitalization for congestive heart failure that occurred after randomization . the hazard ratio of bromocriptine - qr versus placebo for the occurrence of the composite cardiovascular end point was 0.60 ( 95% ci 0.370.96 ) . the effect of treatment was estimated from the unadjusted cox proportional - hazard model that used all the available data . the frequency of deaths that occurred while on a study drug or within 30 days of stopping a study drug was similar between the treatment groups ( 0.19% bromocriptine - qr , 0.20% placebo ) . five patients randomized to bromocriptine - qr and one randomized to placebo died in excess of 30 days after stopping the study drug . saes occurred among 9.6% of placebo - treated patients versus 8.6% of bromocriptine - qr  treated patients . aside from the cardiac soc class , the frequency of all remaining saes grouped by soc was similar between bromocriptine - qr and placebo . it should be noted that the cardiac soc includes a much broader definition comprising thirty - seven preferred terms ( i.e. , arrhythmia , chest pain , syncope ) as opposed to the prespecified cardiovascular end point . saes by soc and all - cause safety and composite cardiovascular end point * soc as determined by meddra coding of preferred term provided by study investigator . patients may appear in more than one system organ category if they experienced multiple aes belonging to different socs . * * the cardiac soc includes 37 different preferred terms such as arrhythmia , myocardial infarction , chest pain , and coronary artery disease ; however the composite cardiovascular end point comprised events that met the prespecified end point criteria set forth by an independent aeac that was blinded to treatment assignment . patients may appear in more than one component of the composite cardiovascular end point if they experienced multiple cardiovascular aes . in the analysis of time to first all - cause sae , the and upper bound of the one - sided confidence limit support noninferiority between bromocriptine - qr and placebo , ( hr 1.02 [ 96% one - sided ci 1.27 ] ) . the treatment effect did not change appreciably with the addition of the baseline covariates of age , duration of diabetes , insulin usage , sex and race . the composite cvd end point occurred in 37 bromocriptine - qr  treated ( 1.8% ) and 32 placebo - treated ( 3.2% ) patients resulting in a 40% cvd relative risk reduction ( hr 0.60 [ 95% two - sided ci 0.370.96 ] ; table 2 ) . the observed cvd risk reduction did not change appreciably with the addition of the baseline covariates of age , baseline a1c level , sex , race , and prior history of stroke or prior history of coronary revascularization . figure 1 shows the kaplan - meier estimates of the proportion of patients by treatment that experienced an event within the composite end point and demonstrates a clear separation in the curves that begins after 3 months of treatment . kaplan - meier curve of the occurrence of the prespecified composite cardiovascular end point among patients randomized to bromocriptine - qr or placebo . the composite cardiovascular end point consisted of the time to first myocardial infarction , stroke , coronary revascularization , hospitalization for unstable angina , or hospitalization for congestive heart failure that occurred after randomization . the hazard ratio of bromocriptine - qr versus placebo for the occurrence of the composite cardiovascular end point was 0.60 ( 95% ci 0.370.96 ) . the effect of treatment was estimated from the unadjusted cox proportional - hazard model that used all the available data . the frequency of deaths that occurred while on a study drug or within 30 days of stopping a study drug was similar between the treatment groups ( 0.19% bromocriptine - qr , 0.20% placebo ) . five patients randomized to bromocriptine - qr and one randomized to placebo died in excess of 30 days after stopping the study drug . saes occurred among 9.6% of placebo - treated patients versus 8.6% of bromocriptine - qr  treated patients . aside from the cardiac soc class , the frequency of all remaining saes grouped by soc was similar between bromocriptine - qr and placebo . it should be noted that the cardiac soc includes a much broader definition comprising thirty - seven preferred terms ( i.e. , arrhythmia , chest pain , syncope ) as opposed to the prespecified cardiovascular end point . saes by soc and all - cause safety and composite cardiovascular end point * soc as determined by meddra coding of preferred term provided by study investigator . patients may appear in more than one system organ category if they experienced multiple aes belonging to different socs . * * the cardiac soc includes 37 different preferred terms such as arrhythmia , myocardial infarction , chest pain , and coronary artery disease ; however the composite cardiovascular end point comprised events that met the prespecified end point criteria set forth by an independent aeac that was blinded to treatment assignment . patients may appear in more than one component of the composite cardiovascular end point if they experienced multiple cardiovascular aes . in the analysis of time to first all - cause sae , the and upper bound of the one - sided confidence limit support noninferiority between bromocriptine - qr and placebo , ( hr 1.02 [ 96% one - sided ci 1.27 ] ) . the treatment effect did not change appreciably with the addition of the baseline covariates of age , duration of diabetes , insulin usage , sex and race . the composite cvd end point occurred in 37 bromocriptine - qr  treated ( 1.8% ) and 32 placebo - treated ( 3.2% ) patients resulting in a 40% cvd relative risk reduction ( hr 0.60 [ 95% two - sided ci 0.370.96 ] ; table 2 ) . the observed cvd risk reduction did not change appreciably with the addition of the baseline covariates of age , baseline a1c level , sex , race , and prior history of stroke or prior history of coronary revascularization . figure 1 shows the kaplan - meier estimates of the proportion of patients by treatment that experienced an event within the composite end point and demonstrates a clear separation in the curves that begins after 3 months of treatment . kaplan - meier curve of the occurrence of the prespecified composite cardiovascular end point among patients randomized to bromocriptine - qr or placebo . the composite cardiovascular end point consisted of the time to first myocardial infarction , stroke , coronary revascularization , hospitalization for unstable angina , or hospitalization for congestive heart failure that occurred after randomization . all cardiovascular events were independently adjudicated . the hazard ratio of bromocriptine - qr versus placebo for the occurrence of the composite cardiovascular end point was 0.60 ( 95% ci 0.370.96 ) . the effect of treatment was estimated from the unadjusted cox proportional - hazard model that used all the available data . the frequency of deaths that occurred while on a study drug or within 30 days of stopping a study drug was similar between the treatment groups ( 0.19% bromocriptine - qr , 0.20% placebo ) . five patients randomized to bromocriptine - qr and one randomized to placebo died in excess of 30 days after stopping the study drug . adverse events ( aes ) occurred in 89% of bromocriptine - qr  treated and 83% of placebo - treated patients . aes were not commonly reported as severe in either treatment group ( 17% events reported as severe on bromocriptine - qr compared with 14% on placebo ) . more patients discontinued bromocriptine - qr than placebo due to an adverse event ( 24% vs. 11% , respectively ) . the most commonly reported adverse event among patients who discontinued bromocriptine - qr was nausea ( 7.6% bromocriptine - qr vs. 1% placebo ) . the only aes that occurred at a frequency rate of at least 5% and were numerically greater in the bromocriptine - qr arm were nausea , vomiting , dizziness , headache , and diarrhea . nausea was the most common adverse event ( 32.2% bromocriptine - qr vs. 7.6% placebo ) . the majority of the commonly occurring adverse events attributed to bromocriptine - qr occurred during the initial titration phase were dose related and transient in nature ( mean duration of < 14 days ) . after the initial titration phase , commonly occurring adverse events were reported at a frequency similar to that observed in the placebo treated arm . somnolence ( 4.3 bromocriptine - qr vs. 1.3% placebo ) and hypoesthesia ( 1.4 bromocriptine - qr vs. 1.1% placebo ) were the only aes within the nervous system organ class that were reported at a rate of < 5% and 1% and that occurred at a numerically greater frequency among bromocriptine - qr - treated patients . additionally , 15 ( 0.7% ) of patients on bromocriptine - qr and 14 ( 1.4% ) on placebo reported depression or depressed mood , and 13 ( 0.6% ) patients on bromocriptine - qr and 8 ( 0.8% ) on placebo reported anxiety . hypoglycemic aes occurred infrequently , with 6.9% bromocriptine - qr patients reporting an event versus 5.3% in the placebo - treated arm . there were no significant differences between the treatment arms in changes from baseline in hematology or chemistry laboratory values . there were minimal changes from baseline in lipid measures and blood pressure in both groups ( online appendix iv , table b ) . compared with those on placebo , heart rate among patients randomized to bromocriptine - qr decreased 1 bpm from a baseline study population mean heart rate of 68 bpm at week 52 ( p = 0.02 ) . the corrected qt interval decreased , albeit nonsignificantly , from baseline to week 52 among bromocriptine - qr  treated patients by 3.2 ms ( baseline average 418 ms ) and by 1.9 ms for the placebo arm ( baseline average 420 ms ) . there was no difference in the mean change in body weight from baseline to week 52 for either bromocriptine - qr ( + 0.2 kg ) or placebo ( + 0.1 kg ) . the present studyis the first to assess , as a primary objective and end point , the overall and cardiovascular safety of a new oral antidiabetes therapy in a large population of patients with type 2 diabetes . the findings from this trial indicate that morning bromocriptine - qr therapy is noninferior to placebo for overall safety . the overall frequency of all - cause saes and the proportion of saes observed in each soc among patients taking bromocriptine - qr was noninferior to the frequency among patients in the placebo arm . furthermore , the frequency of the composite cardiovascular end point was statistically significantly reduced in the bromocriptine - qr group compared with the placebo group . the kaplan - meier estimates indicate that among 1,000 patients allocated to bromocriptine - qr , 13 first myocardial infarctions , strokes , coronary revascularizations , hospitalizations for congestive heart failure , or hospitalizations for unstable angina would be avoided over 1 year . simply stated , 79 patients would need to be treated for 1 year to avoid one first important cvd event . it should be appreciated that the reduction in cvd events occurred among a study population where the majority of the patients were receiving appropriate cardioprotective medications and where blood pressure , glucose and lipids on average were optimally controlled . furthermore , these results were demonstrated among patients with an average duration of type 2 diabetes of 8 years and in which a third had preexisting cardiovascular disease . bromocriptine - qr was developed to provide a discrete and brief daily interval of circulating bromocriptine at a particular time of day ( morning ) and thereby provide a timed pulse of dopamine activity centrally . this formulation / treatment feature differentiates bromocriptine - qr bioavailability and dosing from the multiple - times per day and higher overall dosing of traditional formulations of bromocriptine for other indications such as parkinson 's disease or acromegaly , which may deliver higher circulating drug levels throughout the day and as a consequence prolonged dopamine stimulation centrally . the mechanism by which such timed bromocriptine - qr may reduce cardiovascular outcomes is not clear . in this trial , treatment with bromocriptine - qr was associated with reductions in fasting triglyceride levels , blood pressure , and heart rate but not to the extent one would expect to explain the observed cvd risk reduction . improvements in a host of cvd risk factors in addition to glycemic control are likely necessary to truly attenuate the excessive risk of cvd events experienced by patients with type 2 diabetes ( 20 ) . the peripheral cardiometabolic effects of bromocriptine - qr on cardiovascular risk may be in part the consequence of its attenuation of central nervous system and hypothalamic functions potentiating sympathetic nervous system over - activity to the vasculature , visceral adipose , and liver as well as attenuation of increased hypothalamic - pituitary - adrenal axis activity , ( 14 ) which are known to increase cvd risk if overactive ( 21,22 ) . improvements in postprandial hyperglycemia and hyperlipidemia ( 16 ) have been observed with this treatment and may have contributed to the cvd event reduction in this trial . moreover , recent studies in animal models of insulin resistance have demonstrated marked improvements in both liver inflammatory pathways potentiating vascular damage and endothelial dysfunction during treatment with a parental formulation of bromocriptine ( a.c . , unpublished data ) . although increased sympathetic tone ( 23 ) , postprandial dysmetabolism ( 24 ) , endothelial dysfunction and inflammation ( 25 ) are important cvd risk factors that have been attenuated with bromocriptine therapy in previous clinical and preclinical studies , the impact of bromocriptine - qr on these measures was not assessed in this study . much more work is required to completely understand the complex biochemical and physiological mechanisms by which timed bromocriptine - qr produces its potential cardiovascular effects . a study of longer duration and sufficient size to provide a greater number of cardiovascular outcomes could allay any concerns that the results in this trial are a chance finding while further quantifying the potential long - term reduction in cardiovascular events . for the majority of patients experiencing nausea , the symptoms occurred during the initial titration of the drug and lasted less than 2 weeks . the gastrointestinal side effects associated with bromocriptine - qr are dose related and the  forced  titration scheme ( rechallenge with study drug after an ae at a given dose and attempt to continue to uptitrate to achieve a maximum tolerated dose of 4.8 mg ) likely contributed to a higher than expected discontinuation rate . the incidence rates of hypoglycemia were low and similar between bromocriptine - qr and placebo groups . importantly , the lack of hypoglycemic aes was observed even when bromocriptine - qr was used as add - on therapy to a variety of antidiabetes agents including insulin . this is most likely because bromocriptine - qr does not increase insulin levels and primarily reduces postprandial glucose by way of improving the body 's responsiveness to insulin ( 16 ) . bromocriptine - qr represents a new treatment modality for type 2 diabetes . in patients with type 2 diabetes , the addition of bromocriptine - qr to routine standard of care therapies was shown to be safe and associated with fewer cardiovascular outcomes . this first - in - class therapy may provide a new approach to addressing the comorbidities associated with type 2 diabetes .
objectivequick - 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 methodsa total of 3,095 patients with type 2 diabetes were randomized 2:1 to bromocriptine - qr or placebo in conjunction with the patient 's 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).resultsin 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 0.350.96 ] ) . 
 nausea was the most commonly reported adverse event in the bromocriptine - qr group.conclusionsthe 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 .