The current findings of 39% and 52% relative risk reductions in the CV death-inclusive composite cardiovascular and MACE end points, respectively, among bromocriptine-QR versus placebo subjects in the Cycloset Safety Trial corroborate and extend the original observations from this trial on bromocriptine-QR impact on prespecified adverse cardiovascular outcomes that excluded CV death.5
Moreover, the effect of bromocriptine-QR on the CV death-inclusive composite cardiovascular end point when stratified by demographic subgroup indicates that the magnitude and direction of the CV disease risk reduction of bromocriptine-QR was similar regardless of age, sex, BMI, race, preexisting CV disease, or duration of diabetes (). Realizing the limitation of the small number of events in this study, this subgroup interaction analysis was conducted to explore the possibility that a spurious subject demographic among those examined that could influence cardiovascular event rate may have influenced the outcome observed. The results of this analysis suggested no such occurrence. These findings are best appreciated when viewed in the context of the unique study population and trial design employed in the Cycloset Safety Trial, which had few restrictions on enrollment of subjects with comorbid conditions commonly associated with type 2 diabetes (such as CHF or preexisting cardiovascular disease or events). Moreover, approximately one third of the study subjects had preexisting CV disease at baseline; most were taking cardioprotective medications and 2 antihyperglycemic medications (including insulin) prior to randomization.5
Consequently, the study population on average was in moderate to good metabolic control, with a median HbA1c of 7.0±1.0%, plasma triglyceride level of 179±137 mg/dL, plasma LDL level of 98±32 mg/dL, and systolic blood pressure of 128±14 mm Hg.5
In addition, investigators were instructed to adjust concomitant diabetes treatments (including glycemic-lowering agents) in order to attempt to achieve recommended ADA therapeutic targets. This trial design provided the opportunity to assess the effect of bromocriptine-QR on cardiovascular outcomes in a T2DM population that, on average, was in relatively good metabolic control and against a background of routine diabetes standard of care.
Despite the generally good metabolic control of the population and the instruction for investigators to intervene during the trial to attempt to achieve the glycemic goals of the American Diabetes Association, the placebo arm of the trial had a serious cardiovascular event rate for the CV death inclusive end point of 3.2% and of the MACE end point of 1.5%. These event rates were not different from those of other large T2DM cardiovascular outcomes trials. For instance, in the ADVANCE (Action in Diabetes and Vascular Disease) and ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial standard treatment arms, the MACE rate per 1000 person-years was 21.2 and 19.6, respectively, which is similar to that observed in the placebo arm of the Cycloset Safety Trial (16.4). The Cycloset Safety Trial population was similar to ADVANCE and ACCORD in age, duration of diabetes, and sex, but the average baseline lipids, blood pressure, and HbA1c metabolic parameters were indicative of better control in the Cycloset Safety Trial study population.8,9
Intensive glucose-lowering therapies over a 3.5- to 5-year period in the ACCORD and ADVANCE studies did not result in any significant reduction in nonfatal MI, nonfatal stroke, and cardiovascular death (MACE). In contrast, bromocriptine-QR therapy for only 1 year was associated with a 52% relative risk reduction in the MACE end point. These results occurred in the midst of modest improvements in hyperglycemia, hypertension, plasma triglyceride level, and heart rate (modest effects due primarily to the generally good control of these parameters represented in the baseline bromocriptine-QR and placebo populations),5
which may have contributed to the CV outcome observed.
The results of analyses of the original prespecified CV composite (including ischemic and nonischemic cardiovascular end points5
), the present CV-death-inclusive composite, and the MACEs (only ischemic cardiovascular end points) are internally consistent and suggest a positive impact of bromocriptine-QR on adverse CV outcomes in this T2DM population. The results of these analyses and the subgroup interaction analysis conducted in this sudy in total suggest that the observed effect of bromocriptine-QR on CV outcomes is not driven by a particular component of the CV composite studied or by any particular subject demographic investigated. The obvious question that remains is how bromocriptine-QR exposure produced this consistently observed result on cardiovascular outcomes. The Cycloset Safety Trial did not include assessment of any mechanistic data, so any insights on possible mechanisms for this bromocriptine-QR response at the present time must be gleaned from other existing information relating to the impact of bromocriptine on cardiometabolic physiology. The scientific literature on this topic from both preclinical and clinical studies is briefly summarized as follows.
Timed daily bromocriptine administration to insulin-resistant animals normalizes multiple hypothalamic neurophysiological derangements characterized by low hypothalamic dopaminergic tone, elevated ventromedial hypothalamic noradrenergic and serotonergic activity, and elevated paraventricular hypothalamic neuropeptide Y and corticotrophin-releasing factor levels.10
This cluster of derangements can potentiate overactivation of the hypothalamic-pituitary-adrenal axis (ie, cortisol release) and of the sympathetic nervous system drive to the liver, adipose, and the cardiovascular system,10
as well as increased responsiveness to sympathetic stimulation.11
Increased sympathetic activity in adipose results in increased free fatty acid (FFA) mobilization,12,13
which in turn can act to induce hepatic very low-density lipoprotein triglyceride synthesis and secretion (postprandially), lipotoxicity, secretion of inflammatory proteins, and insulin resistance.14
Increased cortisol and sympathetic drive in the liver increases hepatic glucose output and decreases hepatic glucose disposal, particularly after a meal, which potentiates postprandial hyperglycemia.15–17
Increased sympathetic drive to the vasculature induces hypertension18,19
and to the heart (including as part of cardiac autonomic neuropathy) can be a major contributor to cardiac disease.20–26
Increases in (postprandial) plasma FFA, glucose, and triglycerides as well as in inflammatory proteins and noradrenaline under the vasoconstrictive influence of elevated sympathetic nervous system tone can potentiate generation of vascular reactive oxygen species and increase inflammation, endothelial dysfunction, hypercoagulation, and arteriosclerosis.27–34
And increased sympathetic tone itself is a contributor to insulin resistance syndrome.35–39
Timed daily administration of bromocriptine to insulin-resistant animals acts centrally to reverse these sequelae of neuroendocrine and metabolic events (overactive hypothalamic pituitary adrenal axis and sympathetic tone and insulin resistance syndrome, respectively) (reviewed in10
). Finally, and potentially of significant import, bromocriptine therapy of hypertensive, insulin-resistant, arteriosclerotic rats has been shown to reduce arterial stiffness and endothelial nitric oxide synthase uncoupling,40
a phenomenon seen with diabetes that results in reduced nitric oxide generation and overproduction of reactive oxygen and nitrogen species in vessel walls that can induce prodigious damage to the vasculature.41
It is not known whether the use of bromocriptine to correct these hypothalamic aberrations that precipitate multiple parallel pathophysiological events known to potentiate CV disease is involved in its ability to reduce the MACE end point in the present study. Although not measured in the Cycloset Safety Trial, bromocriptine-QR therapy simultaneously reduced postprandial glucose, FFA, and triglyceride levels in T2DM subjects in other studies.1,2
In the Cycloset Safety Trial, bromocriptine-QR produced meaningful reductions in HbA1c and blood pressure among those with elevated HbA1c (≥7.5%) or blood pressure (systolic blood pressure >130 mm Hg) at baseline.42,43
And the general sympatholytic effect of bromocriptine in humans has been well appreciated for many years.44–46
Although these findings offer intriguing possibilities for identifying pathways by which bromocriptine-QR may produce the results on the cardiovascular end points reported here, much additional research in this area is needed to fully delineate these mechanisms.
The major limitation of this investigation is the inability to fully assess the potential impact of bromocriptine-QR across various demographic subgroups. Because of the number of outcomes, subgroup demographic groupings needed to be broad to assess the impact of bromocriptine-QR on any one of them. Multivariate models of analysis were also not possible on the subgroups investigated. Also, because of the 1-year duration of the study, there were too few deaths to comment on the intervention's influence on total mortality. Nonetheless, the relative risk reduction of the CV death-inclusive composite cardiovascular end point (and the supportive analysis across various subgroups) and of the MACE end point in the bromocriptine-QR-exposed group reaffirms and extends the previous observation of bromocriptine-QR treatment on CV outcomes in T2DM subjects.5