Bromocriptine-QR therapy for the management of type 2 diabetes mellitus: developmental basis and therapeutic profile summary

Abstract

An extended series of studies indicate that endogenous phase shifts in circadian neuronal input signaling to the biological clock system centered within the hypothalamic suprachiasmatic nucleus (SCN) facilitates shifts in metabolic status. In particular, a diminution of the circadian peak in dopaminergic input to the peri-SCN facilitates the onset of fattening, insulin resistance and glucose intolerance while reversal of low circadian peak dopaminergic activity to the peri-SCN via direct timed dopamine administration to this area normalizes the obese, insulin resistant, glucose intolerant state in high fat fed animals. Systemic circadian-timed daily administration of a potent dopamine D2 receptor agonist, bromocriptine, to increase diminished circadian peak dopaminergic hypothalamic activity across a wide variety of animal models of metabolic syndrome and type 2 diabetes mellitus (T2DM) results in improvements in the obese, insulin resistant, glucose intolerant condition by improving hypothalamic fuel sensing and reducing insulin resistance, elevated sympathetic tone, and leptin resistance. A circadian-timed (within 2 hours of waking in the morning) once daily administration of a quick release formulation of bromocriptine (bromocriptine-QR) has been approved for the treatment of T2DM by the U.S. Food and Drug Administration. Clinical studies with such bromocriptine-QR therapy (1.6 to 4.8 mg/day) indicate that it improves glycemic control by reducing postprandial glucose levels without raising plasma insulin. Across studies of various T2DM populations, bromocriptine-QR has been demonstrated to reduce HbA1c by -0.5 to -1.7. The drug has a good safety profile with transient mild to moderate nausea, headache and dizziness as the most frequent adverse events noted with the medication. In a large randomized clinical study of T2DM subjects, bromocriptine-QR exposure was associated with a 42% hazard ratio reduction of a pre-specified adverse cardiovascular endpoint including myocardial infarction, stroke, hospitalization for congestive heart failure, revascularization surgery, or unstable angina. Bromocriptine-QR represents a novel method of treating T2DM that may have benefits for cardiovascular disease as well. ARTICLE HISTORY

Effect of bromocriptine-QR therapy on glycemic control in subjects with type 2 diabetes mellitus whose dysglycemia is inadequately controlled on insulin

“…Hyperinsulinemic-euglycemic clamp studies indicate that B-QR improves maximally insulin-stimulated glucose disposal [21]. Moreover, consistent with B-QR's meal-time insulin sensitizing properties, the HbA1c-lowering effect of B-QR has been shown to correlate with the postprandial insulin level [26]. In a previous small open-label pilot study [38], B-QR therapy in T2DM subjects with inadequate glycemic on metformin plus high-dose basal-bolus insulin resulted in a significant mean % HbA1c reduction of −1.76 with a concurrent 27% reduction in total daily insulin dose (TDID) and a 32% decrease in postprandial glucose response to a mixed-meal tolerance test with no significant change in fasting plasma glucose (FPG) level.…”

“…24 h later) the short pulsed duration of bromocriptine into the circulation following its circadian-timed morning administration [37,38], which supports the preclinical data suggesting a 'resetting' of aberrant neuroendocrine responsiveness to mealtime feeding to improve postprandial insulin sensitivity with this therapy [27][28][29][30][31][32][33][34][35][36]. Mechanistic insights into this metabolic phenomenon can be gained from a series of neurophysiological studies that established a facilitatory role for the circadian peak in dopaminergic input activity to the body pacemaker clock system (suprachiasmatic nuclei [SCN]) in the maintenance of normal insulin sensitivity and glucose tolerance in animal models of insulin resistance [26][27][28][29][30][31][32][33][34] described as follows.…”

“…The normal circadian peak in neuronal dopaminergic input activity to the SCN is diminished in insulin-resistant states and selectively reducing such peak activity in normal animals by targeted biochemical disruption of dopaminergic function at the SCN induces the insulin-resistant and glucose-intolerant condition [26,32]. Moreover, high fat feeding that induces insulin resistance/glucose intolerance results in a marked reduction in the circadian peak of dopaminergic activity at the SCN [40].…”

“…Importantly, in animals made insulin resistant by such high fat feeding, a 1-min administration of dopamine to the SCN made once daily for a 2-week period at the time of day that dopamine activity peaks at the SCN of normal insulin-sensitive animals reverses the insulin resistance/glucose intolerance while animals are maintained on the high fat diet [27]. Such circadiantimed dopamine treatment at the SCN reduces abnormally elevated noradrenergic (NA) input activity to the ventromedial hypothalamus (VMH) and the paraventricular nuclei (PVN) and is coupled to decreases in elevated neuropeptide Y (NPY) and corticotropin releasing hormone (CRH) at the PVN [25][26][27][28]31], two neurophysiological conditions precipitating the insulin resistance syndrome [25,26,28,30,33,[41][42][43] in part by inducing overactivation of sympathetic tone and hypothalamic-pituitary axis (HPA) drive to the viscera and vasculature that potentiate the syndrome [43][44][45][46][47]. That is, a diminution of the circadian peak dopaminergic activity at the SCN is a neuromodulatory signal that initiates output signals from the SCN to other hypothalamic nuclei (e.g.…”

“…Bromocriptine-QR (B-QR), a quick-release, high absorbing formulation of the potent dopamine D2 receptor agonist bromocriptine, approved in the United States for the treatment of T2DM, is a unique insulin sensitizer with a good safety profile [17][18][19][20][21][22][23]. Circadian-timed administration (within 2 h of waking) of this quick-release formulation of bromocriptine results in a discrete and brief daily interval of circulating bromocriptine, thereby providing a timed pulse of increased dopaminergic activity centrally at the time of day that studies suggest is the natural daily peak of central dopaminergic activity in healthy individuals [24] which studies suggest is diminished in insulin-resistant individuals [25,26].…”