Bromocriptine improves glycaemic control and serum lipid profile in obese Type 2 diabetic subjects: a new approach in the treatment of diabetes

Abstract

Bromocriptine, a potent dopamine D(2) receptor agonist, has been shown to reduce insulin resistance, glucose intolerance and hyperlipidaemia in both numerous animal studies and in Phase II studies. Bromocriptine has been used worldwide for over 20 years to treat Parkinson's disease, macroprolactinoma and other disorders; it has been found to be generally safe. We therefore investigated the possible beneficial effects of Ergoset(R) (Ergo Science Corp.), a new quick release formulation of bromocriptine, on glycaemic control and serum lipid profile in obese Type 2 diabetic subjects in two large Phase III studies. A large, randomised, double-blind placebo-controlled study was conducted in which Ergoset was given once daily at 8 am. (4.8 mg maximum dose) for 24 weeks as adjunctive therapy to sulphonylurea (485 subjects) to obese Type 2 diabetics held on a weight- maintaining diet. Treatment efficacy parameters included change from baseline in glycated haemoglobin A(1c) (HbA(1c)), fasting and post-prandial serum glucose, insulin, triglyceride and free fatty acid levels. Baseline glycated haemoglobin, fasting glucose, insulin, triglyceride and free fatty acid levels did not differ between treatment groups. and on average were 9.4 +/- 0.05%, 222 +/- 2 mg/dl, 24 +/- 1 µU/ml, 248 +/- 11 mg/dl, and 850 +/- 32 µEq/l, respectively. A similarly designed study of Ergoset as monotherapy in Type 2 diabetics (154 subjects) with similar baseline clinical characteristics was conducted. Addition of Ergoset treatment to sulphonylurea reduced percent glycated HbA(1c) by 0.55 (P < 0.0001) (approximately 1.0 for responders, 65% of population), fasting and post-prandial glucose by 23 and 26 mg/dl (P < 0.0002), fasting and post-prandial triglycerides by 72 and 63 mg/dl (P < 0.005) and fasting and post-prandial free fatty acids by 150 and 165 µEq/l (P < 0.05), relative to placebo. Twelve percent of all Ergoset subjects, compared to 3% of placebo subjects, withdrew from the study due to adverse events. The most common events causing withdrawal were nausea, dizziness, asthenia, and rhinitis (representing 4.5, 3.3, 2.0, and 0.8% of the total Ergoset populations, respectively). The incidence of serious adverse events did not differ between Ergoset- (3.4%) and placebo- (4.3%) treated subjects. Ergoset as monotherapy also improved glycaemic control (0.56 HbA(1c) decrease relative to placebo after 24 weeks of treatment; P < 0.02). Once daily Ergoset treatment improves glycaemic control and serum lipid profile and is well-tolerated in obese Type 2 diabetics.

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

“…Bromocriptine-QR therapy reduced mean postprandial glucose levels from 135 ± 5 mg/dl to 117 ± 3 mg/dl (P < 0.05) and fasting and postprandial plasma insulin levels from 27 ± 6 μU/ml and 99 ± 13 μU/ml to 15 ± 2 μU/ml and 50 ± 7 μU/ml, respectively (P < 0.05) (Figure 7). The above study of bromocriptine-QR impact on mealtime glucose and insulin was reconducted in T2DM subjects naïve to any anti-diabetes drug treatment [161,162]. Average study population baseline demographics included a percent-glycated HbA1c of 8.9, BMI of 31.5, duration of diabetes of 3.9 years (however, the study was conducted at a time when a fasting glucose level of 140 mg/dl was used as a diagnosis of T2DM so dysglycemia likely was present for a longer period of time), and age of 55 years.…”

“…Subsequent clinical studies investigated the possible beneficial effects of bromocriptine-QR on glycemic control in obese T2DM subjects whose dysglycemia was poorly controlled on SU and/or metformin therapies. One such study investigated the impact of morning administration (8 a.m.) of bromocriptine-QR (1.6-4.8 mg/day; titrated up at a rate of 0.8 mg/week until a maximum tolerated dose of 1.6-4.8 mg/day was achieved) or placebo upon glycemic control in obese T2DM subjects very poorly controlled on baseline SU therapy (485 subjects) while held on a weight maintaining diet for 24 weeks (the SU add-on study) [161]. Average population baseline demographics included a percent-glycated HbA1c level of 9.4, BMI of 32.1, duration of disease of 6.3 years (the study was conducted at a time when a fasting glucose level of 140 mg/dl was used as a diagnosis of T2DM so dysglycemia likely was present for a longer period of time) and age of 55 years.…”

“…These studies indicate that such bromocriptine administration reduces plasma TG and FFA levels by reducing TG synthesis and secretion in liver and TG mobilization from adipose tissue. Therefore, the SU add-on study also investigated the impact of bromocriptine-QR therapy upon diurnal plasma TG and FFA levels [161,162]. Diurnal TG levels were assessed from 0700 to 1900 hours including 1 h before and 1 and 2 h after each of breakfast, lunch, and dinner standardized meals, before and 24 weeks after treatment.…”

Weighted Effects of Bromocriptine Treatment on Glucose Homeostasis during Hyperglycemic versus Euglycemic Clamp Conditions in Insulin Resistant Hamsters: Bromocriptine as a Unique Postprandial Insulin Sensitizer

“…However in these studies, fasting plasma glucose reductions in response to such treatment varied from not at all to moderate depending upon the prevailing glucose level. In Type 2 Diabetes Mellitus (T2DM) subjects, such once daily (morning) treatment with bromocriptine-QR, a Food and Drug Administration (FDA) approved quick release formulation of bromocriptine for the treatment of T2DM, reduced postprandial glucose across the three meals of the day and, these postprandial glucose reductions were larger than those observed in the pre-prandial (intermeal) state [5,6]. Collectively these findings suggest that the plasma glucose disposal/glucose homeostasis effects of timed bromocriptine administration may be more potent during the postprandial versus fasting state and that such bromocriptine treatment may potentially act as a unique postprandial "weighted" insulin sensitizer.…”

Bromocriptine mesylate in type 2 diabetes mellitus: A novel approach

“…[21] A 24 weeks randomized controlled trial by Cincotta et al in 1999 showed a significant reduction in plasma free fatty acids and triglycerides after administration of bromocriptine mesylate in obese T2DM patients. [22] …”