Bromocriptine: A Sympatholytic, D2-dopamine Agonist for the Treatment of Type 2 Diabetes

Ralph A. DeFronzo, MD

Disclosures

Diabetes Care. 2011;34(4):789-794. 

In This Article

Mechanism of Action—Human Trials

A number of phase 2 trials have been performed to examine the mechanism of action of Cycloset. In a small study of 12 nondiabetic obese hyperinsulinemic (≥20 μU/mL) subjects,[38] bromocriptine (1.6 mg/day for 2 weeks) reduced the fasting and postprandial (standardized meals) glucose levels without change in body weight and with a decrease in both fasting and postprandial plasma insulin concentrations by ~50% (Supplementary Fig. 1).

In a similar study, 8 weeks of timed bromocriptine reduced day-long plasma glucose, triglyceride, and FFA levels without change in body weight and a small decrease in plasma insulin concentration in 13 nondiabetic obese women (Supplementary Fig. 2).[31] Insulin-stimulated glucose disposal, measured with the insulin suppression test, was not altered. Since the insulin suppression test primarily reflects insulin-mediated glucose disposal in muscle, the improvement in postprandial plasma glucose levels[31] most likely reflects enhanced suppression of hepatic glucose production by insulin, similar to what has been described in animals.[26] However, to date, no study has examined hepatic glucose production following glucose ingestion or in response to a physiologic increase in plasma insulin concentration in man. The decline in postprandial plasma FFA and triglyceride concentrations[32] is similar to observations in animals.[26,38]

Figure 2.

Change in HbA1c in Cycloset (total group) and placebo-treated diabetic subjects. Cycloset responders (defined as a ≥0.3% decrease in HbA1c at week 8) had a significantly greater decline in HbA1c (placebo-subtracted ΔHbA1c = 1.0%) than the total group (ref. 29). SU, sulfonylurea. *P < 0.01; **P < 0.001; †P < 0.04 for Cycloset responders vs. total Cycloset group; ††P < 0.0001 for Cycloset responders vs. placebo.

In a 16-week double-blind, placebo-controlled study in 22 obese type 2 diabetic subjects treated with Cycloset for 16 weeks, HbA1c declined by 1.2%, fasting plasma glucose by 54 mg/dL, and mean plasma glucose during oral glucose tolerance test by 46 mg/dL without change in plasma insulin concentration, body weight, or percent body fat[30] (Supplementary Fig. 3). During a two-step euglycemic-hyperinsulinemic clamp, there was no improvement in insulin sensitivity during the first, physiologic insulin clamp step (80 μU/mL), although maximally insulin-stimulated (377 μU/mL) glucose disposal was increased. These results are consistent with those observed with the insulin suppression test[31] and demonstrate that, within the physiologic range of hyperinsulinemia, Cycloset does not improve insulin action in muscle. During the first insulin clamp step, suppression of hepatic glucose production was not enhanced by Cycloset. However, the steady-state plasma insulin concentration, although physiologic for muscle, was far above that required for half-maximal suppression of hepatic glucose production, making it difficult to ascertain whether hepatic insulin sensitivity was enhanced by insulin.

Figure 3.

Top: Kaplan-Meier plot of time to first cardiovascular event (myocardial infarction, stroke, hospitalization for angina or CHF, coronary revascularization, and death) in 3,070 type 2 diabetic subjects treated with Cycloset or placebo for 52 weeks (ref. 41). Bottom: Kaplan-Meier plot of time to first cardiovascular (MACE) event (myocardial infarction, stroke, and death) in type 2 diabetic subjects treated with Cycloset or placebo for 52 weeks (ref. 41). CVEs, cardiovascular events.

In a provocative study,[39] insulin-treated type 2 diabetic subjects were randomized to placebo (n = 11) or Cycloset (n = 21) (4.8 mg/day) for 12 weeks. Compared with placebo, Cycloset reduced HbA1c by 0.7% and mean plasma glucose concentration (7 A.M. to 7 P.M.) by 8% without change in body weight. These results are consistent with an improvement in insulin sensitivity, although the site, i.e., liver versus muscle, remains to be defined.

In a small (n = 17) double-blind, placebo-controlled study[38] in nondiabetic obese individuals with elevated diurnal prolactin levels (changes in plasma prolactin parallel seasonal changes in insulin sensitivity and glucose tolerance in vertebrates[7]), Cycloset (1.6–2.4 mg/day) plus a 25% calorie-restricted diet significantly reduced body weight and body fat content compared with placebo plus diet. However, in a larger (n = 387) placebo-controlled 24-week study, Cycloset plus diet failed to produce a greater weight loss than placebo plus diet in obese nondiabetic subjects.[29] Of interest, a post hoc analysis revealed that obese subjects with elevated diurnal prolactin levels (who represented ~1/4 of the group) lost more weight (5.7 vs. 3.0 kg) than subjects with a normal prolactin rhythm.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....