Bromocriptine-QR may reduce CVD risk in type 2 patients independent of its effect on glycemic control.
Note: This study came out in 2015, but because the results may have a huge impact on the treatment of diabetes, we decided to review this study, which could have a major impact on the quality of life for those with diabetes.
Cardiovascular disease (CVD) is the leading cause of death in type 2 diabetes patients (T2DM). Large studies in the past have demonstrated a strong association between vascular complications and glycemic exposure, especially as the HbA1c climbs over 7.0%. However, it has also been found that simply reversing hyperglycemia does not quickly or easily reverse the incidence of CVD. To that point, even T2DM patients with good glycemic control experience increased risk of CVD events. This may be due to other factors such as endothelial dysfunction and increased sympathetic tone, which may escalate the risk of a cardiovascular event in an insulin-resistant state. It is in this regard that bromocriptine-QR may reduce the risk of CVD in T2DM independent of its reduction in plasma glucose levels.
Cycloset©, the brand name for quick-release bromocriptine, was approved by the FDA in 2009 for the treatment of hyperglycemia in patients with T2DM; however, it is not indicated to reduce the risk of CVD events. The Cycloset Safety Trial (CST), provided an opportunity to conduct a cohort study using the same patient population to test the hypothesis that even in participants with good glycemic control, the CVD rate may still be high and these participants may benefit from bromocriptine-QR for rapid reduction in CVD events due to its positive effects on the neuroendocrine system independent of its glycemic lowering properties.
For this cohort, 1,834 study subjects with an HbA1c <7% (615 receiving placebo and 1219 receiving bromocriptine-QR) were selected from the CST. The CST was a 12-month, multi-center, placebo-controlled, double-blinded, parallel-group safety and efficacy trial in T2DM. All participants were between the ages of 30-80 years old with a BMI of <43kg/m2. The Bromocriptine-QR was titrated by 0.8mg per week until a maximum tolerated dose was achieved (1.6-4.8 mg/day). It was taken with the morning meal within 2 hours of waking. Participants’ typical antihyperglycemic regimens were continued throughout the trial. The endpoint of the cohort trial was the same as the composite CVD endpoint in the CST, a composite of stroke, MI, coronary revascularization, and hospitalization due to angina or CHF occurring after randomization.
Serious adverse events were monitored by an independent adjudication committee. Cox proportional-hazards regression was used to perform statistical analysis. This study utilized an intention to treat protocol, which included all patients receiving at least 1 dose of the study drug. An on-treatment protocol was also utilized in the analysis to account for any confounding variable associated with early termination. Superiority between bromocriptine-QR and placebo was determined using a 2-sided 95% confidence interval. The cumulative incidence rate of CVD was determined using a log-rank test with a significant p value of <0.05.
At week 52, 1,203 participants remained for analysis, 750 in the bromocriptine-QR group and 453 in the placebo group. In the intention-to-treat analysis, the composite CVD endpoint occurred in 1.6% of bromocriptine-QR participants and 3.1% of the placebo participants, representing a 48% CVD hazard risk reduction in the bromocriptine-QR group (HR: 0.52, CI: 0.28-0.98). The on-treatment analysis achieved a 52% CVD risk reduction (HR: 0.48, CI: 0.24-0.95). According to the log-rank test, there was a statistical difference between treatments at 1 year with p=0.041. There was no statistical difference between groups with regard to plasma lipid levels or heart rate. The only statistically significant adverse events reported more frequently in the bromocriptine-QR group were nausea, dizziness, fatigue and vomiting, with severity reported as mild-moderate in over 90% of participants.
By limiting the participants of this cohort study to those with good glycemic control (HbA1c 6.3 +/- 0.5), and limiting the endpoint to 52 weeks, this study was able to make the association that treatment with bromocriptine-QR quickly decreases the risk of CVD events in patients with T2DM independent of the drug’s glucose-lowering effects.
- There may be biochemical pathologies in the T2DM population aside from hyperglycemia, hyperlipidemia and hypertension putting them at risk for CVD events.
- There are likely benefits of bromocriptine-QR beyond its glucose-lowering effect, which reduces risk of CVD events T2DM.
- Patients with T2DM with good glycemic control may benefit from the addition of bromocriptine-QR to reduce their risk of CVD events without the risk of serious adverse events.
Researched and prepared by Devon Brooks, Doctor of Pharmacy Candidate from LECOM College of Pharmacy, reviewed by Dave Joffe, BSPharm, CDE
Chamarthi B, Gaziano JM, Blonde L, Et al. “Timed bromocriptine-QR therapy reduces progression of cardiovascular disease and dysglycemia in subjects with well-controlled type 2 diabetes mellitus.” Journal of Diabetes Research. (2015):1-13. Print.