In the continuing effort to demonstrate carvedilol’s superiority over metoprolol, comes a study in this week’s JAMA looking at metabolic side-effects of these two beta-blockers in diabetic hypertensives.
Patients with diabetes and hypertension, but without major cardiac disease, who were receiving ACE inhibitors or ARB’s, were first taken off their other anti-hypertensives (if any), but continued on the ACEI or ARB. They were then randomized to carvedilol or metoprolol tartrate, at increasing doses, until either blood pressure was adequately controlled or the maximum dose was attained. At that point, if BP was still not controlled, HCTZ and/or a calcium channel blocker was added to obtain satisfactory BP levels. The primary endpoint was change in HgbA1c levels; insulin levels and lipid levels were also looked at.
In both groups, adequate blood pressure control was achieved, with the same percentage of patients in each group requiring the addition of HCTZ (44%) and a calcium blocker (25%). The mean doses of study medications that were required were carvedilol 17.5 mg bid and metoprolol 128 mg bid. Approximately half the patients in each group required the maximum dose of the study medication: carvedilol 25 mg bid and metoprolol 200 mg bid.
Patients in the carvedilol group had better metabolic results overall. HgbA1c in the carvedilol group increased insignificantly from 7.21 to 7.23; in the metoprolol group it increased significantly by 0.15 from 7.19 to 7. 34 (a 2% change). The urinary albumin/creatinine ratio decreased by 14% in the carvedilol group but increased by 2.5% in the metoprolol group. Lipid changes were slightly in favor of carvedilol, as was insulin sensitivity.
The dose of metoprolol tartrate used in this study was very high. The target dose before adding another anti-hypertensive agent was 200 mg twice daily. Not surprisingly, there was more bradycardia in the metoprolol group. The same percentage of patients in each group required “rescue” antihypertensive treatment. Therefore, the chosen maximum doses of the drugs probably represent an approximately equal antihypertensive effect. Since carvedilol has both alpha and beta adrenergic blocking activity, whereas metoprolol is only a beta-blocker, it is not a complete surprise that a high dose of metoprolol was required to equal the antihypertensive effect of carvedilol. But in the real world, I doubt very much that practitioners would push metoprolol to such a limit, rather than adding a different medication. Which makes one wonder whether the metabolic advantage of carvedilol would have been as great if a more normal metoprolol dose had been chosen.
I was unable to find out the exact rationale behind the dose choices that were made. In the article, the authors state that “A detailed description of the study design and statistical methods has been published elsewhere”. But the reference, #17, indicates an article in press, which is not yet available.
It is interesting to note that in the COMET trial, comparing the beneficial effects of carvedilol to metoprolol in patients with CHF, the target dose of carvedilol was 25 mg bid, that of metoprolol was 50 mg bid. So, when looking at beneficial effects of these drugs, the investigators chose a rather low dose of the “competitor”, when looking at side-effects, they chose a mega-dose.