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Metabolic Effects of Carvedilol vs Metoprolol in Patients with Type 2 Diabetes Mellitus and Hypertension: A Randomized Controlled Trial

Background: Beta-blockers are recommended to achieve/maintain adequate blood pressure (BP) control in hypertensive patients and have been shown to decrease cardiovascular risks in patients with hypertension and diabetes mellitus. However, beta-blockers have been implicated in increasing fasting blood glucose and HbAlc levels in diabetic patients.

Objective: The purpose of this study was to determine if one of two beta-blockers, carvedilol or metoprolol, presented more favorable metabolic and glycemic effects on patients with diabetes and hypertension who were also using a renin-angiotensin (RAS) blocker, which is known to improve glycemic control.

Methods: This was a double blind, randomized, parallel group, controlled trial. The study took place at 205 different sites within the United States from June 2001 through April 2004. Men and women between the ages of 36 and 85 were enrolled in the study if they presented with the following criteria: had type 2 diabetes mellitus with “stable treatment” over the past three months, and had stage I or stage II hypertension with “stable treatment” over the past one month which included treatment with a RAS blocker. The RAS blocker could be an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB). Patients were excluded from participating in the study if they had taken a non-ocular beta-blocker within the past three months, if they had either pulmonary disease, “significant” cardiovascular disease, or if they had stage 3 or above kidney disease. Following a washout period to free all participants of other BP medications other than a RAS blocker, 1,235 patients were then randomized to receive either carvedilol (498 patients) or metoprolol (737 patients) and enrolled in the study for no more than 35 weeks. Each study participant’s dosage of study medication was titrated up to a maximum of 25 mg twice a day of carvedilol or 200 mg twice a day of metoprolol over the study to attain target BP goals. If target BP goals were not reached with these dosages, investigators were permitted to first add 12.5 mg of hydrochlorothiazide, and then a dihydropyridine calcium channel blocker to attain target BP goals if needed. Patients received no more than five months of either carvedilol or metoprolol. The power of the study was based on three different outcomes. The primary outcome measured to see if there was a change in baseline HbAlc after five months of treatment with either carvedilol or metoprolol. To measure this, power was based at 90%. Secondary hypotheses were tested to see if metoprolol worsens glycemic control, and if carvedilol does not worsen glycemic control via changes in HbAlc. Power for both of these hypotheses were set at 80% respectively. Unless told differently, the data was expressed as mean standard deviation, and the primary and secondary outcomes were based on an analysis of covariance. Confidence intervals (CI) of 95% were reported along with two-sided P values.

Results: The primary endpoint, the mean difference between carvedilol and metoprolol in the change in HbAlc from baseline, was (0.13%; 95% CI, -0.22% to -0.04%, P=0.004) in the modified intention to treat analysis. HbAlc levels rose with metoprolol administration (0.15%, P<0.001) and did not with carvedilol administration (0.02%, P=0.65). Metabolic results returned a favorable affect with carvedilol, but not with metoprolol. Insulin sensitivity was improved with carvedilol (-9.1%, P=0.004) but not with metoprolol (-2.0%, P=0.48). In addition, the number of patients progressing to microalbuminuria was lower with carvedilol than with metoprolol. BP readings were comparable in both groups.

Strengths: The study utilized good randomization techniques to ensure proper distribution of equal characteristics in each group as evidenced by Table 1. The investigators also used a good method to blind the patients and researchers from which study drug was being given to each participant. It was also good how the investigators used a washout period to discontinue all other BP medications other than the ACE or ARB before the study began.

Weaknesses: The investigators used surrogate markers to measure outcomes instead of definite outcomes (i.e. cardiovascular events and mortality). Some of the investigators worked directly for GlaxoSmithKline, who manufacturers carvedilol, and the trial itself was funded by the corporation. Additionally, some patient characteristics, such as both groups BMI, and participant’s concurrent use of one or multiple diabetic agents could have affected results by affecting insulin resistance values and HbAlc.

Conclusions: Although carvedilol seems to be a better choice for utilization as a beta-blocker for patients with diabetes and hypertension than metoprolol based on this study, some key issues still must be addressed in future studies. Anti-diabetic drug regimens should be standardized in both groups to see if the drop or stabilization of HbAlc is due to the actual beta-blocker or from anti-diabetic medication. A cost-benefit analysis should be conducted to see if the extra expense of prescribing carvedilol actually benefits patients and third parties in the long run compared to prescribing metoprolol, a much cheaper alternative. And lastly, the authors should see if carvedilol significantly provides a decrease in definite outcomes such as cardiovascular events and mortality compared to metoprolol or other beta-blockers.

Bakris GL, Fonesca V, Katholi RE, McGill JB, Messerli FH, Phillips RA, et al. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension a randomized controlled trial. JAMA 2004; 292(18): 2227-2235.

Kristopher L. Chiplinski, PharmD. Candidate