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Glycemic Effects in Diabetes Mellitus: Carvedilol - Metoprolol Comparison in Hypertensives Trial - GEMINI
Description:
The goal of the trial was to evaluate the effect of two different beta-blockers, carvedilol and metoprolol titrate, on glycemic control in patients with hypertension and type 2 diabetes.
Study Design
Study Design:
Patients Screened: 3,021
Patients Enrolled: 1,235
Mean Follow Up: 35 weeks
Mean Patient Age: Mean age 61 years
Female: 45
Patient Populations:
Documented type 2 diabetes, stage 1 or 2 hypertension, stable antidiabetic treatment for at least three months, stable hypertensive treatment for at least one month, and use of an ACE inhibitor or ARB
Exclusions:
Significant cardiovascular disease, pulmonary disease, stage 3 or higher kidney disease, or use of nonocular beta-blocker in the prior three months
Primary Endpoints:
Comparison by treatment group of mean change from baseline HgA1c following five months of maintenance therapy
Secondary Endpoints:
Change from baseline HgA1c following five months of maintenance therapy in the individual treatment groups, changes in systolic and diastolic blood pressure, fasting glucose and insulin, insulin resistance assessed with the HOMA-IR score, cholesterol, triglycerides, urinary albumin/creatinine ratio, and withdrawals due to worsening glycemic control
Drug/Procedures Used:
Patients were randomized to carvedilol (6.25-25 mg dose, twice daily) (n=498) or metoprolol tartrate (50-200 mg dose, twice daily) (n=737).
Concomitant Medications:
If needed, open-label hydrochlorothiazide and a calcium antagonist were used to achieve blood pressure target.
Principal Findings:
Baseline characteristics were well matched between the treatment groups. Mean body mass index at baseline was 34, and hemoglobin A1c (HbA1c) was 7.2%. Multiple antidiabetic medications were used in 55% of patients, and 8% of patients were insulin-dependent. In addition to 99% of patients taking angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) at baseline, 45% were taking a statin. Treatment duration was slightly but significantly longer in the carvedilol group (155 days vs. 147 days for metoprolol, p=0.01).
Mean change in HbA1c from baseline differed significantly by treatment group (0.12%, p=0.006), with no change in the carvedilol group (0.02%, p=0.65) and an increase in the metoprolol group (0.15%, p<0.001). Study drug discontinuation due to worsening glycemic control was higher in the metoprolol group (2.2% vs. 0.6%, p=0.04). Homeostatic model assessment-insulin resistance (HOMA-IR) was reduced from baseline in the carvedilol group (-9.1%, p=0.004), but did not differ in the metoprolol group (-2.0%, p=0.48) for a significant between group difference (-7.2%, p=0.004). Triglycerides were increased from baseline in the metoprolol group (13.2%), but did not differ in the carvedilol group (2.2%), with a significant between group difference (p<0.001). There was no treatment difference in change in low-density lipoprotein cholesterol or high-density lipoprotein, but total cholesterol decreased more in the carvedilol group (-3.3% vs. -0.4%, p=0.001 for between group difference).
Blood pressure and heart rate did not differ by treatment group. The albumin/creatinine ratio decreased more in the carvedilol group (-14.0% vs. +2.5%, p=0.003 for between group difference). The frequency of most adverse events was similar between treatment group, with the exception of a higher rate of bardycardia in the metoprolol group (4.1% vs. 1.4%, p=0.007).
Interpretation:
Among patients with hypertension and type 2 diabetes who were taking a renin-angiotensin system blocker, treatment with carvedilol was associated with more stabilized glycemic control and improved insulin resistance compared with metoprolol when used to achieve target blood pressure goals.
Beta-blockers, which have been shown to be effective in reducing high blood pressure, have also been associated with impairment in glycemic control in diabetic patients. While the present study demonstrated better glycemic control with carvedilol compared with metoprolol, the study was not powered to show differences in clinical outcomes. A larger trial would be needed to determine if the improvements in glycemic control and insulin resistance with carvedilol would translate into differences in clinical outcomes.
References:
Bakris G, Fonseca V, Katholi RE, et al. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. JAMA 2004;292:2227-36.
Presented by George Bakris at the American Heart Association Scientific Sessions, November 2004, New Orleans, LA.
Keywords: Diabetes Mellitus, Type 2, Renin-Angiotensin System, Blood Pressure, Propanolamines, Creatinine, Insulins, Insulin Resistance, Heart Rate, Cholesterol, Hemoglobins, Carbazoles, Body Mass Index, Hypoglycemic Agents, Metoprolol, Triglycerides, Hypertension
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