Carvedilol versus metoprolol in diabetic hypertensive patients

The recently published Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial reported that blood pressure—lowering therapy with the vasodilating beta blocking agent carvedilol (Coreg) did not adversely affect glycemic control in diabetic patients.1 Furthermore, carvedilol was significantly better than the beta blocker metoprolol (Lopressor, Toprol) in preserving glycemic control when added to a regimen of an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB). These findings are of particular clinical importance considering the reluctance to use beta blockers to treat hypertension in diabetic patients despite their proven ability to reduce mortality and hospitalizations in patients with coronary heart disease and heart failure, which are highly prevalent in the diabetic population. We review the GEMINI study and its results as they apply to clinical practice.

Background

It has been well documented that patients with diabetes can reduce their cardiovascular risk by lowering blood pressure and achieving better glycemic control.2,3 Diabetic patients usually require a minimum of two antihypertensive drugs to achieve the recommended target blood pressure (< 130/80 mm Hg). Treatment with ACE inhibitors and ARBs protects the diabetic patient from nephropathy, neuropathy, retinopathy, and cardiovascular disease. Therefore, it should be the first choice along with a thiazide diuretic for the treatment of diabetic hypertension.4 Because at least 70% of deaths in diabetic patients are related to heart disease, the next drug should not be a vasodilator or a calcium channel blocker (CCB), but a beta blocker.5 Beta blockers have been shown to reduce mortality and morbidity in patients with diabetes even more than in patients without diabetes and should, therefore, be utilized earlier rather than later in these patients.4,6,7

Nevertheless, there has been a general reluctance to use beta blockers in diabetic and nondiabetic patients because of their association with an increased incidence of new-onset diabetes and worsening glycemic control in established diabetes, both resulting from increases in insulin resistance8; however, a new generation of vasodilating beta blockers has been developed that does not decrease insulin sensitivity and, therefore, does not lower high-density lipoprotein cholesterol levels or raise glucose levels.9 Carvedilol is the only drug in this class to be approved for clinical use in the United States, and it has been shown to improve insulin sensitivity in both the diabetic and nondiabetic hypertensive patient and also to have a potent antioxidant effect.10,11

Before GEMINI, there had not been a study that investigated the effect of beta blockade on glycemic control in diabetic hypertensive patients who were concurrently receiving an ACE inhibitor or an ARB, both of which are known to improve glycemic control by lowering insulin resistance. GEMINI compared the effects of carvedilol with those of metoprolol, a beta blocker known to decrease insulin sensitivity.11 The primary end point of GEMINI was change in glycosylated hemoglobin level (A1C), which in addition to reflecting average glycemic control during the previous 2- to 3-month period, is also a prognosticator of cardiovascular risk in both diabetic and nondiabetic patients.12

Patients and methods

GEMINI was a randomized, double-blind, clinical trial carried out in 205 sites in the United States, which included 1,235 patients with type 2 diabetes (A1C, 6.5%—8.5%) and documented stage 1 or 2 hypertension. Patients were receiving stable doses of either an ACE inhibitor or an ARB. Inclusion criteria were blood pressure between 130/80 mm Hg and 179/109 mm Hg for 2 to 4 weeks after discontinuing all antihypertensive medications with the exception of an ACE inhibitor or an ARB.

Qualifying patients were randomly assigned to treatment with either carvedilol or metoprolol tartrate. To achieve a target blood pressure below 130/80 mm Hg, doses of each drug were initiated and uptitrated according to the manufacturer’s recommendations at 1- to 2-week intervals for 2 to 7 weeks. Carvedilol was started at 6.25 mg twice daily and was raised in two steps to a maximum of 25 mg twice daily. Metoprolol was started at 50 mg twice daily and was raised in two steps to 200 mg twice daily. Hydrochlorothiazide, 12.5 mg, and a dihydropyridine CCB were sequentially added if the target blood pressure was not reached with the maximum beta blocker dose. Participants were then entered into a 5-month maintenance period after reaching the target blood pressure.

The primary outcome was the percent change in A1C between baseline and 5 months of maintenance therapy between the two groups. Secondary outcomes are listed in the Table and include measures of insulin resistance, lipid levels, and endothelial function.

Results

Patients enrolled in GEMINI had a mean baseline blood pressure of 149/87 mm Hg and an A1C level of 7.2%. Both drugs similarly controlled blood pressure to an average of 132/77 mm Hg. The mean beta blocker doses required to achieve this blood pressure were 17.5 mg of carvedilol twice daily and 128 mg of metoprolol twice daily, with both treatment groups requiring similar additional blood pressure medication. Eighty percent of the carvedilol group and 74% of the metoprolol group completed 5 months of maintenance therapy.

Although carvedilol had a neutral effect on mean A1C levels (P = .65), metoprolol increased mean A1C by 0.15% (P < .001). Figure 1 shows the progressive rise in A1C for patients receiving metoprolol compared with those receiving carvedilol. The primary outcome showed significantly better glycemic control with carvedilol (0.12% difference in A1C from baseline) than with metoprolol (95% confidence interval, —0.20 to –0.03; P = .006). An increase in A1C of at least 1% was twice as frequent with metoprolol (14%) as it was with carvedilol (7%). More metoprolol patients (2.2%) than carvedilol patients (0.6%) withdrew because of worsening glycemic control (fasting blood glucose > 270 mg/dL). Differences in glycemic control were due to changes in insulin resistance as shown in Figure 2. Although there was a nonsignificant increase in insulin resistance with metoprolol, there was a significant decrease with carvedilol (P = .006), with a mean difference of 7.2% between the treatment groups (P = .004).

There were also significantly different changes in blood lipids at 5 months (Figure 2). Metoprolol increased triglycerides by 13% (P < .001), whereas carvedilol had no significant effect. Carvedilol lowered total cholesterol

significantly more than metoprolol

(P = .001), and twice as many metoprolol patients than carvedilol patients had an HMG-CoA reductase inhibitor (statin) initiated or increased during the maintenance phase of the study (4.9% versus 2.4%; P = .04). No between-treatment differences were seen in either low- or high-density lipoprotein cholesterol levels. Endothelial function was also favorably affected by carvedilol because of decreased insulin resistance and/or oxidative stress, but not by metoprolol. Microalbuminuria, defined as a urinary albumin-to-creatinine ratio of 30 to 300 mg/g, was present in 19% of patients at baseline. Carvedilol use was associated with a significant 16% reduction in albumin-to-creatinine ratio, whereas there was a nonsignificant increase with metoprolol, resulting in a significant between-treatment difference (P = .003). In addition, fewer carvedilol than metoprolol patients with baseline albumin-to-creatinine ratios below 30 mg/g progressed to microalbuminuria (6.4% versus 10.3%; P = .04). Adverse drug effects were comparable between the two groups, although significant weight gain and bradycardia were more common with metoprolol.

Implications

GEMINI is the first trial to study the metabolic effects of beta blockade when added to ACE inhibitor or ARB therapy in the treatment of diabetic hypertension. Patients were typical of those encountered in clinical practice, with blood pressures above recommended levels despite renin-angiotensin system blockade. Both carvedilol, a vasodilating beta blocker with antioxidant properties, and metoprolol, a beta1 selective blocker, successfully lowered blood pressure, although higher doses of metoprolol were required to do so.

Glycemic control was significantly worsened by metoprolol but not by carvedilol because of an improvement in insulin sensitivity with carvedilol and a nonsignificant decrease in insulin sensitivity with metoprolol. The improvement in insulin resistance, endothelial function, and glycemic control seen with carvedilol in the GEMINI study translates into a decrease in cardiac risk for the diabetic patient; however, an outcome trial is needed to assess whether these decreases in cardiac risk translate into improved cardiovascular outcomes.

Conclusions

The GEMINI study demonstrates that in the presence of agents that block the renin-angiotensin system, the use of a beta blocker that has been shown to reduce insulin resistance and improve endothelial function, such as carvedilol, will improve glycemic control and avoid the negative effects on metabolic factors that may compromise the reduction in cardiac risk associated with beta blockade.