Carvedilol reduces microalbuminuria more than metoprolol

Susan Jeffrey

March 14, 2005

Orlando, FL - A new study suggests that treatment with the beta blocker carved ilol (Coreg®, GlaxoSmithKline) reduced microalbuminuria among patients with type 2 diabetes and hypertension who had it at baseline and reduced the development of microalbuminuria in those who were normoalbuminuric at baseline, relative to treatment with another beta blocker, metoprolol tartrate (Lopressor®, Novartis/generic).

The study, focusing on a prespecified end point of the previously published Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial,[1] was presented here at the American College of Cardiology 2005 Scientific Sessions.

Dr George L Bakris

The main GEMINI results showed that treatment with carvedilol stabilized hemoglobin A1c (HbA1c), a measure of glycemic control, improved insulin resistance, and slowed the development of microalbuminuria compared with metoprolol in these patients.

"If you take these data together with the main trial, it suggests that carvedilol is probably the preferred beta blocker in those with type 2 diabetes, because it doesn't work against glycemic control and blocks inflammatory effects on top of traditional therapy used in those patients," Dr George L Bakris (Rush University Medical Center, Chicago, IL) told heart wire .

Switching to carvedilol in patients on metoprolol whose glucose is well controlled and who have no side effects from beta-blocker treatment is not necessary based on these results, he added. "But if you're just starting or you have someone with issues with glucose or other inflammatory markers, then it would be worth giving them a shot."

Differential effects

Beta blockers have been shown to decrease CV risk in patients with type 2 diabetes and hypertension, but some components of the metabolic syndrome, including lipids and glucose control, are worsened by most beta blockers, Bakris said. However, beta blockers are now commonly used with renin angiotensin system (RAS) blockers that improve insulin resistance and so might diminish these adverse metabolic effects.

Carvedilol has antioxidant and alpha-1 blocking properties, he noted, and small studies have suggested that carvedilol improves insulin resistance. GEMINI was designed to compare carvedilol with metoprolol in their effects on long-term glucose control, measured by HbA1c, among patients with type 2 diabetes and hypertension in the presence of RAS blockade.

The trial was a double-blind parallel-group study that randomized 1235 patients to titration from 6.25 to 25 mg of carvedilol or 50 to 200 mg of metoprolol, each twice daily. Follow-up was 35 weeks. All patients were receiving RAS blockade with ACE inhibitors or angiotensin receptor blockers but washed out of all other antihypertensive medications before randomization to one of the beta blockers. BP was treated to a target of <130/80 mm Hg; hydrochlorothiazide or a dihydropyridine calcium antagonist could be added to the beta blockers to reach this goal.

Average duration of treatment was significantly less with metoprolol, due mainly to tolerability issues, the researchers noted. The mean dose was 17.5 mg bid with carvedilol and 128 mg bid with metoprolol. About 50% of each group received a diuretic and/or a calcium antagonist.

The primary outcome was the difference between groups in the change in HbA1c from baseline after five months of maintenance therapy. They found a significant difference between the two groups in the mean change in HbA1c from baseline of 0.13% (95% CI -0.22 to 0.04, p=0.004).

In this study, Bakris et al examined the effect of carvedilol vs metoprolol on end points related to kidney function; the change from baseline in urine albumin:creatinine ratio (ACR), the development of new-onset microalbuminuria, and the change in ACR among those normal at baseline.

Microalbuminuria, a urine albumin:creatinine ratio (ACR) of 30 to 300 mg/g in patients with hypertension and diabetes, was present at baseline in 19% of carvedilol and 15% of metoprolol patients. Bakris reported that after five months, the ACR was significantly reduced with carvedilol, while no significant change was seen with metoprolol.

GEMINI: Change in urine albumin:creatinine ratio (ACR) from baseline in all participants with metoprolol and carvedilol treatment

Treatment % change in ACR from baseline 95% CI p
Carvedilol -14.0 -22.3 to -5.0 0.003
Metoprolol 2.5 -6.1 to 11.9 0.579

The difference in ACR between treatment groups was 16.2% (95% CI 6%-25%), a highly significant difference with a p value of 0.003.

Importantly, in the 79% of patients free of microalbuminuria at baseline, progression to microalbuminuria, an important CV risk marker, was seen in more patients on metoprolol than carvedilol, despite the fact that all patients were receiving RAS blockade, Bakris said.

GEMINI: Progression to microalbuminuria with carvedilol vs metoprolol treatment

End point Metoprolol Carvedilol Odds ratio (95% CI) p
Progression to microalbuminuria (%) 11.1 6.6 0.53 (0.30-0.93) 0.03

Among those who remained normoalbuminuric throughout the study, there was significant reduction in the ACR with carvedilol but not metoprolol.

Notably, blood pressure was not different between the groups, Bakris said, "so this is not a blood-pressure effect. And it's not a cytokine effect because beta blockers don't affect things like TGF-beta in the way ACE inhibitors do. These people are already on ACE inhibitors, so this is an additional mechanism," he told heartwire .

One candidate mechanism is reduction in oxidative stress. Recent studies showed antioxidant effects of carvedilol vs other beta blockers,[2,3] he noted. The differential antioxidant properties of metoprolol and carvedilol probably arise from the greater lipophilicity of carvedilol, he added. "The more you can get into the membranes, the more you can affect, because that's where oxidant stress is occurring. Drugs like metoprolol, atenolol, don't get anywhere near the membrane because they're more water soluble."

Bakris is a consultant to GlaxoSmithKline, AstraZeneca, Biovail, Boehringer Ingelheim, and Novartis, among several other companies.

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