ORLANDO, FLA. — Treatment with carvedilol cut the incidence of new-onset microalbuminuria by 47%, compared with metoprolol, in a study of more than 700 patients with type 2 diabetes and hypertension.
Carvedilol's ability to prevent microalbuminuria is probably due to its antioxidant properties—an effect that gives carvedilol an advantage over other β-blockers and perhaps over other classes of antihypertensive medications as well, George L. Bakris, M.D., said at the annual meeting of the American College of Cardiology.
“These findings should be taken into account when selecting an antihypertensive medication,” especially for patients with type 2 diabetes, said Dr. Bakris, director of the Hypertension/Clinical Research Center at Rush University in Chicago.
Even among hypertensive patients who do not have diabetes, carvedilol may be a good option if they have indications of impaired glucose control or if they have inflammatory markers, Dr. Bakris told this newspaper. However, he cautioned that this doesn't mean that a patient whose diabetes is currently well controlled and who is tolerant of another β-blocker or other antihypertensive regimen should be switched to carvedilol.
The new findings came from a prespecified subanalysis of the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial, sponsored by GlaxoSmithKline, the company that markets carvedilol (Coreg). Dr. Bakris has received research grants from and is a speaker and consultant for GlaxoSmithKline. He has also received research grants from and is a speaker and consultant for Novartis, which markets the trade formulation of metoprolol (Lopressor). Metoprolol is also available in several generic formulations.
The primary objective of the GEMINI trial was to compare the effects of carvedilol and metoprolol on glycemic and metabolic control in 1,235 patients with type 2 diabetes and hypertension. Virtually all patients in the study were on optimized treatment with an ACE inhibitor or an angiotensin-receptor blocker. The study results showed that after 5 months of β-blocker treatment, patients treated with carvedilol had significantly better glycemic control and better improvements in measures associated with metabolic syndrome—insulin resistance, body weight, total cholesterol, and triglycerides—compared with metoprolol-treated patients (JAMA 2004;292:2227-36).
A prespecified subanalysis of the study focused on the 88% patients who had albuminuria at enrollment. The vast majority of these patients had a modest level, with a urinary albumin-to-creatinine ratio of less than 30 mg/g. A total of 191 patients had microalbuminuria, defined as a ratio of more than 30 mg/g but less than 301 mg/g. Microalbuminuria was the focus of this study because it reflects diffuse endothelial dysfunction in the renal vasculature and has been an independent predictor of cardiovascular events in patients with diabetes as well as in patients without diabetes. Microalbuminuria is also a marker of systemic inflammation that mirrors levels of high-sensitivity C-reactive protein.
Patients in the study were randomized to treatment with either carvedilol or metoprolol, and their dosages were up-titrated over a 7-week period. Carvedilol treatment began at a daily dosage of 6.25 mg b.i.d and was increased as tolerated to a daily maximum of 25 mg b.i.d. Metoprolol was begun at 50 mg b.i.d and was raised to a maximum dosage of 200 mg b.i.d. Patients who entered the study with a blood pressure of at least 140/90 mm Hg were treated to achieve a pressure of 135/85 mm Hg or less. Those who began at a pressure of 130-139/80-89 mm Hg were treated to reach a goal pressure of 130/80 mm Hg or less.
After 5 months of treatment, 388 patients treated with carvedilol had an average drop in their urinary albumin-to-creatinine ratio of 14%, compared with an average increase in the ratio of 2.5% among 542 patients treated with metoprolol—a statistically significant difference.
Among the patients who began the trial with a ratio of less than 30 mg/g, 6.6% of patients treated with carvedilol developed new-onset microalbuminuria during the 5-month follow-up, compared with 11.1% of the patients treated with metoprolol—a statistically significant difference. Treatment with carvedilol cut the risk of developing microalbuminuria by 47%, compared with patients treated with metoprolol. Carvedilol was also more effective than metoprolol for cutting urinary albumin levels in patients who were normoalbuminuric when they started treatment.
The protective effect of carvedilol, compared with metoprolol, was independent of the drugs' antihypertensive effects. The achieved blood pressures among the patients in both treatment groups were essentially identical. This led Dr. Bakris to speculate that carvedilol's ability to prevent microalbuminuria was due to the drug's antioxidant properties. He cautioned that reductions in microalbuminuria have not yet been proved to cut the rate of cardiovascular events.