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A Randomized Controlled Trial

George L. Bakris, MD; Vivian Fonseca, MD; Richard E. Katholi, MD; Janet B. McGill, MD; Franz H. Messerli, MD; Robert A. Phillips, MD, PhD; Philip Raskin, MD; Jackson T. Wright, Jr, MD, PhD; Rosemary Oakes, MS; Mary Ann Lukas, MD; Karen M. Anderson, PhD; David S. H. Bell, MD; for the GEMINI Investigators

JAMA. 2004;292:2227-2236.

Context  -Blockers have been shown to decrease cardiovascular risk in patients with hypertension and type 2 diabetes mellitus (DM); however, some components of the metabolic syndrome are worsened by some -blockers.

Objective  To compare the effects of -blockers with different pharmacological profiles on glycemic and metabolic control in participants with DM and hypertension receiving renin-angiotensin system (RAS) blockade, in the context of cardiovascular risk factors.

Design, Setting, and Participants  A randomized, double-blind, parallel-group trial (The Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives [GEMINI]) conducted between June 1, 2001, and April 6, 2004, at 205 US sites that compared the effects of carvedilol and metoprolol tartrate on glycemic control. The 1235 participants were aged 36 to 85 years with hypertension (>130/80 mm Hg) and type 2 DM (glycosylated hemoglobin [HbA_1c], 6.5%-8.5%) and were receiving RAS blockers. Participants were followed up for 35 weeks.

Interventions  Participants were randomized to receive a 6.25- to 25-mg dose of carvedilol (n = 498) or 50- to 200-mg dose of metoprolol tartrate (n = 737), each twice daily. Open-label hydrochlorothiazide and a dihydropyridine calcium antagonist were added, if needed, to achieve blood pressure target.

Main Outcome Measures  Difference between groups in mean change from baseline HbA_1c following 5 months of maintenance therapy. Additional prespecified comparisons included change from baseline HbA_1c in individual treatment groups, treatment effect on insulin sensitivity, and microalbuminuria.

Results  The 2 groups differed in mean change in HbA_1c from baseline (0.13%; 95% confidence interval [CI], –0.22% to –0.04%; P = .004; modified intention-to-treat analysis). The mean (SD) HbA_1c increased with metoprolol (0.15% [0.04%]; P<.001) but not carvedilol (0.02% [0.04%]; P = .65). Insulin sensitivity improved with carvedilol (–9.1%; P = .004) but not metoprolol (–2.0%; P = .48); the between-group difference was –7.2% (95% CI, –13.8% to –0.2%; P = .004). Blood pressure was similar between groups. Progression to microalbuminuria was less frequent with carvedilol than with metoprolol (6.4% vs 10.3%; odds ratio, 0.60; 95% CI, 0.36-0.97; P = .04).

Conclusions  Both -blockers were well tolerated; use of carvedilol in the presence of RAS blockade did not affect glycemic control and improved some components of the metabolic syndrome relative to metoprolol in participants with DM and hypertension. The effects of the 2 -blockers on clinical outcomes need to be compared in long-term clinical trials.

Author Affiliations: Department of Preventive Medicine, Rush University Medical Center, Chicago, Ill (Dr Bakris); Department of Medicine, Tulane University, New Orleans, La (Dr Fonseca); Department of Medicine, St John’s Hospital, Springfield, Ill (Dr Katholi); Department of Medicine, Washington University School of Medicine, St Louis, Mo (Dr McGill); Department of Medicine, St Luke’s-Roosevelt, New York, NY (Dr Messerli); Department of Medicine, Mt Sinai School of Medicine, New York, NY (Dr Phillips); Department of Medicine, University of Texas Southwestern Medical Center, Dallas (Dr Raskin); Departments of Medicine, University Hospitals of Cleveland and the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio (Dr Wright); GlaxoSmithKline, Philadelphia, Pa (Drs Lukas and Anderson, and Ms Oakes); and Department of Medicine, University of Alabama, Birmingham (Dr Bell).

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