Lowering Blood Pressure With β‐Blockers in Combination With Other Renin‐Angiotensin System Blockers in Patients With Hypertension and Type 2 Diabetes: Results From the GEMINI Trial

Abstract

The effects of β‐blockade in addition to more specific renin‐angiotensin system (RAS) blockers on blood pressure (BP) in patients with diabetes are described. After washout of medications other than angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers, patients were titrated to a BP level <130/80 mm Hg using therapy with carvedilol 6.25 to 25 mg bid (n=498) or metoprolol tartrate 50 to 200 mg bid (n=737). At the end of the β‐blocker titration period, a BP level <130/80 mm Hg was achieved in 37% of carvedilol‐treated and 36% of metoprolol‐treated participants who continued to receive a renin‐angiotensin system blocker. In the approximately 60% of participants in whom a BP level <130/80 mm Hg was not attained with renin‐angiotensin system blockade plus β‐blockade, hydrochlorothiazide was added in 43% and 44% of carvedilol and metoprolol groups, respectively; 25% (both arms) also required a calcium channel blocker. Among those in whom goal BP was not achieved, 42% of carvedilol‐ and 40% of metoprolol‐treated participants were not titrated to the highest dose of β‐blocker. The use of carvedilol compared with metoprolol did not effect glycemic control.

Patients with type 2 diabetes and/or hypertension have a significant risk of developing coronary artery disease, stroke, and heart failure. ¹ The presence of diabetes doubles the risk of cardiovascular disease in men and triples the risk in women. ² Blood pressure (BP) is more strongly correlated with cardiovascular mortality in patients with diabetes than in those without it. ³ The current guidelines from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) ¹ recommend thiazide diuretics as first‐step therapy for most patients with hypertension without compelling indications. For patients with hypertension and type 2 diabetes, many guidelines, including JNC 7, recommend angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients with nephropathy, along with diuretics, calcium channel blockers (CCBs), and β‐blockers for protection against cardiovascular events. Because of the high risk associated with hypertension and diabetes, current recommendations indicate that BP should be reduced to levels ≤130/80 mm Hg; achieving this goal will frequently require the use of multiple agents. ¹

The combination of ACE inhibitors or ARBs with β‐blockers has been reported to be less effective in lowering BP than some other combinations. ⁴ , ⁵ Clinical data highlight the importance of even small decreases in BP to reduce the risk of cardiovascular events, particularly in hypertensive patients with diabetes. They also emphasize the importance of more aggressive BP reduction. ⁶ At least one‐half of hypertensive patients with diabetes will require 2 or more antihypertensive medications from different pharmacologic classes to achieve adequate BP control. ¹ In fact, in all hypertensive patients for whom lower BP goals have been set, such as persons with diabetes, kidney disease, or substantially elevated BP, 3 or more antihypertensive drugs may be required. ⁷ , ⁸

The Glycemic Effect in Diabetes Mellitus: Carvedilol‐Metoprolol Comparison in Hypertensives (GEMINI) trial ⁹ is a large, randomized, controlled, double‐blind clinical trial designed to evaluate the effects of combined β‐blockade and more specific renin‐angiotensin system (RAS) blockade on BP control and glycemic control in patients with hypertension and diabetes. The primary end point of the study was the difference between the 2 different β‐blocker groups in changes in hemoglobin A_1c (HbA_1c) following 5 months of maintenance therapy. Changes in systolic and diastolic BP levels were among the prespecified secondary outcomes. ⁹ This analysis of the GEMINI trial compares the efficacy of treatment with carvedilol, a β‐blocker with α‐blocking effects, with metoprolol tartrate, a cardioselective β‐blocker, when given with ACE inhibitors or ARBs, on BP reduction in high‐risk patients.

METHODS

The complete design and rationale of the GEMINI trial has been previously published. ¹⁰ In summary, study participants included men and women aged 36 to 85 years with documented type 2 diabetes (HbA_1c level 6.5%–8.5%) systolic BP level between 130 and 179 mm Hg, and diastolic BP level between 80 and 109 mm Hg. Diabetes treatment must have been stable for 3 months and BP therapy stable for 1 month before enrollment with an ACE inhibitor or ARB as part of the antihypertensive regimen. Patients with significant cardiovascular, pulmonary, or kidney disease were excluded. Patients were also excluded from participation in the trial if they had been taking a β‐blocker within 3 months of screening. Eye drops containing β‐blockers were permissible throughout the trial. Written informed consent was obtained from all participants; protocol and procedures were approved by the institutional review board at each participating center. ⁹ , ¹⁰

After a washout of antihypertensive medications for 2 to 4 weeks (except ACE inhibitors and ARBs, which were continued at their regular dosage), patients were randomized 2:3 to receive carvedilol or metoprolol tartrate (in a double blind fashion). Doses were up‐titrated progressively at 1‐ to 2‐week intervals toward target BP levels with carvedilol (6.25, 12.5, 25.0 mg bid) or metoprolol tartrate (50, 100, 200 mg bid) (Figure 1). ¹⁰ These dosages were chosen based on the current US product labeling for the agents. Commercial preparations of both drugs were used and were similarly overencapsulated for blinding. At the inception of the protocol, the target BP level was <135/85 mm Hg; this level was lowered to <130/80 mm Hg when newer guidelines were published. ¹⁰ If necessary, additional therapy with hydrochlorothiazide (HCTZ) 12.5 mg followed by a dihydropyridine calcium antagonist was allowed in an attempt to achieve BP targets. Once target BP level or maximum dosage was reached, the study drug regimens were maintained for 5 months. ⁹

Figure 1.

Glycemic Effect in Diabetes Mellitus: Carvedilol‐Metoprolol Comparison in Hypertensives (GEMINI) study design. The GEMINI trial was a randomized, double‐blind, parallel‐group, multicenter (United States) trial of patients with stage 1 or 2 hypertension and type 2 diabetes who were receiving angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor blocker (ARBs). DBP indicates diastolic blood pressure; SBP, systolic blood pressure. Reprinted with permission from Bakris et al. ¹⁰

Statistical analyses for efficacy involved only patients with baseline and posttherapy assessments. Maintenance month 5 was the primary time point of interest. Missing values at month 5 were imputed using the last observation (on therapy values) carried forward (LOCF) model. For BP and heart rate, baseline was defined as the randomization visit; for HbA_1c, baseline assessments were from the prerandomization visit; and for albumin: creatinine ratio (ACR), baseline was from the screening visit. The analyses of change from baseline in BP level and heart rate as well as the correlation analysis between BP level and HbA_1c value were prespecified as secondary end points in the GEMINI study. The correlation analysis between BP level and ACR was defined post hoc. Treatment differences for the BP level change and heart rate change were assessed via analysis of covariance adjusting for study baseline values and for baseline thiazolidinedione and baseline ARB use (which were protocol‐specified stratification factors). Correlation analyses were performed to assess linear association between changes in BP and change from baseline in ACR and HbA_1c. ACR values at baseline and maintenance month 5 (LOCF) were log‐transformed for the analyses. Summary statistics were provided for various subsets of the data, including uses of antihypertensives (CCBs, HCTZ) and use of an ACE inhibitor/ARB at baseline and maintenance month 5. Treatment comparisons were tested at a significance level of 0.05, with no adjustment for multiplicity.

RESULTS

A total of 1235 patients were randomized to receive either carvedilol (n=498) or metoprolol tartrate (n=737). Baseline demographics and baseline ACE inhibitor and ARB use were similar between the 2 treatment groups (Table I). At the conclusion of the study, almost all patients were receiving ACE inhibitors or ARBs. Similar numbers of patients in the carvedilol and metoprolol tartrate groups had a diuretic added to achieve BP goals (approximately 40%), and approximately 20% in each group also had a CCB added (Figure 2).

Table I.

Baseline Demographic Characteristics of the Randomized Population

Characteristic	Carvedilol (n=498)	Metoprolol Tartrate (n=737)
Age, ya	60.8±9.3	61.1±9.6
Women	198 (39.8)	354 (48.0)
Race/ethnicity
White	355 (77.3)	496 (75.2)
Black	55 (12.0)	86 (13.1)
Other	49 (10.7)	77 (11.7)
Body mass index, kg/m2a	33.5±5.8	33.7±6.1
ACE inhibitor only	349 (76.0)	503 (76.3)
ARB only	97 (21.1)	151 (22.9)
Both ACE inhibitor and ARB	3 (0.7)	2 (0.3)
Neither ACE inhibitor nor ARB	10 (2.2)	3 (0.5)
Data are presented as No. (%) unless otherwise indicated. aMean ± SD. Abbreviations: ACE, angiotensin‐converting enzyme; ARB, angiotensin receptor blocker.

Figure 2.

Antihypertensive use at study end. ACE indicates angiotensin‐converting enzyme; ARB, angiotensin receptor blocker; HCTZ, hydrochlorothiazide; DHP‐CA, dihydropyridine‐calcium antagonist.

The mean BP throughout the study did not vary between groups; however, mean heart rate at month 5 was statistically but not clinically significantly lower in the metoprolol tartrate group (at month 5, heart rate in carvedilol group = 67.6 beats per minute [bpm]; in metoprolol tartrate group = 66.0 bpm) (Figure 3). At baseline, only approximately 4% of patients in each group had a BP level <135/85 mm Hg despite RAS therapy. At the end of the titration of β‐blocker therapy and before the addition of other agents, 37% of patients receiving carvedilol and 36% of patients receiving metoprolol had achieved a BP goal of 130/80 mm Hg. At the end of β‐blocker titration, a BP level of 135/85 mm Hg was achieved in 66% of patients receiving carvedilol and 65% of patients receiving metoprolol plus an RAS inhibitor and in 94.5% of patients taking carvedilol and 92.6% of patients taking metoprolol, a BP level ≤140/90 mm Hg was attained. Table II shows the BP by dose level in the carvedilol and metoprolol tartrate groups at baseline and at the end of the trial. Sixty‐eight percent of carvedilol patients and 67% of metoprolol tartrate patients achieved a BP level <130/80 mm Hg with the addition of other agents, such as a thiazide diuretic or a CCB. Mean total daily doses in the trial were 35±0.79 mg for carvedilol and 256±5.38 mg for metoprolol tartrate. Among the 32% of patients who received carvedilol in whom a BP level of 130/80 mm Hg was not achieved, 58% had been titrated to 25 mg bid (42% had not been titrated to the highest level); among the 33% of patients who received metoprolol in whom a BP level of 130/80 mm Hg was not reached, 60% had been titrated to 200 mg bid (40% had not been titrated to the highest level).

Figure 3.

Blood pressure and heart rate at baseline and study end. CI, confidence interval; SBP, systolic blood pressure; DBP indicates diastolic blood pressure; HR, heart rate.

Table II.

Blood Pressure Over Time by Dosage

Visit	Parameter	Statistic	Carvedilol Final Dosage, bid			Metoprolol Tartrate Final Dosage, bid
			6.25 mg (n=135)	12.5 mg (n=83)	25 mg (n=236)	50 mg (n=225)	100 mg (n=120)	200 mg (n=291)
Baseline value	SBP, mm Hg	Mean	143.5	148.9	152.8	144.0	149.0	153.0
		SD	8.5	11.6	11.3	10.4	10.4	11.4
	DBP, mm Hg	Mean	84.4	87.0	89.4	84.8	85.9	88.6
		SD	7.4	8.5	7.9	7.5	7.8	8.7
Month 5 value	SBP, mm Hg	Mean	128.8	132.1	132.8	128.5	133.2	134.8
		SD	11.6	10.9	14.2	13.5	12.6	15.1
	DBP, mm Hg	Mean	75.8	79.2	78.0	75.9	77.8	77.2
		SD	7.9	7.9	9.4	8.2	7.9	8.7
Month 5 change from baseline	SBP, mm Hg	Mean	−14.7	−16.8	−20.0	−15.5	−15.8	−18.2
		SD	11.7	14.2	16.1	14.1	15.1	15.9
	DBP, mm Hg	Mean	−8.6	−7.8	−11.3	−8.9	−8.1	−11.4
		SD	8.0	7.5	9.8	8.1	7.7	8.5
Abbreviations: bid, twice a day; DBP, diastolic blood pressure; SBP, systolic blood pressure.

The GEMINI study included 141 (approximately 12.5%) African American patients. As shown in Table III, these participants tended to have a higher BP level at baseline, and BP goals were reached in fewer of them than in other groups. Among African American participants, 18% and 24% of patients achieved a goal BP level of 130/80 mm Hg at the end of β‐blocker titration (before the addition of other medication) in the carvedilol and metoprolol groups, respectively.

Table III.

Baseline and End‐of‐Study Blood Pressure (mm Hg) by Race

Baseline	Caucasian and Other		African American
	Carvedilol (n=400)	Metoprolol (n=554)	Carvedilol (n=54)	Metoprolol (n=82)
SBP, mean ± SE	148.8±0.64	148.8±0.56	154.2±1.59	151.9±1.29
DBP, mean ± SE	86.7±0.46	85.9±0.40	89.3±1.36	88.9±0.93
End of (β‐Blocker Titration a
SBP, mean ± SE	136.5±0.84	137.3±0.73	141.0±2.08	138.8±1.65
DBP, mean ± SE	78.5±0.43	78.2±0.37	83.0±1.06	79.3±0.84
Change from baseline in SBP (95% CI)	−12.7 (−14.3, −11.0)	−11.8 (−13.3, −10.4)	−8.2 (−12.3, −4.1)	−10.4 (−13.6, −7.2)
Change from baseline in DBP (95% CI)	−8.5 (−9.3, −7.6)	−8.8 (−9.5, −8.0)	−4.0 (−6.1, −1.9)	−7.7 (−9.3, −6.0)
End of Study (Month 5)
SBP, mean ± SE	131.1±0.74	132.5±0.64	132.6±1.83	131.2±1.49
DBP, mean ± SE	77.0±0.42	76.9±0.37	77.7±1.04	76.1±0.85
Change from baseline in SBP (95% CI)	−18.1 (−19.5, −16.6)	−16.7 (−18.0, −15.4)	−16.5 (−20.1, −12.9)	−18.0 (−20.9, −15.0)
Change from baseline in DBP (95% CI)	−10.1 (−10.9, −9.2)	−10.2 (−11.0, −9.5)	−9.3 (−11.4, −7.3)	−10.9 (−12.6, −9.2)
aPatients who had another medication (such as a calcium channel blocker or hydrochlorothiazide) added during the β‐blocker up‐titration phase of the study were not included in this part of the table to accurately show the blood pressure (BP)‐lowering effect of the angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker and (β‐blocker only. The numbers of patients included were as follows: carvedilol: non‐African American, 362; African American, 48 and metoprolol: non‐African American, 502; African American, 77. All patients were again included at study end (month 5). Abbreviations: CI, confidence interval; DBP, diastolic BP; SBP, systolic BP

In the carvedilol group, 34% of patients were titrated to a level 1 final dosage (6.25 mg bid), 16% were titrated to level 2 (12.5 mg bid), and 49% were titrated to level 3 (25.0 mg bid). In the metoprolol tartrate group, 41% of patients were titrated to a level 1 final dosage of level 1 (50 mg bid), 20% were titrated to level 2 (100 mg bid), and 39% were titrated to level 3 (200 mg bid). More African American patients (>70%) were titrated to the highest dose level in both the carvedilol and metoprolol groups (Table IV).

Table IV.

Percentages of Patients in Final Titration Levels

	Final Titration Dosage Level
	1	2	3
All patients
Carvedilol	34	16	49
Metoprolol	41	20	39
African Americans
Carvedilol	13	11	77
Metoprolol	23	11	71
Non‐African Americans
Carvedilol	33	19	50
Metoprolol	39	21	44
Dosage level 1, carvedilol 6.25 mg twice a day (bid), metoprolol tartrate 50 mg bid. Dosage level 2, carvedilol 12.5 mg bid, metoprolol tartrate 100 mg bid. Dosage level 3, carvedilol 25 mg bid, metoprolol tartrate 200 mg bid.

HCTZ was prescribed in 43.4% and 44.1% of the carvedilol and metoprolol tartrate groups, respectively; 24.7% and 25.6% also required a calcium antagonist to reach a target BP level goal of 130/80 mm Hg. The use of adjunct therapy was similar in the groups; however, the changes in diastolic BP varied with the use of a CCB or thiazide diuretic (Figure 4A). Changes in systolic BP also varied with the use of agents in addition to RAS blockade and carvedilol or metoprolol (Figure 4B). There was no significant correlation between BP level and change in HbA_1c or ACR. Poor glycemic control was the reason for discontinuation in 0.6% of carvedilol participants and 2.2% of metoprolol participants.

Figure 4.

Additional diastolic blood pressure (DBP) reduction with use of adjunct medication in addition to carvedilol (Carv) or metoprolol (Met) and specific renin‐angiotensin system inhibitors (A). Additional systolic blood pressure (SBP) reduction with use of adjunct medication in addition to Carv or Met and specific renin‐angiotensin system inhibitors (B). HCTZ indicates hydrochlorothiazide; CCB, calcium‐channel blocker.

The percentage of participants who completed 5 months of maintenance therapy was significantly higher in the carvedilol group; more metoprolol‐treated patients dropped out because of adverse events. Discontinuation due to adverse events occurred in 8.8% of carvedilol‐treated participants and in 11.3% of metoprolol‐treated participants.

DISCUSSION

This report from the GEMINI trial demonstrates that the addition of β‐blockers to a regimen of ACE inhibitors or ARBs adequately controls BP in almost 40% of patients with diabetes and hypertension. In the published primary results from the GEMINI trial, it was reported that while carvedilol and metoprolol were equally efficacious in lowering BP, their effect on glycemic control varied. ⁹ Metoprolol tartrate significantly increased levels of HbA_1c, whereas carvedilol did not worsen glycemic control. In addition, at the dosages required to control BP, significantly more patients on metoprolol tartrate were withdrawn from the trial because of worsening glycemic control (defined as fasting plasma glucose level >270 mg/dL, change in diabetes medication, or hyperglycemia or hypoglycemia of clinical concern).

The GEMINI trial studied a population of patients with diabetes and hypertension, nearly all of whom were receiving moderate doses of RAS blockers (ACE inhibitors or ARBs). In similar numbers of patients, additional diuretic treatment (and a calcium antagonist if needed) was used to achieve target BP levels. Comparable BP levels were achieved with carvedilol and metoprolol tartrate; most patients received the low or middle dosage levels. It is worth noting that the mean dosage of metoprolol tartrate that was required to achieve BP goals (256 mg/d) was higher than that most frequently used in clinical practice. Because this trial titrated patients to BP goal, not to tolerability, it may be that some patients in clinical practice may not be able to tolerate a dosage of metoprolol tartrate that would lower BP to a similar degree as a commonly used dosage of carvedilol (17.5 mg bid).

As expected, BP reduction in African Americans at the end of β‐blocker titration was less than in non‐African Americans. In non‐African American and Asian patients, the addition of a β‐blocker to therapy with an ACE inhibitor or ARB produced substantial and equivalent reductions in systolic BP (−12.7 mm Hg and −11.8 mm Hg for carvedilol and metoprolol, respectively). No race‐related difference in BP reduction or level achieved was noted by the end of the trial after a diuretic or a CCB was given. It has been well established that in African Americans, a diuretic or CCB is more effective in lowering BP than is an ACE inhibitor, ARB, or a β‐blocker as monotherapy. In Caucasians, the addition of a β‐blocker to therapy with an ACE inhibitor or ARB appears to be additive. This pattern of BP response by race was also seen in the ACE inhibitor arm of the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ¹¹

The combination of an ACE inhibitor and a β‐blocker may be required in patients with hypertension and diabetes, a group at high risk for coronary artery and kidney disease. Some guidelines recommend that the first‐step therapy in patients with diabetes, especially those with proteinuria, should be an ACE inhibitor or an ARB to reduce cardiovascular risk and especially renal disease progression. ¹ , ¹² , ¹³ Because of some previous concerns about metabolic complications with β‐blocker therapy, ¹⁴ , ¹⁵ , ¹⁶ it has not generally been considered second‐step therapy. The above analysis of the GEMINI study results suggests that the combination of an RAS inhibitor and carvedilol or metoprolol substantially reduces BP (especially in non‐African American patients) and, as previously reported, that carvedilol does not appear to adversely affect glycemic control.

CONCLUSIONS

Patients with diabetes and hypertension are at significantly higher risk for cardiovascular disease; clinical evidence indicates that careful control of BP levels provides both renal and cardiac protection in these patients. Studies also indicate that combination therapy is essential, not only to help attain target BP levels of <130/80 mm Hg but also to offer to the possibility of more cardioprotection. In the GEMINI trial, approximately 36% of patients were able to attain this goal BP level with the use of ACE inhibitors or ARBs plus a β‐blocker. Additional therapy with a thiazide diuretic with or without a calcium antagonist was necessary to achieve the lower target BP level in nearly all of these high‐risk patients. With carvedilol, this was achieved without compromising glycemic control. β‐Blockers and RAS blockers have additive antihypertensive efficacy, especially in non‐African Americans, and may be used together to reduce BP in high‐risk patients with hypertension and diabetes.

Disclosure:

Jackson T. Wright Jr, MD, PhD, has received research grants, honoraria, and consulting fees from Abbott, AstraZeneca, Sanofi‐Aventis, Bayer, Bristol‐Myers Squibb, Eli Lilly and Company, Encysive Pharmaceuticals, GlaxoSmithKline, Merck & Co, Novartis, and Pfizer. George L. Bakris, MD, has been funded for investigator‐initiated clinical trials by the National Institutes of Health (NIH) (The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/National Heart, Lung, and Blood Institute), GlaxoSmithKline, Merck & Co, Myogen, and Novartis. He has also served as a consultant for Forest Labs, GlaxoSmithKline, Merck, and Novartis. David S. H. Bell, MB, has received honoraria, research grants, and consulting fees from GlaxoSmithKline. He has also received honoraria from Roche Pharmaceuticals. Vivian Fonseca, MD, has received research support (to Tulane University) from the American Diabetes Association, AstraZeneca, Daiichi‐Sankyo, Eli Lilly and Company, GlaxoSmithKline, the NIH (5M01RR05096 and RR‐00827), Novartis, Pfizer, Sanofi‐Aventis, and Takeda Pharmaceuticals. Dr Fonseca has received honoraria for consulting and lectures from Eli Lilly and Company, GlaxoSmithKline, Novartis, Pfizer, Sanofi‐Aventis, and Takeda Pharmaceuticals. All of Dr Fonseca's honoraria and research grants have been paid to Tulane University. Richard E. Katholi, MD, has received honoraria and consulting fees from GlaxoSmithKline. Janet B. McGill, MD, has received research funding from GlaxoSmithKline; she has also received speaking and consulting fees from AstraZeneca and GlaxoSmithKline. Franz H. Messerli, MD, has been a consultant and speaker for Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Forest Laboratories, GlaxoSmithKline, Novartis, Pfizer, Daiichi‐Sankyo, and Sanofi‐Aventis. Robert A. Phillips, MD, PhD, has received research support from NIH‐NIDDK and King/Monarch Pharmaceuticals; is a speaker and consultant for AstraZeneca, GlaxoSmithKline, and Pfizer; and is a consultant for Bristol‐Myers Squibb and Merck & Co. Philip Raskin, MD, reports that he is on the advisory board for Novo Nordisk and is a member of the Speakers' Bureau for Novartis, Novo Nordisk, Pfizer, and Takeda Pharmaceuticals. He has received research funds from Eli Lilly and Company, GlaxoSmithKline, Merck & Co, Novartis, Novo Nordisk, and Pfizer. Fred K. Holdbrook, PhD, was an employee of GlaxoSmithKline. Mary Ann Lukas, MD, is an employee of GlaxoSmithKline. Malini Iyengar, PhD, is an employee of GlaxoSmithKline.