Pharmacotherapy Original research| Volume 34, ISSUE 8, P1735-1750, August 2012

Comparison of the Efficacy and Safety Profiles of Two Fixed-Dose Combinations of Antihypertensive Agents, Amlodipine/Benazepril Versus Valsartan/Hydrochlorothiazide, in Patients With Type 2 Diabetes Mellitus and Hypertension: A 16-Week, Multicenter, Randomized, Double-Blind, Noninferiority Study

  • I-Te Lee
    Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung City, Taiwan

    School of Medicine, Chung Shan Medical University, Taichung City, Taiwan

    School of Medicine, National Yang-Ming University, Taipei City, Taiwan
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  • Yi-Jen Hung
    Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan
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  • Jung-Fu Chen
    Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan
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  • Chih-Yuan Wang
    Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan
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  • Wen-Jane Lee
    Department of Medical Research, Taichung Veterans General Hospital, Taichung City, Taiwan
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  • Wayne Huey-Herng Sheu
    Address correspondence to: Wayne Huey-Herng Sheu, MD, PhD, Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, #160, Section 3, Chung Kang Road, Taichung 407, Taiwan
    Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung City, Taiwan

    School of Medicine, Chung Shan Medical University, Taichung City, Taiwan

    School of Medicine, National Yang-Ming University, Taipei City, Taiwan

    Institute of Medical Technology, College of Life Science, National Chung Hsing University, Taichung, Taiwan
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      Hypertension is a prevalent condition that is closely associated with chronic complications in patients with diabetes. Fixed-dose combination therapy is currently recommended for the treatment of hypertension due to the advantage of reducing the pill burden. However, the effects of combination therapy may be diverse because of the different components.


      We examined blood pressure reduction and metabolic alterations after amlodipine/benazepril and valsartan/hydrochlorothiazide treatment in patients with type 2 diabetes mellitus and hypertension and microalbuminuria.


      This randomized, double-blind, parallel comparison, noninferiority clinical trial included patients with type 2 diabetes mellitus and hypertension and microalbuminuria detected within the past year. After a 2-week, placebo run-in period, patients were assigned to treatment with amlodipine/benazepril or valsartan/hydrochlorothiazide for 16 weeks. The primary end point was mean change in diastolic blood pressure. The prespecified boundary for noninferiority was 3.5 mm Hg of the mean change in diastolic blood pressure between treatments (amlodipine/benazepril minus valsartan/hydrochlorothiazide). If the upper limit of the 95% CI fell within 3.5 mm Hg, amlodipine/benazepril would be considered noninferior to valsartan/hydrochlorothiazide.


      Of the 226 patients assessed for eligibility, 169 satisfied the inclusion/exclusion criteria and were assigned to a treatment group; 83 patients (54.2% male, mean age of 60.5 [10.0] years) in the amlodipine/benazepril group and 84 patients (64.3% male, mean age of 59.0 [10.6] years) in the valsartan/hydrochlorothiazide group received at least 1 dose of study medication and were included in the intention-to-treat population. In the per-protocol population, amlodipine/benazepril (n = 74) was noninferior to valsartan/hydrochlorothiazide (n = 78) with regard to the mean change in diastolic blood pressure (difference, −0.9 mm Hg; 95% CI, −3.5 to 1.6). The mean change in systolic blood pressure was not significantly different (2.4 mm Hg; 95% CI, −1.2 to 6.0) between study groups (P = 0.195) in the per-protocol population. However, data from the intention-to-treat population suggest that patients in the amlodipine/benazepril group may have better metabolic outcomes than those in the valsartan/hydrochlorothiazide group; specifically, a preservation of the estimated glomerular filtration rate (5.7 mL/min/1.73 m2 [95% CI, 1.9 to 9.6]; P = 0.004) and improvements in glycosylated hemoglobin (−0.5% [95% CI, −0.7 to −0.2]; P < 0.001), fasting triglycerides (−0.4 mmol/L [95% CI, −0.7 to −0.2]; P = 0.002), HDL-C (0.07 mmol/L [95% CI, 0.01 to 0.12]; P = 0.022), and uric acid (−57.5 μmol/L [95% CI, −74.8 to −40.3]; P < 0.001). There were no significant differences in adverse effects between groups, with the exception of more respiratory disorders in the amlodipine/benazepril group than in the valsartan/hydrochlorothiazide group (17 vs 5; P = 0 .006).


      The study results suggest that amlodipine/benazepril is noninferior to valsartan/hydrochlorothiazide with regard to blood pressure reduction and that this combination exerts beneficial effects on renal function, glucose control, HDL-C, and triglyceride levels compared with valsartan/hydrochlorothiazide. However, respiratory adverse events (particularly coughing) were more frequently reported in the amlodipine/benazepril group. identifier: NCT01375322.

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        • Kearney P.M.
        • Whelton M.
        • Reynolds K.
        • et al.
        Global burden of hypertension: analysis of worldwide data.
        Lancet. 2005; 365: 217-223
        • Erdine S.
        • Aran S.N.
        Current status of hypertension control around the world.
        Clin Exp Hypertens. 2004; 26: 731-738
        • Egan B.M.
        • Zhao Y.
        • Axon R.N.
        US trends in prevalence, awareness, treatment, and control of hypertension, 1988-2008.
        JAMA. 2010; 303: 2043-2050
        • Mittal B.V.
        • Singh A.K.
        Hypertension in the developing world: challenges and opportunities.
        Am J Kidney Dis. 2010; 55: 590-598
        • Lloyd-Jones D.
        • Adams R.
        • Carnethon M.
        • et al.
        Heart disease and stroke statistics—2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.
        Circulation. 2009; 119: e21-e181
        • Kabakov E.
        • Norymberg C.
        • Osher E.
        • et al.
        Prevalence of hypertension in type 2 diabetes mellitus: impact of the tightening definition of high blood pressure and association with confounding risk factors.
        J Cardiometab Syndr. 2006; 1: 95-101
        • Fuller H.
        • Stevens L.K.
        Prevalence of hypertension among diabetic patients and its relation to vascular risk.
        J Hum Hypertens. 1991; 5: 237-243
      1. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38 [published correction appears in BMJ. 1999;318:29].
        BMJ. 1998; 317: 703-713
        • Bakris G.L.
        • Williams M.
        • Dworkin L.
        • et al.
        Preserving renal function in adults with hypertension and diabetes: a consensus approach.
        Am J Kidney Dis. 2000; 36: 646-661
        • Yang W.
        • Chang J.
        • Kahler K.H.
        • et al.
        Evaluation of compliance and health care utilization in patients treated with single pill vs. free combination antihypertensives.
        Curr Med Res Opin. 2010; 26: 2065-2076
        • American Diabetes Association
        Standards of medical care in diabetes—2011.
        Diabetes Care. 2011; 34: S11-S61
        • Ismail H.
        • Mitchell R.
        • McFarlane S.I.
        • Makaryus A.N.
        Pleiotropic effects of inhibitors of the RAAS in the diabetic population: above and beyond blood pressure lowering.
        Curr Diab Rep. 2010; 10: 32-36
        • Chiang C.E.
        • Wang T.D.
        • Li Y.H.
        • et al.
        Hypertension Committee of the Taiwan Society of Cardiology.
        J Formos Med Assoc. 2010; 109: 740-773
        • Williams B.
        • Poulter N.R.
        • Brown M.J.
        • et al.
        British Hypertension Society guidelines for hypertension management 2004 (BHS-IV): summary.
        BMJ. 2004; 328: 634-640
        • Young C.H.
        • Zhang K.
        • Poret A.W.
        Patterns of antihypertensive therapy in new users of angiotensin II-receptor blockers.
        Am J Health Syst Pharm. 2005; 62: 2381-2385
        • Black H.R.
        • Bailey J.
        • Zappe D.
        • Samuel R.
        Valsartan: more than a decade of experience.
        Drugs. 2009; 69: 2393-2414
        • Lacourcière Y.
        • Poirier L.
        • Hebert D.
        • et al.
        Antihypertensive efficacy and tolerability of two fixed-dose combinations of valsartan and hydrochlorothiazide compared with valsartan monotherapy in patients with stage 2 or 3 systolic hypertension: an 8-week, randomized, double-blind, parallel-group trial.
        Clin Ther. 2005; 27: 1013-1021
        • Wellington K.
        • Faulds D.M.
        Valsartan/hydrochlorothiazide: a review of its pharmacology, therapeutic efficacy and place in the management of hypertension.
        Drugs. 2002; 62: 1983-2005
        • Chrysant S.G.
        Fixed combination therapy of hypertension: focus on valsartan/hydrochlorothiazide combination (Diovan/HCT).
        Expert Rev Cardiovasc Ther. 2003; 1: 335-343
        • Jamerson K.
        • Weber M.A.
        • Bakris G.L.
        • et al.
        • ACCOMPLISH Trial Investigators
        Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients.
        N Engl J Med. 2008; 359: 2417-2428
        • Bakris G.L.
        • Sarafidis P.A.
        • Weir M.R.
        • et al.
        • ACCOMPLISH Trial Investigators
        Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial.
        Lancet. 2010; 375: 1173-1181
        • Weber M.A.
        • Bakris G.L.
        • Jamerson K.
        • et al.
        • ACCOMPLISH Investigators
        Cardiovascular events during differing hypertension therapies in patients with diabetes.
        J Am Coll Cardiol. 2010; 56: 77-85
        • Bakris G.L.
        • Toto R.D.
        • McCullough P.A.
        • et al.
        Effects of different ACE inhibitor combinations on albuminuria: results of the GUARD study.
        Kidney Int. 2008; 73: 1303-1309
        • Yusuf S.
        • Teo K.K.
        • Pogue J.
        • et al.
        Telmisartan, ramipril, or both in patients at high risk for vascular events.
        N Engl J Med. 2008; 358: 1547-1559
        • Mann J.F.
        • Schmieder R.E.
        • McQueen M.
        • et al.
        ONTARGET Investigators.
        Lancet. 2008; 372: 547-553
        • Barnett A.H.
        • Bain S.C.
        • Bouter P.
        • et al.
        Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy.
        N Engl J Med. 2004; 351: 1952-1961
        • Maione A.
        • Navaneethan S.D.
        • Graziano G.
        • et al.
        Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and combined therapy in patients with micro- and macroalbuminuria and other cardiovascular risk factors: a systematic review of randomized controlled trials.
        Nephrol Dial Transplant. 2011; 26: 2827-2847
        • National Kidney Foundation
        K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.
        Am J Kidney Dis. 2002; 39: S1-S266
        • Piaggio G.
        • Elbourne D.R.
        • Altman D.G.
        • et al.
        • CONSORT Group
        Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement.
        JAMA. 2006; 295: 1152-1160
        • Scott I.A.
        Non-inferiority trials: determining whether alternative treatments are good enough.
        Med J Aust. 2009; 190: 326-330
        • Van Breukelen G.J.
        Analysis of covariance in medical research.
        J Clin Epidemiol. 2006; 59: 920-925
        • Grady J.J.
        Analysis of change.
        Methods Mol Biol. 2007; 404: 261-271
        • O'Gorman T.W.
        • Woolson R.F.
        • Jones M.P.
        A comparison of two methods of estimating a common risk difference in a stratified analysis of a multicenter clinical trial.
        Control Clin Trials. 1994; 15: 135-153
        • Blevins L.
        • McDonald C.J.
        Fisher's exact test: an easy-to-use statistical test for comparing outcomes.
        MD Comput. 1985; 2 (68): 15-19
        • Porta N.
        • Bonet C.
        • Cobo E.
        Discordance between reported intention-to-treat and per protocol analyses.
        J Clin Epidemiol. 2007; 60: 663-669
        • Bangalore S.
        • Kamalakkannan G.
        • Parkar S.
        • Messerli F.H.
        Fixed-dose combinations improve medication compliance: a meta-analysis.
        Am J Med. 2007; 120: 713-719
        • Wald D.S.
        • Law M.
        • Morris J.K.
        • et al.
        Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials.
        Am J Med. 2009; 122: 290-300
        • Hackam D.G.
        • Khan N.A.
        • Hemmelgarn B.R.
        • et al.
        The 2010 Canadian Hypertension Education Program recommendations for the management of hypertension: part 2—therapy.
        Can J Cardiol. 2010; 26: 249-258
        • Wagstaff A.J.
        Valsartan/hydrochlorothiazide: a review of its use in the management of hypertension.
        Drugs. 2006; 66: 1881-1901
        • Lacourcière Y.
        • Poirier L.
        • Samuel R.
        Valsartan plus hydrochlorothiazide for first-line therapy in hypertension.
        Expert Rev Cardiovasc Ther. 2009; 7: 1491-1501
        • Pollare T.
        • Lithell H.
        • Berne C.
        A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension.
        N Engl J Med. 1989; 321: 868-873
        • Eriksson J.W.
        • Jansson P.A.
        • Carlberg B.
        • et al.
        Hydrochlorothiazide, but not candesartan, aggravates insulin resistance and causes visceral and hepatic fat accumulation: the mechanisms for the diabetes preventing effect of candesartan (MEDICA) study.
        Hypertension. 2008; 52: 1030-1037
        • Fogari R.
        • Preti P.
        • Zoppi A.
        • et al.
        Effect of valsartan addition to amlodipine on insulin sensitivity in overweight-obese hypertensive patients.
        Intern Med. 2008; 47: 1851-1857
        • Ishimitsu T.
        • Numabe A.
        • Masuda T.
        • et al.
        Angiotensin-II receptor antagonist combined with calcium channel blocker or diuretic for essential hypertension.
        Hypertens Res. 2009; 32: 962-968
        • Burris J.F.
        • Ames R.P.
        • Applegate W.B.
        • et al.
        Double-blind comparison of amlodipine and hydrochlorothiazide in patients with mild to moderate hypertension.
        J Cardiovasc Pharmacol. 1988; 12: S98-S102
        • Poldermans D.
        • Glazes R.
        • Kargiannis S.
        • et al.
        Tolerability and blood pressure-lowering efficacy of the combination of amlodipine plus valsartan compared with lisinopril plus hydrochlorothiazide in adult patients with stage 2 hypertension.
        Clin Ther. 2007; 29: 279-289
        • Neutel J.M.
        Choosing among renin-angiotensin system blockers for the management of hypertension: from pharmacology to clinical efficacy.
        Curr Med Res Opin. 2010; 26: 213-222
        • Vijan S.G.
        Angiotensin-converting enzyme inhibitors (ACEIs), not angiotensin receptor blockers (ARBs), are preferred and effective mode of therapy in high cardiovascular risk patients.
        J Indian Med Assoc. 2009; 107: 178-182
        • Ninomiya T.
        • Perkovic V.
        • de Galan B.E.
        • et al.
        • ADVANCE Collaborative Group
        Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes.
        J Am Soc Nephrol. 2009; 20: 1813-1821