Efficacy and Safety of a Fixed-Dose Combination of Candesartan and Rosuvastatin on Blood Pressure and Cholesterol in Patients With Hypertension and Hypercholesterolemia: A Multicenter, Randomized, Double-Blind, Parallel Phase III Clinical Study



      The aim of this study was to evaluate the blood pressure–lowering and cholesterol-lowering effects of a fixed-dose combination therapy using candesartan (CND)/rosuvastatin (RSV) compared with CND or RSV monotherapy in patients with hypertension and hypercholesterolemia.


      This study was a 12-week, randomized, double-blind, placebo-controlled, multicenter study. A total of 394 patients were screened. After a 4-week run-in period, 219 of these patients with hypertension and primary hypercholesterolemia were randomized. Patients received 1 of 3 regimens for 8 weeks: (1) CND 32 mg/RSV 20 mg, (2) RSV 20 mg, or (3) CND 32 mg. The primary outcome variables were changes in the systolic blood pressure (SBP) and diastolic blood pressure (DBP) and the percentage changes in LDL-C from baseline to the drug treatment at 8 weeks. The secondary outcome variables were percentage changes of total cholesterol, triglycerides, HDL-C, non–HDL-C, apolipoprotein B, apolipoprotein A-I, high-sensitivity C-reactive protein, and glucose metabolic indices, including percentage changes of the homeostasis model assessment of insulin resistance (HOMA-IR), adiponectin, and hemoglobin A1c. Tolerability of combination therapy was compared with other monotherapy groups.


      The percentage changes of LDL-C were −48.6% (from 157.2 to 80.1 mg/dL) in the RSV group and −49.8% (from 160.2 to 78.9 mg/dL) in the CND/RSV group from baseline to the end of 8 weeks of treatment. Mean SBP and DBP were significantly decreased in the CND/RSV and CND groups after 8 weeks (P < 0.001 for all); however, no significant differences were found between the 2 groups. Total cholesterol levels, triglycerides, non–HDL-C, and apolipoprotein B were significantly reduced in the CND/RSV and RSV groups, with no significant differences between the groups compared with the CND group (P < 0.001 for all). The percentage changes of HOMA-IR, adiponectin, and hemoglobin A1c had no significant differences between the combination groups and monotherapy groups. However, in a 2-sample t test, HOMA-IR was significantly decreased in the CND/RSV group compared with the RSV group in nondiabetic patients (mean [SD] percentage change of HOMA-IR, −8.7% [37.6%] vs 17.1% [53.1%]; P = 0.048). There were no significant differences in metabolic indices between the diabetic groups. Adverse events in the CND/RSV group were similar to those in the monotherapy group.


      Once-daily fixed-dose combination therapy with CND/RSV is an effective, tolerable, convenient treatment option for patients with essential hypertension and hypercholesteremia. identifier: NCT02770261.


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        • Ansell B.J.
        Evidence for a combined approach to the management of hypertension and dyslipidemia.
        Am J Hypertens. 2005; 18: 1249-1257
        • Lee S.H.
        Update on familial hypercholesterolemia: diagnosis, cardiovascular risk, and novel therapeutics.
        Endocrinol Metab. 2017; 32: 36-40
        • Stone N.J.
        • Robinson J.G.
        • Lichtenstein A.H.
        • et al.
        2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines.
        Circulation. 2014; 129: S1-S45
        • Oesterle A.
        • Laufs U.
        • Liao J.K.
        Pleiotropic effects of statins on the cardiovascular system.
        Circ Res. 2017; 120: 229-243
        • Lim S.
        • Sakuma I.
        • Quon M.J.
        • Koh K.K.
        Differential metabolic actions of specific statins: clinical and therapeutic considerations.
        Antioxid Redox Signal. 2014; 20: 1286-1299
        • Mora S.
        • Glynn R.J.
        • Hsia J.
        • MacFadyen J.G.
        • Genest J.
        • Ridker P.M.
        Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity c-reactive protein or dyslipidemia: results from the justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials.
        Circulation. 2010; 121: 1069-1077
        • Ridker P.M.
        • Pradhan A.
        • MacFadyen J.G.
        • Libby P.
        • Glynn R.J.
        Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial.
        Lancet. 2012; 380: 565-571
        • Yoon J.S.
        • Lee H.W.
        Diabetogenic effect of statins: a double-edged sword?.
        Diabetes Metab J. 2013; 37: 415-422
        • Silverman M.G.
        • Ference B.A.
        • Im K.
        • et al.
        Association between lowering LDL-c and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis.
        JAMA. 2016; 316: 1289-1297
        • Ference B.A.
        • Robinson J.G.
        • Brook R.D.
        • et al.
        Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes.
        N Engl J Med. 2016; 375: 2144-2153
        • Potier L.
        • Roussel R.
        • Elbez Y.
        • et al.
        REACH Registry Investigators. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in high vascular risk.
        Heart. 2017; 103: 1339-1346
        • Elliott W.J.
        • Meyer P.M.
        Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis.
        Lancet. 2007; 369: 201-207
        • Benson S.C.
        • Pershadsingh H.A.
        • Ho C.I.
        • et al.
        Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPAR gamma-modulating activity.
        Hypertension. 2004; 43: 993-1002
        • Kim S.H.
        • Jo S.H.
        • Lee S.C.
        • et al.
        Blood pressure and cholesterol-lowering efficacy of a fixed-dose combination with irbesartan and atorvastatin in patients with hypertension and hypercholesterolemia: a randomized, double-blind, factorial, multicenter Phase III study.
        Clin Ther. 2016; 38: 2171-2184
        • Jang J.Y.
        • Lee S.H.
        • Kim B.S.
        • et al.
        Additive beneficial effects of valsartan combined with rosuvastatin in the treatment of hypercholesterolemic hypertensive patients.
        Korean Circ J. 2015; 45: 225-233
        • Glorioso N.
        • Troffa C.
        • Filigheddu F.
        • et al.
        Effect of the HMG-CoA reductase inhibitors on blood pressure in patients with essential hypertension and primary hypercholesterolemia.
        Hypertension. 1999; 34: 1281-1286
        • Nazzaro P.
        • Manzari M.
        • Merlo M.
        • et al.
        Distinct and combined vascular effects of ACE blockade and HMG-CoA reductase inhibition in hypertensive subjects.
        Hypertension. 1999; 33: 719-725
        • O'Driscoll G.
        • Green D.
        • Taylor R.R.
        Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month.
        Circulation. 1997; 95: 1126-1131
        • Lewis T.V.
        • Cooper B.A.
        • Dart A.M.
        • Chin-Dusting J.P.
        Responses to endothelium-dependent agonists in subcutaneous arteries excised from hypercholesterolaemic men.
        Br J Pharmacol. 1998; 124: 222-228
        • Borghi C.
        • Prandin M.G.
        • Costa F.V.
        • Bacchelli S.
        • Degli Esposti D.
        • Ambrosioni E.
        Use of statins and blood pressure control in treated hypertensive patients with hypercholesterolemia.
        J Cardiovasc Pharmacol. 2000; 35: 549-555
        • Kaesemeyer W.H.
        • Caldwell R.B.
        • Huang J.
        • Caldwell R.W.
        Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions.
        J Am Coll Cardiol. 1999; 33: 234-241
        • Nickenig G.
        • Baumer A.T.
        • Temur Y.
        • Kebben D.
        • Jockenhovel F.
        • Bohm M.
        Statin-sensitive dysregulated AT1 receptor function and density in hypercholesterolemic men.
        Circulation. 1999; 100: 2131-2134
        • Rajagopalan S.
        • Zannad F.
        • Radauceanu A.
        • et al.
        Effects of valsartan alone versus valsartan/simvastatin combination on ambulatory blood pressure, C-reactive protein, lipoproteins, and monocyte chemoattractant protein-1 in patients with hyperlipidemia and hypertension.
        Am J Cardiol. 2007; 100: 222-226
        • Lotta L.A.
        • Sharp S.J.
        • Burgess S.
        • et al.
        Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: a meta-analysis.
        JAMA. 2016; 316: 1383-1391
        • Cederberg H.
        • Stancakova A.
        • Yaluri N.
        • Modi S.
        • Kuusisto J.
        • Laakso M.
        Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6-year follow-up study of the metsim cohort.
        Diabetologia. 2015; 58: 1109-1117
        • Koh K.K.
        • Sakuma I.
        • Quon M.J.
        Differential metabolic effects of distinct statins.
        Atherosclerosis. 2011; 215: 1-8
        • Yan W.H.
        • Pan C.Y.
        • Dou J.T.
        • Meng J.H.
        • Wang B.A.
        • Mu Y.M.
        Candesartan cilexetil prevents diet-induced insulin resistance via peroxisome proliferator-activated receptor-γ activation in an obese rat model.
        Exp Ther Med. 2016; 12: 272-278
        • Erbe D.V.
        • Gartrell K.
        • Zhang Y.L.
        • et al.
        Molecular activation of PPAR gamma by angiotensin II type 1-receptor antagonists.
        Vascul Pharmacol. 2006; 45: 154-162
        • Rizos C.V.
        • Milionis H.J.
        • Kostapanos M.S.
        • et al.
        Effects of rosuvastatin combined with olmesartan, irbesartan, or telmisartan on indices of glucose metabolism in Greek adults with impaired fasting glucose, hypertension, and mixed hyperlipidemia: a 24-week, randomized, open-label, prospective study.
        Clin Ther. 2010; 32: 492-505
        • Elliott W.J.
        • Meyer P.M.
        Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis.
        Lancet. 2007; 369: 201-207
        • Cheung B.M.
        • Cheung G.T.
        • Lauder I.J.
        • et al.
        Meta-analysis of large outcome trials of angiotensin receptor blockers in hypertension.
        J Hum Hypertens. 2006; 20: 37-43
        • Goossens G.H.
        • Blaak E.E.
        • van Baak M.A.
        Possible involvement of the adipose renin-angiotensin system in the pathophysiology of obesity and obesity-related disorders.
        Obes Rev. 2003; 4: 43-55
        • Jandeleit-Dahm K.A.
        • Tikellis C.
        • Reid C.M.
        • Johnston C.I.
        • Cooper M.E.
        Why blockade of renin-angiotensin system reduces the incidence of new-onset diabetes.
        J Hypertens. 2005; 23: 463-473
        • Semple R.K.
        • Chatterjee V.K.
        • O'Rahilly S.
        PPAR gamma and human metabolic disease.
        J Clin Invest. 2006; 116: 581-589
        • Zorad S.
        • Dou J.T.
        • Benicky J.
        • et al.
        Long-term angiotensin II AT1 receptor inhibition produces adipose tissue hypotrophy accompanied by increased expression of adiponectin and PPARgamma.
        Eur J Pharmacol. 2006; 552: 112-122
        • Villapol S.
        • Yaszemski A.K.
        • Logan T.T.
        • Sánchez-Lemus E.
        • Saavedra J.M.
        • Symes A.J.
        Candesartan, an angiotensin II AT₁-receptor blocker and PPAR-γ agonist, reduces lesion volume and improves motor and memory function after traumatic brain injury in mice.
        Neuropsychopharmacology. 2012; 37: 2817-2829