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Comparative effects of candesartan and hydrochlorothiazide on blood pressure, insulin sensitivity, and sympathetic drive in obese hypertensive individuals: results of the CROSS study
Abstract
OBJECTIVE: The increase in blood pressure that accompanies the obese state is almost invariably associated with alterations in metabolism (insulin resistance and dyslipidaemia) and the neurohumoral profile (activation of the renin-angiotensin system, sympathetic overactivity), which potentiate the cardiovascular risk associated with hypertension. However, debate remains as to the antihypertensive drug on which treatment of obesity-related hypertension should be based. The CROSS (Candesartan Role on Obesity and on Sympathetic System) study was undertaken to examine the antihypertensive, neuroadrenergic, and metabolic effects of an angiotensin II receptor blocker in comparison with a diuretic in obese hypertensive individuals. METHODS: In 127 obese hypertensive individuals aged 50.7 +/- 5.1 years (mean +/- SD), we measured clinic blood pressure, heart rate, plasma glucose, and insulin at rest and during an oral glucose load before and 12 weeks after treatment with either candesartan cilexetil (8-16 mg once daily) or hydrochlorothiazide (HCTZ, 25-50 mg once daily), administered orally in accordance with a double-blind, randomized, placebo-controlled, two-parallel-groups study design. Insulin sensitivity was expressed as insulin resistance index (IRI), calculated as the ratio of the area under the curve (AUC) for glucose to that for insulin. In a subgroup of patients, measurements also included direct microneurographic recording of muscle sympathetic nerve activity (MSNA) in the peroneal nerve. RESULTS: Candesartan cilexetil caused a significant (P < 0.01) reduction in both mean blood pressure (from 114.2 +/- 5.1 to 99.6 +/- 6.0 mmHg) and MSNA (from 51.0 +/- 12.3 to 40.4 +/- 12.5 bursts per 100 heart beats), and a significant (P < 0.02) increase in insulin sensitivity (AUC IRI: from -23.2 +/- 22.1 to -17.6 +/- 12.2). In contrast, HCTZ did not significantly affect MSNA and worsened insulin sensitivity, while achieving blood pressure reductions similar to those produced by candesartan cilexetil. CONCLUSIONS: These data provide evidence that, in obese hypertensive individuals, treatment with candesartan cilexetil has an antihypertensive effect similar to that of HCTZ. Unlike diuretic treatment, however, treatment with candesartan cilexetil improves insulin sensitivity and exerts sympathoinhibitory effects.
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In the citing paper
“As mentioned above, blockade of the RAAS with AngII receptor blockers, angiotensin-converting enzyme (ACE) inhibitors or renin inhibitors reduces BP in patients with obesity and hypertension64–66.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [65]
In the citing paper
“Therefore, although we cannot completely exclude an effect of medications in our 2 hypertensive groups, they could not have entirely caused the excessive sympathetic hyperactivity.”
From Sympathetic Neural Activation in Nondiabetic Metabolic Syndrome and Its Further Augmentation by Hypertension (2004) · cites this paper as [23]
In the citing paper
“Although we cannot entirely exclude some influence of these agents, it is known in hypertensive patients that chronic ACE inhibitor therapy does not affect MSNA levels, 22 ARBs may decrease it, 23 and -blockers may have no effect or decrease MSNA.24,25”
From Sympathetic Neural Activation in Nondiabetic Metabolic Syndrome and Its Further Augmentation by Hypertension (2004) · cites this paper as [23]
In the citing paper
“In obese hypertensive subjects, chronic hydrochlorothiazide therapy that lowers arterial pressure did not significantly affect MSNA levels.23”
From Sympathetic Neural Activation in Nondiabetic Metabolic Syndrome and Its Further Augmentation by Hypertension (2004) · cites this paper as [23]
Citations
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Cited by
Sorted by citations
Obesity-Induced Hypertension: Interaction of Neurohumoral and Renal Mechanisms
Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z., & Hall, M. E. (2015) · Circulation Research · doi:10.1161/circresaha.116.305697 · Cited by 1,360
Benson, S. C., Pershadsingh, H. A., Ho, C. I., Chittiboyina, A. G., Desai, P. V., Pravenec, M., Qi, N., Wang, J., Avery, M. A., & Kurtz, T. W. (2004) · Hypertension · doi:10.1161/01.hyp.0000123072.34629.57 · Cited by 1,076
Seravalle, G., & Grassi, G. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.05.013 · Cited by 909
Self-citationObesity, kidney dysfunction and hypertension: mechanistic links
Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z., & Hall, M. E. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-019-0145-4 · Cited by 654
Obesity, hypertension, and chronic kidney disease
Hall, J., Juncos, L., Wang, Z., Hall, M., do Carmo, J., & da Silva, A. (2014) · International Journal of Nephrology and Renovascular Disease · doi:10.2147/ijnrd.s39739 · Cited by 520
Metadata
- Authors
- Grassi, G., Seravalle, G., Dell'Oro, R., Trevano, F. Q., Bombelli, M., Scopelliti, F., Facchini, A., & Mancia, G.
- Affiliations
- IRCCS Istituto Auxologico Italiano (IT)
- University of Milano-Bicocca (IT)
- Azienda Ospedaliera San Gerardo (IT)
- Corresponding author
- Mancia, Giuseppe
- Venue
- Journal of Hypertension
- Published
- 2003-09
- Volume
- 21
- Issue
- 9
- Pages
- 1761-1769
- ISSN
- 0263-6352 (ISSN-L)
- OpenAlex
- W2007653610
- Cited by
- 225
- References
- 40
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 4 · 2023: 9 · 2022: 2 · 2021: 5 · 2020: 4 · 2019: 8 · 2018: 2 · 2017: 9 · 2016: 10 · 2015: 12 · 2014: 13 · 2013: 5 · 2012: 12
- FWCI
- 12.52
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Hypertension (publishedVersion)
- PubMed (publishedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- candesartan cilexetil, hydrochlorothiazide, obesity-related hypertension, angiotensin receptor blockers, diuretics, insulin resistance, insulin sensitivity, muscle sympathetic nerve activity, sympathetic nervous system, blood pressure reduction, renin-angiotensin system, antihypertensive drug comparison, microneurography, oral glucose tolerance test
- MeSH terms
- Adolescent, Adult, Aged, Antihypertensive Agents, Benzimidazoles, Biphenyl Compounds, Blood Glucose, Blood Pressure, Female, Humans, Hydrochlorothiazide, Hypertension, Insulin Resistance, Male, Middle Aged, Obesity, Sympathetic Nervous System, Tetrazoles, Lipid Metabolism
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