Effect of Doxazosin on Insulin Resistance in Hypertensive Patients with Obesity

Abstract

We determined the effect of α-adrenergic blocking agent doxazosin on insulin resistance in 19 hypertensive patients (blood pressure [BP] >160/90 mmHg) with obesity (mean body mass index [BMI]: 26.7 ± 1.9 kg/m²). Patients received doxazosin 4 mg/day for 12 months. Systolic and diastolic BP decreased from 169 ± 10.8 mmHg to 147 ± 11.9 mmHg (p < 0.0001) and from 102 ± 8.1 mmHg to 87 ± 5.0 mmHg (p < 0.0001), respectively. Insulin resistance and fasting immunoreactive insulin (IRI) were lower at study end vs. baseline (HOMA-R = 1.29 ± 0.38 vs. 3.58 ± 2.23 [p = 0.022]; IRI = 6.00 ± 1.88 µU/ml vs 13.74 ± 8.51 µU/ml [p = 0.046]). Total cholesterol was significantly reduced following treatment. Circulating TNF-α and leptin levels decreased significantly within 3 months of treatment; leptin was independently associated with insulin resistance when adjusted for BMI. We conclude that doxazosin improves insulin resistance and improves dyslipidemia in obese hypertensive patients, and has a beneficial effect on adipose endocrine activity.

Key words

Hypertension - Obesity - Doxazosin - Insulin - Leptin - Adrenergic Alpha-Antagonists - Tumor Necrosis Factor

References

• 1 Mokdad A H, Bowman B A, Ford E S, Vinicor F, Marks J S, Koplan J P. The continuing epidemics of obesity and diabetes in the United States.  JAMA. 2001;  286 1195-1200
• 2 McLaughlin T, Abbasi F, Kim H S, Lamendola C, Schaaf P, Reaven G. Relationship between insulin resistance, weight loss, and coronary heart disease risk in healthy, obese women.  Metabolism. 2001;  50 795-800
• 3 McLaughlin T, Reaven G. Insulin resistance and hypertension. Patients in double jeopardy for cardiovascular disease.  Geriatrics. 2000;  55 28-32, 35
• 4 Valantine H, Rickenbacker P, Kemna M, Hunt S, Chen Y D, Reaven G. et al . Metabolic abnormalities characteristic of dysmetabolic syndrome predict the development of transplant coronary artery disease: a prospective study.  Circulation. 2001;  103 2144-2152
• 5 Ahima R S, Flier J S. Adipose tissue as an endocrine organ.  Trends Endocrinol Metab. 2000;  11 327-332
• 6 Hotamisligil G S, Shargill N S, Spiegelman B M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.  Science. 1993;  259 87-91
• 7 Hotamisligil G S, Arner P, Caro J F, Atkinson R L, Spiegelman B M. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.  J Clin Invest. 1995;  95 2409-2415
• 8 Kirchgessner T G, Uysal K T, Wiesbrock S M, Marino M W, Hotamisligil G S. Tumor necrosis factor-alpha contributes to obesity-related hyperleptinemia by regulating leptin release from adipocytes.  J Clin Invest. 1997;  100 2777-2782
• 9 Coleman D L. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice.  Diabetologia. 1978;  14 141-148
• 10 Considine R V, Sinha M K, Heiman M L, Kriauciunas A, Stephens T W, Nyce M R. et al . Serum immunoreactive-leptin concentrations in normal-weight and obese humans.  N Engl J Med. 1996;  334 292-295
• 11 Kageyama S, Yamamoto J, Mimura A, Sakurai T, Ishibashi K, Aihara K. et al . Doxazosin improves insulin sensitivity in hypertensive patients.  Clin Ther. 1993;  15 829-837
• 12 Giorda C, Appendino M. Effects of doxazosin, a selective alpha 1-inhibitor, on plasma insulin and blood glucose response to a glucose tolerance test in essential hypertension.  Metabolism. 1993;  42 1440-1442
• 13 Andersson P E, Johansson J, Berne C, Lithell H. Effects of selective alfa 1 and beta 1-adrenoreceptor blockade on lipoprotein and carbohydrate metabolism in hypertensive subjects, with special emphasis on insulin sensitivity.  J Hum Hypertens. 1994;  8 219-226
• 14 Andersson P E, Lithell H. Metabolic effects of doxazosin and enalapril in hypertriglyceridemic, hypertensive men. Relationship to changes in skeletal muscle blood flow.  Am J Hypertens. 1996;  9 323-333
• 15 Matthews D R, Hosker J P, Rudenski A S, Naylor B A, Treacher D F, Turner R C. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.  Diabetologia. 1985;  28 412-419
• 16 Calo L, Davis P A, Cantaro S, Bonfante L, Castrignano R, Carraro G. et al . Effect of doxazosin in mild to moderate hypertensive patients with insulin-dependent diabetes mellitus.  Acta Diabetol. 1998;  35 96-100
• 17 Toth K, Nemes J, Czopf L, Kapronczay P, Kesmarky G, Juricskay I. Effects of doxazosin on hemorheological, hemodynamic and lipid parameters in patients with essential hypertension.  Clin Hemorheol Microcirc. 1999;  20 57-61
• 18 Shionoiri H, Ashino K, Yamanaka K, Shindo K, Hiroto S, Arita T. Effect of doxazosin therapy on glucose tolerance and lipid metabolism in hypertensive patients with impaired glucose tolerance.  Clin Ther. 1997;  19 527-536
• 19 Hirano T, Yoshino G, Kashiwazaki K, Adachi M. Doxazosin reduces prevalence of small dense low density lipoprotein and remnant-like particle cholesterol levels in nondiabetic and diabetic hypertensive patients.  Am J Hypertens. 2001;  14 908-913
• 20 Kinoshita M, Shimazu N, Fujita M, Fujimaki Y, Kojima K, Mikuni Y. et al . Doxazosin, an alpha1-adrenergic antihypertensive agent, decreases serum oxidized LDL.  Am J Hypertens. 2001;  14 267-270
• 21 Tamasawa N, Matsui J, Ogawa Y, Gotoh T, Hinata T, Murakami H. et al . Effect of doxazosin on the size of LDL particle in the type 2 diabetic patients with hypertension.  J Diabetes Complications. 2000;  14 135-139
• 22 Ueshiba H, Tsuboi K, Miyachi Y. Effects of amlodipine on serum levels of adrenal androgens and insulin in hypertensive men with obesity.  Horm Metab Res. 2001;  33 67-169
• 23 Beer N A, Jakubowicz D J, Beer R M, Nestler J E. The calcium channel blocker amlodipine raises serum dehydroepiandrosterone sulfate and androstenedione, but lowers serum cortisol, in insulin-resistant obese and hypertensive men.  J Clin Endocrinol Metab. 1993;  76 1464-1469
• 24 Brook R D. Mechanism of differential effects of antihypertensive agents on serum lipids.  Curr Hypertens Rep. 2000;  2 370-377
• 25 Reneland R, Andersson P E, Haenni A, Lithell H. Metabolic effects of long-term angiotensin-converting enzyme inhibition with fosinopril in patients with essential hypertension: relationship to angiotensin-converting enzyme inhibition.  Eur J Clin Pharmacol. 1994;  46 431-436
• 26 Haenni A, Andersson P E, Lind L, Berne C, Lithell H. Electrolyte changes and metabolic effects of lisinopril/bendrofluazide treatment. Results from a randomized, double-blind study with parallel groups.  Am J Hypertens. 1994;  7 615-622
• 27 Luzio S D, Dunseath G, Owens D R. Acute effects of valsartan on insulin sensitivity in obese, non-hypertensive subjects with and without type 2 diabetes.  Horm Metab Res. 2002;  34 271-274
• 28 Pollare T, Lithell H, Selinus I, Berne C. Application of prazosin is associated with an increase of insulin sensitivity in obese patients with hypertension.  Diabetologia. 1988;  31 415-420
• 29 Fukuzawa M, Satoh J, Ohta S, Takahashi K, Miyaguchi S, Qiang X. et al . Modulation of tumor necrosis factor-alpha production with anti-hypertensive drugs.  Immunopharmacology. 2000;  48 65-74
• 30 Kahn B B, Flier J S. Obesity and insulin resistance.  J Clin Invest. 2000;  106 473-481
• 31 González-Ortiz M, Martínez-Abundis E, Balcázar-Munatildeoz B R. Serum leptin concentrations in young insulin-sensitive and insulin-resistant volunteers.  Horm Metab Res. 2000;  32 273-276