Eur J Clin Pharmacol (1992) 43: 365-368
© Springer-Verlag 1992
Effect of doxazosin on insulin sensitivity in hypertensive non-insulin dependent diabetic patients R. Huupponen ~, A. Lehtonen s, and M. V/ih~italo s 1Department of Clinical Pharmacology,University of Turku, ~Department of Medicine,Turku City Hospital and s Turku City Health Centre, Turku, Finland Accepted: September 28, 1991/Accepted in revised form: April 6, 1992
Smnmary. The effect of doxazosin, an cq-adrenoceptor blocking drug, on blood pressure, sensitivity to insulin and serum tipids has been evaluated in 14 hypertensive, noninsulin dependent diabetic patients. The dose was titrated individually upwards from i mg until the diastolic blood pressure was below 90 mm Hg, side-effects precluded further dosage increase or the maximum daily dose of 16 mg was achieved. After 12 weeks of treatment (mean doxazosin dose 5.6 _+5.1 mg daily), the supine and standing diastolic blood pressure of the patients had declined by about 7 mmHg, whereas their systolic blood pressure and heart rate were not significantly changed. The metabolic clearance rate of glucose increased from 2.35 to 3.37 ml. min- 1. kg- 1during treatment, suggesting improved sensitivity to insulin. Fasting plasma glucose was 11.9 mmol.1 t before and 10.9 mmol- 1- ~after doxazosin therapy (NS). Serum electrolytes and lipids did not change significantly but serum uric acid decreased from 305 to 281 gmol. 1-1. Doxazosin may be a useful alternative for the treatment of hypertension in N I D D M patients.
Key words: Doxazosin, Hypertension, Diabetes mellitus; non-insulin dependent diabetes mellitus, insulin sensitivity, serum lipids, adverse drug effects
The ultimate goal in the treatment of hypertension is not only to lower blood pressure but also to prevent longterm complications, such as stroke, left ventricular hypertrophy and renal insufficiency. It was realised early on that hypertensive patients were often also hyperinsulinaemic [Welborn et al. 1966]. This finding has been confirmed in recent studies and its significance for the development of hypertension has begun to emerge. It is now generally accepted that hypertension, like non-insulin dependent diabetes mellitus (NIDDM), is associated with peripheral insulin resistance [Shen et al. 1988, DeFronzo and Ferrannini 1991]. The mechanisms by which hyperinsulinaemia and insulin resistance elevate blood pressure are still obscured but they may include insulin-induced renal sodium reten-
tion, fundamental changes in the responsiveness of vascular smooth muscle cells to pressor amines in insulin resistant patients or stimulation of the sympathetic nervous system by insulin [DeFronzo and Ferrannini t991]. The results of several prospective clinical trials in hypertension have revealed a phenomenon called coronary artery disease paradox - active treatment reduces mortality and cerebrovascular disease but does not prevent coronary artery disease [Black 1990]. It has been suggested that deterioration of the metabolic-risk-factor profile caused by some antihypertensive drugs may be responsible for the paradox [Pollare et al. 1989a, Black 1990]. Worsening of insulin sensitivity and dyslipoproteinaemia should be avoided, therefore, when treating hypertensive patients. Particular care must be taken when choosing antihypertensive therapy for patients who have a cluster of cardiovascular risk factors, like hypertension and NIDDM. A previous study in obese, non-diabetic hypertensive patients indicated that peripheral insulin sensitivity was improved during therapy with prazosin, an O~l-adrenoceptor blocker [Pollare et al. 1988]. In another study it was shown that doxazosin, a long-acting ¢l-adrenoceptor blocking drug, reduced fasting blood glucose and plasma insulin when given as maintenance treatment to nondiabetic hypertensive patients [Lehtonen 1990]. In the present study, the effect of doxazosin on blood pressure, insulin sensitivity and serum lipids has been evaluated in 14 patients with both hypertension and NIDDM.
Subjects and methods
Patients and stud}, design After giving informed consent, t4 hypertensive (diastolic blood pressure > 95 mmHg) patients (8 f, 6 m), who also had non-insulin dependent diabetes meilitus according to the WHO criteria, were enrolled into this open, non-comparative study. The study design was approved by the local ethics Committee. The mean age of the patients was 63 (9) y. At entry, the mean duration of NIDDM in the patients was 8.2 (3.7) y, their mean weight was 76.5 (13.9) kg and
366 mean height 169 (7) cm. After a two week washout of previous antihypertensive treatment, the patients were put on placebo for a further 2 week period, whereafter they entered the 12 week titrationmaintenance phase. They initiallyreceived doxazosin 1 mg daily; the patient then visited the ward and the blood pressure was measured at biweekly intervals. The doxazosin dose was doubled every other week until the diastolic blood pressure had fallen below 90 mm Hg, the maximum daily dose of 16 mg had been reached or adverse effects precluded any further increase in dose. The highest effective and tolerable dose was subsequently maintained to the end of the titration-maintenance phase. The antidiabetic treatment (diet, sulphonylureas and/or metformin) was kept constant over the entire study period. Blood chemistry, including fasting glucose, lipids and electrolytes, estimation of insulin sensitivity and oral glucose tolerance test were performed at the end of placebo and doxazosin periods.
infusion rate of exogenous glucose equals glucose disposal. A substantial suppression of hepatic glucose output is expected, even in NIDDM patients, at the plasma insulin levels produced here [Heine et al. I985; Nankervis et aL 1982], although some residual output may persist in certain diabetic patients. However, incomplete suppression of hepatic glucose output is itself a manifestation of insulin resistance, and in that case the results would reflect peripheral as well as hepatic insulin sensitivity [Bergman et al. 1985].
Oral glucose tolerance test A standard oral glucose tolerance test (blood samples for glucose at 0,1 and 2 h) was performed after swallowing 75 g glucose (Glucodyn mixt, Huhtamfiki Oy Leiras, Helsinki, Finland) at least 2 days after the combined glucose-insulininfusions, both before and at the end of the doxazosin treatment,
Biochemical analyses Glucose was analyzed by the hexokinase method, blood HbAI0 by liquid chromatography and plasma insulin by RIA (Phadeseph Insulin RIA, Pharmacia Diagnostics, Uppsala, Sweden). The interassay and intra-assay coefficients of variation of plasma glucose determinations were 3 % and 1%, respectively. Serum sodium and potassium, cholesterol, HDL-cholesterol, triglycerides, uric acid, aspartate amine transferase (ASAT) and creatinine were analyzed by standard techniques, using an Ol~anpus AU 5021 Automated Chemistry Analyzer (Olympus Optical Co., LTD, Tokyo, Japan),
Statistical analysis The results are given as mean with (SD). The t-test for paired data was used to compare the values before and after doxazosin treatment. Analysis of variance for repeated measures was applied to compare blood glucose levels during the oral glucose tolerance tests before and after treatment.
Results
Determination of insulin sensitivity The determination was carried out using a combined fixed-rate infusion of glucose and insulin as previously described [Heine et al. 1985; Heine et al. 1986]. In brief, the patients came to the laboratory at 08.00 h after an overnight fast. Plastic IV cannulae were placed in contralateral arms, one for concomitant infusion of 20 % glucose (6mg-kg-l-min ~) and dilute insulin (1U.ml -I in saline, 50 mU. kg ~.h -1, Velosulin Human, Novo-Nordisk, Denmark) for 150 rain, and one for collection of frequent blood samples. The insulin infusion was commenced with a bolus calculated to elevate plasma insulin to the desired level Glucose was infused with a volumetric infusion pump (Imed 960, Oxon, England) and the diluted insulin with an IVAC 700 syringe pump (IVAC Corporation, San Diego, CA, USA). 'Ib reduce the binding of insulin to the infusion apparatus, the system was thoroughly flushed with the infusate prior to connecting it to the patient. Samples for plasma glucose and insulin were taken twice basally, every 15 min for 2 h and then every 5 min over the test period of 120 to t50 min. The patient emptied the bladder before and after the infusion, and the urine was collected and analysed for glucose.
Calculation of the results Steady state plasma glucose (SSPG) and insulin (SSP1) concentrations during the combined glucose-insulin infusion were determined as the mean of the values recorded between 120 and 150 min. The mean coefficient of variation of the SSPG concentrations was 3.5 (1.9) %. SSPG is a direct measure of insulin sensitivity but during hyperglycaemic conditions it is biased by urinary glucose loss [B ergman et aI. 1985]. Therefore, the metabolic clearance rate of glucose (MCR), corrected for urinary glucose output, was used as a measure of the insulin sensitivity. "tlae MCR was calculated as "therate of glucose infusion/steady state plasma glucose concentration with a correction for urinary glucose output during the test. The equation is based on the assumption that hepatic glucose output is suppressed during the glucose-insufin infusions; under these circumstances the
B o t h s u p i n e ( P = 0.04) a n d s t a n d i n g ( P = 0.03) diastolic b l o o d p r e s s u r e d e c r e a s e d b y 7 a n d 8 % , r e s p e c t i v e l y during d o x a z o s i n t r e a t m e n t w h e r e a s systolic b l o o d p r e s s u r e a n d h e a r t rate did n o t c h a n g e (Table 1). T h e c h a n g e in supine diastolic b l o o d p r e s s u r e was i n v e r s e l y c o r r e l a t e d with t h e p r e s s u r e at the e n d of p l a c e b o p e r i o d (r = - 0.72, P = 0.006). T h e daily d o s e of d o x a z o s i n at the end o f t h e m a i n t e n a n c e p h a s e r a n g e d f r o m 1 m g (3 p a t i e n t s ) t o 16 m g (2 p a t i e n t s ) , m e a n 5.6 (5.1) mg. T h e p a t i e n t s g a i n e d w e i g h t b y 1.0 (1.6) kg ( P = 0.04) d u r i n g t h e t r e a t m e n t . T h e r e w e r e no significant c h a n g e s in s e r u m e l e c t r o lytes, lipids or c r e a t i n i n e , w h e r e a s s e r u m uric acid dec r e a s e d b y 8 % w h e n on d o x a z o s i n ( P -- 0.05; T a b l e 2). D u r i n g b o t h insulin sensitivity tests, i d e n t i c a l S S P I levels of a b o u t 530 p m o l . 1 1 w e r e r e a c h e d w i t h i n 90 to 105 m i n a n d w e r e m a i n t a i n e d until the e n d o f the infusion
Table L Blood pressure (mmHg) and heart rate (beats-min-~) before (end of placebo phase) and after 12 weeks of doxazosin treatment. Mean with (SD) Before
After
Supine - Systolic blood pressure - Diastolic blood pressure - Heartrate
156 (15) 95 (8) 80 (10)
154 (16) 87 (8)* 81 (10)
Standing - Systolic blood pressure - Diastolic blood pressure - Heart rate
155 (19) 96 (7) 84 (7)
t48 (27) 88 (8)** 83 (10)
Significance of difference from pre-treatment: * P = 0.04; ** P = 0.03 (Student's t-test for paired data)
367 Table 2. Effect of doxazosin treatment on serum biochemistry.
Mean with (SD) Cholesterol (mmol. 1 1) HDL-cholesterol (mmol. 1-1) HDL/total cholesterol Trigtycerides (mmol. ! 1) Sodium (mmol. 1- t) Potassium (mmol-1- l) Chloride (mmot-1-1) Magnesium (mmot. 1-~) Creatinine (Ixmol.1 1) ASAT (U. l t) Uric acid (~tmol. 1-1)
Before 5.1 (1.2) 1.1 (0.2) 0.23 (0.06) 1.6 (0.6) 142 (4) 4.1 (0.3) 109 (2) 0.8 (0.1) 83 (13) 20 (8) 305 (85)
After 4.9 (1.2) 1.2 (0.3) 0.26 (0.08) 1.6 (0.6) 144 (3) 4.0 (0.4) 109 (3) 0.8 (0.1) 81 (13) 19 (9) 281 (106)*
*significantly different from value before treatment (P = 0.049, Student's t~test for paired data) Table 3. Effect of doxazosin treatment on carbohydrate metabolism. Mean with (SD) fP-glucose (mmol-1 -~) m-HbAl~ (%) fP-insulin (pmoi. 1 t) SSPI (pmoI-I -I) MCR (ml-rain - 1. kg -~)
Before 11.9 (3.3) 8.0 (1.5) 96 (43) 533 (159) 2.35 (1.64)
After 10.9 (3.1) 8.2 (1.5) 95 (52) 525 (146) 3.37 (2.70)*
SSPG steady state plasma glucose, SSPI steady state plasma insulin, MCR metabolic clearance rate of glucose (corrected for urinary glucose losses).* higher than before treatment (P = 0.03, Student's t-test for paired data)
(Table 3). The SSPG concentration decreased from 14.9 (4.4)mmol.1 1 during the placebo period to 12.6 (5.4) mmol. 1-1 after doxazosin treatment (P = 0.06). The insulin sensitivity, expressed as the M C R of glucose and corrected for urinary glucose loss, improved significantly from 2.35 (1.64) ml.min -t-kg -I to 3.37 (2.7) ml-min l. kg- 1 during doxazosin treatment (P = 0.03). A similar but weaker trend was seen in fasting plasma glucose, which dropped by about i mmol. 1-1 during the therapy. Fasting plasma insulin did not change (Table 3). Before treatment, blood glucose increased during the oral glucose tolerance test from the basal value of 9.7 (2.8) mmol. 1-1 to 17.0 (3.1) and 16.8 (4.0) mmol. 1-1 after i and 2 h, respectively. Similar blood glucose values were recorded after doxazosin treatment (basal 9.2 (2.8) mmol. 1-1, at i h 16.7 (3.8) mmol. 1-1, and at 2 h 16.9 (4.5) mmol. 1-1; treatment effect: F = 0.40, P = 0.54; treatment x time interaction F = 1.20; P = 0.32). In general, doxazosin was well tolerated. In one patient the highest daily dose of 16 mg caused an orthostatic reaction. The s)~nptoms rapidly resolved after reduction of the dose to 8 mg daily.
Discussion
Doxazosin reduced both supine and standing diastolic blood pressures in the present hypertensive N I D D M patients to a similar degree as that reported earlier in hypertensive patients [Young and Brogden 1988], but it had a
minimal effect on supine systolic blood pressure. The standing systolic blood pressure was reduced by about 5 %, although the effect was not statistically significant. The less pronounced effect of doxazosin on supine than on standing systolic blood pressure and the lack of effect on heart rate is in accordance with previous reports [Young and Brogden 1988]. Insulin resistance in N I D D M appears to be a syndrome associated with clustering of metabolic disorders, including hypertension, lipid abnormalities and atherosclerotic cardiovascular disease [DeFronzo and Ferrannini 1991]. Hydrochlorothiazide [Pollare et al. 1989a] and the fiadrenoceptor blocking drugs metoprolol and atenolol [Pollare et al. 1989b] decrease insulin sensitivity, whereas the calcium entry blocker diltiazem has no effect [Pollare et al. 1989c]. Data on previously untreated obese hypertensive patients indicate that prazosin improves insulin sensitivity [Pollare et al. 1988], whereas terazosin had no effect in nonobese normotensive subjects [Ferrari et al. 1991]. The ACE-inhibitor captopril has also been shown to improve insulin sensitivity in hypertensive patients [Jauch et al. 1987; Pollare et al. 1989 a]. Improved peripheral insulin sensitivity has been demonstrated after 10 days of captopril treatment in N I D D M [Ferriere et al. 1985], and even after a single 25 mg oral captoprit dose in normotensive patients [Jauch et al. 1987]. It is not known if there are differences in this respect between antihypertensive drugs of to the same class [Black 1990]. Previous studies of drug effects on insulin sensitivity have mostly dealt with hypertensive patients without manifest diabetes mellitus. The present study was done to clarify the effect of doxazosin on insulin sensitivity in a clinically important subgroup of hypertensive patients, namely non-insulin dependent diabetics. The results have demonstrated that doxazosin, a longacting c~1-adrenoceptor blocking drug, improved insulin sensitivity" in this patient population. The effect cannot be explained by weight loss, since these patients experienced a slight weight gain during the study. The study has corroborated the earlier suggestion of improved insulin sensitivity during doxazosin treatment, based on reduction in fasting plasma glucose and insulin in a larger group of hypertensive non-diabetic patients on maintenance therapy [Lehtonen 1990]. In keeping with the results of the captopril study, the concentrations of fasting plasma glucose and hemoglobin Alo concentrations in the patients did not change despite the improved sensitivity to insulin [Pollare et al. 1989a]. It must be emphasized that peripheral insulin resistance and hepatic glucose production during fasting are important determinants of blood glucose concentration [DeFronzo et al. 1982], whereas during glucose insulin infusion the contribution of peripheral glucose uptake is predominant. Every effort was taken to control confounding factors during the study. Antidiabetic treatment and diet were kept constant and the patients were told to keep their living habits unchanged during the study. The time of the entry of the patients into the study was scattered throughout the calendar year to make any contribution of seasonal factors to the results improbable. Together with earlier studies on prazosin [Pollare et al. 1988] and doxa-
368 zosin [Lehtonen 1990], the present study strongly suggests that a l - a d r e n o c e p t o r blocking drugs may have a beneficial effect on insulin sensitivity, at least in insulin-resistant patients. The mechanism by which as-blocking drugs improve insulin sensitMty remains speculative. As discussed for prazosin [Pollare et al. 1988], i m p r o v e m e n t of peripheral blood flow in skeletal muscle tissues due to the relaxation of arterioles [Westheim et al. 1986] may improve the tissue response to glucose and insulin. Since the stimulation of hepatic glucose production may also be mediated through c~-adrenergic receptors in man [Rosen et al. 1983], and c~- together with fl2-receptors form the predominant adrenergic receptor subtype in h u m a n liver plasma m e m branes [Kawai et al. 1986], the use of an as-receptor blocking drug may also have interfered with hepatic glucose production. Many antihypertensive drugs, including some diuretics and t-blockers, adversely affect plasma lipids, whereas the a t - a d r e n o c e p t o r blocking drugs prazosin and doxazosin m a y have a beneficial effect on them. With the exception of triglycerides, a similar trend was noted in the diabetic patients here, but due to the limited n u m b e r of patients required for the insulin sensitivity test, the lipid effects were not statistically significant (Table 2). Hypertension is one of the primary risk factors for coronary artery disease. To reach the desired therapeutic goal, nonpharmacological haterventions aimed at reducing both blood pressure and hyperinsulinaemia, together with weight loss, are strongly recommended. Nevertheless, drug therapy is often unavoidable. It is logical to accomplish the p h a r m a c o t h e r a p y in a way that not only reduces blood pressure but also leaves insulin and glucose metabolism and the lipid profile unchanged or preferably improved [Lithell 1991]. This is of special importance in patients with clustering of several cardiovascular risk factors, e.g. in patients who have both hypertension and N I D D M . According to the present results, doxazosin fulfills the desired criteria both in terms of improved insulin sensitivity and lack of deleterious effects on serum lipids.
Acknowledgements. We thank Mr. R Koskinen for performing the statistical calculations, and Mrs. E. Kahra for her expert technical assistance with the insulin sensitivity determinations. The diabetic nurses of the Turku City Health Centre, Mrs. I. H~im~lfiinen and T. Taivatantti provided valuable support. The study was supported by a grant from Pfizer Oy, Helsinki.
References Bergman RN, Finegood DT, Ader M (1985) Assessment of insulin sensitivity in vivo. Endocrine Rev 6:45-86 Black HR (1990) The coronary artery paradox: the role of hyperinsulinemia and insulin resistance and implications for therapy. J Cardiovasc Pharmaco115 [Suppl 5]: $26-$38 DeFronzo RA, Simonson D, Ferrannini E (1982) Hepatic and peripheral insulin resistance: a common feature of type 2 (non-insulin-dependent) and type i (insulin-dependent) diabetes mellitus. Diabetologia 23:313-319 DeFronzo RA, Ferrannini E (1991) Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension,
dyslipidemia and atherosclerotic cardiovascular disease. Diabetes Care 14:173-194 Ferrari P, Rosman J, Neuner N, Shaw S, Riesen W, Weidmann P (1991) Postsynaptic ~z-blockade with terazosin does not modify insulin sensitivity in nonobese normotensive subjects. J Cardiovasc Pharmaco118:106-110 Ferriere M, Lachkar H, Richard J-L, Bringer J, Orsetti A, Mirouze J (1985) Captopril and insulin sensitivity. Ann Intern Med 109-:134135 Heine RJ, Bilo HJG, Meer J van der, Veen EA van der (1986) Sequential infusions of glucose and insulin at prefixed rates: a simple method for assessing insulin sensitivity and insulin responsiveness. Diabetes Res 3:453-461 Heine R J, Home PD, Poncher M, Orskov It, Hammond V, McCulloh AJ, Hanning I, Alberti KGMM (1985) A comparison of 3 methods for assessing insulin sensitivity in subjects with normal and abnormal glucose tolerance. Diabetes Res 2:113-120 Jauch K-W, Hartl W, Guenther B, Wicklmayr M, Rett K, Dietze G (1987) Captopril enhances insulin responsiveness of forearm muscle tissue in non-insulin-dependent diabetes mellitus. Eur J Clin Invest 17:448-454 Kawai Y, Powell A, Arinze IJ (1986) Adrenergic receptors in human liver plasma membranes: predominance of beta2- and alphas-receptor subtypes. J Clin Endocrinol Metab 62:827-832 Lehtonen A (1990) Lowered levels of serum insulin, glucose and cholesterol in hypertensive patients during treatment with doxazosin. Curr Ther Res 47:278--284 Lithetl HOL (1991) Effect of antihypertensive drugs on insulin, glucose and lipid metabolism. Diabetes Care 14:203-209 Nankervis A, Proietto J, Aitken E Harewood M, Alford F (1982) Differential effects of insulin therapy on hepatic and peripheral insulin sensitivity in type 2 (non-insulin-dependent) diabetes. Diabetologia 23:320-325 Pollare T, Lithell H, Selinus I, Berne C (1988) Application of prazosin is associated with an increase of insulin sensitivity in obese patients with hypertension. Diabetologia 31:415-420 Pollare T, Lithell H, Berne C (1989 a) A comparison of the effects of hydrochlorthiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl J Med 321:868-873 Potlare T, Lithell H, Selinus I, Berne C (1989 b) Sensitivity to insulin during treatment with atenolol and metoprolol: a randomised double blind study of effects on carbohydrate and lipoprotein metabolism in hypertensive patients. Br Med J 298:1152-1157 Pollare T, Lithell H, MOrlin C, Prantare H, Hvarfner A, Ljunghall S (1989 c) Metabolic effects of diltiazem and atenolol: results from a randomized, double-blind study with parallel groups. J Hypertens 7:551-559 Rosen SG, Clutter WE, Shah DS, Miller JR Bier DM, Cryer PE (1983) Direct ~-adrenergic stimulation of hepatic glucose production in human subjects. Am J Physio1245:E616-E626 Shen D-C, Shieh S-M, Fuh M-T, Wu D-A, Chen Y-DI, Reaven GM (1988) Resistance to insulin-stimulated-glucose uptake in patients with hypertension. J Clin Endocrinol Metab 66:580-583 Welborn TA, Breckenridge A, Rubinstein AH, Dollery CT, Fraser TR (1966) Serum insulin in essential hypertension and in peripheraI vascular disease. Lancet 1:1336-1337 Westheim A, Koss A, Sivertssen E (1986) Hemodynamic effects at rest and during exercise in long-term treatment with prazosin in chronic congestive heart failure. Acta Med Scand 219:449-453 Young RA, Brogden RN (1988) Doxazosin. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in mild or moderate hypertension. Drugs 35:525-541 R. Huupponen, M. D. Department of Clinical Pharmacology University of Turku Kiinamyllynkatu 10 SF-20520 Turku Finland
© Springer-Verlag 1992
Effect of doxazosin on insulin sensitivity in hypertensive non-insulin dependent diabetic patients R. Huupponen ~, A. Lehtonen s, and M. V/ih~italo s 1Department of Clinical Pharmacology,University of Turku, ~Department of Medicine,Turku City Hospital and s Turku City Health Centre, Turku, Finland Accepted: September 28, 1991/Accepted in revised form: April 6, 1992
Smnmary. The effect of doxazosin, an cq-adrenoceptor blocking drug, on blood pressure, sensitivity to insulin and serum tipids has been evaluated in 14 hypertensive, noninsulin dependent diabetic patients. The dose was titrated individually upwards from i mg until the diastolic blood pressure was below 90 mm Hg, side-effects precluded further dosage increase or the maximum daily dose of 16 mg was achieved. After 12 weeks of treatment (mean doxazosin dose 5.6 _+5.1 mg daily), the supine and standing diastolic blood pressure of the patients had declined by about 7 mmHg, whereas their systolic blood pressure and heart rate were not significantly changed. The metabolic clearance rate of glucose increased from 2.35 to 3.37 ml. min- 1. kg- 1during treatment, suggesting improved sensitivity to insulin. Fasting plasma glucose was 11.9 mmol.1 t before and 10.9 mmol- 1- ~after doxazosin therapy (NS). Serum electrolytes and lipids did not change significantly but serum uric acid decreased from 305 to 281 gmol. 1-1. Doxazosin may be a useful alternative for the treatment of hypertension in N I D D M patients.
Key words: Doxazosin, Hypertension, Diabetes mellitus; non-insulin dependent diabetes mellitus, insulin sensitivity, serum lipids, adverse drug effects
The ultimate goal in the treatment of hypertension is not only to lower blood pressure but also to prevent longterm complications, such as stroke, left ventricular hypertrophy and renal insufficiency. It was realised early on that hypertensive patients were often also hyperinsulinaemic [Welborn et al. 1966]. This finding has been confirmed in recent studies and its significance for the development of hypertension has begun to emerge. It is now generally accepted that hypertension, like non-insulin dependent diabetes mellitus (NIDDM), is associated with peripheral insulin resistance [Shen et al. 1988, DeFronzo and Ferrannini 1991]. The mechanisms by which hyperinsulinaemia and insulin resistance elevate blood pressure are still obscured but they may include insulin-induced renal sodium reten-
tion, fundamental changes in the responsiveness of vascular smooth muscle cells to pressor amines in insulin resistant patients or stimulation of the sympathetic nervous system by insulin [DeFronzo and Ferrannini t991]. The results of several prospective clinical trials in hypertension have revealed a phenomenon called coronary artery disease paradox - active treatment reduces mortality and cerebrovascular disease but does not prevent coronary artery disease [Black 1990]. It has been suggested that deterioration of the metabolic-risk-factor profile caused by some antihypertensive drugs may be responsible for the paradox [Pollare et al. 1989a, Black 1990]. Worsening of insulin sensitivity and dyslipoproteinaemia should be avoided, therefore, when treating hypertensive patients. Particular care must be taken when choosing antihypertensive therapy for patients who have a cluster of cardiovascular risk factors, like hypertension and NIDDM. A previous study in obese, non-diabetic hypertensive patients indicated that peripheral insulin sensitivity was improved during therapy with prazosin, an O~l-adrenoceptor blocker [Pollare et al. 1988]. In another study it was shown that doxazosin, a long-acting ¢l-adrenoceptor blocking drug, reduced fasting blood glucose and plasma insulin when given as maintenance treatment to nondiabetic hypertensive patients [Lehtonen 1990]. In the present study, the effect of doxazosin on blood pressure, insulin sensitivity and serum lipids has been evaluated in 14 patients with both hypertension and NIDDM.
Subjects and methods
Patients and stud}, design After giving informed consent, t4 hypertensive (diastolic blood pressure > 95 mmHg) patients (8 f, 6 m), who also had non-insulin dependent diabetes meilitus according to the WHO criteria, were enrolled into this open, non-comparative study. The study design was approved by the local ethics Committee. The mean age of the patients was 63 (9) y. At entry, the mean duration of NIDDM in the patients was 8.2 (3.7) y, their mean weight was 76.5 (13.9) kg and
366 mean height 169 (7) cm. After a two week washout of previous antihypertensive treatment, the patients were put on placebo for a further 2 week period, whereafter they entered the 12 week titrationmaintenance phase. They initiallyreceived doxazosin 1 mg daily; the patient then visited the ward and the blood pressure was measured at biweekly intervals. The doxazosin dose was doubled every other week until the diastolic blood pressure had fallen below 90 mm Hg, the maximum daily dose of 16 mg had been reached or adverse effects precluded any further increase in dose. The highest effective and tolerable dose was subsequently maintained to the end of the titration-maintenance phase. The antidiabetic treatment (diet, sulphonylureas and/or metformin) was kept constant over the entire study period. Blood chemistry, including fasting glucose, lipids and electrolytes, estimation of insulin sensitivity and oral glucose tolerance test were performed at the end of placebo and doxazosin periods.
infusion rate of exogenous glucose equals glucose disposal. A substantial suppression of hepatic glucose output is expected, even in NIDDM patients, at the plasma insulin levels produced here [Heine et al. I985; Nankervis et aL 1982], although some residual output may persist in certain diabetic patients. However, incomplete suppression of hepatic glucose output is itself a manifestation of insulin resistance, and in that case the results would reflect peripheral as well as hepatic insulin sensitivity [Bergman et al. 1985].
Oral glucose tolerance test A standard oral glucose tolerance test (blood samples for glucose at 0,1 and 2 h) was performed after swallowing 75 g glucose (Glucodyn mixt, Huhtamfiki Oy Leiras, Helsinki, Finland) at least 2 days after the combined glucose-insulininfusions, both before and at the end of the doxazosin treatment,
Biochemical analyses Glucose was analyzed by the hexokinase method, blood HbAI0 by liquid chromatography and plasma insulin by RIA (Phadeseph Insulin RIA, Pharmacia Diagnostics, Uppsala, Sweden). The interassay and intra-assay coefficients of variation of plasma glucose determinations were 3 % and 1%, respectively. Serum sodium and potassium, cholesterol, HDL-cholesterol, triglycerides, uric acid, aspartate amine transferase (ASAT) and creatinine were analyzed by standard techniques, using an Ol~anpus AU 5021 Automated Chemistry Analyzer (Olympus Optical Co., LTD, Tokyo, Japan),
Statistical analysis The results are given as mean with (SD). The t-test for paired data was used to compare the values before and after doxazosin treatment. Analysis of variance for repeated measures was applied to compare blood glucose levels during the oral glucose tolerance tests before and after treatment.
Results
Determination of insulin sensitivity The determination was carried out using a combined fixed-rate infusion of glucose and insulin as previously described [Heine et al. 1985; Heine et al. 1986]. In brief, the patients came to the laboratory at 08.00 h after an overnight fast. Plastic IV cannulae were placed in contralateral arms, one for concomitant infusion of 20 % glucose (6mg-kg-l-min ~) and dilute insulin (1U.ml -I in saline, 50 mU. kg ~.h -1, Velosulin Human, Novo-Nordisk, Denmark) for 150 rain, and one for collection of frequent blood samples. The insulin infusion was commenced with a bolus calculated to elevate plasma insulin to the desired level Glucose was infused with a volumetric infusion pump (Imed 960, Oxon, England) and the diluted insulin with an IVAC 700 syringe pump (IVAC Corporation, San Diego, CA, USA). 'Ib reduce the binding of insulin to the infusion apparatus, the system was thoroughly flushed with the infusate prior to connecting it to the patient. Samples for plasma glucose and insulin were taken twice basally, every 15 min for 2 h and then every 5 min over the test period of 120 to t50 min. The patient emptied the bladder before and after the infusion, and the urine was collected and analysed for glucose.
Calculation of the results Steady state plasma glucose (SSPG) and insulin (SSP1) concentrations during the combined glucose-insulin infusion were determined as the mean of the values recorded between 120 and 150 min. The mean coefficient of variation of the SSPG concentrations was 3.5 (1.9) %. SSPG is a direct measure of insulin sensitivity but during hyperglycaemic conditions it is biased by urinary glucose loss [B ergman et aI. 1985]. Therefore, the metabolic clearance rate of glucose (MCR), corrected for urinary glucose output, was used as a measure of the insulin sensitivity. "tlae MCR was calculated as "therate of glucose infusion/steady state plasma glucose concentration with a correction for urinary glucose output during the test. The equation is based on the assumption that hepatic glucose output is suppressed during the glucose-insufin infusions; under these circumstances the
B o t h s u p i n e ( P = 0.04) a n d s t a n d i n g ( P = 0.03) diastolic b l o o d p r e s s u r e d e c r e a s e d b y 7 a n d 8 % , r e s p e c t i v e l y during d o x a z o s i n t r e a t m e n t w h e r e a s systolic b l o o d p r e s s u r e a n d h e a r t rate did n o t c h a n g e (Table 1). T h e c h a n g e in supine diastolic b l o o d p r e s s u r e was i n v e r s e l y c o r r e l a t e d with t h e p r e s s u r e at the e n d of p l a c e b o p e r i o d (r = - 0.72, P = 0.006). T h e daily d o s e of d o x a z o s i n at the end o f t h e m a i n t e n a n c e p h a s e r a n g e d f r o m 1 m g (3 p a t i e n t s ) t o 16 m g (2 p a t i e n t s ) , m e a n 5.6 (5.1) mg. T h e p a t i e n t s g a i n e d w e i g h t b y 1.0 (1.6) kg ( P = 0.04) d u r i n g t h e t r e a t m e n t . T h e r e w e r e no significant c h a n g e s in s e r u m e l e c t r o lytes, lipids or c r e a t i n i n e , w h e r e a s s e r u m uric acid dec r e a s e d b y 8 % w h e n on d o x a z o s i n ( P -- 0.05; T a b l e 2). D u r i n g b o t h insulin sensitivity tests, i d e n t i c a l S S P I levels of a b o u t 530 p m o l . 1 1 w e r e r e a c h e d w i t h i n 90 to 105 m i n a n d w e r e m a i n t a i n e d until the e n d o f the infusion
Table L Blood pressure (mmHg) and heart rate (beats-min-~) before (end of placebo phase) and after 12 weeks of doxazosin treatment. Mean with (SD) Before
After
Supine - Systolic blood pressure - Diastolic blood pressure - Heartrate
156 (15) 95 (8) 80 (10)
154 (16) 87 (8)* 81 (10)
Standing - Systolic blood pressure - Diastolic blood pressure - Heart rate
155 (19) 96 (7) 84 (7)
t48 (27) 88 (8)** 83 (10)
Significance of difference from pre-treatment: * P = 0.04; ** P = 0.03 (Student's t-test for paired data)
367 Table 2. Effect of doxazosin treatment on serum biochemistry.
Mean with (SD) Cholesterol (mmol. 1 1) HDL-cholesterol (mmol. 1-1) HDL/total cholesterol Trigtycerides (mmol. ! 1) Sodium (mmol. 1- t) Potassium (mmol-1- l) Chloride (mmot-1-1) Magnesium (mmot. 1-~) Creatinine (Ixmol.1 1) ASAT (U. l t) Uric acid (~tmol. 1-1)
Before 5.1 (1.2) 1.1 (0.2) 0.23 (0.06) 1.6 (0.6) 142 (4) 4.1 (0.3) 109 (2) 0.8 (0.1) 83 (13) 20 (8) 305 (85)
After 4.9 (1.2) 1.2 (0.3) 0.26 (0.08) 1.6 (0.6) 144 (3) 4.0 (0.4) 109 (3) 0.8 (0.1) 81 (13) 19 (9) 281 (106)*
*significantly different from value before treatment (P = 0.049, Student's t~test for paired data) Table 3. Effect of doxazosin treatment on carbohydrate metabolism. Mean with (SD) fP-glucose (mmol-1 -~) m-HbAl~ (%) fP-insulin (pmoi. 1 t) SSPI (pmoI-I -I) MCR (ml-rain - 1. kg -~)
Before 11.9 (3.3) 8.0 (1.5) 96 (43) 533 (159) 2.35 (1.64)
After 10.9 (3.1) 8.2 (1.5) 95 (52) 525 (146) 3.37 (2.70)*
SSPG steady state plasma glucose, SSPI steady state plasma insulin, MCR metabolic clearance rate of glucose (corrected for urinary glucose losses).* higher than before treatment (P = 0.03, Student's t-test for paired data)
(Table 3). The SSPG concentration decreased from 14.9 (4.4)mmol.1 1 during the placebo period to 12.6 (5.4) mmol. 1-1 after doxazosin treatment (P = 0.06). The insulin sensitivity, expressed as the M C R of glucose and corrected for urinary glucose loss, improved significantly from 2.35 (1.64) ml.min -t-kg -I to 3.37 (2.7) ml-min l. kg- 1 during doxazosin treatment (P = 0.03). A similar but weaker trend was seen in fasting plasma glucose, which dropped by about i mmol. 1-1 during the therapy. Fasting plasma insulin did not change (Table 3). Before treatment, blood glucose increased during the oral glucose tolerance test from the basal value of 9.7 (2.8) mmol. 1-1 to 17.0 (3.1) and 16.8 (4.0) mmol. 1-1 after i and 2 h, respectively. Similar blood glucose values were recorded after doxazosin treatment (basal 9.2 (2.8) mmol. 1-1, at i h 16.7 (3.8) mmol. 1-1, and at 2 h 16.9 (4.5) mmol. 1-1; treatment effect: F = 0.40, P = 0.54; treatment x time interaction F = 1.20; P = 0.32). In general, doxazosin was well tolerated. In one patient the highest daily dose of 16 mg caused an orthostatic reaction. The s)~nptoms rapidly resolved after reduction of the dose to 8 mg daily.
Discussion
Doxazosin reduced both supine and standing diastolic blood pressures in the present hypertensive N I D D M patients to a similar degree as that reported earlier in hypertensive patients [Young and Brogden 1988], but it had a
minimal effect on supine systolic blood pressure. The standing systolic blood pressure was reduced by about 5 %, although the effect was not statistically significant. The less pronounced effect of doxazosin on supine than on standing systolic blood pressure and the lack of effect on heart rate is in accordance with previous reports [Young and Brogden 1988]. Insulin resistance in N I D D M appears to be a syndrome associated with clustering of metabolic disorders, including hypertension, lipid abnormalities and atherosclerotic cardiovascular disease [DeFronzo and Ferrannini 1991]. Hydrochlorothiazide [Pollare et al. 1989a] and the fiadrenoceptor blocking drugs metoprolol and atenolol [Pollare et al. 1989b] decrease insulin sensitivity, whereas the calcium entry blocker diltiazem has no effect [Pollare et al. 1989c]. Data on previously untreated obese hypertensive patients indicate that prazosin improves insulin sensitivity [Pollare et al. 1988], whereas terazosin had no effect in nonobese normotensive subjects [Ferrari et al. 1991]. The ACE-inhibitor captopril has also been shown to improve insulin sensitivity in hypertensive patients [Jauch et al. 1987; Pollare et al. 1989 a]. Improved peripheral insulin sensitivity has been demonstrated after 10 days of captopril treatment in N I D D M [Ferriere et al. 1985], and even after a single 25 mg oral captoprit dose in normotensive patients [Jauch et al. 1987]. It is not known if there are differences in this respect between antihypertensive drugs of to the same class [Black 1990]. Previous studies of drug effects on insulin sensitivity have mostly dealt with hypertensive patients without manifest diabetes mellitus. The present study was done to clarify the effect of doxazosin on insulin sensitivity in a clinically important subgroup of hypertensive patients, namely non-insulin dependent diabetics. The results have demonstrated that doxazosin, a longacting c~1-adrenoceptor blocking drug, improved insulin sensitivity" in this patient population. The effect cannot be explained by weight loss, since these patients experienced a slight weight gain during the study. The study has corroborated the earlier suggestion of improved insulin sensitivity during doxazosin treatment, based on reduction in fasting plasma glucose and insulin in a larger group of hypertensive non-diabetic patients on maintenance therapy [Lehtonen 1990]. In keeping with the results of the captopril study, the concentrations of fasting plasma glucose and hemoglobin Alo concentrations in the patients did not change despite the improved sensitivity to insulin [Pollare et al. 1989a]. It must be emphasized that peripheral insulin resistance and hepatic glucose production during fasting are important determinants of blood glucose concentration [DeFronzo et al. 1982], whereas during glucose insulin infusion the contribution of peripheral glucose uptake is predominant. Every effort was taken to control confounding factors during the study. Antidiabetic treatment and diet were kept constant and the patients were told to keep their living habits unchanged during the study. The time of the entry of the patients into the study was scattered throughout the calendar year to make any contribution of seasonal factors to the results improbable. Together with earlier studies on prazosin [Pollare et al. 1988] and doxa-
368 zosin [Lehtonen 1990], the present study strongly suggests that a l - a d r e n o c e p t o r blocking drugs may have a beneficial effect on insulin sensitivity, at least in insulin-resistant patients. The mechanism by which as-blocking drugs improve insulin sensitMty remains speculative. As discussed for prazosin [Pollare et al. 1988], i m p r o v e m e n t of peripheral blood flow in skeletal muscle tissues due to the relaxation of arterioles [Westheim et al. 1986] may improve the tissue response to glucose and insulin. Since the stimulation of hepatic glucose production may also be mediated through c~-adrenergic receptors in man [Rosen et al. 1983], and c~- together with fl2-receptors form the predominant adrenergic receptor subtype in h u m a n liver plasma m e m branes [Kawai et al. 1986], the use of an as-receptor blocking drug may also have interfered with hepatic glucose production. Many antihypertensive drugs, including some diuretics and t-blockers, adversely affect plasma lipids, whereas the a t - a d r e n o c e p t o r blocking drugs prazosin and doxazosin m a y have a beneficial effect on them. With the exception of triglycerides, a similar trend was noted in the diabetic patients here, but due to the limited n u m b e r of patients required for the insulin sensitivity test, the lipid effects were not statistically significant (Table 2). Hypertension is one of the primary risk factors for coronary artery disease. To reach the desired therapeutic goal, nonpharmacological haterventions aimed at reducing both blood pressure and hyperinsulinaemia, together with weight loss, are strongly recommended. Nevertheless, drug therapy is often unavoidable. It is logical to accomplish the p h a r m a c o t h e r a p y in a way that not only reduces blood pressure but also leaves insulin and glucose metabolism and the lipid profile unchanged or preferably improved [Lithell 1991]. This is of special importance in patients with clustering of several cardiovascular risk factors, e.g. in patients who have both hypertension and N I D D M . According to the present results, doxazosin fulfills the desired criteria both in terms of improved insulin sensitivity and lack of deleterious effects on serum lipids.
Acknowledgements. We thank Mr. R Koskinen for performing the statistical calculations, and Mrs. E. Kahra for her expert technical assistance with the insulin sensitivity determinations. The diabetic nurses of the Turku City Health Centre, Mrs. I. H~im~lfiinen and T. Taivatantti provided valuable support. The study was supported by a grant from Pfizer Oy, Helsinki.
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