Effect of trimazosin on serum lipid profiles in hypertensive patients

Abnormalities in the serum lipid profile correlate strongly with the presence and severity of atherosclerosis. Increases in serum lipids and a reduction in high-density lipoprotein (HDL) cholesterol have been demonstrated following treatment with some beta blockers and diuretics, either alone or in combination. A new alpha-1-adrenoceptor antagonist, trimazosin, was studied to determine its effects on serum lipids. Ninety-six hypertensive patients were randomly assigned in double-blind fashion to trimarosin or placebo for 8 weeks. Trimazosin was associated with a significant reduction (p 5 0.01) in total cholesterol when compared with the placebo group. This effect was seen in all patients regardless of whether or not they were taking a diuretic concomitantly. In addition, a g-month, double-blind parallel comparison was made of trimazosin and propranolol. Trimarosin was found to be superior to propranolol in its effect on HDL cholesterol and the HDL/total cholesterol ratio. These studies have demonstrated that, in contrast to placebo and propranolol, trimarosin lowers total serum cholesterol without undesirable effects on other serum lipid fractions. When polythiaride is given concomitantly, it diminishes the favorable effects of trimazosin and accentuates the opposite, adverse effects of propranolol. (AM HEART J 106:1265, 1983.)

Walter Singleton, M.A., B.M., B.Ch., and Colin R. Taylor, M.D. Sandwich, England, and Groton, Conn.

According to the lipid hypothesis, several types of abnormalities of the lipoprotein profile predispose to the development of atheroma, leading to coronary heart disease, cerebrovascular disease, and other illnesses resulting from impairment of blood flow to tissues. High concentrations of total serum choles- terol, cholesterol-rich low-density lipoprotein (LDL), and triglyceride-rich very low density lipo- protein (VLDL), together with low concentrations of high-density lipoprotein (HDL), are closely corre- lated with the presence and severity of atherosclero- sis. Although the causal relationship is not proved, the correlations are so strong that it is widely accepted that modification of abnormal serum lipid profiles is an important aim of drug treatment.‘e4

Increases in serum triglycerides and a fall in HDL cholesterol have been observed following treatment with some beta-adrenoceptor-blocking drugs,5-8 thi- azide diuretics,g and combinations of these.‘O These changes were not observed after combined beta- and alpha-adrenoceptor blockade with labetalol.” Al- pha-adrenoceptor blockade with prazosin results in

From Pfizer Central Research.

Reprint requests: Walter Singleton, Pfizer Central Research, Sandwich, Kent CT13 9NJ, England.

a fall in total serum cholesterol and serum triglyc- eride concentrations and an improvement in the HDL/LDL + VLDL cholesterol ratio.6 This report summarizes the effects of trimazosin, a new antihy- pertensive alpha-adrenoceptor antagonist, on serum lipid profiles in long-term open studies and in a dou- ble-blind comparison with placebo and propranolol in patients being treated for hypertension.

METHODS AND RESULTS

Long-term open studies and double-blind placebo comparison. After 1 year of open trimazosin therapy, 96 patients were randomly assigned in double-blind fashion either to continue taking trimazosin (mean dosage, 655 mg/day) for another 8 weeks or to receive placebo. Serum lipid parameters were measured in these patients. Of the 96 patients, 44 were taking polythiazide concomitantly (0.5 to 4 mg/day) during part or all of the 12-month open-treatment period, and this was continued during the double-blind comparative phase.

Not all patients had lipid values available at each of the three time points of interest for analysis (i.e., baseline, end of open trial, and end of double-blind trial). Thus patient numbers differ for each lipid parameter in the analysis of the open and double-blind parts of the study. There were no significant differences between the patient groups in terms of baseline values for all lipid parameters (Ta- ble I).

For the open part of this study, comparisons were made

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American Heart Journal

Table 1. Serum lipids at baseline and after long-term open trimazosin therapy -

Total serum cholesterol HDL cholesterol Total serum triglycerides

(m&W (mgldl) (mgldl) Treatment

groups n Mean SEM n Mean SEM n Mean SEM

All patients Baseline End of open

Patients not taking diuretics Baseline End of open

Patients taking diuretics Baseline End of open

90 225.3 3.6 35 53.4 2.9 74 137.3 10.6 90 218.6 3.5 35 52.1 2.9 74 151.0 12.2

48 226.3 5.5 22 50.2 3.8 40 134.1 12.6 48 217.8 4.8 22 51.2 4.2 40 141.3 15.6

42 224.1 4.6 13 58.8 4.1 34 141.0 17.8 42 219.4 5.2 13 53.5 3.5 34 162.3 19.3

Table II. Serum lipids before and after double-blind therapy

Treatment groups

Total serum cholesterol HDL cholesterol Total serum triglycerides (mgldl) (mgldl) (mgldl)

n Mean SEM n Mean SEM n Mean SEM

Trimazosin Before DB 44 220.2 5.3 17 47.2 3.8 44 130.3 10.1 End DB 44 210.7 4.4 17 46.1 3.3 44 126.4 10.7

Placebo Before DB 42 220.8 5.1 18 57.0 4.2 42 157.4 16.6 End DB 42 232.3 5.5 18 50.3 3.4 42 177.3 21.1

No diuretics Before DB 43 220.8 4.9 19 53.0 4.7 43 128.3 11.1 End DB 43 220.4 5.7 19 48.3 3.3 43 121.6 10.8

Diuretics Before DB 43 220.2 5.5 16 51.3 5.3 43 158.7 15.7 End DB 43 222.0 4.8 16 48.3 3.6 43 180.8 20.4

DB = double-blind therapy.

between pretreatment values (i.e., at baseline) and values at the end of open therapy for total cholesterol, HDL cholesterol, and triglycerides (Table I). Trimazosin thera- py was associated with significant reduction (p < 0.05) in total cholesterol from baseline; this effect was seen in all patients whether or not they were taking diuretics.

For the double-blind part of this study, comparisons were made between values before double-blind therapy (i.e., end of open therapy) and values at the end of double-blind therapy for total cholesterol, HDL cholester- ol, and triglycerides. During the double-blind phase, tri- mazosin was associated with a significant reduction (p < 0.01) in total cholesterol when compared with the placebo group; there were no significant effects after diuretic use or because of interaction between diuretic and drug. During the g-week double-blind period, patients receiving trimazosin experienced a reduction of 9.5 mg/dl in total cholesterol, whereas those taking placebo experi- enced an increase of 11.5 mg/dl in total cholesterol (Ta- ble II).

There were no significant effects of trimazosin on HDL cholesterol or triglycerides during double-blind therapy.

Long-term double-blind comparison of trimazosln and propranolol. The indication of potentially beneficial effects of trimazosin therapy on serum lipids, as described previously, prompted a further investigation of these laboratory parameters in a ‘I-month double-blind parallel comparison of trimazosin (100 to 400 mg/day) and pro- pranolol (80 to 320 n&day) in hypertensive patients. Patients received trimazosin or propranolol alone for the initial 12 weeks of therapy, after which time diuretic therapy (polythiazide up to 1 mg/day) could be added for patients who required additional antihypertensive effect. Data analysis was performed both after 12 weeks of therapy (without concomitant administration of a thiazide diuretic) and after 7 months of therapy (with a thiazide diuretic in less-than-optimum responders).

After 12 weeks of therapy (Table III), when the mean daily doses of trimazosin and propranolol were 291 and 208 mg/day, respectively, and when no patients were

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Number 5, Part 2 Trimazosin’s effects on serum lipids 1267

Table Ill. Lipid values after 12-week double-blind treatment with trimazosin or propranolol (mean at baseline, change +- SEM after treatment)

Statistical Parameter Trimazosin Propranolol significance *

Total cholesterol (mg/dl) Baseline 266 262 Change -12.8 Z!I 4.1 -8.5 + 5.0 NS

n 65 63 HDL cholesterol (mg/dl) Baseline 50.0 51.5

Change 1.4 -I- 1.1 -4.4 * 1.2 p < 0.001 n 65 62

Total triglycerides (mg/dl) Baseline 135 138 Change -8.4 + 7.8 -5.4 + 8.0 NS

n 57 58

*t Test on difference between treatment of mean changes from baseline.

Table IV. Mean change from baseline (+SEM) after 7 months of double-blind trimazosin or propranolol therapy ( * polythiazide)*

Trimatosin Propranolol

Lipids Alone +Diuretic Alone +Diuretic

Total cholesterol (mg/dl) Mean -5.7 -3.6 -2.0 +2.9 SE 5.4 7.2 4.8 8.4 n 35 30 45 16

HDL cholesterol (mg/dl) Mean +5.2 -0.1 -2.7 -6.1 SE 1.6 2.0 1.2 2.8 n 35 30 44 16

Total triglycerides (mg/dl) Mean -17.1 +16.0 +14.7 +12.4 SE 14.2 16.6 9.1 19.5 n 33 25 41 16

*Analysis of variance: p < 0.001, trimazosin vs propranolol, for HDL cholesterol; p < 0.05, diuretic YS no diuretic, for HDL cholesterol.

receiving polythiazide, trimazosin was found to be superi- or to propranolol in its effects on HDL cholesterol (p < 0.001). Trimazosin also tended to be superior to propranolol in its effects on concentrations of total serum cholesterol and total serum triglycerides, although these differences were not statistically significant. Consequent- ly, the HDL/total cholesterol ratio of the trimazosin group significantly improved compared with that of the pro- pranolol group (+8.3 % from baseline versus -2.6% ; p < 0.05).

After 7 months of therapy, at a time when 46% of trimazosin patients and 26 % of propranolol patients were receiving concomitant diuretic therapy, trimazosin (mean dose 308 mglday) was again found to be superior to propranolol (mean dose, 218 mg/day) in its effects on HDL cholesterol (p < 0.001; Table IV) and the HDL/total cholesterol ratio. Thiazide use had a significantly worse effect (p < 0.05) on HDL cholesterol and the HDL/total cholesterol ratio than did therapy without thiazides. The changes for the HDL/total cholesterol ratio were +13.4% from baseline with trimazosin versus -5.8% from baseline with propranolol in those patients not receiving concomi- tant diuretic therapy. In patients receiving concomitant diuretic therapy, the changes for HDL/total cholesterol

ratio with trimazosin were +1.5% from baseline versus -12.1% from baseline with propranolol.

In summary, when compared with placebo, propranolol, and thiazide use, trimazosin therapy resulted in favorable changes in the plasma cholesterol fractions. The effect of polythiazide was, in part, to antagonize the favorable effects of trimazosin and to accentuate the adverse effects of propranolol.

CONCLUSIONS

Trimazosin has been shown in many clinical studies to be an effective, well-tolerated antihyper- tensive agent. 12-16 The studies summarized here demonstrate that trimazosin does not share the adverse effect on serum cholesterol fractions asso- ciated with the use of some beta-adrenoceptor anta- gonists and diuretics commonly used in the manage- ment of hypertension. Indeed, those changes induced by trimazosin could be regarded as having a beneficial effect in terms of the risk of cardiovascu- lar morbidity.

Despite many extensive clinical trials, the most recent of which is the Multiple Risk Factor Inter-

1266 Singleton and Taylor

vention Trial,17 the expected life-saving benefits of aggressive risk factor reduction have not been con- clusively demonstrated. Nevertheless, it is undesir- able that drugs used for the treatment of coronary heart disease, hypertension, and other vascular dis- orders should predispose to either the development or exacerbation of any risk factor. Drugs whose use is associated with lowering of total cholesterol and triglyceride levels and with the maintenance of HDL cholesterol are to be preferred for these conditions, especially in the treatment of young patients who may require life-long therapy.

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