Improvement of the lipid Profile During Long-Term Administration of Pindolol and Hydrochlorothiazide

in Patients with Hypertension

PAUL SAMUEL, MD, BRUCE CHIN, MD, RALPH W. FENDERSON, MD, ‘BARTON H. SCHOENFELD, MD, LEONAFD M. GONASUN, PhD,

and SIDNEY LIEBERMAN, PhD

The effect of the combined administration of pindolol (10 or 20 mg daily) and hydrochlorothiazlde (50 mg daily) on the serum lipkl and lipoprotein levels of 34 hypertensive patients was lnvestlgated for 6 to 16.5, months (mean 13.3). Placebo control data were compared with the results obtained during treatment perk&sin each patient by paired t tests. Mean levels of high-density lipoprotein cholesterol increased by 17% (p <O.Ol), low-density llpopro- tein,colesterol decreased by 4% (p <O.Ol) and the

high-dens’ky lipoprotein:low-densiiy lipoprotein cho- lesterol ratio increased by 26% (p <O.Ol). Total serum cholesterol, serum trlglycerkles and very low-density lipoproteln cholesterol showed no statls- tically significant changes from control values. lhese findings suggest that the long-term adminls- tration of this p blocker combined with a diuretic re- sults in serum lipid changes considered beneficial in the evaluation of risk factors for coronary artery disease. (Am J Cardid lg66;57:24C-26C)

I n 1955 Perry and Schroeder1 reported that reduction of arterial blood pressure by hydralazine coincided with decreased serum cholesterol levels in patients with hypertension. A year later, Orvis et al2 showed the same decrease in serum cholesterol with the use of ganglionic-blocking agents. In 1958, Deming et al3 con- firmed these observations in humans and rats, and suggested that there might be a direct correlation be- tween blood pressure and serum cholesterol. During the past 2 decades, however, scores of studies have been published reporting diametrically opposite find- ings: namely, that reduction of ‘high blood pressure, specifically by diuretics or /3 blockers, increased serum lipids or decreased the concentration of high-density lipoprotein (HDL] cholesterol.4-14 The shift toward a more atherogenic lipid profile in exchange for the re- duction of high blood pressure initiated grave con-

From the Long Island Jewish-Hillside Medical Center, New Hyde Park, New York, and The Albert Einstein College of Medicine, Bronx, New York. This study was supported in part by the Coronary Heart Disease Research Foundation, Inc.

Address for reprints: Paul Samuel, MD, Long Island Jewish Medical Center, 1554 Northern Boulevard, Manhasset, New York 11030.

terns in the evaluation of risk factors for coronary artery disease.

In the present study, contrary to previously report- ed data regarding fi blockers and diuretics, we found that the long-term combined administration of pindo- 101 (a fl blocker with intrinsic sympathomimetic activi- ty) and hydrochlorothiazide (HCTZ) resulted in signif- icant increases of HDL cholesterol and of the HDL:low-density lipoprotein (LDL) cholesterol ratio, as well as in a small but significant decrease of LDL cholesterol. We found no statistically significant change in other lipid parameters.

Methods Thirty-four patients (14 men and 20 women) were

studied. Their ages ranged from 39 to 70 years (mean f standard deviation = 58 f 8). The mean diastolic blood pressure was 2100 mm Hg in the supine position after a 3- or a-week placebo baseline or washout phase. Patients with diabetes mellitus (insulin treated], alco- holic hyperlipidemia, evidence of congestive heart failure, kidney or liver disease or failure to complete 6 months of treatment with the study medication were excluded. The project was approved by the Institution- al Review Board and informed consent was obtained.

24c

February 12.1986 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 57 25C

At the end of the 3- to &week placebo period, each patient was given 10 mg of pindolol and 50 mg of HCTZ once daily; when necessary this regimen was supplemented by potassium administration. In 15 pa- tients the dosage of pindolol was increased to 20 mg [with 50 mg of HCTZ) once daily after 2 to 4 weeks of treatment, because of inadequate blood pressure re- sponse. In the remaining 19 subjects the dosage was left unchanged. The patients’ food intake was uncon- trolled, but they were instructed to adhere to a low salt diet.

Blood samples were obtained weekly after a l2- hour fast for 3 to 4 weeks during the placebo period. At the conclusion of this, study medication was started and administered for 6 to 18.5 months (mean f stan- dard deviation = 13.3 f 3.5). The number of fasting blood samples varied from 7 to 22 (mean f standard deviation = 15 f 4) during the active treatment periods and consisted of biweekly blood drawings for the ini- tial 4 to 6 weeks, with monthly samples thereafter. Total serum cholesteroP and triglyceride@ were de- termined by enzymatic methods, and cholesterol in plasma lipoprotein fractions was measured by the Beckman airfuge procedure.17 Eleven of the 34 pa- tients had hypercholesterolemia, 2 had combined hy- perlipidemia and 2 had hypertriglyceridemia. Drugs known to influence serum lipid levels were not given. The weight of the patients remained within f 2 kg throughout the study.

Results The results of the long-term combined administra-

tion of pindolol and HCTZ on serum lipid concentra- tions are shown in Table I. The overall mean value of HDL cholesterol level was increased by 1770, and LDL cholesterol decreased by 4% during administration of the combined regimen. The HDL:LDL cholesterol ra- tio increased by 28%. All of these changes were statis- tically significant (paired t tests) (Table I). Conversely, mean values for total serum cholesterol, triglycerides and very low-density lipoprotein cholesterol showed no statistically significant differences from control lev- els (Table I). The subset of patients taking 20 mg of pindolol showed no significant difference in response compared with those taking 10 mg daily.

Control lipid values were calculated as the mean of 3 to 4 blood samples obtained during the placebo- washout period. However, to rule out the possible in- fluence of prior antihypertensive medication on the data, a comparison was made between the last point of the washout phases (3 to 4 weeks off medication] vs the mean control values, to the active treatment period. There was no statistically significant difference in the results between the 2 methods of calculation.

Analysis of the data in individual patients indicated that HDL cholesterol increased in 28 of the 34 patients studied (82%). It decreased in 3 and remained un- changed in 3. Conversely, LDL cholesterol decreased in 26 of the 34 subjects (76%), increased in 6 and did not change in 2. The HDL:LDL cholesterol ratio in- creased in 30 patients (88%) and decreased in the re- maining 4.

TABLE I Effect of Combined Administratlon of Pindolol and Hydrochlorothlazlde (HCTZ) on Serum Llplds In 34 Hyperlenslve Patlents for 6 to 18.5 Months (mean 13.3)

Placebo Mean f SD

@?3W

Pindolol + HCTZ

Mean f SD % Diff-

@WJl) erence P

Cholesterol Triglycerides HDL C LDL C VLM C HDL ClLDL C

268zk51 271% 18 +1 NS 117f65 122 f 67 +4 NS 48f 18 58f18 +17 <O.Ol

161 f 42 154 * 43 -4 <o.oi 57 * 22 61 f 21 +7 NS

0.338 f 0.27 0.431 f 0.41 +28 <O.Ol

HDL C = high-density lipoprotein cholesterol; LDL C = low-den&y lipopro- tein cholesterol; VLDL C = very low-density lipoproteln cholesterol: NS = difference not signlflcant; SD = standard deviation.

Figure 1 shows the mean percentage of change in HDL cholesterol throughout the study and includes the number of patients completing different lengths of the experiment. It is of interest that mean levels of HDL cholesterol progressively increased during the initial 40 weeks of treatment and remained at the upper pla- teau for the rest of the experiment.

There were no major adverse effects during the study. The effect of pindolol and its combined admin- istration with HCTZ on blood pressure18 and on other hemodynamic or physiologic parameters has been re- ported previously.lg Adverse effects, if they occur, are usually minor.20

Discussion The results of the present study clearly suggest that

the long-term combined administration of pindolol and HCTZ induced changes in the lipid profile consid- ered beneficial in the evaluation of risk factors for coronary artery disease. 2l This is in sharp contrast to most of the recently published findings on this subject.

Diuretics: After Schoenfield and Goldbergeti re- ported that thiazide diuretics adversely affected serum cholesterol concentrations in cardiac patients, serum lipid changes were monitored by several groups of

30

t

20 I

10 t

24 34 34 33 29 22 No. of patients 0 10 20 20 40 50 So

WEEKS

FIGURE 1. Mean percentage of change In serum high-density tlpo- protein cholesterol durlng admlnlstratlon of plndolol and hydrochlo- rothlazlde. NS = difference not slgnlflcant.

2% A SYMPOSIUM: LIPIDS AND HYPERTENSION IN THE ELDERLY

investigators in patients being treated for hyperten- sion, Most investigators agreed that short-term admin- istration of diuretics caused acute changes in the lipid profile. Ames and Hill5 reported that treatment by chlorthalidone resulted in increased serum cholester- ol and triglyceride levels (5% and 26%, respectively) during a 6-month study period in 32 hypertensive pa- tients. Grimm et al6 found that the administration of HCTZ or chlorthalidone for 6 weeks increased total plasma cholesterol by 6% and 8%, triglycerides by 17% and 15% and LDL cholesterol by 6% and 4%,

respectively. Although the differences were small, they were statistically significant. Data on the long- term effect of diuretics, on the other hand, were rather contradictory. In the Oslo Study7v8 HCTZ caused no significant change in plasma cholesterol, triglyceride or HDL cholesterol levels after 4 years of administra- tion. Goldman et aLg however, reported that the treat- ment of 434 mildly hypertensive patients with chlor- thalidone resulted in increased total cholesterol levels (by 5%) after only 1 year and increased triglycerides and LDL cholesterol [both by lo%), with no significant change in HDL cholesterol.

Beta blockers: In 1976 Tanaka et allo observed for the first time that the administration of propranolol to 10 patients for 8 weeks decreased the level of HDL cholesterol. A few years later in the Veterans Adminis- tration Cooperative Studyll propranolol administra- tion was shown to increase triglyceride levels by 25% in 302 patients, after a treatment period of 12 months. In a double-blind, randomized, crossover trialI the administration of atenolol, metoprolol, oxprenolol and propranolol for 3 months each resulted in increased triglyceride concentrations (mean increase 45%), and decreased HDL cholesterol levels (mean decrease 14%) in 53 patients; there was no change in total serum cholesterol or LDL cholesterol. In the Oslo Study13 the administration of propranolol induced very similar changes in the lipid profile. A detailed review14 of the available published data also indicated that cardiose- lective and noncardioselective 6 blockers were similar in their action on serum lipids.

In this same review, Ballantyne and Ballantyne14 reviewed data on combined therapy with thiazide diuretics and @ blockers. Again, the main effect was an increase in plasma triglycerides and a decrease in HDL cholesterol. It is of some importance that in the present study we have shown that the long-term ad- ministration of a /3 blocker with intrinsic sympathomi- metic activity together with a diuretic significantly im- proved the lipid profile.

In the Oslo Study22 combined short-term treatment (10 weeks] with pindolol and HCTZ had no effect on serum lipids. Meier et al23 described the reversal of diuretic-induced increases of LDL cholesterol by the addition of pindolol to the regimen of a group of hyper- tensive patients. However, Miettinen et a124 reported that the administration of pindolol had inconsistent effects on serum HDL cholesterol; withdrawal of pin- dolol at the end of the study caused a small but signifi- cant increase of HDL cholesterol, suggesting [although

in retrospect] that the drug may have caused a slight decrease in this lipoprotein. Nevertheless, in another studyz5 the 12-week administration of pindolol slightly increased HDL cholesterol, with no effect on other lipid parameters.

What are the mechanisms involved? It has been demonstrated that the activity of 2 enzymes-serum lecithin cholesterol acyltransferase26 and lipoprotein lipase27--are of primary importance in the formation of HDL cholesterol. Whereas the administration of pindolol increased the activity of lecithin cholesterol acyltransferase with no effect on lipoprotein lipase,28 propranolol was shown to inhibit lipoprotein lipase activity.lO It is conceivable that these 2 enzymes play important roles in the mediation of the effects of /3 blockers on HDL metabolism. Those agents with in- trinsic sympathomimetic activity may stimulate leci- thin cholesterol acyltransferase activity and raise HDL levels; in contrast, those without intrinsic sympathomi- metic activity may inhibit lipoprotein lipase activity and thus diminish HDL concentrations.

The treatment of hypertension is at a crossroad. The classic report of the Veterans Administration Coopera- tive Studyag [which did not include /3 blockers), dem- onstrating that drug treatment of hypertension pre- vented congestive heart failure and stroke but had no influence on coronary heart disease mortality, was somewhat disappointing. Yet, 15 years and several long-term controlled clinical trials later, we still have no clear-cut evidence that the recommended treat- ment of hypertension could prevent or improve the prognosis of coronary artery disease. In fact, the results of the Multiple Risk Factor Intervention TriaPO caused serious concern. In this 7-year study the subgroup of patients in the special intervention group with hyper- tension and electrocardiographic changes [even mini- mal) had a 65% higher mortality rate from coronary heart disease than did the control patients. The sub- jects in the special intervention group were treated by a vigorous stepped-care antihypertensive drug proto- co1,31 which included diuretics in all and propranolol in many. The use of diuretics was associated with an increase in triglycerides and a slight decrease of HDL cholesterol. The combination of diuretics plus pro- pranolol caused a substantial decrease of HDL cholesterol.31

What caused the increased mortality in this popula- tion remains a very important but unanswered ques- tion. There is no direct proof that the moderate in- crease in serum triglycerides or LDL cholesterol or the decrease in HDL cholesterol induced by many diure- tics and 0 blockers results in increased coronary mor- tality. Neither can we show that antihypertensive medications that improve serum lipids are beneficial to patients with coronary artery disease. However, it is perhaps prudent to turn to compounds that have been shown to improve rather than worsen the lipid profile, although only a large-scale, controlled clinical trial can give us the final answer. We believe that hyperten- sion must be treated with vigor, but the drugs should be carefully chosen.

February 12, 1986 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 57 27c

Acknowledgment: We are indebted to Estelle F. Fisher, Lois Markowski and Rose Seidman for their assistance.

References 1. Perry HM, Schroeder HA. Depression of cholesterol levels in human plasma following ethylenediamine tetracetate and hydralazine. r Chronic Dis 1955;2:520-533. 2. Orvis HH, Tamagna IG, Evans jM. The serum lipids in hypertensive patients treated with pentolinium. Clin Res Proc 1956;4:108. 3. Deming QB. Hodes ME, Baltazar A, Edreira jG, Torosdag S. The changes in concentration of cholesterol in the serum of hypertensive patients during antihypertensive therapy. Am 1 Med 1958;24:882-892. 4. Schoenfeld MR, Goldberger E. Hypercholesterolemia induced by thia- zides: a pilot study. Curr Therap Res 1964;6:180-184. 5. Ames RP, Hill P. Increase in serum lipids during treatment of hypertension with chlorthalidone. Lancet 1976;1:721-723. 6. Grimm RH Jr, Leon AS, Hunninghake DB, Lenz K, Hannan P, Blackburn H. Effects of thiazide diuretics on plasma lipids and lipoproteins in mildly hyper- tensive patients. Ann Intern Med 1981;94:7-11. 7. Helgeland A, Hjermann I, Holme I. Leren P. Serum triglycerides and serum uric acid in untreated and thiazide-treated patients with mild hyper- tension. Am 1 Med 1978;64:34-38. 8. Helgeland A, Hjermann I, Leren P, Enger S, Holme I. High-density Iipo- protein cholesterol and antihypertensive drugs: the Oslo Study. Br Med [ 1978;2:403. 9. Goldman AI, Steele BW, Schnaper HW, Fitz AE, Frohlich ED, Perry M Ir. Serum lipoprotein levels during chlorthalidone therapy. {AMA 1980:244: X91-1695. 10. Tanaka N. Sakaguchi S, Oshige K, Niimura T. Kanehisa T. Effect of chronic administration of propranolol on lipoprotein composition. Metabo- lism 1976;25:1071-1075. 11. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Comparison of propranolol and hydrochlorothiazide for the initial treatment of hypertension. [AMA 1982;248:1996-2011. 12. Day IL, Metcalfe J. Simpson CN. Adrenergic mechanisms in control of plasma lipid concentrations. Br Med 1 1982;284:1145-1148. 13. Leren P. Helgeland A, Holme I, Foss PO, Hjermann I, Lund-Larsen PG. Effect of propranolol and prazosin on blood lipids. Lancet 1980;2:4-6. 14. Ballantyne D. Ballantyne FC. Thiazides, beta blockers and lipoproteins. Postgrad Med 1 1983;59:483-488. 15. Allain CC, Poon LC. Chan CSG. Richmond W, Fu PC. Enzymatic determi- nation of total serum cholesterol. Clin Chem 1974;20:470-475. 16. Bucolo G. David H. Quantitative determination of serum triglycerides by

the “se of enzymes. Clin Chem 1973;19:476-482. 17. Bronzert T, Brewer HB Jr. New micromethodformeasuring cholesterolin plasma lipoprotein fractions. Clin Chem 1977:23:2089-2098, 18. Fanchamps A. Therapeutic trials ofpindolol in hypertension: comparison and combination with other drugs. Am Heart r 1982:104:388-406. 19. Svensson A. Gudbrandsson T. Silvertsson R. Hansson L. Haemodynamic effects of metoprolol and pindolol: a comparison in hypertensive patients. Br \ CIin Pharmacol 1982;13:259s-267s. 20. Gonasun LM. Langrall H. Adverse reactions to pindolol administration. Am Heart r 1982;104:482-486. 21. Eder HA. Gidez LI. The clinical significance of the plasma high density lipoproteins. Med CIin North Am 1982:66:431-440. 22. Leren P, Eide I, Foss OP, Helgeland A. Hjermann I, Holme I, Kjeldsen SE, Lund-Larsen PG. Antihypertensive drugs and blood lipids: the Oslo study. Br I CIin Pharmacol 1982;13:supp/:44ls-444s. 23. Meier A, Schiffl H. Weidmann P, Mordasini R, Riesen W, Bachmann C. /3- receptor blocking agents may reverse or prevent diuretic-induced increases in serum low-density lipoprotein cholesterol. Clin Sci 1981;61:suppI: 437s-439s. 24. Miettinen TA, Vanhanen H, Huttunen JK. Naukkarinen V. Mattila S, Strandberg T, Kumlin T. HDL cholesterol and b-adrenoceptor blocking agents in a 5 year multifactorial primary prevention trial. Br r CIin Pharmacol 1982;13:suppb431-434s. 25. Pasotti C, Capra A, Fiorella G, Vibelli C. Chierichetti SM. Effects of pindolol and metoprolol on plasma lipids and lipoproteins. Br 1 Clin Pharma- co1 1982;13:s”ppI:435s-439s. 26. Leiss 0. Muranowski U, Egge H. Lecithin cholesterol acyltransferase activity in relation to lipoprotein concentration and lipid composition. Stand r CIin Lab Invest 1978;38:suppl 150:77-84. 27. Taskinen MR. Nikkilfi EA. High density lipoprotein subfractions in rela- tion to lipoprotein lipase activity of tissue in man; evidence for reciprocal regulation of HDL, and HDLs levels by lipoprotein Upase. CJin Chim Acta 1981;112:325-332. 28. Lehtonen A, Hietanen E, Marniemi J, Peltonen P, Niskanen J. Effect of pindolol on serum lipids and lipid metabolizing enzymes. Br r Clin Pharmacol 1982;13:445s-447s. 29. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension: II. Results in patients with diastolic blood pressure averaging90 through 114 mmHg. lAMA 1970;213:1143-1152. 30. Multiple Risk Factor Intervention Trial Research Group. Multiple Risk Factor Intervention Trial (MRFITI: risk factor changes and mortality results. [AMA 1982;248:1465-1477. 31. Lasser NL. Grandits G. Caggiula AW, Cutler IA, Grimm RH, Kuller LH. Sherwin RW, Stamler J. Effectiof antihypertensiie therapy on plasma lipids and lipoproteins in the Multiple Risk Factor Intervention Trial. Am 1 Med 1984;76:suppl 2A:52-66.

Discussion

Question: Two questions regarding your study of the effects of pindolol and hydrochlorothiazide on the plasma lipids. First, how many blood samples were drawn to establish your baseline in the study? Second, how did you control for diet during the study? If you are attributing favorable effects on plasma lipids to the drug combination, I think it is very important to control for diet.

Dr. Samuel: Four samples were drawn to establish the base- line, yet I was rather unhappy because a number of the patients were tapered off other medication. Because the identity of the other antihypertensive medications was known before patients entered the washout phase of the study, I requested our statisti- cians to calculate the mean of the control period with the stan- dard deviations, then to discard the first 3 points of the control period and retain only the last point before the study medication was begun. Therefore, patients had not been taking antihyper- tensive medication for either 3 or 4 weeks. When we took the

mean of 4 points vs the 1 last point, the comparison of the results in each individual patient was the same. Each patient was regu- larly seen by a nutritionist at our clinic. A low salt diet was the only restriction imposed. To be a purist, I must add that the diet remained uncontrolled because these patients followed instruc- tions to continue to eat the same diet after they had returned home.

Question: How intensively do you treat a post-myocardial infarction patient in whom you find elevated lipids?

Dr. Samuel: I treat him very intensively. First, I determine the level of his lipids and lipoproteins. Then having a solid baseline, I put him on an appropriate diet for several weeks to see whether or not he responds. If he does not, I put him on drug treatment.

Question: Are you implying that it is the intrinsic sympatho- mimetic activity of pindolol that made the difference in your

2% A SYMPOSIUM: LIPIDS AND HYPERTENSION IN THE ELDERLY

cholesterol levels, and have you considered repeating this study effects of a drug with intrinsic sympathomimetic activity associ- with a @blocker that does not contain intrinsic sympathomimetic ated with a thiazide diuretic. It is likely that the intrinsic sympa- activity? thomimetic activity of pindolol made the difference. The effects

Dr. Samuel: I cannot imply anything. All I can tell you is that of pindolol, of course, must be further explored. In fact, we are this is what we found. In looking at published findings, the drugs now comparing the effects of pindolol with propranolol in a with intrinsic sympathomimetic activity did not change the lip- double-blind, randomized, controlled study in another group of ids. We then decided to do this pilot study on the long-term hypertensive patients.