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Effect of probucol on plasma lipids and lipoproteins in type IIb hyperlipoproteinemia
469
Atherosclerosis, 37 (1980) 469-474 0 Elsevier/North-Holland Scientific
Publishers,
Ltd.
EFFECT OF PROBUCOL ON PLASMA LIPIDS AND LIPOPROTEINS TYPE IIb HYPERLIPOPROTEINEMIA
DONALD
B. HUNNINGHAKE,
CATHERINE
Departments of Pharmacology 55455 (U.S.A.)
and Medicine,
(Received 3 March, 1980) (Revised, received 28 April, (Accepted 29 April, 1980)
BELL and
LINDA
IN
OLSON
University of Minnesota, Minneapolis, MN
1980)
Summary Probucol was administered for 4 months in 20 adult males with Type IIb HLP in a total daily dose of 1.0 g per day. All patients had achieved a stable weight and diet response prior to entering the study. Plasma lipid and lipoprotein determinations were done at monthly intervals. Probucol produced mean reductions in TPC of -38.8 mg/dl (P < O.OOOl), in LDL of -26.7 mg/dl (P < 0.001) and HDL of -8.1 mg/dl (P < 0.0001) for the entire treatment period. The mean LDL/HDL ratio increased from 5.43 to 6.08 (P < 0.02). There was no significant change in TG levels. During the study a progressive decrease in mean HDL levels from 38.9 to 29.2 mg/dl was noted. A progressive increase in the LDL/HDL ratio from 5.43 to 6.35 was also observed. These findings suggest that probucol should be used cautiously in patients with Type IIb HLP, because an inverse relationship between HDL levels and IHD incidence has been demonstrated in epidemiologic studies. Key words:
Plasma lipids - Plasma lipoproteins hyperlipoproteinemia
- Probucol
-
Triglycerides
-
Type IIb
Introduction Probucol has been reported to be an effective hypocholesterolemic agent in multiple studies which have recently been summarized [ 1,2] and lowers choThis work was supported in part by NH&B1 Contrac.t No. 1 HV 2-2195-L. Correspondence and reprint requests to: Donald B. Hunninghake. M.D., University of Minnesota, Department of Pharmacology, i-260 Millard Hall. 435 Delaware Street S.E., Minneapolis, MN 55455, U.S.A. Abbreviations: HDL, high density lipoproteins; HLP. hyperlipoproteinemia; IHD, ischemic heart disease; LDL, low density lipoproiein; TG. triglycerides; TPC. total plasma cholesterol.
470
lesterol in a variety of lipoprotein abnormalities [ 3-51. The above studies have primarily focused on the effect of probucol on serum lipids. Two studies have evaluated the effects on lipoprotein levels. In a placebo-controlled, doubleblind study, LeLorier et al. reported that its primary effect was a reduction in LDL, but noted some decrease in HDL in patients with either Type IIa or IIb HLP (6). Anderson and Schroeder, in a small number of cardiac transplant recipients with Type IIa or IIb HLP, noted a reduction in both HDL and LDL, but the LDL/HDL ratios were unchanged following probucol administration. The above observations led us to evaluate the effect of probucol on lipoprotein levels in patients with Type IIb HLP, which is characterized by lower HDL levels than Type IIa HLP, utilizing the methods for lipoprotein determinations developed by the Lipid Research Clinics Program [ 81. We have previously reported that the response to hypolipidemic agents in Type IIb may be significantly different from that observed in Type IIa patients [9]. The prolonged plasma half-life of probucol also suggested that serial changes in lipoprotein levels should be evaluated [lo]. Subjects and Methods Twenty adult males ranging in age from 35 to 62 years (mean age 52.8 + 1.3) were selected for study from our Lipid Clinic on the basis of lipid and lipoprotein levels. Familial history of HLP was not a requirement. Informed consent was obtained after the nature of the study had been explained. Only subjects who had demonstrated good adherence to diet and had maintained a stable weight for 18 months were selected. Prior to diet, all subjects had LDL levels >190 mg/dl and TG >200 mg/dl. The criteria for entry into this study was LDL >175 mg/dl and TG >200 mg/dl while on diet. Minimal dietary requirements included a cholesterol intake of <350 mg/day and a P/S ratio approximating 0.8. Stable weight and caloric restrictions had been achieved prior to obtaining the baseline dietary lipid and lipoprotein levels. Two dietary control periods were available. The first represented the mean of 3 determinations of plasma lipid and lipoprotein levels prior to entering a l-year drug study which has previously been reported [9]. The second represents the mean of 2 determinations performed at monthly intervals after the patients had been off all lipid-lowering drugs for at least 6 weeks. The mean values for the 2 control periods were very similar. Patients with a history of more than 10 alcoholic drinks per week or taking medications known to alter plasma lipids were excluded. Plasma lipid determinations were done utilizing an Autoanalyzer II (Technicon) and methods developed by the Lipid Research Clinics Program, and lipoprotein cholesterol determinations were done utilizing a combination of heparin-manganese precipitation and ultracentrifugation [ 81. No patient in this study had a VLDL cholesterol/triglyceride ratio 20.25, effectively excluding patients with Type III HLP. Probucol was administered in a total daily dose of 1.0 g in 2 divided doses for 4 months. Plasma lipid and lipoprotein levels were determined at monthly intervals. Adherence was measured by pill count. Weight and diet adherence were recorded at each visit. Routine hematologies, urine and biochemical screening procedures were
471
performed at the onset and termination was used for statistical comparisons.
of probucol
therapy.
The paired t-test
Results The means of all the plasma lipid and lipoprotein determinations during the probucol treatment period were compared to the means of all the determinations during the 2 diet control periods in Table 1. Following probucol administration, mean reductions in TPC of -13.0% (P < O.OOOl), in LDL of -12.6% (P < 0.001) and in HDL of -20.8% (P< 0.0001) were noted. The mean LDL/HDL ratio was increased +12.0% during probucol therapy (P < 0.02). No significant change in TG levels or weight was noted. Mean adherence for the entire probucol treatment period was 95.1%. Nineteen patients demonstrated decreases in HDL following probucol administration, while one patient showed no change. Patients with higher HDL levels during the control periods, tended to have greater absolute reductions in HDL. The per cent reduction in HDL was fairly consistent for all patients, however. Fourteen had reductions ranging from 15 to 28%, 2 greater than 30%, and 3 less than 15%. The mean LDL/HDL ratio during the entire probucol treatment period was increased in 15, unchanged in 2 and decreased in 3 patients. The means of the individual 4-monthly treatment periods are illustrated in Table 2. There were no significant differences between any of the 4-monthly values for TPC and LDL, although TPC and LDL levels tended to be slightly lower at month 4. There was considerable fluctuation in TG levels during probucol therapy, but no consistent changes were noted. TG levels tended to increase over time, but these changes were not statistically significant. The maximum reduction in HDL levels and increases in LDL/HDL ratios generally occurred within 3 months from the onset of probucol administration. The first 18 patients completing this study had 2 repeat HDL determinations after probucol therapy had been discontinued for at least 10 weeks. They were TABLE I MEAN PLASMA LIPID, LIPOPROTEIN PROBUCOL TREATMENT PERIODS
LEVELS AND LDL/HDL
RATIOS FOR DIET CONTROL
AND
TPC
TG
LDL
HDL
(meldI)
@x%/dl)
(mg/dI)
LDLjHDL ratio
Weight
(mgldl)
291.4 f 2.6 = 299.7 f 3.1 298.3 f 2.5
270.1 278.6 273.4
f 9.2 k 16.3 f 8.4
204.4 202.6 203.7
zt 3.1 * 2.7 f 2.2
38.4 f 1.1 3.9.6 f 1.4 38.9 * 0.9
6.36 f 0.22 6.52 f 0.19 5.43 * 0.15
82.1 83.0 82.5
259.5
216.3
* 13.2
177.0
* 2.6
30.8 * 0.9
6.08 * 0.17
63.3
(kg)
Diet control periods First Second Mean of the two Probucol Mean of 4 visits A from mean diet control
f 2.4
(mrldl) % Change from
-38.8
diet P-value
-13.0 <0.0001
a SEM.
+1.9
-26.7
+0.7
-12.6
ILS.
-8.1 -20.8 <0.0001
+0.66 +12.0 <0.02
TABLE 2 SERIAL
CHANGES
IN PLASMA
LIPID, LIPOPROTEIN
LEVELS
AND
RATIOS
WITH PROBUCOL
TREATMENT TG
TPC Month Month Month Month
1 2 3 4
259.1 261.8 261.4 255.7
* * * f
4.5 4.6 4.5 4.4
268.2 270.7 277.7 284.5
LDL f f f f
25.2 26.8 25.6 30.4
175.8 181.4 177.2 173.5
LDL/HDL
HDL f * * f
5.3 5.9 5.6 6.2
33.8 31.1 29.5 29.2
f * f *
1.7 1.4 1.0 0.9
5.48 6.17 6.33 6.35
f f f f
0.30 0.33 0.34 0.37
P-values Months
HDL LDL/HDL
1 “S 2
1 vs 3
1 “S 4
2 vs,3
<0.05 <0.05
ll.S.
n.s.
n.s.
ILS.
3 “8 4
not receiving any hypolipidemic drugs. The mean of 2 HDL determinations for each patient immediately before probucol therapy, months 3 and 4 of probucol therapy, and after discontinuing probucol therapy were 38.7, 28.5 and 37.4 mg/dl, respectively. The post-treatment levels are not significantly different from the pre-treatment values. Discussion The results in this study indicate that probucol decreases both HDL and LDL levels in patients with Type IIb HLP, but the decrease in HDL is relatively greater than the reduction in LDL. The 15% decrease in TPC with no significant change in TG levels is consistent with previous observations [l-7]. The reductions in LDL and HDL levels in this study are consistent with the observations of LeLorier et al. [6] and Anderson and Schroeder [ 71 who studied patients with either Type IIa or IIb HLP. This study also demonstrated that the LDL/HDL ratio was significantly increased following probucol administration. The above 2 studies either did not report their ratios [6] or had quantitative determinations in only 5 patients [ 71. The serial determinations of lipoprotein levels indicated that the maximum mean reduction in HDL and increase in LDL/HDL ratio had occurred within 3 month8 of initiating probucol therapy. However, some patients appeared to still have continuing decreases in HDL at the 4th month of therapy. There is considerable interest in the predictive value of lipoprotein levels for future risk of IHD. This risk appears to be inversely related to HDL levels and positively correlated with LDL levels [ 11,121. After age 50, HDL levels appear to be the most important lipid determinant of risk [ll]. Some emphasis has also been placed on plasma lipid and/or LDL/HDL ratios as enhancing the predictability for future risk of IHD [ll]. HDL2/HDL3 and/or Apo A-I/APO A-II levels may more accurately reflect overall HDL metabolism [ 131. These latter determinations were not performed, but should be incorporated into future studies.
473
Considerable controversy still exists regarding the therapeutic benefit of pharmacologic alteration of plasma lipid and lipoprotein levels in terms of reducing morbidity and mortality from IHD. However, we feel that our findings indicate that it is essential to monitor lipoprotein levels in all patients receiving probucol therapy. It would be difficult to ignore the observation of a significant decrease in HDL or an increase in LDL/HDL ratio. Nineteen of 20 patients in this study demonstrated a decrease in HDL following probucol administration. Studies on the effect of probucol on HDL metabolism in other lipoprotein disorders, especially in Type IIa HLP, are clearly indicated. The mechanism of the hypocholesteremic effect of probucol has not been established. It does not significantly affect the incorporation of mevalonate or acetate substrates into cholesterol [14,15] or influence the late stages of cholesterol biosynthesis [ 61. Inhibition of lipoprotein formation and/or impaired mucosal transport of cholesterol have been suggested [ 14,151. The decrease in HDL levels was not related to changes in weight or triglyceride levels, but our study does not further elucidate the mechanism of action of probucol. We feel that the observations made in this study are valid even though this was not a placebo-controlled, double-blind study. The participating subjects had demonstrated stable diet responses and weight for a prolonged period of time. This was confirmed by the consistent plasma lipid and lipoprotein levels and weight in the 2 separate diet control periods. The temporal changes in HDL levels and LDL/HDL ratios during probucol administration were very significant. The return of the HDL levels to their pre-treatment values following the cessation of probucol administration indicates a reversible effect. The study was not designed to define the specific time course for termination of the effect of probucol. This study demonstrates that probucol significantly decreased HDL levels and increased the LDL/I-IDL ratio in patients with Type IIb HLP. Further studies are indicated to clarify the effects of probucol on HDL metabolism, both in Type IIb and in other lipoprotein disorders. In the interim, we feel that all patients receiving probucol should be monitored with lipoprotein levels. Since the benefit to risk ratio for pharmacologic intervention on plasma lipids and lipoproteins has not been clearly established, an alternative form of therapy is suggested for patients who have either a significant decrease in HDL levels or an increase in the LDL/HDL ratio. Acknowledgements The authors are indebted to Kay Posthumus for assistance in the preparation of this manuscript, and to I.D. Frantz, Jr., M.D., Ph.D. and Kanta Kuba, M.S. and the staff of the Lipid Research Clinic Core Laboratory for the lipid and lipoprotein analyses. References 1 Heel, R.C., Brogden. R.N., Speight, T.M. and Avery. G.S., Probucol -A review of its pharmacological properties and therapeutic use in patients with hypercholesterolaemia, Drugs, 15 (1978) 409. 2 Taylor. H.L.. Nolan. R.B., Tedeschi. R’.E. and Mauratk;, C.J.. Combined results of the study of probucol at 1 g/day in eight centers, Clin. Pharmacol. Ther.. 23 (1978) 131.
474 F.. Boyle, E. and Aparicio, A., Long-term hypocholesteremic drug therapy with probucol (DH-581) in human subjects, Clfn. Pharmacol. Ther.. 17 (1975) 230. Harris, R.S.. Gihnore. H.R., Bricker. L.A., Kiem, I.M. and Rubin. E., Long-term administration of probucol [4-4’-(isopropylidenedithio) bis (2.6-d&t-butyphenol)] (DH-581) in the management of hypercholesterolaemia. J. Amer. Geriat. Sot., 22 (1974) 167. Miettinen, T.A., Treatment of hyperhpoproteinemias with neomycin, probucol and tibric acid, Adv. Exp. Med. Biol.. 82 (1977) 483. LeLorier. J.. DuBreuil-Quidoz. S.. Lussier-Cacan, S., Huang, Y.S.. and Davignon, J.. Diet and probucol in lowering cholesterol concentration, Arch. Int. Med., 137 (1977) 1429. Anderson, J.L. and Schroeder, J.S.. Effects of probucol on hyperhpidemic patients with cardiac aBografts, J. Csrdiovasc. Pharmacol., 1 (1979) 353. Lipid Research Clinics Program, Manual of Laboratory Operations, Vol. 1 (Lipid and Lipoprotein Analyses) (DHEW Publication No (NIH) 75-628). NHLBI, NIH. Bethesda, MD 20014. Hunninghake, D.B.. Drug treatment of Type II hyperhpoproteinemia - Effect on blood lipids and lipoproteins, Atherosclerosis, V, Springer-Verlag, Berlin, 1980, In press. Bsrnhart. J.W., Johnson, J.D.. Rytter, D.J. and Failey. R.B., The effect of probucol (DH-581) on cholesterol metabolism. Adv. Exp. Med. Biol.. 26 (1972) 275. Gordon, T., CasteRi. W.P., Hjortland, M.C.. Kannel. W.B. and Dawber, T.R.. High density lipoprotein as a protective factor against coronary heart disease - The Framingham Study, Amer. J. Med., 62 (1977) 707. Rhoads, G.G.. Gulbrandsen. C.L. and Kagan. A., Serum lipoproteins and coronary heart disease in a population study of Hawaii Japanese men, New EngI. J. Med.. 294 (1976) 293. Gotto. A.M. and Jackson, R.L.. Plasma Iipoproteins - Recent developments, Adv. Exp. Med. Biol., 82 (1977) 15. Miettinen. T.A.. Mode of action of a new hypocholesteremic drug (DH-581) in familial hypercholesterolemia, Atherosclerosis, 15 (1972) 163. Barnhart. J.W., Rytter. D.W. and MoleIIo. J.A.. An overview of the biochemical pharmacology of probucol, Lipids, 12 (1977) 29.
3 Canosa,
4
5 6 7 8 9 10 11
12 13 14 15
Atherosclerosis, 37 (1980) 469-474 0 Elsevier/North-Holland Scientific
Publishers,
Ltd.
EFFECT OF PROBUCOL ON PLASMA LIPIDS AND LIPOPROTEINS TYPE IIb HYPERLIPOPROTEINEMIA
DONALD
B. HUNNINGHAKE,
CATHERINE
Departments of Pharmacology 55455 (U.S.A.)
and Medicine,
(Received 3 March, 1980) (Revised, received 28 April, (Accepted 29 April, 1980)
BELL and
LINDA
IN
OLSON
University of Minnesota, Minneapolis, MN
1980)
Summary Probucol was administered for 4 months in 20 adult males with Type IIb HLP in a total daily dose of 1.0 g per day. All patients had achieved a stable weight and diet response prior to entering the study. Plasma lipid and lipoprotein determinations were done at monthly intervals. Probucol produced mean reductions in TPC of -38.8 mg/dl (P < O.OOOl), in LDL of -26.7 mg/dl (P < 0.001) and HDL of -8.1 mg/dl (P < 0.0001) for the entire treatment period. The mean LDL/HDL ratio increased from 5.43 to 6.08 (P < 0.02). There was no significant change in TG levels. During the study a progressive decrease in mean HDL levels from 38.9 to 29.2 mg/dl was noted. A progressive increase in the LDL/HDL ratio from 5.43 to 6.35 was also observed. These findings suggest that probucol should be used cautiously in patients with Type IIb HLP, because an inverse relationship between HDL levels and IHD incidence has been demonstrated in epidemiologic studies. Key words:
Plasma lipids - Plasma lipoproteins hyperlipoproteinemia
- Probucol
-
Triglycerides
-
Type IIb
Introduction Probucol has been reported to be an effective hypocholesterolemic agent in multiple studies which have recently been summarized [ 1,2] and lowers choThis work was supported in part by NH&B1 Contrac.t No. 1 HV 2-2195-L. Correspondence and reprint requests to: Donald B. Hunninghake. M.D., University of Minnesota, Department of Pharmacology, i-260 Millard Hall. 435 Delaware Street S.E., Minneapolis, MN 55455, U.S.A. Abbreviations: HDL, high density lipoproteins; HLP. hyperlipoproteinemia; IHD, ischemic heart disease; LDL, low density lipoproiein; TG. triglycerides; TPC. total plasma cholesterol.
470
lesterol in a variety of lipoprotein abnormalities [ 3-51. The above studies have primarily focused on the effect of probucol on serum lipids. Two studies have evaluated the effects on lipoprotein levels. In a placebo-controlled, doubleblind study, LeLorier et al. reported that its primary effect was a reduction in LDL, but noted some decrease in HDL in patients with either Type IIa or IIb HLP (6). Anderson and Schroeder, in a small number of cardiac transplant recipients with Type IIa or IIb HLP, noted a reduction in both HDL and LDL, but the LDL/HDL ratios were unchanged following probucol administration. The above observations led us to evaluate the effect of probucol on lipoprotein levels in patients with Type IIb HLP, which is characterized by lower HDL levels than Type IIa HLP, utilizing the methods for lipoprotein determinations developed by the Lipid Research Clinics Program [ 81. We have previously reported that the response to hypolipidemic agents in Type IIb may be significantly different from that observed in Type IIa patients [9]. The prolonged plasma half-life of probucol also suggested that serial changes in lipoprotein levels should be evaluated [lo]. Subjects and Methods Twenty adult males ranging in age from 35 to 62 years (mean age 52.8 + 1.3) were selected for study from our Lipid Clinic on the basis of lipid and lipoprotein levels. Familial history of HLP was not a requirement. Informed consent was obtained after the nature of the study had been explained. Only subjects who had demonstrated good adherence to diet and had maintained a stable weight for 18 months were selected. Prior to diet, all subjects had LDL levels >190 mg/dl and TG >200 mg/dl. The criteria for entry into this study was LDL >175 mg/dl and TG >200 mg/dl while on diet. Minimal dietary requirements included a cholesterol intake of <350 mg/day and a P/S ratio approximating 0.8. Stable weight and caloric restrictions had been achieved prior to obtaining the baseline dietary lipid and lipoprotein levels. Two dietary control periods were available. The first represented the mean of 3 determinations of plasma lipid and lipoprotein levels prior to entering a l-year drug study which has previously been reported [9]. The second represents the mean of 2 determinations performed at monthly intervals after the patients had been off all lipid-lowering drugs for at least 6 weeks. The mean values for the 2 control periods were very similar. Patients with a history of more than 10 alcoholic drinks per week or taking medications known to alter plasma lipids were excluded. Plasma lipid determinations were done utilizing an Autoanalyzer II (Technicon) and methods developed by the Lipid Research Clinics Program, and lipoprotein cholesterol determinations were done utilizing a combination of heparin-manganese precipitation and ultracentrifugation [ 81. No patient in this study had a VLDL cholesterol/triglyceride ratio 20.25, effectively excluding patients with Type III HLP. Probucol was administered in a total daily dose of 1.0 g in 2 divided doses for 4 months. Plasma lipid and lipoprotein levels were determined at monthly intervals. Adherence was measured by pill count. Weight and diet adherence were recorded at each visit. Routine hematologies, urine and biochemical screening procedures were
471
performed at the onset and termination was used for statistical comparisons.
of probucol
therapy.
The paired t-test
Results The means of all the plasma lipid and lipoprotein determinations during the probucol treatment period were compared to the means of all the determinations during the 2 diet control periods in Table 1. Following probucol administration, mean reductions in TPC of -13.0% (P < O.OOOl), in LDL of -12.6% (P < 0.001) and in HDL of -20.8% (P< 0.0001) were noted. The mean LDL/HDL ratio was increased +12.0% during probucol therapy (P < 0.02). No significant change in TG levels or weight was noted. Mean adherence for the entire probucol treatment period was 95.1%. Nineteen patients demonstrated decreases in HDL following probucol administration, while one patient showed no change. Patients with higher HDL levels during the control periods, tended to have greater absolute reductions in HDL. The per cent reduction in HDL was fairly consistent for all patients, however. Fourteen had reductions ranging from 15 to 28%, 2 greater than 30%, and 3 less than 15%. The mean LDL/HDL ratio during the entire probucol treatment period was increased in 15, unchanged in 2 and decreased in 3 patients. The means of the individual 4-monthly treatment periods are illustrated in Table 2. There were no significant differences between any of the 4-monthly values for TPC and LDL, although TPC and LDL levels tended to be slightly lower at month 4. There was considerable fluctuation in TG levels during probucol therapy, but no consistent changes were noted. TG levels tended to increase over time, but these changes were not statistically significant. The maximum reduction in HDL levels and increases in LDL/HDL ratios generally occurred within 3 months from the onset of probucol administration. The first 18 patients completing this study had 2 repeat HDL determinations after probucol therapy had been discontinued for at least 10 weeks. They were TABLE I MEAN PLASMA LIPID, LIPOPROTEIN PROBUCOL TREATMENT PERIODS
LEVELS AND LDL/HDL
RATIOS FOR DIET CONTROL
AND
TPC
TG
LDL
HDL
(meldI)
@x%/dl)
(mg/dI)
LDLjHDL ratio
Weight
(mgldl)
291.4 f 2.6 = 299.7 f 3.1 298.3 f 2.5
270.1 278.6 273.4
f 9.2 k 16.3 f 8.4
204.4 202.6 203.7
zt 3.1 * 2.7 f 2.2
38.4 f 1.1 3.9.6 f 1.4 38.9 * 0.9
6.36 f 0.22 6.52 f 0.19 5.43 * 0.15
82.1 83.0 82.5
259.5
216.3
* 13.2
177.0
* 2.6
30.8 * 0.9
6.08 * 0.17
63.3
(kg)
Diet control periods First Second Mean of the two Probucol Mean of 4 visits A from mean diet control
f 2.4
(mrldl) % Change from
-38.8
diet P-value
-13.0 <0.0001
a SEM.
+1.9
-26.7
+0.7
-12.6
ILS.
-8.1 -20.8 <0.0001
+0.66 +12.0 <0.02
TABLE 2 SERIAL
CHANGES
IN PLASMA
LIPID, LIPOPROTEIN
LEVELS
AND
RATIOS
WITH PROBUCOL
TREATMENT TG
TPC Month Month Month Month
1 2 3 4
259.1 261.8 261.4 255.7
* * * f
4.5 4.6 4.5 4.4
268.2 270.7 277.7 284.5
LDL f f f f
25.2 26.8 25.6 30.4
175.8 181.4 177.2 173.5
LDL/HDL
HDL f * * f
5.3 5.9 5.6 6.2
33.8 31.1 29.5 29.2
f * f *
1.7 1.4 1.0 0.9
5.48 6.17 6.33 6.35
f f f f
0.30 0.33 0.34 0.37
P-values Months
HDL LDL/HDL
1 “S 2
1 vs 3
1 “S 4
2 vs,3
<0.05 <0.05
ll.S.
n.s.
n.s.
ILS.
3 “8 4
not receiving any hypolipidemic drugs. The mean of 2 HDL determinations for each patient immediately before probucol therapy, months 3 and 4 of probucol therapy, and after discontinuing probucol therapy were 38.7, 28.5 and 37.4 mg/dl, respectively. The post-treatment levels are not significantly different from the pre-treatment values. Discussion The results in this study indicate that probucol decreases both HDL and LDL levels in patients with Type IIb HLP, but the decrease in HDL is relatively greater than the reduction in LDL. The 15% decrease in TPC with no significant change in TG levels is consistent with previous observations [l-7]. The reductions in LDL and HDL levels in this study are consistent with the observations of LeLorier et al. [6] and Anderson and Schroeder [ 71 who studied patients with either Type IIa or IIb HLP. This study also demonstrated that the LDL/HDL ratio was significantly increased following probucol administration. The above 2 studies either did not report their ratios [6] or had quantitative determinations in only 5 patients [ 71. The serial determinations of lipoprotein levels indicated that the maximum mean reduction in HDL and increase in LDL/HDL ratio had occurred within 3 month8 of initiating probucol therapy. However, some patients appeared to still have continuing decreases in HDL at the 4th month of therapy. There is considerable interest in the predictive value of lipoprotein levels for future risk of IHD. This risk appears to be inversely related to HDL levels and positively correlated with LDL levels [ 11,121. After age 50, HDL levels appear to be the most important lipid determinant of risk [ll]. Some emphasis has also been placed on plasma lipid and/or LDL/HDL ratios as enhancing the predictability for future risk of IHD [ll]. HDL2/HDL3 and/or Apo A-I/APO A-II levels may more accurately reflect overall HDL metabolism [ 131. These latter determinations were not performed, but should be incorporated into future studies.
473
Considerable controversy still exists regarding the therapeutic benefit of pharmacologic alteration of plasma lipid and lipoprotein levels in terms of reducing morbidity and mortality from IHD. However, we feel that our findings indicate that it is essential to monitor lipoprotein levels in all patients receiving probucol therapy. It would be difficult to ignore the observation of a significant decrease in HDL or an increase in LDL/HDL ratio. Nineteen of 20 patients in this study demonstrated a decrease in HDL following probucol administration. Studies on the effect of probucol on HDL metabolism in other lipoprotein disorders, especially in Type IIa HLP, are clearly indicated. The mechanism of the hypocholesteremic effect of probucol has not been established. It does not significantly affect the incorporation of mevalonate or acetate substrates into cholesterol [14,15] or influence the late stages of cholesterol biosynthesis [ 61. Inhibition of lipoprotein formation and/or impaired mucosal transport of cholesterol have been suggested [ 14,151. The decrease in HDL levels was not related to changes in weight or triglyceride levels, but our study does not further elucidate the mechanism of action of probucol. We feel that the observations made in this study are valid even though this was not a placebo-controlled, double-blind study. The participating subjects had demonstrated stable diet responses and weight for a prolonged period of time. This was confirmed by the consistent plasma lipid and lipoprotein levels and weight in the 2 separate diet control periods. The temporal changes in HDL levels and LDL/HDL ratios during probucol administration were very significant. The return of the HDL levels to their pre-treatment values following the cessation of probucol administration indicates a reversible effect. The study was not designed to define the specific time course for termination of the effect of probucol. This study demonstrates that probucol significantly decreased HDL levels and increased the LDL/I-IDL ratio in patients with Type IIb HLP. Further studies are indicated to clarify the effects of probucol on HDL metabolism, both in Type IIb and in other lipoprotein disorders. In the interim, we feel that all patients receiving probucol should be monitored with lipoprotein levels. Since the benefit to risk ratio for pharmacologic intervention on plasma lipids and lipoproteins has not been clearly established, an alternative form of therapy is suggested for patients who have either a significant decrease in HDL levels or an increase in the LDL/HDL ratio. Acknowledgements The authors are indebted to Kay Posthumus for assistance in the preparation of this manuscript, and to I.D. Frantz, Jr., M.D., Ph.D. and Kanta Kuba, M.S. and the staff of the Lipid Research Clinic Core Laboratory for the lipid and lipoprotein analyses. References 1 Heel, R.C., Brogden. R.N., Speight, T.M. and Avery. G.S., Probucol -A review of its pharmacological properties and therapeutic use in patients with hypercholesterolaemia, Drugs, 15 (1978) 409. 2 Taylor. H.L.. Nolan. R.B., Tedeschi. R’.E. and Mauratk;, C.J.. Combined results of the study of probucol at 1 g/day in eight centers, Clin. Pharmacol. Ther.. 23 (1978) 131.
474 F.. Boyle, E. and Aparicio, A., Long-term hypocholesteremic drug therapy with probucol (DH-581) in human subjects, Clfn. Pharmacol. Ther.. 17 (1975) 230. Harris, R.S.. Gihnore. H.R., Bricker. L.A., Kiem, I.M. and Rubin. E., Long-term administration of probucol [4-4’-(isopropylidenedithio) bis (2.6-d&t-butyphenol)] (DH-581) in the management of hypercholesterolaemia. J. Amer. Geriat. Sot., 22 (1974) 167. Miettinen, T.A., Treatment of hyperhpoproteinemias with neomycin, probucol and tibric acid, Adv. Exp. Med. Biol.. 82 (1977) 483. LeLorier. J.. DuBreuil-Quidoz. S.. Lussier-Cacan, S., Huang, Y.S.. and Davignon, J.. Diet and probucol in lowering cholesterol concentration, Arch. Int. Med., 137 (1977) 1429. Anderson, J.L. and Schroeder, J.S.. Effects of probucol on hyperhpidemic patients with cardiac aBografts, J. Csrdiovasc. Pharmacol., 1 (1979) 353. Lipid Research Clinics Program, Manual of Laboratory Operations, Vol. 1 (Lipid and Lipoprotein Analyses) (DHEW Publication No (NIH) 75-628). NHLBI, NIH. Bethesda, MD 20014. Hunninghake, D.B.. Drug treatment of Type II hyperhpoproteinemia - Effect on blood lipids and lipoproteins, Atherosclerosis, V, Springer-Verlag, Berlin, 1980, In press. Bsrnhart. J.W., Johnson, J.D.. Rytter, D.J. and Failey. R.B., The effect of probucol (DH-581) on cholesterol metabolism. Adv. Exp. Med. Biol.. 26 (1972) 275. Gordon, T., CasteRi. W.P., Hjortland, M.C.. Kannel. W.B. and Dawber, T.R.. High density lipoprotein as a protective factor against coronary heart disease - The Framingham Study, Amer. J. Med., 62 (1977) 707. Rhoads, G.G.. Gulbrandsen. C.L. and Kagan. A., Serum lipoproteins and coronary heart disease in a population study of Hawaii Japanese men, New EngI. J. Med.. 294 (1976) 293. Gotto. A.M. and Jackson, R.L.. Plasma Iipoproteins - Recent developments, Adv. Exp. Med. Biol., 82 (1977) 15. Miettinen. T.A.. Mode of action of a new hypocholesteremic drug (DH-581) in familial hypercholesterolemia, Atherosclerosis, 15 (1972) 163. Barnhart. J.W., Rytter. D.W. and MoleIIo. J.A.. An overview of the biochemical pharmacology of probucol, Lipids, 12 (1977) 29.
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