Treatment of Hyperlipidemia in the Nephrotic Syndrome: The Effects of Pravastatin Therapy

Treatment of Hyperlipidemia in the Nephrotic Syndrome: The Effects of Pravastatin Therapy Samuel Spitalewitz, MD, Jerome G. Porush, MD, Daniel Cattran, MD, and Noel Wright, MD • The hyperlipidemia of the nephrotic syndrome is characterized by an elevation of total cholesterol (TC) and lowdensity lipoprotein cholesterol (LDLC), with a nonnal or low high-density lipoprotein cholesterol (HDLC), and an increase in triglycerides (TGs) later in the course of the disease. If sustained, this lipid profile probably places these patients at increased risk for cardiovascular disease. Despite extensive trials of diet and drug therapy in patients with primary hyperlipidemias, few such trials exist in patients with the nephrotic syndrome. We conducted a randomized, prospective, double-blind, placebo-controlled trial to investigate the efficacy and safety of pravastatin, the newest cholesterol synthesis inhibitor, in the treatment of the hyperlipidemia of the nephrotic syndrome. After dietary modification was implemented, 13 patients received pravastatin and eight received placebo. All patients were maintained on a low-fat, low-cholesterol diet for the duration of the trial (24 weeks). The dose of pravastatin was increased from the initial 20 mg/d to 40 mg/d at week 10 or 18 if TC remained elevated (>50th percentile). A bile acid sequestrant was added at week 18 if TC remained elevated and if the patient was already receiving the maximal pravastatin dosage. Dietary modification did not significantly change the lipid profile. Pravastatin (20 mg/d) reduced TC by 22% from a baseline of 301 ± 28 mg/dL (P < 0.05) and LDLC by 28% from a baseline of 222 ± 28 mg/dL (P < 0.05). When used at 40 mgt d (in six patients) no further change in the lipid profile was observed. Pravastatin caused no significant changes in the HDLC fraction (baseline, 44 ± 3 mg/dL) or in TGs (baseline, 221 ± 37 mg/dL). There was, however, a trend for HDLC to increase (8%) and TGs to decrease (19%). Although difficult to evaluate because of poor compliance, bile acid sequestrants (used in six patients) effected no change in the lipid profiles in patients of either group. Placebo baseline TC, LDLC, HDLC and TG values were similar to the pravastatin group and remained unchanged throughout the study. No patient was dropped from the study because of adverse events attributed to the study medication. Renal function and protein excretion were unaffected by pravastatin. Six diabetic patients treated with pravastatin and patients (n = 8) with chronic renal insufficiency (serum creatinine >1.5 mg/dL) had a response to pravastatin similar to that of the other patients. Our results are similar to other studies using 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors and demonstrate the efficacy and safety of pravastatin in the treatment of the hyperlipidemia of the nephrotic syndrome. The lipid profile, however, was not totally normalized even with maximal pravastatin therapy, indicating the need for combination drug therapy. Long-term trials are clearly necessary to determine the long-term safety and efficacy of drug therapy in the treatment of the hyperlipidemia of the nephrotic syndrome and to establish whether the probable risk of atherosclerosis can be reversed and progression of renal insufficiency (suggested to occur in part secondary to the hyperlipdemia per se) slowed. © 1993 by the National Kidney Foundation, Inc. INDEX WORDS: Hyperlipidemia; nephrotic syndrome; pravastatin.

T

HE hyperlipidemia of the nephrotic syndrome is characterized by an elevation of total cholesterol (TC) and low density lipoprotein cholesterol (LDLC), with a normal or low highdensity lipoprotein cholesterol (HDLC).1,2 Hypertriglyceridemia may be observed later in the course of the disease. 1 There is little reason to doubt that this lipid profile places patients with prolonged, untreated nephrotic syndrome at higher risk for coronary heart disease, since it clearly does so in the general population. 2. 5 In spite of this increased risk and the potential for reversal with treatment,6-8 there has been a paucity of studies testing the safety and efficacy of both non pharmacologic and pharmacologic methods oflowering lipids in nephrotic patients. 9 Especially lacking are large, long-term studies of nephrotic diabetic patients who are particularly at risk for accelerated generalized atherosclerosis.'o" , Since the introduction of a unique class of cholesterol-lowering drugs, inhibitors of 3-hy-

droxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase (the rate-limiting enzyme in the synthesis of cholesterol), 12,13 and because hyperlipidemia per se may contribute to the progression of chronic renal insufficiency,14-1 6 there has

From the Hypertension and Renal Clinics and the Division of Nephrology and Hypertension, The Brookdale Hospital Medical Center, Brooklyn, NY; the Department of Medicine, SUNY, Health Science Center at Brooklyn, Brooklyn, NY; the Department of Medicine, Division of Nephrology, Toronto General Hospital Toronto, Ontario, Canada; and the Service of Clinical Pharmacology and Toxicology, St Joseph's Hospital, McMaster University, Hamilton, Ontario, Canada. Received November 4, 1992; accepted in revised form January6, 1993. Supported in part by a grant from Bristol-Myers Squibb, Co Inc. Address reprint requests to Samuel Spitalewitz, MD, The Brookdale Hospital Medical Center, Division of Nephrology and Hypertension, Room 169, Linden Blvd at Brookdale Plaza, Brooklyn, NY 11212. © 1993 by the National Kidney Foundation, Inc. 0272-6386/93/2201-0022$3.00/0

American Journal of Kidney Diseases, Vol 22, No 1 (July), 1993: pp 143-150

143

144

SPIT ALEWITZ ET AL

been renewed interest in treating hyperlipidemia in patients with nephrotic syndrome.2,9,17 This report describes our experience with the newest HMG-CoA reductase inhibitor, pravastatin, 18-20 in the treatment of hyperlipidemia of nephrotic syndrome due to a variety of renal diseases and summarizes the previous studies of the nonpharmacologic and pharmacologic therapy of the hyperlipidemia seen in the nephrotic syndrome.

METHODS Patient Population Patients between the ages of 18 and 70 years were included in this study if they had nephrotic syndrome (defined for this study as a urinary protein excretion ~2.0 g/24 hr and a serum albumin of <3.5 g/dL) and the mean of two plasma TC levels (obtained I week apart) above the 75th percentile for the US population by age and gender and higher than 220 mg/dL. 2' Excluded from the study were patients with a serum creatinine ~5.0 mg/dL, poorly controlled diabetes mellitus (fasting glucose >200 mg/dL), taking more than 60 mg of prednisone (or its equivalent) or other immunosuppressive agents, thyroid disease, primary hyperlipidemia, significant liver disease, excessive obesity (>40% above ideal body weight), or excessive ethanol consumption. Patients on thiazide diuretics, beta-adrenergic blockers, and other drugs known to affect blood lipids were included only if the drug and dose had been constant for 8 weeks prior to the study and was expected to be constant throughout the study period. The protocol was approved by the institutional review boards ofthe participating institutions and informed consent was obtained from each patient prior to participation.

Study Design This was a prospective, double-blind, placebo-controlled study with eligible patients randomized 2: I to receive either pravastatin, administered once daily, or placebo. All lipid-lowering drugs were withdrawn at least 6 to 12 weeks prior to study. At that time, patients were placed on a low-fat, low-cholesterol diet containing approximately 30% fat and 300 mg/d or less of cholesterol. At 4 weeks prior to randomization, dietary compliance was established by a nutritionist who reviewed a diary kept by the patient that recorded quantities of all foods ingested. Baseline lipids and 24-hour urinary protein excretion and creatinine clearance were determined and repeated at 2- to 4-week intervals throughout the study. Just prior to randomization a history and physical examination were performed as well as a complete blood cell count, Chem-20 (including creatine phosphokinase, to be repeated at 2- to 4-week intervals) thyroid profile, electrocardiogram, chest x-ray, and an ophthalmologic examination (including a slit lamp). Qualifying patients were then randomized to receive either pravastatin 20 mg (one tablet) or placebo, each given once daily. Patients returned at 2- to 4week intervals for the clinical and laboratory evaluation of the safety and efficacy of therapy. At the 10th week of therapy, a dose change of the study medication was implemented.

If TC at week 8 was higher than the 50th percentile the dose was increased to two tablets per day; if it was between the 25th and 50th percentile there was no dose change; if it was less than the 25th percentile but ~ 130 mg/dL there was no dose change, and ifit was less than the 25th percentile and less than 130 mg/dL the dose was decreased to half a tablet per day. At week 18 the regimen was altered again. If the TC at week 16 was higher than the 50th percentile the dose was increased to two tablets or a bile acid-binding resin (20 to 30 g/d) was added if the patient was already taking two tablets per day; if it was between the 25th and 50th percentile there was no dose change; if it was less than the 25th percentile but more than 130 mg/dL there was no dose change, and if it was less than the 25th percentile and ::0; 130 mg/dL the dose was decreased to half a tablet per day if the patient was taking one tablet. Liprotein a [Lp(a)] was determined in the first six patients (two on placebo, four on pravastatin) at weeks 2, 8, and 24. Glycosolated hemoglobin (HgBA,C) was determined in the 10 diabetic patients seen at The Brookdale Hospital Medical Center at baseline and at weeks 8, 16, and 24. At completion of the trial, a repeat ophthalmologic examination (including slit lamp) was done, as well as a repeat physical examination and electrocardiogram.

Analytical Methods Complete blood cell count and blood and urine chemistries were determined by standard autoanalyzer. Total cholesterol and triglycerides (TGs) were determined using standard enzymatic methods. Plasma lipoprotein fractions were measured using Lipid Research Clinics methodology.22 Lipoprotein (a) was assayed using enzyme-linked immunosorbent assay (Terumo International, Somerset, NJ).

Statistical Analysis The differences observed after treatment in each group were analyzed with the Wilcoxon signed rank test. The nonparametric Iman-Conover test was used to compare the percentage of changes in the placebo and pravastatin groups.

RESULTS Patient characteristics are summarized in Tables 1 and 2. Thirteen patients received pravastatin and eight received placebo. Three patients in the pravastatin group did not complete the protocol. One was dropped after week 2 because of poor compliance, one was lost to follow-up after week 12, and another was dropped after week 12 at her own request. Only one patient in the placebo group was dropped (at her own request) after week 16. No patient had to be dropped because of either a clinical or laboratory adverse effect attributed to medication. Four patients reported four separate instances of adverse events (congestive heart failure [CHF], transient ischemic attack [TIA], rash, chest pain) unrelated to the study medication.

145

HYPERLIPIDEMIA OF THE NEPHROTIC SYNDROME

Table 1. Baseline Patient Characteristics: Placebo Group

Patient No.

Age (yr)/Gender

1. 2. 3. 4. 5. 6. 7. 8.

64JM 64JM 45JF 50JF

57JM 59JM 60JF 55

Creatinine Clearance (mL/min)

3.6 3.1 2.5 1.2 5.3 1.3 1.0 0.7

42JM

± SEM

Mean

Serum Creatinine (mg/dL)

±3

2.3

36 34

18 90 140 122

± 0.6

73

The patients ranged in age from 29 to 69 years with a mean age of 55 ± 3 years in the placebo group and 48 ± 4 years in the pravastatin group. The placebo group was composed of five men and three women; six (75%) were white and two (25%) were black. The pravastatin group comprised seven men and six women; there were six (46%) whites, six (46%) blacks, and one (8%) oriental. There were no renal diagnostic differences between the two treatment groups (Tables 1 and 2). Creatinine clearance was 73 ± 21 mL/min and 62 ± 11 mL/min, the serum creatinine was 2.3 ± 0.6 mg/dL and 1.9 ± 0.2 mg/dL, and the 24-hour protein excretion was 6.5 ± 1.9 g and 5.4 ± 0.6 g in the placebo and pravastatin groups, respectively.

± 21

Protein Excretion (g/24 hr)

Diagnosis

2.4 7.6 17.3 2.6 11.3 3.4 3.6 3.4

Necrotizing vasculitis Focal glomerulosclerosis Diabetic nephropathy Focal glomerulosclerosis Diabetic nephropathy Diabetic nephropathy Diabetic nephropathy Unknown

6.5

± 1.9

Effect of Therapy on Blood Lipids Dietary modification had no significant impact on the lipid profile of either group. Figure 1 shows the effect of pravastatin compared with placebo on TC. Through week 24, TC decreased an average of 22% (P < 0.05) from a baseline of 301 ± 28 mg/dL compared with no significant change in the placebo group (baseline TC, 281 ± 25 mg/ dL). At each time interval, TC was significantly reduced by pravastatin and a significant difference between the two treatment groups was observed (P varied between <0.05 and 0.001). Six of the 13 pravastatin-treated patients required an increase in the dose at 10 weeks to 40 mg/d, which did not reduce TC any further (264 ± 29 mg/dL to 263 ± 37 mg/dL). At week 18, cholestyramine

Table 2. Baseline Patient Characteristics: Pravastatin Group

Patient No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Mean

± SEM

Age (yr)/Gender 61JF

38JM 54JM 30JM 31JM 45JM 64JM 59JF 29JF 39JF 69JF

58JM 51JF 48

±4

Serum Creatinine (mg/dL)

Creatinine Clearance (mL/min)

Protein Excretion (g/24 hr)

Diagnosis

2.1 0.8 0.8 1.9 2.8 2.1 2.9 1.9 1.3 2.6 2.6 1.3 1.4

23 134 53 62

6.4 8.6 4.5 2.7 5.3 2.8 4.6 3.9 3.3 9.6 5.2 5.2 8.6

Diabetic nephropathy Focal glomerulosclerosis Membranoproliferative glomerulonephritis Diabetic nephropathy IgA nephropathy IgA nephropathy Diabetic nephropathy Diabetic nephropathy Focal glomerulosclerosis Focal glomerulosclerosis Diabetic nephropathy Diabetic nephropathy Focal glomerulosclerosis

1.9

± 0.2

26 40 39 67 42 30 96 134 62

± 11

5.4

± 0.6

146

SPITALEWITZ ET AL

15 30 10

20 10

JJ

)

b,d

b.d

o -1 0 - 20 - 30 b.-

b ,_

~

8

0 -5

I

I

- 50

15

12

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b,e

20

16

-10 b.d

I 2_

I

- 15

2

Week

Fig 1. Effects of pravastatin on TC. a, P < 0.05 compared with baseline; b, P < 0.001 compared with baseline; c, P < 0.05 between groups; d, P < 0.001 between groups.•, Control; ~, pravastatin.

or colestipol (20 to 30 g/d) was added to two of the six patients receiving the maximal pravastatin dose and four of the seven remaining patients on placebo. The addition of the resin did not reduce TC in either group and, as noted, the difference in TC between the two groups was maintained. Since compliance to resin was not specifically checked, the significance of these findings is unclear. Figure 2 summarizes the effects of pravastatin compared with placebo on LOLC. Through week 24, there was an average decrease in LOLC of 28% (P < 0.05) from a baseline of 222 ± 28 mg/ dL, while placebo had no significant effect on the baseline LOLC of 208 ± 22 mg/dL. As with TC, the increased dose of pravastatin to 40 mg/d at week 10 did not lower LOLC any further in six patients (179 ± 20 mg/dL to 181 ± 35 mg/dL).

I 8

12 Week

16

20

Fig 3. Effects of pravastatin on HOLC. a, P < 0.05 compared with baseline; b, P < 0.001 between groups. ., Control; ~, pravastatin.

The addition of resin did not lower LOLC in either group. As noted in Fig 3, except for significant increases in HOLC (compared with the baseline of 44 ± 3 mg/dL) in the pravastatin group of7.7% ± 2.9% at week 4 and 9.4% ± 3.4% at week 20, no other significant changes were noted in this lipid fraction. The baseline HOLC of 43 ± 4 mg/ dL in the placebo group remained unchanged. Neither the increased dose of pravastatin nor the addition of resin led to a change in HOLC in either group. Since no consistent change in HOLC was observed while LOLC decreased with pravastatin therapy, the LOLC to HOLC ratio decreased significantly. The effects of pravastatin and placebo on TG are shown in Fig 4. Baseline TG values were 221 ± 37 mg/dL and 182 ± 31 mg/dL in the pravastatin and placebo groups, respectively. A significant difference was noted between the two groups

o

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-5

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- 10

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- 15

20

-20

10 0

-25 -30

-35

•

1 b,d

bod I

I

~

8

b.d

-10 -20

••d

I

I

12

16

••C

I 20

b

b.c

I2~

Week

Fig 2. Effects of pravastatin on LOLC. a, P < 0.05 compared with baseline; b, P < 0.001 compared with baseline; c, P < 0.05 between groups; d, P < 0.001 between groups.•, Control; ~, pravastatin.

- 30

.. c

- ~o

- 50

I 2

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I

I

8

12

1 16

20

2~

Week

Fig 4. Effect of pravastatin on TGs. a, P < 0.05 compared with baseline; b, P < 0.05 between groups; c, P < 0.001 between groups.•, Control; ~, pravastatin.

HYPERLIPIDEMIA OF THE NEPHROTIC SYNDROME

at all weeks except 2 and 16, with the pravastatin group showing an average reduction of 19%. The addition of resin effected no additional change. As noted in Fig 4, there were significant increases in TG in the control group at weeks 4, 8, and 12. There was no change in the Lp(a) in the four pravastatin and two placebo patients measured at weeks 2, 8, and 24. During the 24-week study, serum creatinine, creatinine clearance, and protein excretion did not change significantly in either group, including eight patients in the pravastatin group and four patients in the placebo group with chronic renal insufficiency (serum creatinine, > 1.5 mg/dL). Those patients with renal insufficiency responded to pravastatin similarly to those with normal renal function. When analyzed separately, the response to pravastatin in the six diabetic patients was not different from that of patients with other renal diseases, despite the fact that glucose control, as assessed by fasting blood glucose and HgbA1C, was suboptimal throughout the study (159 ± 12 mg/dL and 8.3% ± 0.3%, respectively). No patient exhibited a significant change in weight, body mass index (kg/m2), or blood pressure during the study. DISCUSSION

Although it is well accepted that an increase in TC and its LDL component places patients with primary hyperlipidemia at increased risk for coronary artery disease, 5 some doubt has been expressed whether this lipid profile, characteristic of the nephrotic syndrome, places nephrotic patients at higher risk. 23 -25 Others, however, stress the high incidence of coronary artery disease in patients with prolonged, unremitting proteinuria and hyperlipidemia and urge that lipid-lowering therapy be included as part of the treatment. 3.4,26.27 Recent data in experimental animals have suggested that hyperlipidemia may contribute to the development and progression of kidney disease by promoting mesangial damage and glomerulosclerosis.1 4-1 6,28 This process may be reversed with normalization oflipids. 29,30 For these reasons, sustained hyperlipidemia of the nephrotic syndrome should be aggressively treated. To date, there has only been one study systematically evaluating dietary modification. D'Amico and Gentile9 demonstrated that a low-fat, vege-

147

tarian diet very rich in polyunsaturated fatty acids (unsaturated to saturated ratio, >2) and fiber lowered TC and LDLC by as much as 28% and 33%, respectively, and prompted a 32% decrease in proteinuria in 24 patients with nephrotic syndrome. These investigators, however, concluded that their findings were the result of short-term dietary manipulation (2 months) that necessitated considerable effort and that prolonged compliance might be difficult. Prior to this study, an overall reduction in TC and LDLC of only 6% has been observed with nonsystematic studies of dietary manipulation. 2,31 The use of bile acid-binding resins recently has been examined by two groups in patients with nephrotic syndrome demonstrating a significant reduction in total cholesterol and in LDLC, with no change in TC or proteinuria in a total of 17 patients studied over 4 to 9 weeks. 32 .33 However, there frequently are significant side effects from resins, including constipation, abdominal bloating, and diarrhea, that make compliance difficult and may explain the lack of response to resins in the present study. Nicotinic acid reduces TC, LDLC, and TG and increases HDLC. 17,34,35 There are no reports available on the use of nicotinic acid in the nephrotic syndrome. It may, however, be a poor choice in these patients (particularly in diabetic patients and in patients with renal insufficiency) since it may worsen hyperglycemia and increase serum uric acid. 2,17 Fibric acids decrease TG and increase HDLC levels, but only minimally inhibit the synthesis of cholesterol. 17,36 Thus, they are of limited usefulness in treating hyperlipidemia in nephrotic patients. Moreover, there is an increase in clofibrate's toxicity in these patients (myopathy), possibly related to an increase in the unbound fraction in serum due to hypoalbuminemia. 37 If used, the dose must be significantly reduced in proportion to the reduction in serum albumin (500 mg of clofibrate per 1.0 g/dL reduction in serum albumin/d). Although gemfibrozil is less toxic than clofibrate it only lowered TC and LDLC minimally in 11 patients studied over 6 weeks. 38 Probucollowers TC, but also lowers HDLC. 39 This latter unfavorable effect may be offset by probucol-induced inhibition of the oxidation of LDLC, an initial step in the pathogenesis of ath-

148

SPITALEWITZ ET AL

erosclerosis?,40,41 Two groups of investigators have used probucol to lower cholesterol in 17 nephrotic patients studied over 12 weeks and demonstrated a significant TC-lowering effect,32,42 Valeri et a1 32 noted a 23% reduction in TC and a 24% decrease is LDLC, with HDLC decreasing 12%, but still leading to a decrease in the LDL to HDL ratio. Iida et a1 42 showed a similar effect of probucol on TC (30% decrease) and LDLC (25% decrease), but with a more marked decrease in HDLC (25%). Neither group reported any side effects. HMG-CoA reductase inhibitors are the newest (and most effective) class oflipid-lowering agents that inhibit cholesterol synthesis and enhance the formation of LDL receptors, promoting hepatic clearance of LDL and VLDL. 2,12,13 Their use in patients with hyperlipidemia and the nephrotic syndrome is summarized in Table 3. Eight studies (including the present study) have been carried out. IO,11,31,33,43-45 In most of these studies approximately 10 to 14 patients were given the drug (open label) for 6 to 12 weeks, with the largest study treating 20 patients for 18 weeks.45 The present study has the longest followup (24 weeks) and is the only one that used a bile-acid resin in combination with an HMGCoA inhibitor. Our data are consistent with the other investigations; namely, TC and LDLC decreased by an average of 22% and 28%, respec-

tively. Although a trend upward was observed, we did not demonstrate a significant change in HDLC. We included a large proportion of diabetic patients and patients with chronic renal insufficiency in whom the response was similar to other patients, Of the 93 nephrotic patients reported in the literature who received an HMGCoA inhibitor, therapy was discontinued in only three because of side effects (two had gastrointestinal distress and one had myalgias).11,31 This class of drug appears to be well tolerated and efficacious in these patients, at least over the short term, It has been proposed that correction of the hyperlipidemia may decrease proteinuria and/or slow the progression of renal failure. 28 ,29 The present study, as well as other studies with HMGCoA reductase inhibitors, did not demonstrate a change in either proteinuria or renal function, possibly because they were relatively short term. No study has yet demonstrated complete normalization of the lipid profile; therefore, combination therapy needs to be more fully investigated. Groggel et a1 38 reported that colestipol added to gemfibrozil further reduced TC from 15% to 41 % and TG from 51 % to 68%. Longterm tolerance for colestipol and other resins has still not been examined in nephrotic patients. Furthermore, Schapel et a146 noted that when cholestyramine and clofibrate were used together

Table 3. Effects of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Inhibitors in Nephrotic Hyperlipidemia

Study

No. of Patients

Drug and Maximum Dose (mg)

Duration (wk)

Vega and Grundy,·3

1988

TC (%)

LDLC (%)

HDLC (%)

TG (%)

3

Lovastatin (40)

6

-31

-33

+43

-34

10

Simvastatin (40)

6

-36

-39

+21

-39

10

Lovastatin (80)

18

-33

-45

+1

-25

13

Lovastatin (40)

6

~27

-27

+8

-30

20

Simvastatin (40)

10

-26

-34

+8

-17

14

Simvastatin (20)

12

-25

-38

+2

-9

10 13

Lovastatin (20) Pravastatin (40)

12 24

-25 -22

-35 -28

+11 +7

-13 -19

12

-27

-35

+9

-21

Rabelink et al,33

1988 Golper et al,"

1989 Kasiske et al,31

1990 Bazzato et al,'s

1991 Hommel et ai,"

1992 Biesenbach and Zazgornik,lO 1992 Present study Mean

HYPERLIPIDEMIA OF THE NEPHROTIC SYNDROME

there was an antagonistic effect, preventing a reduction in TG achieved by either drug alone. Grundy and Vega2 ,17 suggest that other combination therapies be tried in nephrotic patients, including bile acid binding resins added to HMGCoA reductase inhibitors, fibric acids, or nicotinic acid. Probucol can be combined with an HMGCoA inhibitor, particularly if oxidation ofLDLC is a key intermediate step in atherogenesis. The combination of nicotinic acid or a fibric acid with HMG-CoA inhibitor should be avoided because of the risk of severe myopathy. In summary, we and others have demonstrated the short-term efficacy and safety of HMG-CoA reductase inhibitors in the treatment of nephrotic hyperlipidemia. Long-term studies using single and combination drug therapy are needed, however, not only for the demonstration oflong-term reversal of the lipid abnormalities in nephrotic syndrome, but also to examine the effects of these agents on proteinuria and renal function. Furthermore, long-term studies are necessary to determine whether the incidence of coronary artery disease is indeed increased in these patients and can be decreased by lowering their serum lipids.

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