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Effects of cerivastatin in dyslipemia and other cardiovascular risk factors after renal transplantation
Effects of Cerivastatin in Dyslipemia and Other Cardiovascular Risk Factors After Renal Transplantation I. Garcia, P. Errasti, F.J. Lavilla, B. Ballester, J. Manrique, E. Rossich, and A. Purroy
H
YPERLIPIDEMIA is a frequent complication observed in kidney transplant recipients (KTR). Its role as a major factor for the development of atherosclerosis and heart disease is well known.1 In spite of new immunosuppressive drugs and better management of infectious diseases, the incidence of death attributable to cardiovascular disease in KTR is higher than in the general population. Risk factors for the development of vascular disease in KTR include diabetes, hypertension, hyperlipidemia, smoking, hyperfibrinogenemia, hyperhomocysteinemia, and immunosuppressive drugs. Hyperlipidemia also plays an important role in the development of chronic graft dysfunction, the leading cause of late graft loss. The HMG-CoA reductase inhibitors (statins) are the most powerful drugs for lowering cholesterol in KTR.2– 4 The aim of this study was to evaluate the effects of a new statin, cerivastatin (CV; Lipobay, Bayer) on dyslipemia and other vascular risk factors in KTR.
PATIENTS AND METHODS Our study included 45 patients (26 men and 19 women) immunosuppressed with cyclosporine (CyA), azathioprine and prednisone (n ⫽ 29), tacrolimus (n ⫽ 5), and CyA ⫹ mycophenolate mofetil (n ⫽ 11), with stable renal function and a mean creatinine of 1.5 mg/dL (SD 0.54). They had persistent dyslipemia with total cholesterol (TC) ⬎250 mg/dL and low-density lipoprotein (LDL) ⬎150 mg/dL. All patients were previously on a low-cholesterol diet, and those taking other lipid-lowering agents stopped intake at least 1 month before starting CV at a initial dose of 0.2 mg/d, which was
increased to 0.4 mg/d if TC was ⬎240 mg/dL and LDL was ⬎140 mg/dL. Additional risk factors were hypertension (n ⫽ 30), smoking history (n ⫽ 14), diabetes mellitus before (n ⫽ 7) and after (n ⫽ 9) transplantation, and obesity (n ⫽ 10). We measured TC, HDL- and LDL-cholesterol, triglycerides (TG), apolipoprotein A (apoA), apolipoprotein B (apoB), lipoprotein(a) [Lp(a)], homocysteine, fibrinogen, c-reactive protein, microalbuminuria, creatinine, uric acid, liver enzymes (ALT, AST) and CPK, before starting CV and after 1, 3, 6, 12, and 24 months of treatment. Statistical analysis was made by analysis of variance and Student’s t test.
RESULTS
Results are show in Table 1. The use of CV was associated with a significant decrease in TC (21% at 1 month, 27.3% at 12 months, and 25.5% at 24 months). The largest reductions were seen for LDL-cholesterol (34.2%, 34%, and 43% at 1, 12, and 24 months). Reductions in TG levels were significant during the 12-month follow-up (24 additional patients still did not reach the 24-month follow-up control). A significant increase in HDL-cholesterol was observed only at 12 months. Serum level of fibrinogen and homocysteine remained unchanged during the entire follow-up period. Serum creatinine, liver enzymes, CyA blood levels, and From the Renal Unit, University Clinic, University of Navarra, Pamplona (Navarra), Spain. Address reprint requests to Dr P. Errasti, Renal Unit, University Clinic, University of Navarra, Apartado 4209, 31080 Pamplona (Navarra), Spain. E-mail: [email protected].
Table 1. Serum Lipid Levels Before and 1, 3, 6, 12, and 24 Months After Treatment With Cerivastatin
Total cholesterol HDL LDL Triglycerides Lipoprotein (a) ApolipoproteinA ApolipoproteinB Fibrinogen Homocysteine
Basal (n ⫽ 45)
1 Month (n ⫽ 44)
3 Months (n ⫽ 44)
6 Months (n ⫽ 43)
275 ⫾ 33.5 53.3 ⫾ 17 196 ⫾ 29.6 131.8 ⫾ 63 30.5 ⫾ 37 173 ⫾ 36.6 135.3 ⫾ 31.2 323 ⫾ 59.4 14.2 ⫾ 5.3
215.6 ⫾ 38† 51.8 ⫾ 13.5 129 ⫾ 30.5† 115 ⫾ 51.8† 35 ⫾ 38.3 162 ⫾ 36.7 101 ⫾ 22.6† 340.6 ⫾ 58.9 13.9 ⫾ 7.5
208 ⫾ 36.7† 55.7 ⫾ 15.3 129 ⫾ 30.5† 115.2 ⫾ 52† 40 ⫾ 38.7† 166.2 ⫾ 36.5 96.7 ⫾ 23.3† 344.7 ⫾ 23.3 13 ⫾ 5.8
207.3 ⫾ 31† 54.7 ⫾ 16.5 131.2 ⫾ 26.3† 110 ⫾ 43.3† 33.7 ⫾ 28.7† 175.6 ⫾ 38.7 93.7 ⫾ 23.6† 322.8 ⫾ 57 13.6 ⫾ 4.6
12 Months (n ⫽ 41)
199.9 ⫾ 38† 56.9 ⫾ 15.1* 115.7 ⫾ 36† 120.4 ⫾ 55† 28.7 ⫾ 31.8 171.2 ⫾ 50.5 99.7 ⫾ 29.7† 321 ⫾ 69.7 13.2 ⫾ 4.5
24 Months (n ⫽ 21)
205 ⫾ 21.7† 60.5 ⫾ 21.8† 112.8 ⫾ 31† 132.6 ⫾ 65 25.7 ⫾ 17* 145 ⫾ 30 90.7 ⫾ 11.5† 279.7 ⫾ 134.2 15 ⫾ 5
Values expressed as mean ⫾ SD (milligram per deciliter), except homocysteine (which is in microliters per liter). *P ⬍ .05, †P ⬍ .01 versus basal value.
© 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 401–402 (2002)
0041-1345/02/$–see front matter PII S0041-1345(01)02817-2 401
GARCI´A, ERRASTI, LAVILLA ET AL
402
CPK did not change throughout the study period (data not shown). None of the patients reported any significant symptoms or adverse effects attributable to CV treatment. DISCUSSION
This study demonstrates that CV, at the starting dose of 0.2 mg/d, is efficient for lowering TC, LDL-cholesterol apoB, and TG levels in hyperlipidemic KTR. The effect on TC and LDL-cholesterol was obtained at 1 month of initial therapy, and persisted throughout the follow-up period. Cerivastatin was well tolerated and no significant adverse effects were detected in analytic parameters. Statins, by controlling hyperlipidemia and other injury pathways, such
as inhibition of chemotaxis of monocytes, decreasing natural killer cell cytotoxicity, and improving endothelial function, may protect allograft function and decrease mortality, but this remains to be proven in long-term studies.
REFERENCES 1. Aker S, Ivens K, Guo Z, et al: Transplant Proc 30:2039, 1998 2. Wheeler DC: Curr Op in Nephrol Hypertens 7:599, 1998 3. Alvarez ML, Errasti P, Gomez G, et al: Transplant Proc 31:2328, 1999 4. Gomez G, Alvarez ML, Errasti P, et al: Transplant Proc 31:2326, 1999
H
YPERLIPIDEMIA is a frequent complication observed in kidney transplant recipients (KTR). Its role as a major factor for the development of atherosclerosis and heart disease is well known.1 In spite of new immunosuppressive drugs and better management of infectious diseases, the incidence of death attributable to cardiovascular disease in KTR is higher than in the general population. Risk factors for the development of vascular disease in KTR include diabetes, hypertension, hyperlipidemia, smoking, hyperfibrinogenemia, hyperhomocysteinemia, and immunosuppressive drugs. Hyperlipidemia also plays an important role in the development of chronic graft dysfunction, the leading cause of late graft loss. The HMG-CoA reductase inhibitors (statins) are the most powerful drugs for lowering cholesterol in KTR.2– 4 The aim of this study was to evaluate the effects of a new statin, cerivastatin (CV; Lipobay, Bayer) on dyslipemia and other vascular risk factors in KTR.
PATIENTS AND METHODS Our study included 45 patients (26 men and 19 women) immunosuppressed with cyclosporine (CyA), azathioprine and prednisone (n ⫽ 29), tacrolimus (n ⫽ 5), and CyA ⫹ mycophenolate mofetil (n ⫽ 11), with stable renal function and a mean creatinine of 1.5 mg/dL (SD 0.54). They had persistent dyslipemia with total cholesterol (TC) ⬎250 mg/dL and low-density lipoprotein (LDL) ⬎150 mg/dL. All patients were previously on a low-cholesterol diet, and those taking other lipid-lowering agents stopped intake at least 1 month before starting CV at a initial dose of 0.2 mg/d, which was
increased to 0.4 mg/d if TC was ⬎240 mg/dL and LDL was ⬎140 mg/dL. Additional risk factors were hypertension (n ⫽ 30), smoking history (n ⫽ 14), diabetes mellitus before (n ⫽ 7) and after (n ⫽ 9) transplantation, and obesity (n ⫽ 10). We measured TC, HDL- and LDL-cholesterol, triglycerides (TG), apolipoprotein A (apoA), apolipoprotein B (apoB), lipoprotein(a) [Lp(a)], homocysteine, fibrinogen, c-reactive protein, microalbuminuria, creatinine, uric acid, liver enzymes (ALT, AST) and CPK, before starting CV and after 1, 3, 6, 12, and 24 months of treatment. Statistical analysis was made by analysis of variance and Student’s t test.
RESULTS
Results are show in Table 1. The use of CV was associated with a significant decrease in TC (21% at 1 month, 27.3% at 12 months, and 25.5% at 24 months). The largest reductions were seen for LDL-cholesterol (34.2%, 34%, and 43% at 1, 12, and 24 months). Reductions in TG levels were significant during the 12-month follow-up (24 additional patients still did not reach the 24-month follow-up control). A significant increase in HDL-cholesterol was observed only at 12 months. Serum level of fibrinogen and homocysteine remained unchanged during the entire follow-up period. Serum creatinine, liver enzymes, CyA blood levels, and From the Renal Unit, University Clinic, University of Navarra, Pamplona (Navarra), Spain. Address reprint requests to Dr P. Errasti, Renal Unit, University Clinic, University of Navarra, Apartado 4209, 31080 Pamplona (Navarra), Spain. E-mail: [email protected].
Table 1. Serum Lipid Levels Before and 1, 3, 6, 12, and 24 Months After Treatment With Cerivastatin
Total cholesterol HDL LDL Triglycerides Lipoprotein (a) ApolipoproteinA ApolipoproteinB Fibrinogen Homocysteine
Basal (n ⫽ 45)
1 Month (n ⫽ 44)
3 Months (n ⫽ 44)
6 Months (n ⫽ 43)
275 ⫾ 33.5 53.3 ⫾ 17 196 ⫾ 29.6 131.8 ⫾ 63 30.5 ⫾ 37 173 ⫾ 36.6 135.3 ⫾ 31.2 323 ⫾ 59.4 14.2 ⫾ 5.3
215.6 ⫾ 38† 51.8 ⫾ 13.5 129 ⫾ 30.5† 115 ⫾ 51.8† 35 ⫾ 38.3 162 ⫾ 36.7 101 ⫾ 22.6† 340.6 ⫾ 58.9 13.9 ⫾ 7.5
208 ⫾ 36.7† 55.7 ⫾ 15.3 129 ⫾ 30.5† 115.2 ⫾ 52† 40 ⫾ 38.7† 166.2 ⫾ 36.5 96.7 ⫾ 23.3† 344.7 ⫾ 23.3 13 ⫾ 5.8
207.3 ⫾ 31† 54.7 ⫾ 16.5 131.2 ⫾ 26.3† 110 ⫾ 43.3† 33.7 ⫾ 28.7† 175.6 ⫾ 38.7 93.7 ⫾ 23.6† 322.8 ⫾ 57 13.6 ⫾ 4.6
12 Months (n ⫽ 41)
199.9 ⫾ 38† 56.9 ⫾ 15.1* 115.7 ⫾ 36† 120.4 ⫾ 55† 28.7 ⫾ 31.8 171.2 ⫾ 50.5 99.7 ⫾ 29.7† 321 ⫾ 69.7 13.2 ⫾ 4.5
24 Months (n ⫽ 21)
205 ⫾ 21.7† 60.5 ⫾ 21.8† 112.8 ⫾ 31† 132.6 ⫾ 65 25.7 ⫾ 17* 145 ⫾ 30 90.7 ⫾ 11.5† 279.7 ⫾ 134.2 15 ⫾ 5
Values expressed as mean ⫾ SD (milligram per deciliter), except homocysteine (which is in microliters per liter). *P ⬍ .05, †P ⬍ .01 versus basal value.
© 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 401–402 (2002)
0041-1345/02/$–see front matter PII S0041-1345(01)02817-2 401
GARCI´A, ERRASTI, LAVILLA ET AL
402
CPK did not change throughout the study period (data not shown). None of the patients reported any significant symptoms or adverse effects attributable to CV treatment. DISCUSSION
This study demonstrates that CV, at the starting dose of 0.2 mg/d, is efficient for lowering TC, LDL-cholesterol apoB, and TG levels in hyperlipidemic KTR. The effect on TC and LDL-cholesterol was obtained at 1 month of initial therapy, and persisted throughout the follow-up period. Cerivastatin was well tolerated and no significant adverse effects were detected in analytic parameters. Statins, by controlling hyperlipidemia and other injury pathways, such
as inhibition of chemotaxis of monocytes, decreasing natural killer cell cytotoxicity, and improving endothelial function, may protect allograft function and decrease mortality, but this remains to be proven in long-term studies.
REFERENCES 1. Aker S, Ivens K, Guo Z, et al: Transplant Proc 30:2039, 1998 2. Wheeler DC: Curr Op in Nephrol Hypertens 7:599, 1998 3. Alvarez ML, Errasti P, Gomez G, et al: Transplant Proc 31:2328, 1999 4. Gomez G, Alvarez ML, Errasti P, et al: Transplant Proc 31:2326, 1999