The Kidney and Statin Safety

The Kidney and Statin Safety © 2006 National Lipid Association The Kidney and Statin Safety: Rosuvastatin Development Program • Rosuvastatin development led to heightened attention to renal safety issues • >12,000 study participants were included in premarketing studies, with no age or renal impairment exclusions • Proteinuria of 12-15% was seen only in the high rosuvastatin dose of 80 mg, isolated cases of renal failure were described • The highest approved dose of rosuvastatin is 40 mg Package Insert © 2006 National Lipid Association Statins and Proteinuria: Limited Evidence • Clinical trials relied on screening with dipstick and potentially missed mild proteinuria • In case study linking simvastatin with proteinuria (baseline information was not known)1 • Cardiovascular disease endpoint trials, Heart Protection Study (HPS) and PROSPER, showed no association between statin use and proteinuria (unclear how often proteinuria was measured) 2 • NDA data show no convincing association between proteinuria and approved statins at marketed dose – *80mg rosuvastatin associated with 12-15% proteinuria3 1 2 3 Deslypere JP et al. Lancet. 1990;336:1453 Cheung BM et al. Br J Clin Pharmacol. 2004;57:640-651 Jacobson TA. Am J Cardiol. 2006;97:44C-51C © 2006 National Lipid Association Statins and Proteinuria: Physiologic Response? • Albumin absorption in proximal tubule is facilitated by isoprenoid pyrophosphates (IPs) • Statins inhibit generation of IPs • Statins may inhibit renal tubular reabsorption of albumin and other low molecular weight proteins • Modest or transient proteinuria may be a normal physiological event rather than a pathological effect Bays H. Am J Cardiol. 2006;97:6C-26C © 2006 National Lipid Association © 2006 National Lipid Association Types of Proteinuria Normal Blood Glomerular proteinuria Blood Tubular proteinuria Blood Glomerulus Tubule Bladder Waste Products High molecular weight proteins (includes large amounts of albumin) Low molecular weight proteins (includes small amounts of albumin) © 2006 National Lipid Association Inhibition of Albumin Uptake and Cholesterol Synthesis Inhibition of Albumin Uptake (%) 100 80 60 Rosuvastatin Simvastatin Pravastatin 40 20 0 0 10 20 30 40 50 60 70 80 90 100 Inhibition of Cholesterol Synthesis (%) Preclinical data: proximal tubule-derived opossum kidney cell line Sidaway JE et al. Poster presented at: 41st Congress of the European Societies of Toxicology, September 28-October 1, 2003; Florence, Italy © 2006 National Lipid Association Statin Therapy and Renal Function • Atorvastatin reduced proteinuia and slowed progression of kidney disease in patients with chronic kidney disease • Lipid-lowering drugs may preserve glomerular filtration and decrease proteinuria in patients with renal disease Bianchi S et al. Am J Kidney Dis. 2003;41:565-570 Fried LF et al. Kidney Int. 2001;59:260-269 © 2006 National Lipid Association Creatinine and GFR Changes From Baseline to Final Visit Treatment Placebo Rosuvastatin 5 mg 10 mg 20 mg 40 mg 10 mg 20 mg 40 mg 80 mg 10 mg 20 mg 40 mg 80 mg 10 mg 20 mg 40 mg N 371 637 2909 1432 2107 1394 1562 221 535 161 1217 506 500 159 342 745 Creatinine % Change 0.8 -1.6 -1.4 -1.6 -1.3 -1.5 -1.4 -2.0 -3.8 -0.4 -1.4 -1.6 -1.2 -1.8 -2.1 -0.7 Change in GFR -0.3 1.5 1.6 1.9 1.6 1.6 1.5 1.9 3.4 0.5 1.4 1.7 1.5 1.8 1.9 0.8 Atorvastatin Simvastatin Pravastatin Median duration of therapy ~ 8 weeks GFR in mL/min/1.73 m2 Data on file, (DA-CRS-07) AstraZeneca Pharmaceuticals LP. Wilmington, DE © 2006 National Lipid Association Statin Therapy and Acute Renal Failure (ARF) CLINICAL TRIAL DATA: • Major cardiovascular endpoint trials (HPS, PROSPER) did not report ACF as an adverse event associated with statin use1 CASE STUDIES: • One case study reported interstitial nephritis in patient taking a statin2 • Acute, allergic, interstitial nephritis possible mechanism 1 2 Cheung BM et al. Br J Clin Pharmacol. 2004;57:640-651 van Zyl-Smit R et al. Nephrol Dial Transplant. 2004;19:3176-3179 © 2006 National Lipid Association Statin Therapy and Acute Renal Failure (ARF) META-ANALYSIS: • Pravastatin Pooling Project looked at data from 3 double blind randomized clinical trials • Compared pravastatin 40 mg to placebo • Safety analysis included 19,592 patients followed for 5 years • Renal failure was seen in 78 of the 9783 patients taking placebo and 48 of the 9809 patients taking pravastatin • More cases of ARF and other renal diseases were reported in the placebo than in the pravastatin group Pfeffer MA et al. Circulation. 2002;105:2341-2346 © 2006 National Lipid Association Relationship Between Statin Therapy and ARF • In pravastatin pooling project, more cases of ARF and other renal diseases were reported in the placebo group. Pfeffer MA et al. Circulation. 2002;105:2341-2346 © 2006 National Lipid Association Relationship Between Statin Therapy and ARF US Food and Drug Administration (FDA) reviewed 38 cases of renal failure or insufficiency in rosuvastatin patients. “No consistent pattern of clinical presentation or of renal injury (i.e. pathology) is evident among the cases of renal failure reported to date that clearly indicates causation by Crestor (rosuvastatin) or other statins.” FDA Letter to Public Citizen, March 2005 © 2006 National Lipid Association Relationship Between Statin Therapy and ARF The National Lipid Association Kidney Expert Panel, made up of 3 nephrologists, reviewed published and unpublished evidence and found none that suggested that statins, when used in doses currently approved by the US Food and Drug Administration (FDA), cause kidney injury. Kasiske BL et al. Am J Cardiol. 2006;97:82C-85C © 2006 National Lipid Association Recommendations from the NLA Safety Task Force for Renal Issues PATIENT MONITORING • Recommend baseline albumin/creatinine ratio and serum creatinine – To identify patients at risk for cardiovascular disease and chronic kidney disease (CKD), NOT to assess risk for statin use – OK to begin/continue statin therapy in CKD, but some doses require adjustments • Unnecessary to measure proteinuria or serum creatinine during chronic statin treatment McKenney JM et al. Am J Cardiol. 2006;97:89C-94C © 2006 National Lipid Association Recommendations from the NLA Safety Task Force for Renal Issues EVALUATION OF POTENTIAL ADVERSE EVENTS • Increased plasma creatinine – – – – Repeat measurement Rule out rhabdomyolysis Refer to nephrologist as needed No need to discontinue statin unless rhabdomyolysis is present • Proteinuria – Quantify with protein/creatinine ratio and/or albumin/creatinine ratio – Consider referral to nephrologist for clinical proteinuria – No need to discontinue statin McKenney JM et al. Am J Cardiol. 2006;97:89C-94C © 2006 National Lipid Association Recommendations from the NLA Safety Task Force for Renal Issues • The best measure to identify patients at increased risk of CVD and CKD is a baseline albumin/creatinine ratio and serum creatinine. • It is not necessary to measure proteinuria or serum creatinine during chronic statin Rx • If serum creatinine increases (without rhabdo) during statin Rx, there is no need to DC the statin • If proteinuria develops during statin Rx, there is no need to DC the statin McKenney JM et al. Am J Cardiol. 2006;97:89C-94C © 2006 National Lipid Association Conclusions of the NLA Safety Task Force for Renal Issues • Marketed doses of statins do not produce clinically meaningful proteinuria • There is no association between statin use and renal tubular damage • There is no evidence that statin use leads to renal glomerular damage • There is no convincing link between statin use and hematuria • There is no evidence that statin uses causes kidney disease, it might actually be protective Kasiske BL et al. Am J Cardiol. 2006;97:82C-85C © 2006 National Lipid Association