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Statins in CKD

Dr. Rushi Deshpande Mumbai. Statins in CKD. Introduction. CKD Incidence and prevalence increasing worldwide and associated with poor outcomes India - world’s largest democracy with a population of around 1.13 billion CKD is a significant health problem

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Statins in CKD

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  1. Dr. RushiDeshpande Mumbai Statins in CKD

  2. Introduction • CKD • Incidence and prevalence increasing worldwide and associated with poor outcomes • India - world’s largest democracy with a population of around 1.13 billion • CKD is a significant health problem • The incidence rates of ESRD in India • 232 per million population (age adjusted rate) NDT Plus 2010; 3: 203–207 ESRD – End stage renal disease

  3. Introduction • Well documented • Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with CKD • Mild chronic impaired renal function contributes actively to the development of CVD, so the • American Heart Association has recommended that these patients should be classified in the highest risk group for developing cardiovascular events The Open Cardiovascular Medicine Journal 2011;5:41-48

  4. 40% ↑ compared to eGFR ≥ml/min/1.73m2 2 fold ↑ compared to eGFR ≥ml/min/1.73m2 CKD and risk of CV events Adjusted Hazard Ratio for Death from Any Cause, Cardiovascular Events, and Hospitalization among 1,120,295 Ambulatory Adults, According to the Estimated GFR.* N Engl J Med 2004;351:1296-305

  5. Introduction • In patients who finally advance to ESRD and especially dialysis patients, • Prevalence of clinical coronary heart disease is 40% and • CVD mortality is 10 to 30 times higher than in the general population of the same gender, age and race The Open Cardiovascular Medicine Journal 2011;5:41-48

  6. Introduction • Notable among the traditional risk factors for CVD in the general population is dyslipidemia • Also, it is well known that patients with impaired renal function exhibit significant alterations in lipoprotein metabolism, which • in their most advanced form may result in the development of severe dyslipidemia The Open Cardiovascular Medicine Journal 2011;5:41-48

  7. CKD and risk of CV events • Second National Health and Nutrition Examination Survey (NHANES II), • In comparison to eGFR of at least 90 ml/min/1.73m2, eGFR of less than 70 ml/min/1.73 m2 is associated with • 68% ↑ in the risk of death from any cause and • 51% ↑ in the risk of death from cardiovascular causes, J Am Soc Nephrol 2002;13:745-53.

  8. Dyslipidemia in patients with CKD • The most important abnormalities of uremic dyslipidemia are: • elevated levels of trigliceryde trigliceryde-rich particles (VLDL and IDL) and LDL-cholesterol, • increased Lp(a) lipoprotein level, • low concentration of HDL-cholesterol. • Total cholesterol level can be normal, although this is not the rule. • The prevalence of dyslipidemia in CKD is associated with the level of GFR and the level of proteinuria. Seminars in Dialysis, 2003; 16: 148-56 Clin Nephrol, 2002; 57: 327-35

  9. Association Between Cholesterol and Kidney Disease Physician’s Health Study (1982 – 1996) P < 0.01 Schaeffner et al. JASN 2003;14:2084-2091.

  10. Statin-Associated Cardiovascular Disease Risk Benefit across the Stages of CKD • Statins and Nondialysis-Dependent CKD • Clinical trials have demonstrated • Inhibitors of hydroxymethylglutarylCoAreductase (statins) are gaining widespread acceptance as a principal therapy for the primary and secondary prevention of atherosclerosis and CVD • The role of statins in primary prevention of CVD in CKD patients remains to be clarified Am J Nephrol 2011;34:195–202

  11. Statin-Associated Cardiovascular Disease Risk Benefit across the Stages of CKD • Statins and Nondialysis-Dependent CKD • No large randomized clinical trial has provided evidence • Statinsas a primary prevention strategy reduce CVD in these patients • It has been suggested • Statins are effective and appear safe for secondary prevention of cardiovascular events in individuals with mild chronic renal insufficiency Am J Nephrol 2011;34:195–202

  12. Statin-Associated Cardiovascular Disease Risk Benefit across the Stages of CKD • Statins and Nondialysis-Dependent CKD • Meta-analysis and post-hoc analyses have reported benefits of statins on • All-cause and cardiovascular mortality in CKD patients • Post-hoc analysis of the • Aggressive Lipid Lowering Initiation Abates New Cardiac Events (ALLIANCE) study, • Atorvastatin therapy compared with usual care, reduced the relative risk of the first cardiovascular event by 28% in patients with CKD and 11% in patients without CKD Am J Nephrol2011;34:195–202 Am J Kidney Dis 2009; 53: 741–750.

  13. Statin-Associated Cardiovascular Disease Risk Benefit across the Stages of CKD • Statins and Nondialysis-Dependent CKD • The absolute benefit of treatment with a statin seems to be greater among individuals with nondialysis-dependent (NDD)-CKD • In a meta-analysis • 25,017 participants with CKD not requiring dialysis from 26 randomized controlled trials, • Statinsdecreased both • Risk of all-cause mortality and cardiovascular events, [RR 0.81 (95% CI: 0.74–0.89) and RR 0.80 (95% CI: 0.70– 0.90), respectively] Am J Nephrol2011;34:195–202

  14. Statin-Associated Cardiovascular Disease Risk Benefit across the Stages of CKD • Statins and Nondialysis-Dependent CKD • The effect of statins seems to be dose-related • Subanalysisof the Treating to New Targets (TNT) study showed • Compared with atorvastatin 10 mg, • Atorvastatin80 mg reduced the relative risk of major cardiovascular events by 32% in patients with CKD and 15% in patients with normal estimated glomerularfiltration rate (eGFR) Am J Nephrol2011;34:195–202

  15. TNT study: Intensive lipid lowering and kidney function Estimated GFR improved in both treatment groups but was significantly greater with 80 mg than with 10 mg, suggesting this benefit may be dosage related. Clin J Am Soc Nephrol 2: 1131–1139, 2007

  16. TNT trial: Change from baseline estimated glomerular filtration rate (eGFR) among patients with diabetes Mayo Clin Proc. 2008;83(8):870-879

  17. Patients with diabetes, stable coronary artery disease, and mild to moderate CKD experience marked reduction in cardiovascular events with intensive lipid lowering, TNT trial: Time to first major cardiovascular event in patients with diabetes by treatment andbaseline chronic kidney disease (CKD) status. Mayo Clin Proc. 2008;83(8):870-879

  18. TNT: Results Relative Risk Reduction of Major Cardiovascular events in atorvastatin 80mg in comparison to atorvastatin 10, after a median follow-up of 5 years With CKD With normal eGFR Aggressive lipid lowering with atorvastatin 80 mg was both safe and effective in reducing the excess of cardiovascular events in a high-risk population with CKD and CHD. % J Am Coll Cardiol. 2008 Apr 15;51(15):1448-54

  19. Statin-Associated Cardiovascular Disease Risk Benefit across the Stages of CKD • Statins and Dialysis Patients • Clinical studies in end-stage renal disease (ESRD) patients on dialysis did not confirm these results • In Die Deutsche Diabetes Dialyse (4D), a • Multicenter, randomized, double-blind, prospective study of 1,255 subjects with type 2 diabetes mellitus receiving maintenance hemodialysis, randomly assigned to receive • 20 mg of atorvastatin per day or matching placebo for a median followup period of 4 years N Engl J Med 2005; 353:238–248.

  20. Statin-Associated Cardiovascular Disease Risk Benefit across the Stages of CKD • Statins and Dialysis Patients • Die Deutsche Diabetes Dialyse (4D) study • Results • Atorvastatinyielded a nonsignificant 8% reduction in the prespecified primary outcome of • Cardiovascular death, nonfatal myocardial infarction and stroke N Engl J Med 2005; 353: 238–248.

  21. Statin-Associated Cardiovascular Disease Risk Benefit across the Stages of CKD • Statins and Dialysis Patients • AURORA study • (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) • Randomized, double- blind, prospective trial involving 2,776 patients, 50– 80 years of age, who were undergoing maintenance hemodialysis • Patients were randomly assigned to receive rosuvastatin, 10 mg daily or placebo N Engl J Med 2009; 360: 1395–1407.

  22. Statin-Associated Cardiovascular Disease Risk Benefit across the Stages of CKD • Statins and Dialysis Patients • AURORA study • Results • During a median follow-up period of 3.8 years, rosuvastatin lowered LDL-C by 39 mg/dl (1.0 mmol/l), but yielded a nonsignificant 4% reduction in the primary outcome of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke • There was also no significant effect on all-cause mortality N Engl J Med 2009; 360: 1395–1407.

  23. Statin-Associated Cardiovascular Disease Risk Benefit across the Stages of CKD • Statins and Dialysis Patients • 4D, AURORA results suggested a • Different pathogenetic mechanism in ESRD patients for the primary outcomes compared with mild or moderate CKD or normal kidney function • Lowering LDL-C with statin therapy in patients with ESRD did not produce significant reductions in the primary outcomes in these studies Am J Nephrol 2011;34:195–202 .

  24. Statin-Associated Cardiovascular Disease Risk Benefit across the Stages of CKD • Statins and Dialysis Patients • The pathophysiologic implication of the disease has not been completely elucidated • It has been suggested • Advanced atherosclerotic state in chronic dialysis patients and • Increased % of sudden death due to arrhythmia • Plays a significant role and that it is a condition not modifiable by statins Am J Nephrol 2011;34:195–202 .

  25. Statin-Associated Cardiovascular Disease Risk Benefit across the Stages of CKD • Statins and Dialysis Patients • Recently, The Study of Heart and Renal Protection (SHARP) • 9,270 patients with CKD of whom 3,023 patients were receiving maintenance dialysis at randomization, • [2,527 (27%) hemodialysis and 496 (5%) peritoneal dialysis], with creatinine≥ 1.7 mg/dl (150 mol/l) for men and 1.5 mg/dl (130 mol/l) for women • No history of myocardial infarction/coronary revascularization • Mean age 62 years, 63% male, 23% had diabetes mellitus and 15% had a history of vascular disease (angina, stroke or peripheral vascular disease) Lancet 2011; 377: 2181–2192

  26. Statin-Associated Cardiovascular Disease Risk Benefit across the Stages of CKD • Statins and Dialysis Patients • SHARP • Patients were randomized in a ratio of 4: 4:1 • Ezetimibe10 mg plus simvastatin20 mg daily versus matching placebo versus simvastatin 20 mg daily (with the latter arm r randomized at 1 year to ezetimibe 10 mg plus simvastatin 20 mg daily vs. placebo) Lancet 2011; 377: 2181–2192

  27. Statin-Associated Cardiovascular Disease Risk Benefit across the Stages of CKD • Statins and Dialysis Patients • SHARP • Final results • After a median follow-up of 4.9 years, patients randomized to an ezetimibe/simvastatin (10/20 mg) combination experienced a 17% reduction in major atherosclerotic events compared with the placebo group [RR 0.83 (0.74–0.94); long rank p = 0.0021] • Mean LDL-C reductions were 32 mg/dl between treatment groups Lancet 2011; 377: 2181–2192

  28. Statin-Associated Cardiovascular Disease Risk Benefit across the Stages of CKD • Statins and Dialysis Patients • SHARP- subgroup analyses, the evidence that • Proportional effects on major atherosclerotic events differed between patients on dialysis and NDD-CKD patients was not good (x 2 = 1.3, p = 0.25), and • No trends towards smaller proportional reductions in NDD-CKD patients with lower eGFR (trend x 2 = 0.38, p = 0.54). • 1/3 of the patients in both arms progressed to dialysis or transplantation Lancet 2011; 377: 2181–2192

  29. Statin-Associated Cardiovascular Disease Risk Benefit across the Stages of CKD • Statins and Dialysis Patients • Positive effects of SHARP were not found in the 4D and AURORA • This lack of benefit might be attributed to • Differences in the cause of cardiovascular death seen in the dialysis patients and • Smaller ample size, a matter which may be further explored • The lack of benefits in these two studies has been a matter of debate and should now be re-assessed Am J Nephrol 2011;34:195–202

  30. Statin-Associated Cardiovascular Disease Risk Benefit across the Stages of CKD • Statins and Dialysis Patients • Overall, the results from SHARP study suggest • Statinsmay be beneficial in a wide range of patients with CKD and even in dialysis patients Am J Nephrol 2011;34:195–202

  31. Statin Therapy and Kidney Function • Statins and Proteinuria • The presence of proteinuria is an indicator of kidney disease with an increased probability of progressive kidney loss, and is associated with faster loss of GFR compared with little or no proteinuria • There is mounting evidence suggesting that proteinuria reduction slows CKD progression Am J Nephrol 2011;34:195–202

  32. Statin Therapy and Kidney Function • Statins and Proteinuria • The heightened recognition that • Statinsmay reduce proteinuriaand may slow renal disease progression has been an area of growing interest and focus • Clinical studies in this area have yielded conflicting results, and the role of the potential effects of statins in patients with kidney disease is less established Am J Nephrol 2011;34:195–202

  33. Statin Therapy and Kidney Function • Statins and Proteinuria • The heightened recognition that • It is fairly well established that some studies have demonstrated a prominent reduction in proteinuria • The reduction of proteinuria with statins is also evident in patients with normal blood pressure and microalbuminuria Am J Nephrol 2011;34:195–202

  34. Statin Therapy and Kidney Function • Statins and Proteinuria • Meta-analysis of 15 studies involving a total of 1,384 patients examined the proportional reduction in proteinuria with the use of statins • Shown that statins reduced albuminuria and proteinuria in 13 of the 15 studies • Reduction of excretion was > among studies with greater baseline albuminuria or proteinuria • 440 patients with albuminuria≥30 mg/day showed a • 48% reduction of albuminuria relative to placebo Am J Nephrol 2011;34:195–202

  35. Statin Therapy and Kidney Function • Statins and Proteinuria • In striking contrast, however, other studies have shown that statins had no effect on urinary albumin excretion or (on the contrary) that high doses may cause proteinuria • Suggesting • This may be due to reduced receptor-mediated endocytosis in proximal tubular cells Am J Nephrol 2011;34:195–202

  36. Statin Therapy and Kidney Function • Statins and Proteinuria • A differential effect on proteinuriawas also suggested, with • Different statins and a comparative postmarketinganalysis showing • Differences in composite endpoints of proteinuria, nephropathy or renal failure with the use of various statins Am J Nephrol 2011;34:195–202

  37. Statin Therapy and Kidney Function • Statins and Proteinuria • In concert with this, • PLANET I (Prospective Evaluation of Proteinuria and Renal Function in Diabetic Patients with Progressive Renal Disease) and • PLANET II (Evaluation of Proteinuria and Renal Function in Non- Diabetic Patients with Progressive Renal Disease), • 2 related randomized, double-blind, parallel-group, multinational, multicenter, phase IIb trials, evaluated the effects of • Atorvastatin80 mg and rosuvastatin10 and 40 mg on • Urinary protein excretion and kidney function from baseline to week 52 in hypercholesterolemic diabetic and nondiabeticpatients, respectively Am J Nephrol 2011;34:195–202

  38. Statin Therapy and Kidney Function • Statins and Proteinuria • For PLANET I, • Atorvastatin significantly reduced proteinuria by about 15%, whereas rosuvastatinhad no significant effect on proteinuria • In PLANET II, • Atorvastatinreduced proteinuria by 23.8% (p = 0.0056) • These results suggest that these two drugs may exert different effects in favor of atorvastatinand dispelled the idea of a statin class effect; • however, this information remains to be clarified Am J Nephrol 2011;34:195–202

  39. Statin Therapy and Kidney Function • Statins and CKD Progression • There are conflicting data concerning this effect on kidney disease progression in patients with mild-to-moderate kidney failure • The majority of these data also come from post-hoc analyses or from patients randomized for cardiovascular primary endpoint trial • These data suggest that statins slow the rate of renal function decline • However, other studies have shown no benefits Am J Nephrol 2011;34:195–202

  40. Statin Therapy and Kidney Function • Statins and CKD Progression H PS = Heart Protection Study; GREACE = Greek Atorvastatin and Coronary Heart Disease Evaluation Am J Nephrol 2011;34:195–202

  41. Statin Therapy and Kidney Function • Statins and CKD Progression CARE = Cholesterol And Recurrent Events Am J Nephrol 2011;34:195–202

  42. Statin Therapy and Kidney Function • Statins and CKD Progression PREVEND-IT = Prevention of Renal and Vascular End-Stage Disease Intervention Trial; ALLHAT = Antihyhypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial Am J Nephrol 2011;34:195–202

  43. Statin Therapy and Kidney Function • Statins and CKD Progression Am J Nephrol 2011;34:195–202

  44. Potential Mechanisms for Observed Benefits • There are potential explanations for the putative effects of statins on the rate of kidney disease progression and proteinuria • Statins • May exert their protection on kidney disease through a variety of immunomodulatory effects • Attenuates endothelial dysfunction • Enhances renal perfusion and • Reduces abnormal permeability to plasma proteins Am J Nephrol 2011;34:195–202

  45. Potential Mechanisms for Observed Benefits • It has been suggested that • Statins may reduce BP • A metaanalysis showed that this effect is small, but also exists • In general, the higher the baseline BP, the greater the effect of statins on BP • Although small, BP reductions following statin treatment are possibly clinically relevant Am J Nephrol 2011;34:195–202

  46. Safety and Tolerability Considerations for Statinsin CKD • It has become increasingly clear • Side effect profile of statins is similar to that of placebo • The use of high doses of statins has been largely demonstrated to be safe and well tolerated • Statins can cause an elevation of liver function enzymes in a dose-related manner • The totality of the data supports a 0.5–3% occurrence of persistent elevations in aminotransferases in patients receiving statins Am J Nephrol 2011;34:195–202

  47. Safety and Tolerability Considerations for Statins in CKD • Myopathy • Another important side effect, although relatively uncommon • Happens especially when statins are used in high doses • SHARP recently showed that there was no increase in the risk of myopathy, liver and biliary disorders, cancer, or nonvascular mortality • Pravastatinand fluvastatin appear to have much less intrinsic muscle toxicity Am J Nephrol 2011;34:195–202

  48. Safety and Tolerability Considerations for Statins in CKD • Myopathy • The risk is substantially increased for most statins extensively metabolized by cytochrome P-450 3A4, such as lovastatin and simvastatin, and to a • Lesser extent to atorvastatin with concurrent therapy with drugs that interfere with CYP3A4. • Predisposing factors include • Hypothyroidism and inflammatory myopathies, such as polymyositis and dermatomyositis Am J Nephrol 2011;34:195–202

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