Reducing cardiovascular risk in patients with chronic renal disease
EAS 2011
- The new ESC/EAS guidelines for dyslipidemia management emphasize the high risk associated with chronic kidney disease (CKD) and state that this should be regarded as a coronary risk equivalent. According to the guidelines, low-density lipoprotein (LDL) cholesterol is the primary target of lipid-modifying therapy. Statins also have renoprotective effects, slowing the rate of kidney function loss and protecting against the progression of proteinuria.1,2
Despite these recommendations, the management of these high-risk patients is still less than the optimal, according to Professor Ronnie Willenheimer, Associate Professor of Cardiology at Lund University Medical School in Malmö, Sweden. Recent data from a large observational study in more than 22,000 statin-treated patients show that nearly half do not achieve therapeutic LDL-cholesterol goals.3 ‘These data clearly highlight a gap between recommendations and clinical practice.’
However, there may be issues with the tolerability of high-dose statin therapy. In this context, add-on or combination therapy may be worth considering, offering the opportunity for improved achievement of LDL cholesterol goals and better tolerability. Clinical studies show that addition of ezetimibe 10 mg to simvastatin 40 mg resulted in up to twice as many patients achieving LDL cholesterol goals (<100 mg/dL) than statin monotherapy.4,5 Ezetimibe might also improve glycaemic control possibly via an effect mediated by glucagon-like peptide-1 (GLP-1), of relevance given a recent meta-analysis showing an increased risk of new-onset diabetes associated with statin therapy.6
In patients with CKD, the pattern of vascular disease varies from other high-risk patients; data from the US Renal Registry show that among vascular deaths, most are not attributed to coronary death. The SHARP (Study of Heart and Renal Protection) evaluated the effect of LDL cholesterol lowering with ezetimibe 10 mg +simvastatin 20 mg combination treatment in patients with moderate to severe renal disease. SHARP enrolled 9270 patients with established CKD or on dialysis and with elevated creatinine (>1.7 mg/dL for men or >1.5 mg/dL for women) and without prior history of MI or coronary revascularization. LDL cholesterol was lowered by 0.85 mmol/L on combination treatment.
At 5 years, combination treatment was associated with significant 17% (p=0.0021) reduction in the risk of major atherosclerotic events, defined as the combination of coronary death, MI, ischaemic stroke, or any revascularization procedure versus placebo.7 Combination treatment also significantly reduced the risk of non-haemorrhagic stroke (by 25%, p=0.01), any revascularization procedure (by 21%, p=0.0036) and coronary revascularization (by 27%). Dr Martin Landray, co-principal investigator of the study, Nuffield Department of Clinical Medicine, Oxford, UK drew attention to the less than optimal compliance among study patients. At one year, compliance in the active group was about 70%, and about 9% of patients in the placebo group were taking a statin. ‘These data imply that the results of this study are likely to be an underestimation of the true effect of the combination,’ said Dr Landray.
These data contrast with the results of other statin studies – AURORA (a Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events), 4D (Deutsche Diabetes Dialyse Studie) and ALERT (Lescol in Renal Transplantation trial) which failed to show any significant benefit of statin therapy on primary outcomes. The difference between these studies might relate to the choice of primary endpoint. In SHARP the primary endpoint was changed from major vascular events to major atherosclerotic events, whereas in AURORA and 4D, the primary endpoint mainly related to vascular death. In conclusion, Dr Landray said: ‘The SHARP data are at least compatible with the overall picture observed with risk reduction associated with lowering LDL cholesterol as shown by the recent CTT meta-analyses.’
References
1. Reiner Z, Catapano A, de Backer G et al. ESC/EAS guidelines for the management of dyslipidaemias. The Task Force on the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; doi:10.1093/eurheartj/ehr158 [Epub ahead of print].
2. Catapano A, Reiner Z, de Backer G et al. ESC/EAS guidelines for the management of dyslipidaemias. The Task Force on the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis 2011; doi:10.1016/j.atherosclerosis.2011.06.012 [Epub ahead of print].
3. Gitt AK, Drexel H, Feely J et al. Persistent lipid abnormalities in statin-treated patients and predictors of LDL-cholesterol goal achievement in clinical practice in Europe and Canada. Eur J Cardiovasc Prev Rehabil 2011 [Epub ahead of print].
4. Triscari J, Civeira F, Gheorghe A et al. Ezetimibe/simvastatin 10/40 mg versus atorvastatin 40 mg in high cardiovascular risk patients with primary hypercholesterolemia. J Clin Lipidology 2011; 5: 203
5. Bays HE, Davidson MH, Massaad R et al. Safety and efficacy of ezetimibe added on to rosuvastatin 5 or 10 mg versus up-titration of rosuvastatin in patients with hypercholesterolemia (the ACTE Study). Am J Cardiol 2011 May 17. [Epub ahead of print].
6. Preiss D, Seshasai SR, Welsh P et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011;305:2556-64.
7. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomized placebo-controlled trial. Lancet 2011;377:2181-92.