Statin Effects in CKD: Is There a “Point of No Return”?

A higher low-density lipoprotein (LDL) cholesterol level is strongly associated with increased risk of coronary heart disease (CHD) in populations without kidney disease. Statin therapy can reduce the risk of major coronary events, coronary revascularization, and stroke by about one-fifth per 1 mmol/L decrease in LDL cholesterol, largely irrespective of the initial lipid profile.1 A similar effect is seen in people with diabetes mellitus, which has led to the conclusion that statin therapy should be considered for all individuals with diabetes irrespective of whether vascular disease has developed and irrespective of lipid profile.2

Based on this solid evidence in the general population and patients with diabetes, would anyone doubt that patients with chronic kidney disease (CKD) would reap similar benefits from statin treatment? In this issue of the American Journal of Kidney Diseases, Michael Koren et al3 provide information from a post hoc analysis of the Aggressive Lipid Lowering to Alleviate New Cardiovascular Endpoints (ALLIANCE) trial indicating that in the subgroup of patients (n = 579) with CKD (mean estimated glomerular filtration rate [GFR], 51.2 ± 8.1 mL/min/1.73 m2), statin therapy is safe and effective. They show that compared with usual care (as deemed appropriate by patients' regular physicians), focused atorvastatin treatment (LDL cholesterol goal < 80 mg/dL or maximum dose of 80 mg/d) decreased cardiovascular risk for established patients in real-world settings, with no significant difference in treatment effect observed between patients with (estimated GFR < 60 mL/min/1.73 m2) and without CKD.

Similar information had already been available from subgroups of patients who had participated in prospective controlled intervention trials, including the Cholesterol Treatment Trialists' (CTT) Collaborators meta-analysis.1 Post hoc analyses in these subgroups with similarly decreased GFRs suggest that the benefit is at least as high, if not higher, in patients with CKD compared with patients without CKD4, 5 or patients with diabetic kidney disease.6

Why do nephrologists need specific confirmation that high-risk patients with CKD are served well with more aggressive LDL cholesterol–lowering management? First, we have a history of nearly 25 years in trying to understand the misleading association between cholesterol level and vascular outcomes in dialysis patients. Today, we know that the observation of a negative association between total cholesterol level and mortality at less than average cholesterol concentrations in some studies is consistent with confounding by inflammation and both vascular and nonvascular morbidity (ie, reverse causality).7 Second, the negative outcome of Die Deutsche Diabetes Dialyse Studie (the 4D Study) came as a surprise and caused uncertainty about the efficacy of statins in patients with CKD stage 5.8 In that large randomized trial, there was no decrease in mortality from atorvastatin in hemodialysis patients with type 2 diabetes. Third, there is a complete lack of controlled information about the effects of statin treatment on outcome in patients with CKD stage 4, which may preclude treatment.

However, one should note that the 3 conditions causing uncertainty are related to patients with advanced CKD. Epidemiological data clearly show an increased risk of cardiovascular disease in patients with advanced CKD. For example, the death rate of participants in the Kaiser Permanente of Northern California Renal Registry (1996 to 2000) was 11.3 deaths/100 patient-years in those with CKD stage 4 compared with 3.6 deaths/100 patient-years in those with CKD stage 3a (GFR, 45 to 59 mL/min/1.73 m2).9 As discussed next, there is now information that not only the quantity, but also the quality of cardiovascular events is different when GFR decreases to less than 45 mL/min/1.73 m2. Today, the question that needs to be answered from ongoing trials is whether less than half of normal kidney function is the “point of no return” for effective statin treatment.

One possibility is that atherogenesis is accelerated in uremia, as shown in experimental models. Fathi et al10 conducted a small prospective study to compare the effect of aggressive lowering of LDL cholesterol levels with atorvastatin in patients with primary coronary artery disease without advanced CKD with effects in patients with advanced CKD. In patients without advanced CKD, maximum intima-media thickness of the carotid artery (as an index of vascular damage) decreased significantly by using this intervention during a 2-year observation period. However, it was unchanged in patients with advanced CKD. This observation is compatible with the hypothesis that the beneficial effect of statins is counteracted and abrogated by uremia-specific mechanisms.

The mechanism of cardiovascular-related death may differ in patients with advanced kidney disease. According to the US Renal Data System registry and confirmed by the 4D trial, CHD accounted for only a small proportion of cardiovascular deaths, ie, 9%. A greater proportion of patients, ie, 33%, died of sudden death or congestive heart failure. Thus, the pattern of mortality differs markedly between the CTT meta-analysis, in which CHD was the dominant cause of cardiac death, and the 4D Study, in which definite CHD was a minority cause of death. In the 4D trial, it is possible that a statistically significant change in the primary end point was missed because the power of the study to find a significant overall difference in the primary composite end point was insufficient in view of the low frequency of death from CHD. Looking at only coronary artery disease and taking into account that the mean decrease in LDL cholesterol level in the 4D trial was about 1 mmol/L, results of the CTT meta-analysis predict what might have been expected if the effects of lowering cholesterol levels in dialysis patients were similar to those observed in populations without advanced kidney disease (the point-of-no-return hypothesis rejected!).

Analysis of the CKD subgroup of the large statin trials shows that statin treatment is safe and effective in patients with a mean GFR of approximately 50 mL/min/1.73 m2. These patients are served well with statin therapy. We know relatively little about the efficacy of statins in those with CKD stage 4. Future studies should address this population.