Our results show that lovastatin reduces first major cardiovascular events in persons with CKD defined as an estimated GFR <60mL/min/1.73m2. The beneficial effect of lovastatin on patients with CKD persisted after adjustment for important covariates known to be associated with CVD. These findings are of significance as patients with CKD experience a high rate of cardiovascular events.
Lovastatin did not result in a decrease in cardiovascular or coronary heart disease (CHD) mortality. However, the number of deaths in AFCAPS/TexCAPS was low (157 total deaths; 42 cardiovascular deaths, of which 26 were CHD deaths) and the study was not powered to detect treatment differences in these low frequency endpoints. Lovastatin also did not result in a decrease in myocardial infarctions or unstable angina. Since only a small number of these events (8 myocardial infarctions and 9 cases of unstable angina) occurred in patients with CKD, it is difficult to detect differences between the two treatment groups. Although results were not statistically significant, non-significant incidence of unstable angina, fatal and non-fatal myocardial infarction and sudden death events was quantitatively lower (3.4% vs. 7.5%) with the use of lovastatin when compare to placebo in those participants with a decrease in kidney function. Furthermore, lovastatin did not result in any renoprotective effects as it did not decrease: (1) annualized mean rate of decline in estimated GFR; (2) the frequency of a ≥25% decline from baseline in kidney function in those with and without CKD at the initiation of the study and (3) the rate of incident cases of CKD in those with normal or near normal kidney function at baseline.
To our knowledge, this is the first primary prevention study to demonstrate a significant reduction in cardiovascular events from lovastatin therapy in persons with CKD. Statins have also been shown to be effective for secondary prevention of CVD in participants with moderate or more advanced CKD. Tonelli et al9
performed a post-hoc analysis of the Pravastatin Pooling Project (PPP), a database containing results from 3 randomized (1 primary and 2 secondary prevention) controlled trials of pravastatin verses placebo. Among the 4,491 participants with moderate CKD (defined as an estimated GFR between 30 and 59 mL/min/1.73m2
) and with or at risk of CHD, pravastatin showed a 23% reduction in the incidence of the composite outcome of time to myocardial infarction, coronary death, or coronary revascularization. Of note, the effects of pravastatin on primary prevention were not thoroughly examined in this post-hoc analysis.
In our study, lovastatin did not have any renoprotective effects. Studies investigating the renoprotective effects of statins have mainly included patients with prevalent CVD and have yielded contradictory results. In the Heart Protection Study, the overall decline of estimated GFR was smaller in type 2 diabetics receiving simvastatin 40 mg per day compared with placebo.21
In another post-hoc analysis of the PPP,12
participants with moderate CKD treated with pravastatin had a 34% reduction in the rate of kidney function loss, but again the absolute reduction in the rate of loss was small. Moreover, similar to our findings with lovastatin, pravastatin did not reduce the frequency of a ≥25% decline in kidney function in patients with and without moderate CKD or the risk of developing incident CKD. In this analysis, the effects of pravastatin on kidney function loss in the sub-group of participants without prevalent CVD was not examined.
A recent meta-analysis of 27 placebo-controlled trials with 39,704 participants suggested that, compared with placebo, statins reduce the rate of kidney function loss by 1.22 mL/min/1.73m2
The effect of statins on kidney function loss was more pronounced in participants with prevalent CVD but was non significant for studies of participants with diabetic, or hypertensive kidney disease. More recently, Strippoli et al 8
performed a meta-analysis of 50 randomized and quasi-randomized trials of statins in patients with all stages of kidney disease (n
=30,144). The authors found that statins had uncertain renoprotective effects. Thus, statins may decrease the rate of kidney function decline mainly in patients with prevalent CVD but the clinical significance of this effect is unclear.
Many of the risk factors for the development of CKD are also risk factors for the development of CVD such as age, diabetes and hypertension. Given the shared risk factors it is plausible that the pathogenesis of CVD and CKD are very similar and modification of these risk factors could result in prevention. However, as seen in our study, treatment of dyslipidemia resulted in primary prevention of CVD but did not result in primary prevention of CKD or kidney function loss suggesting that the pathogenesis of the two diseases are indeed different.
Dyslipidemia is a significant risk factor for the development of CVD, but its role in CKD is not as clear. In animal studies, dietary cholesterol loading induces mesangial proliferation, glomerulosclerosis and modest proteinuria in animals with normal renal function.22
The Physician’s Health Study23
evaluated the development of renal dysfunction in 4483 men without baseline CKD over 13 years and found that elevated LDL-C levels, total cholesterol levels, and lower HDL-C levels were significantly associated with the development of new kidney dysfunction. However, data on proteinuria was not included in the study, which is an important potential confounder.
Our study has several limitations and strengths that should be considered. First, we were unable to determine the cause and duration of kidney disease and did not have information regarding microalbuminuria or proteinuria. Second, we defined CKD based upon estimated GFR rather than direct measurements of GFR; but direct measurements are rarely used in clinical practice. Third, there were very few patients with advanced kidney disease (stage 4). Hence, the results of this study should not be extrapolated to advance stages of CKD. Fourth, hemodynamic changes that could have occurred from changes in dosage of antihypertensive medications that could potentially affect kidney function were not measured. Fifth, females and minorities were under-represented in the AFCAPS/TexCAPS trial. Finally, because this is a post-hoc analysis, our results should be interpreted with some degree of caution as evaluation of the potential renoprotective effect of lovastatin was not the primary end-point of the AFCAPS/TexCAPS.
Notwithstanding these limitations, our study also has several strengths. First, this is the first study to demonstrate the effectiveness of statins for the primary prevention of cardiovascular events in patients with CKD. Other strengths include the large cohort size, comprehensive dataset, and ability to link demographic and clinical factors with patient outcomes. In addition, all laboratory measurements, including serum creatinine, were performed at a central laboratory. Finally, the AFCAPS/TexCAPS cohort has been shown to have similar demographic and baseline-lipid-level characteristics on average as NHANES III, and therefore of the non-institutionalized US adult patient population19
In conclusion, the benefit of lovastatin for primary cardiovascular prevention and the low rate of adverse events seen in the present study suggest that physicians should consider increasing the use of statins in the CKD population to reduce the burden of CVD. At this time, the use of statins solely for primary renoprotection appears to be ineffective. However, randomized controlled trials are required to definitely resolve this issue and are currently ongoing.