Modest improvement of renal function over time with statin therapy in patients at high risk of or with CVD
Atorvastatin Has a Dose‐Dependent Beneficial Effect on Kidney Function and Associated Cardiovascular Outcomes: Post Hoc Analysis of 6 Double‐Blind Randomized Controlled Trials
Introduction and methods
The development and progression of chronic kidney disease (CKD) shares common risk factors with development of CVD. Kidney function generally declines gradually over the years, and the extent of kidney function decline is informative as an independent risk factor for mortality, CVD and/or end-stage renal disease (ESRD) in CKD and non-CKD populations [1-3]. Especially individual slopes of kidney function over time provide relevant information for CVD and kidney outcomes in the long run .
Consequently, interventions that positively affect the slope over time may also provide CV and renal protection at an early stage. This has for example been demonstrated to be the case with RAAS inhibitors . Statins have been demonstrated to provide CV benefit, both in patients with CKD and in other high-risk patients [6,7]. It is unknown whether this effect of statins may be partially attributable to an effect on kidney function. Various kidney-protective effects of statin therapy have been demonstrated, but some negative effects on kidney function have also been described. The effects may be the consequence of dose and type of statin used.
This study aimed to address whether the high-potency statin atorvastatin has an effect on age-related kidney function decline in patients at risk of or having CVD and whether this effect is dose-dependent. The study also assessed whether individual patient slopes can predict CV outcome measures. Data of six large randomized atorvastatin CV outcome trials conducted in patients not selected for having kidney disease were used (n=30621). Follow-up was at least 12 months. The primary outcome was the slope of kidney function as measured by the reciprocal of the serum creatinine level (which has a linear relationship with glomerular filtration rate [GFR]). Three groups were formed, by pooling data of individual subjects, to assess the slope in placebo patients (placebo arms of ASCOT, CARDS, SPARCL and ASPEN, n=10.057), in those treated with atorvastatin 80 mg (SPARCL, TNT, SAGE, n=12.763), and in those treated with atorvastatin 10 mg (ASCOT, CARDS, ASPEN, n=7.801). As a consequence of differences in disease conditions and study design, baseline characteristics differed significantly between the three groups. Median treatment duration was 4.9 years (range: 1-4.9).
- All treatment groups showed a significant linear slope reflecting decline in kidney function (based on a mean [SD] of 4.7 [1.4] measurements of creatinine level). Slopes were (estimate [SE]) 0.008 [0.0007], 0.011 [0.0005] and 0.014 [0.0006] (mg/dL)^-1/year for placebo and atorvastatin 10 mg and 80 mg, respectively in a multivariable model.
- The TNT data set was used to conduct a formal comparison between atorvastatin doses. Patients randomized to atorvastatin 10 mg showed a significantly less steep slope (0.012 [0.0007]) than those randomized to atorvastatin 80 mg (0.015 [0.0007, P=0.0009]).
- eGFR slopes showed a similar pattern. Slopes of 0.25 [0.068], 0.51 [0.054] and 0.78 [0.056] mL/(min-1.73m²) per year were seen for placebo, atorvastatin 10 mg and 80 mg, respectively. Adjustment had a negligible effect. These effects would translate to eGFR increases of 1.3, 2.6 and 3.9 mL/(min-1.73m²) over a 5 year period in the respective groups.
- In the formal comparison with TNT data, a dose effect was seen, with 0.58 [0.065] and 0.86 [0.065] mL/(min-1.73 m²) for atorvastatin 10 mg and 80 mg (P=0.003).
- In the respective treatment groups, the proportions of patients with an eGFR decrease from baseline to the last visit of >30% were 2.5% (95%CI: 2.2-2.9), 2.1% (95%CI: 1.9-2.4) and 2.0% (1.7-2.4).
In an adjusted Cox proportional hazard model, the effect of average annual change in kidney function (1/creatinine) on major CV events, CV deaths and all-cause mortality was assessed. HRs per 1 SD unit of slope were:
- Major CV events: HR: 0.86 (95%CI: 0.80-0.92) with atorvastatin 80 mg vs HR: 0.94 (95%CI: 0.87-1.02) with placebo.
- CV death: HR: 0.87 (95%CI: 0.76-1.00) with atorvastatin 80 mg vs HR: 0.92 (95%CI: 0.80-1.07) with placebo.
- All-cause mortality: HR: 0.88 (95%CI: 0.81-0.96) with atorvastatin 80 mg vs HR: 0.92 (95%CI: 0.84-1.02) with placebo.
This large post-hoc analysis of individual data from 6 CV outcome trials in patients at risk of or with CVD, but not selected for kidney disease, treatment with atorvastatin modestly improved kidney function over time. The data suggest a dose-dependent effect. A decrease in kidney function was associated with higher CV risk.