atorvastatin retards renal function decline

an article in the Journal of the Am Heart Assn reviewed 6 studies and found that atorvastatin was associated with less decline in kidney function, and the higher the dose the moreso (see statin benefits renal function JAHA2019 in dropbox, or DOI: 10.1161/JAHA.118.010827), with studies showing different outcomes by different statins (esp with their degree of lipophilicity).  Tomorrow will have followup blog on differential CNS effects of different statins

Details:

-- 6 large atorvastatin cardiovascular outcomes trials in patients not selected for having kidney disease (ASCOT, CARDS, ASPEN, SPARCL, TNT, SAGE)

-- 30,621 patients had data on the slopes of their reciprocal serum creatinine levels over time, mean of 4.7 creatinine measurements 

-- demographics (these did very some from study to study): age 62, 75% men, 93% white/3% black/2% Asian, BMI 28, blood pressure 145/85 mmHg, total cholesterol 195/HDL 49/LDL 118, serum creatinine 1.1, eGFR 66 (30%  had eGFR<60), diabetes 30%, smoking 20%. There were significant differences between studies in use of diuretics, RAAS inhibitors, and aspirin

-- patients were categorized into 3 groups: placebo (n= 10,057), atorvastatin 10 mg (n= 12,763), and atorvastatin 80 mg (n= 7801)

-- median treatment duration 3.9 years

Results:

-- the slopes of the reciprocal creatinine levels over time were, in (mg/dL)^-1/yr, adjusting for study, age, sex, BMI, LDL, systolic and diastolic blood pressures, baseline RAAS  inhibitor use, baseline aspirin use, diabetes, smoking, history of CVD, diuretic use, and hypertension:

    -- placebo: 0.009

    -- atorvastatin 10 mg: 0.011

    -- atorvastatin 80 mg: 0.014

    --[i.e., deterioration of renal function was the least in those on the highest dose atorvastatin, and differences between the 3 were at p<0.0001]

-- no difference in these slopes in adjusted models for age, sex, or change in LDL at 3 months from baseline

-- in the TNT trial, the one that had a formal direct comparison of atorvastatin 10 vs 80 mg, the slope was significantly lower for 10 mg at 0.012 vs the 80 mg group at 0.015, confirming a benefit for the higher dose atorvastatin

-- the percentage of patients with a decrease in eGFR of >30%: placebo 2.5%, atorvastatin 10 mg 2.1%, atorvastatin 80 mg 2.0%

-- average annual change in kidney function was a significant predictor within both atorvastatin groups for major cardiovascular events and cardiovascular deaths, adjusting for age, sex, BMI, LDL, systolic and diastolic blood pressure, baseline RAAS inhibitor usage, baseline aspirin use, diabetes, smoking, history of cardiovascular events at baseline, diuretics. [ie, cardiovascular outcomes were higher in those with decreasing kidney function, independent of LDL, though those on atorvastatin 80 did better for both kidney function and LDL]

    --for each SD increment of the slope of kidney function, there was a 13-14% decrease in cardiovascular mortality, independent of the atorvastatin dose [though, again, those on atorvastatin 80 had a greater overall increment of reciprocal creatinine slope]

Commentary:

-- kidney function and cardiovascular disease are related: both increases in creatinine as well as proteinuria (even within the "normal" ranges in some studies) are associated with increased cardiovascular disease and mortality, in both CKD and non-CKD populations; and this study found that changes in renal function tracked with cardiovascular events. Of course, CVD and CKD share many common risk factors (eg hypertension, diabetes, and hyperlipidemia).

-- it has been shown in many studies that the rate of renal dysfunction progresses in an individual in a linear fashion, when looking at the curve of 1/Cr vs time, though the slope may change with interventions (eg treating the blood pressure more aggressively). This study suggests that atorvastatin can positively alter the slope of this line.

-- and, statins do provide cardiovascular benefit in patients with or without CKD (though the data are less clear for those with end-stage renal disease, but see below)

--statins change several biomarkers that might be associated with renal dysfunction, including inflammation, oxidative stress, endothelial dysfunction (which may be associated with albuminuria), and fibrogenesis. And CKD itself is associated with ventricular and vascular remodeling, which can be reversed with statins
--though biomarkers are decreased by all statins, there are studies suggesting that rosuvastatin is less good than atorvastatin in preventing renal deterioration, despite its being a better lipid-lowerer. The PLANET I study, an RCT done in multiple countries, looked at diabetic patients with proteinuria who were assigned to atorvastatin 80 vs rosuvastatin 10 vs rosuvastatin 40.  Post-hoc analysis (which added in the PLANET II study, a similar study but including nondiabetics with proteinuria) found that atorvastatin lowered proteinuria significantly more than either dose of rosuvastatin (see statin proteinuria PLANET study Lancetdiab2015 in dropbox, or doi.org/10.1016/ S2213-8587(14)70246-3).  And increasing proteinuria is associated with increasing likelihood of renal deterioration, in both diabetics and nondiabetics.
-- there is a concern in the literature for many years that not all statins are the same.  there certainly is a hierarchy of potency, though there seems to be equivalence in CVD outcomes if one corrects for the degree of LDL reduction. However, some of the statins are very lipophilic (esp simvastatin and atorvastatin) and some hydrophilic (eg rosuvastatin and pravastatin).  So, the question arises if the lipophilic ones, which cross the blood-brain barrier, lead to more CNS effects (see blog tomorrow) and perhaps more renal effects (improved renal parenchymal penetration??) as suggested in the PLANET study.  A few other comments on this issue:
    --post-hoc analysis of the Treating to New Targets (TNT) study found that those on 80mg atorvastatin vs 10mg had more renal protection (though the above review of 6 studies found that the effects of atorvastatin 10 vs 80mg was the same if corrects for the degree of LDL lowering. this is an important point: statins have an array of non-lipid effects, so-called pleiotropic effects, but this current study reinforces that the renal protection effects tracks with LDL changes and not just with some of these other effects)
    --acute kidney injury associated with statins does occur more with higher dose statins (1 patient on atorvastatin 80mg, none on rosumvastin 10mg but 5 on rosuvastatin 40mg in the PLANET study).  But, the main conclusion of the PLANET study was that there were  larger decreases in eGFR in those on rosuvastatin (ie, whereas atorvastatin found benefit, rosuvastatin negatively affected renal function, and more in those on 40mg than 10mg). this may suggest a benefit of the lipophilicity of atorvastatin (perhaps better able to penetrate the renal tissues) vs the hydrophilic rosuvastatin. 


--one issue evident in this study and several considered above is the relative lack of direct head-to-head comparisons of meds. almost all are med vs placebo, which leads to the awkward network meta-analysesused in some studies, per prior blogs (where the researchers try to mathematically control for different meds in different populations, different inclusion/exclusion criteria, etc, to try to give a hierarchy of efficacy of drugs A and B when the studies just compared A or B to placebo). i strongly suspect that the issue is that drug companies would rather compare their product to placebo (more likely finding a positive effect), than against other active drugs (which might suggest that another company's drug is better...).

--limitations of this study include: not having details about overall changes in patient management over the course of the study (did patients start RAAS inhibitors during the study, which have been shown to modify the reciprocal creatinine slopes??  were there changes in blood pressure during this study, which again can dramatically change the trajectory of renal dysfunction). also, the patients had relatively mild renal dysfunction (median eGFR was 66), and the compilation of studies were highly skewed to white men

--i would like to make a perhaps tangential point: it is commonly held that statins do not have much benefit in those with severe renal disease, especially those on dialysis. These are the “negative” studies and my brief comments:
    --4-D trial: hemodialysis patients on 20mg of atorvastatin [which may be a really small dose in those on hemodialysis,as below]
    --AURORA trial: rosuvastatin 10mg [though there was a major decrease in LDLs, the PLANET study suggests that rosuvastatin may not be so great a statin to use]
    --SHARP trial: simvastatin plus ezetimibe, which included some patients on dialysis, did find a trend to benefit but was not really powered to assess the dialysis population
        --and, these ESRD/dialysis patients are at very high cardiovasc risk.  maybe we need much more aggressive LDL lowering?? and a recent observational study found those with very low LDL levels (even down to 21 mg/dL) was associated with cardiovascular benefit without much harm (see http://gmodestmedblogs.blogspot.com/2018/08/very-low-ldl-levels-benefit-without-harm.html )

so, a few issues here:
--there may well be big differences in the effects of statins on non-cardiac outcomes, esp regarding their relative lipophilicity (though cardiac outcomes seem to be similar, controlling for the different statin potencies)
--renal dysfunction is really, really common (at least in my practice), and many of these patients are on statins (in part because of the increased CVD associated with renal dysfunction, often in combo with their other cardiac risk factors)
--but, this study, along with the PLANET trials noted above, do reinforce the benefit of more aggressive statin treatment, in particular with atorvastatin (and likely extendible to other lipophilic statins, esp simvastatin)

geoff

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