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Reduced statin benefits observed as CKD worsens
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In patients with advanced chronic kidney disease, the benefits of statin therapy on cardiovascular outcomes decreased with declining estimated glomerular filtration rate, according to a recent meta-analysis.
“Our results show that, even after allowing for somewhat smaller reductions in LDL cholesterol as GFR declines, there is a trend towards smaller relative risk reductions for major coronary events and strokes,” researchers from the Cholesterol Treatment Trialists’ (CTT) Collaboration wrote. “In particular, there was little evidence that statin-based therapy was effective in patients starting treatment after dialysis had been initiated.”
Researchers from the CTT analyzed patient data from 28 randomized controlled trials assessing the effects of statin therapy on LDL cholesterol reduction according to baseline renal function (n = 183,419; mean age, 62 years; 73% men; 58% with vascular disease; 20% with diabetes). In 23 trials, a statin-based regimen was compared with control (n = 143,807; mean baseline LDL cholesterol, 3.64 mmol/L; mean difference in LDL cholesterol at 1 year, –1.08 mmol/L; median follow-up, 4.8 years). In the remaining five trials, researchers assessed the effects of an intensive statin regimen vs. standard statin regimen (n = 39,612; mean baseline LDL cholesterol, 2.53 mmol/L; mean difference in LDL cholesterol at 1 year, –0.51 mmol/L; median follow-up, 5.1 years).
Baseline renal function data were available for 99% of patients; 68% had an eGFR of at least 60 mL/min/1.73 m²; 19% had an eGFR between 45 and 60 mL/min/1.73 m²; 6% had an eGFR between 30 to 45 mL/min/1.73 m²; 3% had an eGFR 30 mL/min/1.73 m² or less and were not on dialysis; 4% were on dialysis.
Statin therapy treatment effects were estimated with rate ratio (RR) per mmol/L reduction in LDL cholesterol.
Researchers found that statin-based treatment reduced the risk for a first major vascular event by 21% per mmol/L reduction in LDL cholesterol (RR = 0.79; 95% CI, 0.77-0.81), including reduced risks for major coronary events (RR = 0.76; 95% CI, 0.73-0.79) and stroke (RR = 0.84; 95% CI, 0.8-0.89).
“There was a significant trend towards smaller proportional effects on major vascular events with lower eGFR at randomization (P = .008 for trend),” the researchers wrote. “Within each baseline renal function category, the proportional reduction in major vascular events was similar, irrespective of estimated cardiovascular risk level.”
Researchers also found that, overall, statin therapy reduced the need for coronary revascularization procedures by 25% per mmol/L LDL cholesterol reduction (RR = 0.75; 95% CI, 0.73-0.78); however, there was no trend observed for this outcome by baseline renal function.
Statin therapy also reduced the risk for vascular death overall by 12% per mmol/L reduction in LDL cholesterol (RR = 0.88; 95% CI, 0.85-0.91), and researchers found a trend toward smaller proportional effects on vascular mortality with declining baseline renal function (P = .03 for trend).
“However, reducing LDL cholesterol with statin-based therapy had no significant effect on non-vascular mortality at any level of renal function,” the researchers wrote.
In sensitivity analyses excluding patients undergoing dialysis at randomization, researchers did not observe any trends for vascular outcomes or deaths across eGFR categories (P > .05 for all trend values).
In a commentary accompanying the study, Muh Geot Wong, MBBS, PhD, FRACP, and Vlado Perkovic, PhD, FASN, FRACP, both of The George Institute for Global Health, University of Sydney, Australia, noted the results raise further questions regarding the effects of lipid-lowering in advanced disease and highlight the importance of new trials with highly-effective agents.
“By defining what we still do not know, this analysis will hopefully encourage further studies that improve outcomes for this high-risk patient group,” they wrote. – by Regina Schaffer
Disclosure: Most of the trials included in the meta-analysis were supported by research grants from the pharmaceutical industry. Please see the full study for the authors’ relevant financial disclosures.
Perspective
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John B. Buse
There have been similar findings from other studies, but this analysis really provides additional clarity and precision. If you think about it, it makes sense. With advancing kidney disease, more and more of the risk for vascular disease is related to the kidney disease as opposed to cholesterol, so there is less opportunity for the statin drugs to work. Statins do seem to be a great general tonic for the vascular system, but clearly there are other contributors to vascular disease that are not addressed by statin therapy.
Disclosure: Buse reports various financial ties with Andromeda, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dance Biopharm, Elcelyx, Eli Lilly, GI Dynamics, GlaxoSmithKline, Halozyme Therapeutics, Intarcia Therapeutics, Johnson & Johnson, Lexicon, MacroGenics, Medtronic, Merck, Metavention, Minimed, Novo Nordisk, Orexigen, Osiris, PhaseBio, Quest, Sanofi, Scion NeuroStim, Takeda, Tolerex and vTv Therapeutics.
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