PLANET I and II: Atorvastatin beats rosuvastatin for protecting kidneys in diabetic and nondiabetic patients

Daniel M Keller

July 05, 2010

Munich, Germany - Results of two related trials investigating the effects of statins on urinary protein excretion and kidney function suggest that atorvastatin (Lipitor, Pfizer) may be protective but that rosuvastatin (Crestor, AstraZeneca) seems to have no protective effects and in fact may be harmful[1]. The different effects were seen in both diabetic and nondiabetic patients.

High-dose atorvastatin significantly reduced proteinuria and did not affect renal function, whereas rosuvastatin was associated with a significant decline in function and had no effect on proteinuria, according to results of the Prospective Evaluation of Proteinuria and Renal Function in Diabetic Patients With Progressive Renal Disease (PLANET I) and Prospective Evaluation of Proteinuria and Renal Function in Nondiabetic Patients With Progressive Renal Disease (PLANET II) trials, reported in a late-breaking trials session here at the 2010 European Renal Association-European Dialysis and Transplant Association Congress by Dr Dick deZeeuw (University Medical Center in Groningen, the Netherlands).

In diabetic and nondiabetic patients, proteinuria is a risk factor for further loss of kidney function and progression to end-stage renal disease. Experimental results have suggested that statins reduce proteinuria and preserve kidney function, but clinical studies have produced mixed results.

The two randomized double-blind multinational PLANET trials tested the effects of atorvastatin 80 mg/day or rosuvastatin 10 or 40 mg/day on urinary protein excretion and renal function in hypercholesterolemic patients with moderate proteinuria.

PLANET I involved 325 patients with type 1 or 2 diabetes, and PLANET II involved 220 patients without diabetes. Patients had urinary protein/creatinine ratios of 500 to 5000 mg/g, a fasting LDL-cholesterol level of 90 mg/dL or higher, and had used ACE inhibitors or angiotensin-receptor blockers (ARBs) for at least three months prior to screening.

There was an eight-week lead-in period, and then patients were put on the drug. The patients randomized to receive rosuvastatin 40 mg/day or atorvastatin 80 mg/day took half the daily dose for the first four weeks and then escalated to full doses.

Patients with severe renal disease, defined as an estimated glomerular filtration rate (eGFR) below 40 mL/min per 1.73 m2, or PLANET I patients with a hemoglobin A1c level above 11% were excluded from the study, as were people with active liver disease.

The primary end point of the studies was the change in urinary protein/creatinine ratio from baseline to week 52 or to the last on-treatment observation carried forward. For PLANET I (diabetic patients), de Zeeuw summarized: "Atorvastatin significantly reduces the proteinuria in these patients on top of ACE/ARB therapy, with around a 15% reduction in proteinuria, whereas rosuvastatin, both 10 and 40 mg, had no significant effect at all on proteinuria."

The effect of atorvastatin was evident by week 26 and continued through week 52, but neither rosuvastatin dose lowered proteinuria at either time point.

In PLANET II (the nondiabetic cohort), "we see a similar pattern, even more pronounced," he said. Atorvastatin reduced proteinuria by more than 20% at 26 and 52 weeks, but there was no significant effect with either dose of rosuvastatin. The results for albuminuria were very similar to those for proteinuria.

For eGFR, de Zeeuw said the results were "very surprising," in that in the PLANET I trial, patients on rosuvastatin lost more kidney function over 52 weeks than did those on atorvastatin. Patients on atorvastatin lost about 1 to 2 mL/min per 1.73 m2 over 52 weeks, those on rosuvastatin 10 mg/day lost about 4 mL/min per 1.73 m2, and those on rosuvastatin 40 mg/day lost close to 8 mL/min per 1.73 m2.

In nondiabetic patients (PLANET II), the effects of the treatments on kidney function were slightly less pronounced. There was a significant decline in eGFR with rosuvastatin 40 mg/day but not in the other two treatment groups.

de Zeeuw explained that the differential effects on proteinuria and eGFR in the treatment groups was not a result of differences in lipid lowering. All the treatments lowered total and LDL cholesterol, and there were no significant differences in the amount of lipid lowering.

All the treatments were well tolerated in both trials. A total of six deaths occurred, and all were reported as not of a renal etiology. Although determined by investigators to be not related to drug, the incidence of renal adverse events was higher in the rosuvastatin 40 mg/day group in PLANET I but not in PLANET II.

PLANET I: Summary of renal adverse events (%)

Adverse event Rosuvastatin
10 mg/day
(n = 116)
Rosuvastatin
40 mg/day
(n = 123)
Atorvastatin
80 mg/day
(n = 110)
p
Any renal adverse event 7.8 9.8 4.5 NS
Acute renal failure 0.0 4.1 0.9 <0.05
Serum creatinine doubling 0.0 4.9 0.0 <0.01
Serum creatinine doubling or acute renal failure 0.0 7.3 0.9 <0.01

One limitation of the study was that there was no placebo control group; ethical committees overseeing the study would not allow the investigators to have a no-statin group, "which was quite a surprise to us, because I think there is no proof yet that statins actually help in these patients," de Zeeuw said.

He concluded from these findings that in diabetic and nondiabetic patients with proteinuria, using optimal therapy, including ACE inhibitors and ARBs:

  • Atorvastatin 80 mg/day significantly reduced proteinuria by about 20%.

  • Rosuvastatin 10 or 40 mg/day had no effect on proteinuria.

  • Rosuvastatin 40 mg/day was associated with a significant decline in eGFR of about 8 mL/min per 1.73 m2 per year.

  • Atorvastatin 80 mg/day had no effect on eGFR.

  • Atorvastatin 80 mg/day has a clear advantage over rosuvastatin 40 mg/day in terms of renal protection and renal damage.

After many trials and many years of statin use, cardiologists have largely concluded that most of the lipid effects they see with statins are a class effect and not necessarily unique to any particular one. However, de Zeeuw said this trial "sort of dismembers the class effect," at least for the parameters studied here. Atorvastatin and rosuvastatin were obviously exerting different effects on proteinuria and renal function. One big question remaining is whether atorvastatin is actually protecting the kidneys or whether rosuvastatin is damaging them. Based on the current results, de Zeeuw advised, "If you are considering putting such a patient on a statin, you should not put them on rosuvastatin."

Taking the two PLANET trials together, Dr David Harris (University of Sydney, Australia) said: "It's a very important study because it has dispelled the idea about class effects of statins and has shown that two drugs that we thought were extremely similar have very different effects and, clinically, very significant effects on kidney disease. . . . It certainly would point any practicing nephrologist toward using atorvastatin rather than the other drug in this situation."

But he noted that until there are data on hard end points, such as patients progressing to dialysis or dying, the full story on these drugs in this setting will not be known.

The ongoing Study of Heart and Renal Protection (SHARP) trial with simvastatin and ezetimibe (Zetia, Merck) may provide some answers. The trial is studying whether lowering blood cholesterol using simvastatin and ezetimibe in combination or simvastatin alone is better than placebo for reducing risk of cardiovascular events or delaying the need for dialysis in patients with kidney disease. Data collection is scheduled to complete in late summer 2010.

The PLANET trials were funded by AstraZeneca. de Zeeuw reports being a consultant to and receiving honoraria (to his institution) from Abbott, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Hemocue, Novartis, Noxxon, Merck Sharp & Dohme, and Johnson & Johnson. Harris has disclosed no relevant financial relationships.

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