New Study Supports Our “Do Not Use” Designation for Rosuvastatin

Rosuvastatin (CRESTOR, EZALLOR SPRINKLE) is a cholesterol-lowering statin drug that was approved by the Food and Drug Administration (FDA) in 2003.[1] In the same year, Public Citizen’s Health Research Group designated this statin as a Do Not Use drug immediately after it was approved[2] and in 2004 petitioned the FDA[3] to remove it from the market due to serious safety concerns discussed below.

A new study published in September 2022 showed that patients taking rosuvastatin had a higher risk of proteinuria (abnormal levels of protein in the urine) and hematuria (blood in the urine) than those taking another statin, atorvastatin (LIPITOR).[4] These risks were even higher for patients who were either taking high doses of the drug or were already suffering from severe kidney damage.

Reasons for the Do Not Use designation

Rosuvastatin is one of seven cholesterol-lowering statin drugs, including atorvastatin, fluvastatin (LESCOL XL), lovastatin (ALTOPREV), pitavastatin (LIVALO, ZYPITAMAG), pravastatin (available in generic only) and simvastatin (FLOLIPID, ZOCOR), that are approved to be used along with a low-cholesterol diet and an exercise program to lower cholesterol. Of these, only rosuvastatin and atorvastatin are classified by the American College of Cardiology and American Heart Association as high-intensity statins (when used at high doses).[5]

However, unlike other statins, when rosuvastatin was approved, the available data showed that it did not benefit patients who took it to reduce serious cardiovascular consequences of high cholesterol, such as heart attack or stroke. Rosuvastatin also increased the risk of proteinuria and hematuria, which can be warning signs of worsening kidney injury or failure.[6],[7],[8]

Moreover, although all statin drugs can cause rhabdomyolysis, a muscle-destroying condition that can lead to sudden kidney failure and death, patients taking rosuvastatin are at an increased risk of this serious adverse effect. Importantly, rosuvastatin was also the only statin that was found to cause this dangerous condition in its preapproval clinical trials.[9],[10] Because of these findings, we designated the drug as Do Not Use soon after it was approved.[11]

Predictably, within months after rosuvastatin was approved by the FDA, multiple additional cases of life-threatening muscle damage and kidney failure were reported to the agency. These reports prompted Public Citizen’s Health Research Group to petition the FDA in 2004 to ban the drug.[12] The FDA denied the petition in 2005.

2022 study confirms increased safety risks

Since the approval of rosuvastatin, the concerns over the increased risks of this drug compared with other statins were confirmed, though only in small studies or case reports.[13] Now, a large observational study published in the Journal of the American Society of Nephrology confirmed the increased risks associated with rosuvastatin compared with the other available high-intensity statin, atorvastatin.[14]

In this new study, researchers looked at deidentified electronic health records from over 80 million patients from 40 health care organizations across the United States and identified 152,101 patients who had started taking rosuvastatin between 2011 and 2019 and 795,799 who started atorvastatin during the same period.

For a patient to be included in the study, their health records had to show that they had not taken any statins in the year before they started taking rosuvastatin or atorvastatin; did not have a history of blood or protein in their urine; and did not have kidney failure with replacement therapy (dialysis or a kidney transplant). Patients with a history of rhabdomyolysis also were excluded. The patients in both groups were 18 years of age or older, had comparable cardiovascular risk factors and were similar in terms of demographics and concomitant use of other medications.

Although the cardiovascular benefits for patients taking either statin were similar, patients taking rosuvastatin had a slightly higher risks of developing hematuria, proteinuria and kidney failure with replacement therapy. For instance, 3.4% of patients taking rosuvastatin developed blood in their urine, compared with 2.8% of patients taking atorvastatin. This represented an 8% greater relative risk of hematuria in the rosuvastatin patients. Notably, the incidence rate of hematuria for patients with severe kidney disease who took rosuvastatin was nearly threefold higher than for those with mild kidney disease who took that statin.

Patients on rosuvastatin were also more likely to develop protein in their urine (1.2%) than those taking atorvastatin (0.9%), a relative risk increase of 17%. Patients with severe kidney disease who took rosuvastatin also had an approximately ninefold higher risk of developing proteinuria than those with mild kidney disease who took that drug.

Another important finding of this study was that the majority of patients with severe kidney disease started their statin therapy on a higher-than-recommended daily dose of rosuvastatin. Although this drug is available in 5-, 10-, 20- and 40-milligram (mg) daily doses, in this patient group the drug product labeling recommends a starting dose of 5 mg and a maximum of 10 mg daily. However, 80% of the patients with severe kidney disease included in this study started their treatment on a higher-than-recommended dose, with 44% exceeding the recommended maximum of 10 mg daily.[15] Fourteen percent of these patients even started their treatment on the highest available dose of 40 mg daily. This finding is particularly worrisome, as higher doses of this drug increase patients’ risks of adverse effects.

Although the danger of developing muscle damage with high doses of rosuvastatin was already established, this study confirmed that high doses of this statin also increase patients’ risks of hematuria, proteinuria and kidney failure with replacement therapy.

What You Can Do

Unless you have pre-existing cardiovascular disease, only take a statin for prevention of heart attacks and strokes if diet and exercise alone have failed to bring your cholesterol to the desired level. Even if you need treatment with a statin, do not use rosuvastatin because it has a greater risk of muscle damage and kidney problems than other statins.

Also be aware that certain medications can interact with statins, so make sure to tell your doctor about all other medications you are taking to assess your risk for potentially significant drug interactions. You may need a lower dose, or your prescriber may advise you to stop either the statin you are taking or the interacting drug.

Regardless of what statin you are taking, notify your doctor immediately if you develop muscle pain or weakness, or notice a darkening of your urine.
 

References

[1] AstraZeneca. Label: rosuvastatin (CRESTOR). September 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021366s042lbl.pdf. Accessed December 7, 2022.

[2] Do Not Use! Rosuvastatin (Crestor) - A new but more dangerous cholesterol lowering 'statin' drug. Worst Pills, Best Pills News. October 2003. https://www.worstpills.org/newsletters/view/248. Accessed December 7, 2022.

[3] Public Citizen. Petition to ban cholesterol-lowering drug rosuvastatin (Crestor). March 4, 2004. https://www.citizen.org/article/petition-to-ban-cholesterol-lowering-drug-rosuvastatin-crestor/. Accessed December 7, 2022.

[4] Shin JI, Fine DM, Sang Y, et al. Association of rosuvastatin use with risk of hematuria and proteinuria. J Am Soc Nephrol. 2022;33(9):1767-1777.

[5] Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/ APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082–e1143.

[6] Do Not Use! Rosuvastatin (Crestor) - A new but more dangerous cholesterol lowering 'statin' drug. Worst Pills, Best Pills News. October 2003. https://www.worstpills.org/newsletters/view/248. Accessed December 7, 2022.

[7] Wolfe S. Dangers of rosuvastatin identified before and after FDA approval. Lancet. 2004;363(9427):2189-2190.

[8] Wolfe S. Rosuvastatin: winner in the statin wars, patients’ health notwithstanding. BMJ. 2015 Mar 17;350:h1388.

[9] Muscle damage from interactions between statins and other commonly prescribed drugs. Worst Pills, Best Pills News. July 2009. https://www.worstpills.org/newsletters/view/649. Accessed December 7, 2022.

[10] Do Not Use! Rosuvastatin (Crestor) - A new but more dangerous cholesterol lowering ‘‘statin’ drug. Worst Pills, Best Pills News. October 2003. https://www.worstpills.org/newsletters/view/248. Accessed December 7, 2022.

[11] Ibid.

[12] Public Citizen. Petition to ban cholesterol-lowering drug rosuvastatin (Crestor). March 4, 2004. https://www.citizen.org/article/petition-to-ban-cholesterol-lowering-drug-rosuvastatin-crestor/. Accessed December 7, 2022.

[13] Alsheikh-Ali AA, Ambrose MS, Kuvin JT, Karas RH. The safety of rosuvastatin as used in common clinical practice: a postmarketing analysis. Circulation. 2005;111(23):3051-3057.

[14] Shin JI, Fine DM, Sang Y, et al. Association of rosuvastatin use with risk of hematuria and proteinuria. J Am Soc Nephrol. 2022;33(9):1767-1777.

[15] AstraZeneca. Label: rosuvastatin (CRESTOR). September 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021366s042lbl.pdf. Accessed December 7, 2022.