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Atorvastatin and Rosuvastatin Show Shorter Time to Onset of Musculoskeletal Adverse Events Than Other Statins

In pain patients with high levels of LDL cholesterol, findings could lead to better choice of statins

With Daisuke Kobayashi, MD, Elmer G. Pinzon, MD, MPH, DABIPP, and Gabriel E. Sella, MD, PhD, MPH, MSc

Statin drugs are ubiquitous in the US, with millions taking one of the cholesterol-lowering drugs.1 While statins have been used since the 1980s for the treatment of elevated low-density lipoprotein (LDL) cholesterol and are generally well-tolerated, these drugs have been associated—though rarely—with musculoskeletal adverse events (MAEs) including myalgia, myopathy, and rhabdomyolysis.2,3 In a recent study,4 researchers reported on the time to onset of MAEs for various statins, and that concomitant treatment with a range of other drugs does not appear to shift the timing of onset.

“Many patients with hypercholesterolemia have complicated lifestyle-related diseases, including diabetes mellitus and high blood pressure,” principal investigator Daisuke Kobayashi, MD, department of analytical pharmaceutics and informatics faculty of Pharmacy and Pharmaceutical Sciences at Josai University in Sakado, Japan, told PPM. “These patients are likely to use not only statins but also anti-diabetic and anti-hypertensive drugs. Drug-drug interactions have been observed between statins and some anti-hypertensive drugs (eg, calcium channel blockers). With this study, we could obtain findings that reflected patients with lifestyle-related diseases in clinical settings.”

Time to Onset Study

Dr. Kobayashi and colleagues used data from FDA’s Adverse Events Reporting System (FAERS) to examine4 the onset timing of MAEs associated with statins both as a monotherapy and when used concomitantly with other drugs. The FAERS database includes voluntary (ie, non-validated) reports to FDA of adverse events, medication errors, and product quality complaints resulting in adverse events. The database supports post-marketing safety surveillance for drug and therapeutic biologic products.

The analysis included FAERS quarterly data sets from 2004 to 2017. The researchers identified cases with prescriptions for: atorvastatin, rosuvastatin, simvastatin, lovastatin, fluvastatin, pitavastatin, and pravastatin. Cases were extracted if MAEs were noted—using the terms rhabdomyolysis, myalgia, myoglobinuria, and an increase of blood creatine phosphokinase. Cases were separated by statin use as monotherapy or concomitantly with other drugs.

(Source: 123RF)

Research Findings

Monotherapy cases were included in the analysis if MAEs had occurred within one year of the statin start date. The researchers identified more than 1,400 monotherapy cases with MAEs:

As clinicians know, statins work by inhibiting 3-hydroxy 3-methylglutaryl co-enzyme A reductase (HMG-CoA), an enzyme that controls the metabolic pathway behind cholesterol production in the body. The researchers noted that, “previous study findings and the results of the present study suggest that statins with a high HMG-CoA reductase inhibitory activity, such as atorvastatin and rosuvastatin, not only increase the onset risk of MAEs, but also induce MAEs within a short time.”
Statistical analysis revealed that median MAE onset was significantly faster for atorvastatin and rosuvastatin than for simvastatin. There were no significant differences between atorvastatin and rosuvastatin, both of which are considered high-intensity statins (reducing LDL by more than half).4

The researchers also determined that concomitant use of non-statin drugs did not shift the onset timing of MAEs. A total of 24 drugs were used concomitantly with atorvastatin (at a frequency of 30 or more cases). Twenty-one and 26 drugs were used concomitantly with rosuvastatin and simvastatin, respectively. Aspirin was the most commonly used drug with all three statins.

When compared with simvastatin monotherapy, the concomitant drug with the shortest time to MAE onset was the antihypertensive drug, lisinopril, at a median of 3 days. Similarly, for rosuvastatin and simvastatin, the drugs with the shortest time to onset were ramipril (12 days) and amlodipine (12.5 days), respectively. Both drugs are used for the treatment of high blood pressure.

“It was clarified that even if the concomitant use of statins and drugs that may cause drug-drug interaction can change the MAE onset risk, it is unlikely that the onset timing will be changed. The results also showed that it is unlikely for other concomitant drugs, which are thought to have no drug interaction with statins, to cause changes in the onset timing of MAEs,” they wrote in their published study.4

Potential Implications

The findings of Dr. Kobayashi’s work may carry important implications for reducing and preventing side effects in pain patients with high levels of LDL cholesterol. Clinicians may choose to prescribe a statin with a lower risk of MAEs for patients with existing MSK pain, for example, according to Elmer G. Pinzon, MD, MPH, DABIPP, a physiatrist specializing in musculoskeletal medicine and member of the PPM Editorial Advisory Board. The findings could also guide treatment of patients with new-onset MSK pain. “Switching a patient with new-onset musculoskeletal pain to a different statin, if they had recently started atorvastatin or rosuvastatin—in the absence of other disease signals—would be a good choice, especially since medication side effects can be patient-specific,” he said.

Gabriel E. Sella, MD, PhD, MPH, of the Ohio Valley Medical Center and member of the PPM Editorial Board, thinks that the findings here will not change practice, noting that “the issue is complicated by the reality that insurance contracts interfere so much with what we prescribe.” However, Dr. Sella was ultimately positive about atorvastatin and rosuvastatin and their usage toprotect against cardiovascular disease. “The presence of musculoskeletal pain due to taking statins is relevant only for the patients who get such pain. As such, I would not stop or advise physicians to stop prescribing these two statins.”

Last updated on: April 29, 2019
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