Atorvastatin side effects

INTRODUCTION

Atorvastatin, marketed under the brand name Lipitor®, belongs to a group of drugs called “statins,” which work by inhibiting a key enzyme involved in the synthesis of cholesterol. That enzyme, located in the liver, is known as HMG-CoA reductase. Consequently, healthcare professionals sometimes refer to statins as HMG-CoA reductase inhibitors.

COMMON SIDE EFFECTS

The most common side effects of atorvastatin include muscle damage (“myopathy”) and gastrointestinal disturbances (e.g., nausea and diarrhea).

MYOPATHY – THE #1 MOST COMMON SIDE EFFECT

Myopathy (or “muscle symptoms”) account for up to 72% of all statin-related adverse events (Wiggins et al.). According to one study, the overall risk of myopathy associated with the use of statins is 27.8% (Abed et al.). Myopathy is a broad term that refers to diseased muscle tissue. Common symptoms of myopathy include pain, weakness, cramps, and spasms. In more serious cases, damage to the muscle tissue may produce elevations of a certain enzyme in the blood called creatine kinase. We can break the broad category of myopathy down into three smaller categories, listed below in from least severe to most severe:

  1. Myalgia (muscle pain) — very common (5-20% or more)
  2. Myositis (muscle symptoms + elevated creatine kinase) — rare (1%)
  3. Rhabdomyolysis (muscle symptoms + elevated creatine kinase + kidney failure) — very rare < 0.1%

In rhabdomyolysis,  the urine turns red to brown because of myoglobin in the urine (see image below). Myoglobin is a protein released into the bloodstream when muscle tissue is severely damaged. The problem with myoglobin is that it is toxic to the kidneys. What can kill a person with rhabdomyolysis is not the muscle breakdown but the downstream effects of the muscle breakdown (i.e., the resulting kidney damage).

Image Source: James Heilman, MD, CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons

SERIOUS SIDE EFFECTS

Rhabdomyolysis is the perfect segue into a discussion about the serious side effects of atorvastatin. For this information, we look to the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study, which followed 4,731 patients for an average of 4.9 years. Compared to those taking a placebo, the atorvastatin 80 mg per day group experienced the following serious adverse effects:

  1. Diabetes (61% more likely to develop diabetes)
  2. Liver damage (9X more likely to experience persistent elevations in liver enzymes)
  3. Myopathy with creatine kinase elevations (one in one thousand)

A note should be made here about how things have been expressed statistically. For instance, in the atorvastatin package insert (from the pharmaceutical company), the risk of diabetes associated with the use of atorvastatin 80 mg daily (compared to placebo) is not expressed in terms of relative risk. On the contrary, the pharmaceutical company chooses to express this risk in terms of absolute risk. The absolute risk of developing diabetes in the atorvastatin 80 mg group is 6.1% over a nearly 5-year period compared to 3.8% in the placebo group. While the absolute risk is an undeniably more honest expression of the actual risk (as opposed to the relative risk, which really tells you nothing), the pharmaceutical companies (almost without fail) express the purported benefits of their products in terms of relative risk/benefit. Above, I show that atorvastatin 80 mg daily was associated with a 9X higher risk of liver damage; however, in absolute terms, the risk of liver damage is 0.9% (compared to 0.1% in the placebo group). Why is this important?

Imagine there is a new drug that claims to cut the risk of a heart attack by 50%. That sounds great! However, let’s assume we are dealing with a person whose baseline risk of heart attack is 0.2%. A 50% reduction in the risk of a heart attack would only reduce the absolute risk of a heart attack by 0.1%. In other words, 1,000 people would need to receive this medication for one heart attack to be prevented. Now the drug doesn’t sound to amazing. But drug companies strategically use statistical terms to make a miniscule benefit look earthshattering. I’m not discrediting all pharmaceutical products. I’m merely advocating for a more thorough mathematical analysis.

OVERALL PROBABILITY OF SERIOUS SIDE EFFECTS: 1.4-1.8%

The term “serious side effects” is used to identify the subgroup of side effects that have the potential to cause serious harm, up to an including death. How common are serious side effects with atorvastatin? In a study of more than 10,000 participants (the Treating to New Targets Study), 1.4% of those in the atorvastatin 10 mg group and 1.8% of those in the atorvastatin 80 mg group experienced a serious adverse reaction. Also, 8.1% of those in the atorvastatin 10 mg and 9.9% of those in the atorvastatin 80 mg group quit taking the medication for reasons not specified in the publication. (Waters et al.). Based on this information, assuming that everyone who quit taking the medication did not quit as a consequence of experiencing or being on the verge of experiencing a serious side effect, then the overall risk of serious side effects due to atorvastatin is 1.4-1.8%. So, in the best-case scenario, for every 55 people treated with atorvastatin 80 mg, one person will be harmed. Likewise, for every 71 people treated with atorvastatin 10 mg, one person will be harmed.

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REFERENCES

Atorvastatin [package insert]. Princeton, NJ: Dr. Reddy’s Laboratories Inc; 2022.

Wiggins BS, Backes JM, Hilleman D. Statin-associated muscle symptoms-A review: Individualizing the approach to optimize care [published correction appears in Pharmacotherapy. 2022 Jul;42(7):590]. Pharmacotherapy. 2022;42(5):428-438. doi:10.1002/phar.2681

Abed W, Abujbara M, Batieha A, Ajlouni K. Statin Induced Myopathy Among Patients Attending the National Center for Diabetes, endocrinology, & genetics. Ann Med Surg (Lond). 2022;74:103304. Published 2022 Jan 27. doi:10.1016/j.amsu.2022.103304

Waters DD, Guyton JR, Herrington DM, et al. Treating to New Targets (TNT) Study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit?. Am J Cardiol. 2004;93(2):154-158. doi:10.1016/j.amjcard.2003.09.031

Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA. 2004;292(21):2585-2590.

Ramkumar S, Raghunath A, Raghunath S. Statin Therapy: Review of Safety and Potential Side Effects. Acta Cardiol Sin. 2016;32(6):631-639.