William Simonson, PharmD, BCGP, FASCP *
Oregon State University, Corvallis, OR, USA
Statin drugs are one of the most commonly used classes of medications, and one of the most controversial. The ﬁrst statin, lovastatin, was approved by the US Food and Drug Administration (FDA) in 1987. Additional statins received FDA approval, mostly in the 1990’s. Statins now available as single agent products include atorvastatin (Lipitor), ﬂuvastatin (Lescol, Lescol XL), lovastatin (Mevacor, Altoprev), pravastatin (Pravachol), rosuvastatin (Crestor), simvastatin (Zocor, FloLipid) and pitavastatin (Livalo) and some statins are available in combination products. Fifteen million Americans now take statin drugs making this one of the more popular classes of prescription drugs.
Statins work by inhibiting the action of the naturally-occurring enzyme HMG Co-A reductase which controls cholesterol production by the liver. Inhibition of this enzyme has numerous effects including decreasing both total cholesterol and low-density lipoproteins (LDL or “bad” cholesterol) and increasing high-density lipoproteins (HDL or “good” cholesterol). It has been shown that these modiﬁcations signiﬁcantly decrease the development of atherosclerotic cardiovascular disease (ASCVD). There are many studies documenting the beneﬁcial effects of statins, far too many to address in this short column. Numerous organizations have analyzed these data and made recommendations on statin use and unfortunately, many of these guidelines give different recommendations. For this update I’ll focus my discussion on two of the better-known guidelines. The proper use of any medication – prescription or non-prescription – should always involve a thoughtful consideration of risk v. beneﬁt so that’s the approach I’ll take.
In 2013 the American College of Cardiology and the American Heart Association (ACC/AHA) published guidelines for the use of statins that substantially expanded the population eligible for statin therapy.1 They based their recommendations on an estimated elevated 10-year risk of atherosclerotic cardiovascular disease by basically identifying four high-risk groups: individuals who had already experienced a cardiovascular event (stroke or heart attack), diabetics between the age of 40 and 69, persons with an elevated LDL, and older men. These guidelines are based on an estimation of an individual’s risk of experiencing a cardiovascular event in the next ten years. Their “risk calculator” is available as an “app” that can be downloaded to electronic devices. The guidelines recommend that when an individual’s 10-year risk is 7.5% or greater a dialogue should take place between patient and caregiver regarding the potential beneﬁt of statin use in that individual.
In 2016 the United States Preventative Task Force (USPTF) released their recommendations which differ from the ACC/AHA by using an increased risk threshold for starting statins and the requirement of at least one existing risk factor (i.e. hypertension, diabetes, dyslipidemia or smoking) in addition to elevated risk.2 In an independent comparison it was estimated that if both sets of guidelines were fully applied to the US population the USPTF guide-lines would initiate statins in 16% of adults aged 40 to 75 years of age and without previous cardiovascular disease. This compares with 24% of the population who would be using statins under the ACC/AHA guidelines. Adherence to the USPTF guidelines could lead to decreased use of statins including in many younger adults with a 30-year risk of CVD exceeding 30%.3
The USPTF guidelines only address statin use for primary prevention (prevention of ﬁrst cardiovascular disease event, either a stroke or heart attack) and do not give recommendations for persons over age 75 due to insuﬃcient evidence.2
In contrast, the ACC/AHA guidelines cautiously support the continuation of statins beyond age 75 years in persons who are already taking and tolerating statins and support the use of moderate-intensity statin therapy for secondary prevention (prevention of recurrent stroke or heart attack) in individuals with clinical ASCVD who are >75 years of age. However, the guidelines do not clearly support initiation of high-intensity statin therapy for secondary pre-vention in this older population sub-group.1
I would love to be able to tell you which of these guidelines is the most appropriate to follow but I can’t….that’s what controversy is all about! Some concern has been raised that adherence to the USPTF guidelines will deprive statins from younger adults with high long-term risk of cardiovascular disease while others feel that the ACC/AHA guidelines over-estimate the risk of CVD and encourage unnecessary statin use. What I can recommend is to stay tuned to the literature because existing guidelines will be undoubtedly be modiﬁed and new guidelines will be released as the clinical out-comes of various guidelines are better understood.
And, all of the current statin guidelines may become moot if a powerful new class of new lipid-lowering agents takes over. The FDA has approved two new lipid-lowering medications, alirocumab (Praluent) and evolocumab (Repatha). Known as “PCSK9 inhibitors”, they are more potent than existing statins. They appear to be very effective as demonstrated by a recent study in which evolocumab reduced the risk of cardiovascular death, heart attack and stroke by about 20% in patients who were already taking a statin.4 The fact that two products from this class are on the market – and more are in the developmental pipeline – could help lower their initial price of almost $15,000 a year. Each of these drugs are expected to generate more than $2 billion a year in sales by 2020.5
On the risk side of this discussion some people experience one or more of the following problems when using statins including the following: (this part of the discussion is adapted from a very in-formative publication of the Mayo clinic which the reader is encouraged to review.6)
Muscle pain is one of the most common complaints associated with statins and can be mild muscle soreness, or the pain can be severe enough to make daily activities difficult. Up to 29 percent of the people who start taking statins report muscle pain and many discontinue statins because of it. In some, switching to a different statin will eliminate the pain. Many of these people do well when they are switched to a different statin. Very rarely, a few cases per million statin users per year, can statins cause life-threatening muscle damage called rhabdomyolysis. This includes severe muscle pain, liver damage, kidney failure and death. Rhabdomyolysis can occur when a statin is taken in combination with a fairly long list of potentially interacting medications or if a high dose of statins is used.
(The complete list of medications is presented in the Mayo publi-cation mentioned above.6)
Occasionally, statin use causes an increase in the level of enzymes that signal liver inﬂammation. When this increase is mild the patient can continue to take the statin. If the increase is severe, use of a different statin may eliminate this problem. Liver enzyme tests may be ordered before or shortly after initiation of statin therapy but additional tests should not be necessary and are no longer recommended by the FDA.
Though the risk is low, the FDA has issued a warning that statins may increase blood sugar which may lead to developing type 2 diabetes. The FDA also warns that some people may develop memory loss or confusion while taking statins which reverse when the statin is discontinued.
Not everyone who takes a statin will have side effects, but some people may be at a greater risk than are others. Risk factors include: Taking multiple cholesterol-lowering medications, female gender, small body frame, age 65 and older, kidney or liver disease, exces-sive alcohol intake, taking other medications or foods (including grapefruit juice) that may interact with statins.
It may be possible to reduce statin side effects by changing to a different statin, taking a brief break in therapy, or lowering the statin dose.
It boils down to a risk/beneﬁt analysis. Consider the patient, con-sider their risk of CVD and consider the risks of statin use using one or more guidelines, and by monitoring the patient during therapy to make sure the risk/beneﬁt analysis has not changed. Stay tuned for more guidelines, and for new lipid-lowering medications.
1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. J Am Coll Cardiol. 2014;63:2889–2934.
2. USPTF task force. Statin use for the primary prevention of cardiovascular disease in adults: preventative medication; 2016. Release date November. https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummary Final/statin-use-in-adults-preventive-medication1. Accessed April 19, 2018.
3. Pagidipati NJ, Navar AM, Mulder H, et al. Comparison of recommended eligibility for primary prevention statin therapy based on US preventative services task force recommendations vs, the ACC/AHA guidelines. JAMA. 2017;317:1563–1567.
4. Sabatine MS, Giugliano RP, Keech AC, et al. Evolucumab and clinical outcomes in patients with cardiovascular disease. NEJM. 2017;376:1713–1722.
5. Clarke T. FDA approves new cholesterol-lowering drug. Scientiﬁc American; 2015. https://www.scientiﬁcamerican.com/article/fda-approves-new-cholesterol-lowering-drug/. Accessed April 19, 2018.
6. Mayo Clinic Staff, Statin side effects: Weigh the beneﬁts and risks; 2016. April 4. https://www.mayoclinic.org/diseases-conditions/high-blood-cholesterol/in-depth/statin-side-effects/art-20046013. Accessed April 19, 2018.