September/October 2013

Weighing the Benefits and Risk of Statins

By Mark D. Coggins, PharmD, CGP, FASCP
Today’s Geriatric Medicine
Vol. 6 No. 5 P. 5

Statins (HMG-CoA reductase inhibitors) are the most widely prescribed class of medications used to lower cholesterol. They dramatically lower total and LDL cholesterol, the latter of which can form plaque on artery walls. Over time, plaque can cause narrowing and hardening of the arteries (atherosclerosis), resulting in reduced oxygen to organs and increasing the risk for heart attack, stroke, and peripheral arterial disease. Statins also increase the levels of HDL cholesterol that bind to and carry cholesterol from the blood to the liver where it can be eliminated, thus reducing plaque formation in the arteries.1

Statins exhibit action beyond their lipid-lowering activity in the prevention of atherosclerosis, including improved endothelial function in the lining of arteries, modulation of inflammatory responses (reducing oxidative stress damage to cells), stabilization of existing atherosclerotic plaque, and prevention of thrombus formation.

Randomized controlled trials have shown statins to be most effective in patients with cardiovascular disease (CVD) (secondary prevention). However, these medications also are used extensively in patients without previously diagnosed CVD who have elevated LDL cholesterol levels and risk factors such as diabetes and hypertension that can increase the risk of CVD.1,2

Statin LDL-Lowering Potency
Statins differ in their potency and ability to reduce cholesterol levels (see Table 1 below). Doses should be individualized according to patient characteristics, such as the goal of therapy and the required LDL-lowering response. Using the lowest dose possible to reach the optimal target reduction helps to minimize side effects.

Selected Statin Studies
In the PROVE-IT TIMI 22 study, patients receiving statins at doses to achieve an LDL cholesterol level of less than 70 mg/dL experienced a significant reduction in cardiovascular events, including sudden death, myocardial infarction (MI), and unstable angina. Benefits were more pronounced in older patients (over the age of 70) with a 40% reduction in cardiovascular events vs. patients younger than 70 who experienced a 26% reduction in such events.3

In the Scandinavian Simvastatin Survival Study, patients with angina or previous MI receiving 40 mg/day of simvastatin for secondary prevention of a cardiovascular event experienced a 30% reduced risk of death.1,4

The Cholesterol Treatment Trialists Collaboration conducted a meta-analysis of 97 randomized studies and determined statin therapy prevented 18 major cardiovascular events in patients without existing coronary heart disease (CHD). An even greater benefit was noted in patients with existing CHD receiving statins for more than five years, with 30 major cardiovascular events prevented for every 1,000 patients treated.5

Another meta-analysis demonstrated that statins reduced the risk of stroke in patients with and without vascular disease by 26% and 16%, respectively.6

Statin Therapy Risks
In 2012, the FDA modified warnings for statins based on reports from clinical trial meta-analysis and epidemiological data. Statin product labels were updated to include warnings on memory loss and confusion, increased blood sugar levels, and new contraindications for lovastatin (Mevacor), plus the FDA noted a reduced need to monitor liver enzymes.7 These warnings have gained increased publicity, making it essential for health care professionals to adequately address the benefits and risks associated with statin therapy to prevent patients from unnecessarily reducing doses or discontinuing statin medications.

“This new information should not scare people off statins,” noted Amy G. Egan, MD, MPH, deputy director of safety in the FDA’s division of metabolism and endocrinology products. “The value of statins in preventing heart disease has been clearly established, and … their benefit is indisputable, but they need to be taken with care and knowledge of their side effects.”8

Diabetes
Statin therapy may result in a slight increase in the risk of diabetes due to increases in hemoglobin A1c and/or fasting plasma glucose levels. Based on current information, the risk of diabetes is only slightly increased and although all statins carry this warning, pravastatin may be appropriate for patients with moderate LDL-lowering needs, as some evidence exists that it may actually lower diabetes risk.9,10
Patients receiving statins should have blood sugars monitored more closely; however, patients who develop diabetes or experience worsening diabetes should not stop taking statins, as the cardiovascular benefits typically outweigh the risks associated with diabetes. To put the risk-to-benefit ratio in perspective, for every 1,000 patients taking a statin for one year, there would be one additional case of diabetes but an expected nine fewer cardiovascular events.11

Cognitive Impairment
The FDA has noted rare reports of memory loss, forgetfulness, and confusion with statin therapy.8 However, a review of clinical studies involving statins in which cognition was a primary or secondary end point, as well as observational studies and case reports, have been inconsistent. Some studies report worsening memory function, while others suggest statins may help reduce the risk of developing dementia. It is believed decreased cholesterol in the brain may lead to reduced myelin formation and function as well as a reduction in the coenzyme Q10, which impairs mitochondrial function and increased oxidative stress, thus leading to cognitive impairment.12

Patients over the age of 50 appear to be at greater risk of statin-induced cognitive impairment unrelated to progressive dementia and reversible on discontinuation. The effect can occur at any time after starting a statin and improves after the medication is stopped.

It is important to rule out other causes of cognitive decline. Should memory loss or confusion associated with statin use occur, clinicians should consider withholding the statin for one to three months to see whether symptoms improve or switch to a less lipophilic statin (eg, rosuvastatin [Crestor], pravastatin [Pravachol]).7

Rare Liver Toxicity
FDA labeling for statins now recommends liver enzyme tests be performed before starting therapy and as clinically indicated, such as a patient experiencing symptoms of unexplained nausea, abdominal pain, or jaundice. The reason for the change is that serious injury related to statin use is idiosyncratic and not detected with routine monitoring, if it occurs at all, as there is only about one case of liver failure for every 1 million patients per year on a statin, which is similar to the incidence of liver failure among people not receiving statin therapy.7

Muscle Pain and Breakdown
As many as 30% of patients taking a statin report muscle aches or weakness, with most patients being able to continue statin therapy. In the PRIMO study, patients’ thighs or calves were the predominant sites of complaints in more than 25% of sufferers.13 Patients experiencing muscle pain, soreness, or unexplained weakness should notify their physicians especially if the symptoms are accompanied by a fever, a sick feeling, or dark urine, as this may be a sign of a more serious side effect known as rhabdomyolysis. Rhabdomyolysis can be ruled out by reviewing creatine kinase levels (10 is the upper normal limit), which serve as a marker for muscle breakdown.13-15

Risk factors for statin myopathy include being elderly, small size, a high statin dose, liver or renal disease, diabetes, uncontrolled hypothyroidism, and interacting medications.15 For muscle pain associated with statins that is not linked to rhabdomyolysis, lower doses may be considered if goal LDL levels still can be achieved. It is especially important to avoid interacting drugs, such as the antifungal itraconazole, erythromycin, protease inhibitors, cyclosporine, diltiazem, verapamil, and grapefruit juice, which can interact with statins and increase the risk of myopathies and rhabdomyolysis. An increased risk of rhabdomyolysis or liver failure can occur when statins are taken with niacin, fibric acids such as gemfibrozil, or fenofibrate (Tricor).7,14

For some patients, correcting low vitamin D levels or hypothyroidism can help with muscle pain.16 Although no large controlled studies have been completed, supplementation with coenzyme Q10 may be helpful with both statin-associated pain and cognitive decline caused by reduced levels that occur with statin therapy.17

The FDA also recommends that drugs containing 80 mg of simvastatin be used with caution because of muscle injury risk. Patients typically should take no more than 40 mg/day. The FDA has issued a recommendation to limit the dose of simvastatin to 20 mg/day when used with the calcium channel blocker amlodipine.18

— Mark D. Coggins, PharmD, CGP, FASCP, is a director of pharmacy services for more than 300 skilled nursing centers operated by Golden Living and a director on the board of the American Society of Consultant Pharmacists. He was recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References
1. Pichandi S, Pasupathi P, Raoc Y, et al. The role of statin drugs in combating cardiovascular diseases. Int J Cur Sci Res. 2011;1(2):47-56.

2. Marzilli M. Pleiotropic effects of statins: evidence for benefits beyond LDL-cholesterol lowering. Am J Cariovasc Drugs. 2010;10 Suppl 1:3-9.

3. O’Riordan M. PROVE-IT TIMI 22: large benefit in elderly ACS patients treated to low LDL cholesterol levels. TheHeart.org website. http://www.theheart.org/article/404557.do. March 16, 2005. Accessed July 21, 2013.

4. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344(8934):1383-1389.

5. Studer M, Briel M, Leimenstoll B, Glass TR, Bucher HC. Effect of different antilipidemic agents and diets on mortality: a systematic review. Arch Intern Med. 2005;165(7):725-730.

6. O’Regan C, Wu P, Arora P, Perri D, Mills EJ. Statin therapy in stroke prevention: a meta-analysis involving 121,000 patients. Am J Med. 2008;121(1):24-33.

7. FDA drug safety communication: important safety label changes to cholesterol-lowering statin drugs. US Food and Drug Administration website. http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm. Accessed July 27, 2013.

8. FDA expands advice on statin risks. US Food and Drug Administration website. http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM293705.pdf. February 2012. Accessed July 27, 2013.

9. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011;305(24):2556-2664.

10. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735-742.

11. Baker WL, Talati R, White CM, Coleman CI. Differing effect of statins on insulin sensitivity in non-diabetics: a systematic review and meta-analysis. Diabetes Res Clin Pract. 2010;87(1):98-107.

12. Rojas-Fernandez CH, Cameron JC. Is statin-associated cognitive impairment clinically relevant? A narrative review and clinical recommendations. Ann Pharmacother. 2012;46(4):549-557.

13. Alsheikh-Ali A, Kuvin J, Karas R. Risk of adverse events with fibrates. Am J Cardiol. 2004;94(7):935-938.

14. Jacobson TA. Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors. Am J Cardiol. 2004;94(9):1140-1146.

15. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin. Am J Cardiol. 2005;95(1):120-122.

16. Ahmed W, Khan N, Glueck CJ, et al. Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients. Transl Res. 2009;153(1):11-16.

17. Uses of coenzyme Q10. Pharmacist’s Letter/Prescriber’s Letter. 2010;26(6):260607.

18. FDA: Limit use of 80 mg simvastatin. US Food and Drug Administration website. http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm257884.htm. Updated April 17, 2013. Accessed July 30, 2013.

Table 1

— Source: PL Detail Document, Characteristics of the Various Statins. Pharmacists’s Letter/Prescriber’s Letter. May 2012.