What is Cardiovascular Disease?
Approximately 81 million American adults are living with cardiovascular disease (CVD). Cardiovascular disease includes hypertension, coronary heart disease, heart failure, stroke and/or congenital cardiovascular heart defects. More than 17 million people with CVD have coronary heart disease (also called coronary artery disease), which is a build-up of fat (atherosclerotic plaque) in the walls of the arteries around the heart. Coronary heart disease is the number one cause of death in the United States.
What are Statins?
Statin medications (statins) are drugs that help lower cholesterol levels in the blood. Statins help prevent coronary heart disease in patients without a history of CVD (primary prevention) and those who are at very high risk of developing CVD (such as patients with diabetes, genetic familial hyperlipidemias) or have had some form of CVD, including heart attack, stroke, transient ischemic attack (TIA), angioplasty, coronary artery stent placement or peripheral vascular disease (secondary prevention).
Statins are the first-line treatment of choice for patients with high cholesterol and those diagnosed with coronary heart disease. Statins have additional benefits beyond lowering cholesterol levels (pleiotropic effects); they also help the lining of the blood vessels work better (improved endothelial function), enhance the stability of atherosclerotic plaques, reduce the amount of inflammation and damage done to cells through oxidation (oxidative stress), and keep blood platelets from clumping together (platelet aggregation), thereby reducing the risk of a blood clot (thrombus).
Multiple placebo-controlled trials of statin therapy have demonstrated significant reductions in cardiovascular event rates in both primary and secondary prevention patient populations and across a broad range of LDL cholesterols prior to treatment. Recent trials have demonstrated benefit in at-risk patients even if LDL cholesterols were not significantly elevated and have demonstrated additional reduction in adverse events with higher intensity statin therapy.
The Jupiter Trial (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin) included more than 15,000 patients without CVD. Participants included men over the age of 50 and women over the age of 60 with normal cholesterol levels (their LDL [“bad” cholesterol] level was less than 130 mg/dL), and elevated levels of ultra sensitive C-reactive protein (2.0 mg/L or higher). High levels of C-reactive protein indicates inflammation and is an independent risk factor for CVD. In other words, people with high levels of C-reactive protein are at risk of developing CVD even if they have no other risk factors.
The Jupiter Trial was a randomized, double-blind, placebo-controlled, multicenter trial that involved 1,315 sites in 26 countries. Participants were randomly chosen to be part of one of two groups: those who took rosuvastatin (Crestor) 20 mg daily or those who took a placebo (a pill containing no drug). The trial was scheduled to run for five years, but it was terminated after 1.9 years because there was an overwhelming amount of data that showed that participants who were taking a statin had a reduced risk of CVD.
The trial showed that compared to patients taking the placebo, patients taking a statin had a 54% lower chance of heart attack, 48% lower chance of stroke, 46% lower chance of needing angioplasty or coronary artery bypass surgery, and a 20% lower chance of dying from any cause. In addition, among patients taking a statin, their level of ultra sensitive C-reactive protein was reduced by 37%, and their LDL cholesterol levels were reduced by 50%.
The Jupiter trial also provided the first results to show that statins are highly effective in female and minority patients — groups typically excluded in clinical trials. The take-home message from this study is that patients with higher-than-normal levels of ultra-sensitive C-reactive protein levels, even those with normal cholesterol levels, may benefit from statin therapy.
Other studies have shown that statins can have the same types of benefits in patients with a history of or at high risk of developing CVD. These studies include the Treating to new Targets Study (TNT). The purpose of this trial was to see if lowering LDL levels to below 100 mg/dL with higher intensity statin medications further reduced risk of developing recurrent CVD, and to see how safe this type of treatment was. The trial results showed that patients in this trial also gained additional benefits from taking a statin.
Another secondary prevention clinical trial, Prove IT-TIMI 22, compared the benefits of lowering LDL levels to below 100 mg/dL versus below 70 mg/dL. The study showed that patients whose lipid levels were drastically lowered (intensive statin therapy versus a less intensive statin therapy) had a lower risk of dying and having a major cardiovascular event.
In the ASTEROID trial, researchers studied intensive statin therapy with rosuvastatin (Crestor) 40 mg to see if it can reverse plaque build-up and thickening of the arteries (coronary atherosclerosis). Although further studies are needed to compare the results of the trial to clinical outcomes, researchers found that lowering LDL cholesterol to lower-than-recommended levels plus increases in HDL cholesterol (“good” cholesterol) can, indeed, reverse atherosclerosis in patients with coronary disease.
Fortunately, side effects with statins are not common, occurring in only in up to 3% of people individuals in randomized clinical trials on statins and most are not serious
The most common side effects of statins include:
- Gastrointestinal symptoms such as constipation, nausea, or indigestion.
- Upper respiratory type symptoms.
- Muscle side effects:
- Myalgia or soreness or aching without associated injury (occurs in 1.5-3.5% of patients taking statins in clinical trials. However observational studies suggest that this may be present to some degree and up to 10% of individuals).
- Myopathy or muscle soreness associated with muscle injury (occurs in less than 1/10th of a half of percent of patients taking statins).
- Rhabdomyolysis, the most severe form of myopathy, is very infrequent (occurs 5 in very 10,000 patients taking statin drugs).
- Liver abnormalities (occur in less than 1 percent of people taking statins); found during blood testing and are in most cases reversible with stopping the medication; may even improve with continuing to take the statin drug at the same dose or a reduced dose.
- Diabetes – some patients who are at risk for diabetes have a moderate risk of developing diabetes after starting a statin. Benefits and risks of statin use in these patients should be discussed with the patient. In general it is felt that the benefits of statin therapy in high-risk patients outweigh the risk of diabetes development.
Patients are considered statin intolerant if they develop side effects and are unable to continue to use a statin medication or able to only tolerate lower doses.
Who is at risk for statin intolerance?
- The elderly, over 75 to 80 years
- Having a small body frame or being frail
- Having other medical conditions such as kidney disease or liver disease
- Large amounts of grapefruit or grapefruit juice consumption
- Taking some medications like certain types of drugs used to treat fungal infection, some antibiotics, and some heart medications
These risk factors may increase the levels of stain in the blood and therefore be associated with a higher risk of side effects, so it’s important to let your doctors know any other medications or supplements you are taking.
What to do if you think you are statin intolerant
If you think you are statin intolerant, you should see a lipid specialist (doctor who specializes in the treatment of abnormal cholesterol values) to work with you to achieve your lipid goals.
Cleveland Clinic’s Preventive Cardiology team have found that almost 73 percent of patients who were thought to be intolerant to two or more statin medications were able to obtain the benefits of statin drugs through a careful program. Patients were taken off the statin causing side effects and either re-started on the same drug at a very low dose; or instructed to take a different statin.
Patients who experience muscle discomfort may take Coenzyme Q-10 (CoQ-10) to help relieve the symptoms. Some studies show that patients may better tolerate statins when they take them with CoQ-10. Coenzyme Q-10 is fat-soluble, and it’s better absorbed when taken with a meal containing mono- or polyunsaturated fat. Talk to your doctor before taking Coenzyme Q-10. He or she may want to check to make sure you are having muscle discomfort and not muscle damage first.
Your doctor will discuss these potential side effects with you. If you have any questions about statins or side effects, please be sure to talk to your doctor about your concerns.
Statins are not a Cure-All
Statin medications are not meant to be used as a substitute for a healthy lifestyle that includes regular exercise (about an hour each day), smart food choices and maintaining a healthy weight (body mass index [BMI] below 25). Healthy lifestyle habits also include eating breakfast every day, weighing yourself at least once a week and watching less than 10 hours of TV per week.
Brisk walking is a great form of exercise. Wearing a pedometer can help motivate you to increase the amount of walking you do. A good goal is to walk 10,000 steps per day, which is five miles (2,000 steps per mile, on average).
A heart-healthy diet is the Mediterranean diet, which includes an abundance of fresh vegetables and fruits, healthy fats, moderate amounts of fish and poultry, whole grains, nuts and only small amounts of lean meats. Trans fats should be avoided.
To aid in lowering cholesterol, you may include food in your diet that contains plant stanols and sterols, plant based omega 3 foods, and soluble fiber.
A note about supplements
People often want to take non-medication alternatives to statins. But, be cautious of non-prescription supplements such as red yeast rice. This contains an active ingredient similar to the statin Lovastatin, and therefore should only be used only under your doctor’s supervision, especially if you’ve experienced side effects to prescription statins. In 2007, the FDA released a warning regarding red yeast rice.
Statin medications (also called HMG-CoA reductase inhibitors) include Atorvastatin, Rosuvastatin, Simvastatin, Pravastatin, Lovastatin, Fluvastatin, Pitavastatin and are recommended based on cardiovascular risk factors and LDL cholesterol levels/goals. When lifestyle changes, such as diet and exercise are unable to achieve optimal levels, then a statin may be initiated to decrease risk of heart disease events or progression.
While statin medications remain the first-line therapy in high-risk cardiovascular patients, there are potent drugs are under development.
PCSK9 Inhibitors are a new cholesterol-reducing drug currently undergoing clinical trials. Studies have shown that they can reduce LDL by 50 to 70 percent. PCSK9 inhibitors are human monoclonal antibodies given by injection, once every 2 weeks or every 4 weeks.
PCSK9 inhibitors are currently under review by the FDA for approval. These drugs may be beneficial in people who:
- Have very high cholesterol due to heterozygous hypercholesterolemia, a genetic condition
- Are prescribed the maximum dose of statins but still unable to achieve LDL goal or are having cardiac events
- Are unable to tolerate statin therapy
Very few side effects have been reported so far, but ongoing trials will assess long term safety, as well as impact on reducing heart attack and heart related death.
- Heart Disease and Stroke Statistics *from the American Heart Association 2012 update.
- Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Study Group. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-reactive Protein. N Engl J Med. 2008;359:2195–2207.
- Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, Ford E, Furie K, Gillespie C, Go A, Greenlund K, Haase N, Hailpern S, Ho PM, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott MM, Meigs J, Mozaffarian D, Mussolino M, Nichol G, Roger VL, Rosamond W, Sacco R, Sorlie P, Roger VL, Thom T, Wasserthiel-Smoller S, Wong ND, Wylie-Rosett J; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics–2010 Update: A Report from the American Heart Association. Circulation. 2010;121: e46-e215. Epub 2009 Dec 17. Available at: www.cdc.gov/nchs/fastats/deaths.htm*
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- Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–1504.
- Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J, Erbel R, Fruchart JC, Tardif JC, Schoenhagen P, Crowe T, Cain V, Wolski K, Goormastic M, Tuzcu EM; ASTEROID Investigators. Effect of Very High-Intensity Statin Therapy on Regression of Coronary Atherosclerosis. JAMA. 2006;295:1556–1565.
- Mampuya, Warner M. et al.Treatment strategies in patients with statin intolerance: The Cleveland Clinic experience. American Heart Journal, Volume 166, Issue 3, 597 – 603 http://www.ahjonline.com/article/S0002-8703(13)00376-1/fulltext
- FDA Warns Consumers to Avoid Red Yeast Rice Products Promoted on Internet as Treatments for High Cholesterol Products found to contain unauthorized drug, August 9, 2007
- 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129[suppl 2]:S1-45) http://circ.ahajournals.org/content/129/25_suppl_2/S1.full.pdf+html
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