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Statins

The decision to take a statin is an important one. Stock photo
Fatigue and cataracts are downsides

By David Dunaief, M.D.

Dr. David Dunaief

Statins are one of the most commonly prescribed medications in the United States. Yet, some in the medical community believe that more patients should be on this class of drugs while others think it is one of the most overprescribed medications. Suffice to say, this is one of the most polarizing topics in medicine — probably rightfully so.

The debate is over primary prevention with statins. Primary prevention is treating people with high cholesterol and/or inflammation who may be at risk for a cardiovascular event, such as a stroke or heart attack.

Fortunately, most physicians would agree that statins have their place in secondary prevention — treating patients who have had a stroke or heart attack already or have coronary artery disease.

We are going to look at benefits and risks for the patient population that could take statins for primary prevention. On one side, we have the statin as Rocky Balboa, coming out to fight off cancer risk, both overall and esophageal, as well as improving quality of life and glaucoma. On the other, we have the statin as Evel Knievel, demonstrating that reckless heroics don’t provide longevity, but they do increase diabetes risk, promote fatigue and increase cataracts. Let’s look at some of the evidence.

Effect on cancer

A study published in The New England Journal of Medicine involved 300,000 Danish participants and investigated 13 cancers. It showed that statin users may have a 15 percent decreased risk of death from cancer (1). This is exciting news.

However, there were major limitations with the study. First, the researchers did not control for smoking, which we know is a large contributor to cancer. Second, it was unknown which of the statin-using population might have received conventional cancer treatments, such as radiation and chemotherapy. Third, the dose of statins did not correlate to risk reduction. In fact, those who took 1 to 75 percent of prescribed statin levels showed more benefit in terms of cancer mortality risk than those who took more. We need a better-designed trial that is prospective (forward looking) to determine whether there really is an effect. I would say that Rocky Balboa came out of this fight pretty banged up.

Another study showed that statins may play a role in reducing the risk of esophageal cancer. This is important, since esophageal cancer, especially adenocarcinoma that develops from Barrett’s esophagus, is on the rise. The results showed a 28 percent risk reduction in this type of cancer. The authors of the study surmise that statins may have a protective effect. This was a meta-analysis of 13 observational studies (2).

Although there is an association, these results need to be confirmed with randomized controlled trials. Remember, aspirin has about the same 30 percent reduction in colorectal cancer, yet is not recommended solely for this use because of side effects.

Eye diseases: mixed results

In two common eye diseases, glaucoma and cataracts, statins have vastly different results. In one study, statins were shown to decrease the risk of glaucoma by 5 percent over one year and 9 percent over two years (3). It is encouraging that the longer the duration of statin use, the greater the positive effect on preventing glaucoma.

Statins also help to slow glaucoma progression in patients suspected of having early-stage disease at about the same rate. This was a retrospective (backward-looking or looking in the past) study analyzing statin use with patients at risk for open-angle glaucoma. There is a need for prospective (forward-looking) studies. With cataracts, it is a completely different story. Statins increase the risk of cataracts by over 50 percent, as shown in the Waterloo Eye Study (4). Statins exacerbate the risk of cataracts in an already high-risk group: diabetes patients.

Quality of life and longevity: a mixed bag

In a meta-analysis involving 11 randomized controlled trials, considered the gold standard of studies, statins did not reduce the risk of all-cause mortality in moderate to high-risk primary prevention participants (5). This study analysis involved over 65,000 participants with high cholesterol and at significant risk for heart disease.

However, in this same study, participants at high risk of coronary heart disease saw a substantial improvement in their quality of life with statins. In other words, the risk of a nonfatal heart attack was reduced by more than half and nonfatal strokes by almost half, avoiding the potentially disabling effects of these cardiovascular events.

Fatigue effect

Some of my patients who are on statins ask if statins can cause fatigue. A randomized controlled trial published in the Archives of Internal Medicine reinforces the idea that statins increase the possibility of fatigue (6).

Women, especially, complained of lower energy levels, both overall and on exertion, when they were blindly assigned to a statin-taking group. The trial was composed of three groups: two that took statins, simvastatin 20 mg and pravastatin 40 mg; and a placebo group. The participants were at least 20 years old and had LDL (bad) cholesterol of 115 to 190 mg/dl, with less than 100 mg/dl considered ideal.

In conclusion, some individuals who are at high risk for cardiovascular disease may need a statin, but with the evidence presented, it is more likely that statins are overprescribed in primary prevention. Evidence of the best results points to lifestyle modification, with or without statins, and all patients with elevated LDL (bad) cholesterol should make changes that include a nutrient-dense diet and a reduction in fat intake, as well as exercise.

References:

(1) N Engl J Med 2012;367:1792-1802. (2) Clin Gastroenterol Hepatol. 2013 Jun; 11(6):620–629. (3) Ophthalmology 2012;119(10):2074-2081. (4) Optom Vis Sci 2012;89:1165-1171. (5) Arch Intern Med 2010;170(12):1024-1031. (6) Arch Intern Med 2012;172(15):1180-1182.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, visit www.medicalcompassmd.com or consult your personal physician.

Statin users tend to neglect dietary guidance.

By David Dunaief, M.D.

High cholesterol affects a great number of Americans and cuts across many demographics, affecting young and old and those in between. When we think of hyperlipidemia (high cholesterol), what do you think is the mainstay of medical treatment? If you said “statins” you would be correct.

Do statins deserve this central role in treatment? They have been convincingly shown in studies to significantly lower cholesterol, and they play an important role for those who have cardiovascular disease. However, should we be using statins as liberally as we have? Well, guidelines for the treatment of high cholesterol, released in November 2013, suggest that we should. In fact, if followed, these guidelines would increase the use of this medication, especially in those over the age of 60. Some in the medical community have even joked that statins might as well be put in the drinking water.

This is a medication that patients may be on for life. I don’t know about you, but that thought sends chills down my spine. We know all medications have pros and cons. Statins are no exception; they have been mired in controversy. For one thing, they have side effects. These include possibly increasing the risks of diabetes, myalgias (muscle pain), hepatic (liver) toxicity, kidney disorders and negatively affecting memory.

Statins also may reduce the benefits of exercise, and they may not be as effective in women as they are in men. Because statins are such effective cholesterol-lowering medications, does this mean that patients on these drugs may become complacent with their diets? A new study indicates that this is exactly what might be happening. Let’s look at the evidence.

Statins have been mired in controversy. Stock photo
Statins have been mired in controversy. 

Diet complacency

The “S” in statins does not stand for “superimmune to eating anything.” In a study published in JAMA Internal Medicine, results show that those who are taking statins tend to eat more calories and fats and, ultimately, increase their [body mass index] by gaining weight compared to those who were not taking statins (1).

In fact, in this study that used 11 years of NHANES data, results showed that there were a 14 percent increase in fat intake and an almost 10 percent increase in overall calorie intake among statin users. This resulted in a BMI that rose by 1.3 percent in those on statins, while in nonusers over the same period BMI only rose by 0.4 percent.

In other words, if you took an average male who was 5 feet 9 inches and weighed 200 lb, the difference between statin users and nonusers would be the difference between obesity and being just below obesity. Those on statins were consuming about 200 extra calories a day. This increase in calorie consumption occurred after they were placed on statins. Their weight also increased by 6.6 to 11 lb. This is especially concerning to the researchers, since the guidelines for statin use call for a prudent diet to help reduce fat and calorie intake with the ultimate goal of reducing weight.

However, the opposite was found to have happened — users consumed more calories and gained more weight. This is an observational study with over 27,000 participants, therefore no firm conclusions can be made. However, statins are not a license to gorge at the all-you-can-eat buffet line. We already know that statins may increase the risk of diabetes. Why worsen this risk with dietary indiscretions that are harmful to your BMI?

As an aside, the authors note that this increased calorie and fat consumption may be a contributing reason for the increased risk of diabetes with statins, but it’s too early to tell.

Impact on women

We tend to clump data together from trials that focus predominantly on one demographic, in this case men, and apply the results broadly to both men and women. However, in a May 5, 2014, New York Times article, “A New Women’s Issue: Statins,” some in the medical community, including the editor of JAMA, focus attention on this tendency, noting that this may be a mistake (2).

According to the dissenters, the thought process is that women have been underrepresented in statin trials, and cholesterol may not play the same role in women as it does in men. Yet almost half of the patients treated with statins are women. These physicians were referring to the use of statins in primary prevention, or in those who have high cholesterol but who do not have documented heart disease.

Lest you think their views are based solely on opinion or anecdotal data from clinical experience, this data on women was from the JUPITER trial, which looked at almost 7,000 initially healthy female participants (3). Statins did benefit women by reducing the occurrence of chest pain and reducing the number of stent placements and bypass surgeries, but they did not reach the primary end points of showing statistical significance in reducing the occurrence of a first heart attack, stroke or death.

The caveat is that there were not a large number of cardiovascular events — heart attacks, strokes or death — that occurred in either the treatment group or the control group. These results were in women over the age of 60. This may give slight pause when prescribing statins. By no means do I think these physicians are advocating to not give women statins, just that we may want to weigh the benefits and risks on a case-by-case basis.

Tamping down exercise benefits

If exercise is beneficial for lowering cardiovascular disease risk and so are statins, the logical presumption might be that the two together would create a synergistic effect that is greater than the two alone — or at least an added benefit from combining the two. Unfortunately, what seems straightforward is not always the case.

In a small, yet randomized controlled trial, participants who were put on statins and monitored for cardiopulmonary exercise saw a blunted aerobic effect compared to the control group, which exercised without the medication (4). In the treatment group, there was a marginal 1.5 percent improvement with aerobic exercise, while the control group experienced a much more robust 10 percent gain.

The reason for this disappointing discrepancy is that statins seem to interrupt the enzymes that are responsible for making the mitochondria (the powerhouse or energy source for the cell) more efficient. The most troubling aspect of this trial is that the participants chosen were out-of-shape, overweight individuals in need of aerobic exercise.

Whether or not a patient, male or female, is placed on cholesterol-lowering medication, one thing is clear: There is a strong need to make sure that lifestyle modifications are always emphasized to help reduce the risk of cardiovascular disease to its lowest levels. But the quandary becomes what to do with statins and exercise. And statins, as powerful and effective as they may be, still do have side effects, may reduce exercise benefits and may not have the same effects for women. Thus, they may not be appropriate for everyone. A healthy diet and exercise, however, are appropriate for all.

References: (1) JAMA Intern Med. online April 24, 2014. (2) nytimes.com. (3) N Engl J Med. 2008 Nov 20;359(21):2195-2207. (4) J Am Coll Cardiol. 2013;62(8):709-714.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, visit www.medicalcompassmd.com or consult your personal physician.

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High cholesterol is a problem that affects a countless number of people in the United States. One of the challenges is that it has no noticeable symptoms but may result in an increased risk of cardiovascular disease, including heart attacks and strokes. So what do we do about it?

Currently, the standard medical treatments for high cholesterol are statins. Statins include rosuvastatin (Crestor), atorvastatin (Lipitor), simvastatin (Zocor) and pravastatin (Pravachol). But now a new drug has been approved by the FDA, and it is the first drug in a new class, proprotein convertase subtilisin/kexin type 9 inhibitors or, more affectionately and easier to say, PCSK9 inhibitors.

The first medication approved in this class was Praluent (alirocumab) on Friday, July 24, 2015 (1). PCSK9 inhibitors are monoclonal antibodies that turn off specific proteins in the liver, reducing the levels of LDL, the “bad” cholesterol (2). Right behind, Repatha (evolocumab), another PCSK9 inhibitor, was just recommended by the FDA advisory board. Usually the FDA follows advisory board recommendations.

Therefore, we will likely have two drugs from this class approved and on the market.

Will PCSK9 inhibitors take the place of statins?
Hardly, at this point. The FDA has taken a conservative and narrow approach when it comes to indications for alirocumab (1). Patients who have either heterozygous familial hypercholesterolemia (FH), a genetic disease that affects about 1 in 500 Americans, or those who have atherosclerotic cardiovascular disease (ASCVD), meaning they have had heart attacks, strokes or chest pain due to plaque buildup in the arteries, are presently candidates for treatment. And then, only if both lifestyle modifications and the highest tolerated dose of statins are not sufficient to produce the desired effects. Then, PCSK9 inhibitors may be added to lower LDL further. Patients who are intolerant of statins and who do not have cardiovascular disease are not currently candidates. This may change, but not at the moment.

Class effectiveness of alirocumab and PCSK9
These drugs have been shown to significantly reduce the LDL levels. In five randomized controlled trials, the gold standard of studies, alirocumab was shown to reduce LDL levels by between 36 and 59 percent over placebo (3).

Ironically, though it lowers the LDL considerably, 10-year risk assessment calculator for cardiovascular disease based on the Framingham Heart Study does not include LDL as a consideration (4).

Caveats for this new drug class
There are two significant limitations. One is the outcomes data, and one is the cost. Oh yeah, and I forgot to mention that you need to inject the drug every two weeks.

While this class has shown impressive results in reducing LDL levels, especially compared to statins, it is still in trials to determine whether the reduction in bad cholesterol actually translates into a reduction in cardiovascular events. Trials are not expected to be finished until 2018 (5). This may be one reason for the FDA’s limited treatment population.

Already, drug costs seem to be soaring. Just when we thought they were getting better for statins, since most of them now are generic, here comes a new class of cholesterol-lowering drugs with an even higher price tag. The annual cost for treatment is expected to be around $14,600 (3). This does not help. According to Sanofi and Regeneron Pharmaceuticals, the companies involved, this is a low price for the type of drug, monoclonal antibodies, and the savings from preventing cardiovascular events will be worth the price.

Ironically, the drugs have yet to demonstrate this outcome.

The side effect profile
Unfortunately, with just about every medication there is the dreaded side effect profile. Presently, it seems that alirocumab has a mild side effect profile. These include itchiness, bruising, swelling and pain in the site of injection, flu symptoms and nasopharyngitis (inflammation of the mucous membranes of the nasal passages and pharynx) (3). There were also some allergic reactions that involved hospitalization. As a class, monoclonal antibodies are known to potentially precipitate significant infection. We will have to wait and see whether or not this is the case with PCSK9 inhibitors. Remember, it took a number of years before we knew some of statins’ adverse reactions and the extent of their side effects.

The role of statins
With the recent ACC/AHA guidelines for statin use, published in 2013, these drugs continue to be prescribed for a broader audience of patients. They recommend that those who have LDL levels between 70 and 189 mg/dL and at least a 7.5 percent risk of a cardiovascular event over 10 years are candidates for statins for primary prevention, and this is cost-effective (6). That does not mean these patients necessarily need to have elevated total cholesterol nor elevated bad cholesterol.

In an even broader recommendation, a recent study suggested that people between the ages of 75 and 94 could be on a generic statin for primary prevention of a heart attack or death as a result of coronary heart disease (7). These results were based on using two studies and then forecasting from those results. The authors suggested that this may be both clinically and financially effective. However, they did acknowledge that this would exclude those with adverse reactions to statins.

Have we gone too far with this recommendation? According to an editorial in the same journal, harm from modest side effects would most likely limit the use of these drugs in this population (8).

Impending triglycerides
In two trials, results show that patients who have acute coronary syndrome (ACS) and who are treated with statins have a 50 to 61 percent increased risk of a cardiovascular event in the short term and long term if their triglyceride levels are mildly elevated, either greater than 175 or 195 mg/dL depending on which of the two studies is considered (9). ACS is defined as reduced blood flow to the heart resulting in unstable angina (chest pain), heart attack or cardiac arrest. In one of the two trials, the long-term effects of high triglycerides >175 mg/dL were compared to triglycerides <80 mg/dL. Almost all of the patients were on statins and had LDL levels that were near optimal (<70 mg/dL) with a mean of 73 mg/dL. By the way, “normal” triglycerides, according to most labs, are <150 mg/dL.

Move over bones — vitamin D for healthy cholesterol
In a non-drug-related study, it turns out that high vitamin D levels in children are associated with lower total cholesterol levels, non-HDL “bad” cholesterol levels and triglyceride levels overall (10). The authors note that higher non-HDL levels in children may result in a greater risk of cardiovascular disease in later life.

Though it is exciting to have more options in the arsenal for medical treatment, the moral of the story is that those who do not fit the FDA’s criteria for usage should most likely watch and wait to see how longer term side effects and outcomes play out. Statins are beneficial, as we know, but we may be overreaching in terms of the patient population for treatment. In my clinical experience, lifestyle changes including diet and exercise are important for reducing triglycerides to normal levels. And finally, it is never too early to start mild prevention for cardiovascular disease, such as by managing vitamin D levels.

References:
(1) FDA.gov. (2) health.harvard.edu. (3) medpagetoday.com. (4) cvdrisk.nhlbi.nih.gov. (5) J Am Coll Cardiol. 2015:23;65(24):2638-2651. (6) JAMA 2015; 314:134-141. (7) Ann Intern Med 2015; 162:533-541. (8) Ann Intern Med 2015; 162:590-591. (9) J Am Coll Cardiol 2015; 65:2267-2275. (10) PLoS One. 2015 Jul 15;10(7):e0131938.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, go to the website www.medicalcompassmd.com or consult your personal physician.

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