Pill Pushing©

The Best of Pill Pushing - The statins - Drano for your clogged arteries - (2/12/2018)

By Dr. Ron Gasbarro

The culture at that time: If you thumb through cookbooks from decades ago, you see that many recipes celebrate the addition of bacon, beef, and ham, usually at the expense of healthier chicken and seafood dishes and even vegetables. Organ meats such as Braunschweiger, liver, tongue, pigs’ feet, and the part of the chicken that went over the fence last were consumed with gusto. A gander at the 1984 edition of The Joy of Cooking reveals recipes for brains (baked, broiled, or sautéed), kidneys (with mustard, in Bordeaux), beef tongue (with raisin sauce!) and everyone’s favorite: oxtail stew. 
Too exotic? How about bacon and eggs? The mainstay breakfast for the latter half of the 20th century was bacon and eggs, and most likely, an unfiltered Chesterfield. The USDA (United States Department of Agriculture) defines bacon as “the cured belly of a swine carcass.” And unfertilized chicken eggs could be creamed, curried, deviled, pickled, fried or shirred.  “Yum!” scream your arteries as they slam shut. 

The drugs in question – The statins. 
In the 1960s, it was common for Americans to succumb to heart attacks in their 40s, 50s or 60s [NIH, 2010]. The effects of smoking, cholesterol, high blood pressure, and obesity on the development of heart disease were unknown. Following a heart attack – or myocardial infarction – treatments were limited to correct the damage done to the heart. Those patients who did not die from their heart attack remained severely debilitated. The US death rate for coronary heart disease rose steadily during the first half of the 20th century, reaching a peak in 1968. Now, even though it is still a major cause of American deaths, the incidence has dropped. Why the decline? One major reason – besides flushing your Newports down the toilet – was the discovery of a new class of drugs that reduced cholesterol: the statins. Its star: Mevacor (lovastatin) – the premier statin. 
The good, the bad, and the ugly: Mevacor (generic name – lovastatin) is a “statin,” like so many other cholesterol-reducing medications on the market. It was approved by the FDA in 1987 as the first statin [Endo, 2004]. When used in combination with diet, weight-loss, and exercise, it helps to lower cholesterol and therefore, reduces the risk of cardiovascular disease (CVD). Lovastatin is a naturally occurring drug found in foods such as oyster mushrooms [Gunde-Cimerman, 1995] and red yeast rice [Liu, 2006]. The drug works by blocking an important an enzyme that is a necessary building block for the formation of cholesterol [Alberts, 1998]. 
Lovastatin completely changed the landscape of fighting CVD. A study that looked at cholesterol-lowering drug use from 1978 to 1988 (a year after lovastatin was introduced to the market) showed that 4.4 million prescriptions for cholesterol-lowering drugs were filled in 1978 compared to 13 million in 1988 – a 300% increase. 
Recognizing a golden goose when they see one, other companies quickly developed other statins: 
Crestor® (rosuvastatin)
Lescol® (fluvastatin)
Lipitor® (atorvastatin)
Livalo® (pitavastatin) 
Pravachol® (pravastatin)
Zocor® (simvastatin).
Lovastatin, pravastatin, and fluvastatin, introduced in the US in the late 1980s and 1990s are first-generation statins and represent the class members with the lowest potency [Kapur, 2008]. The second generation of statins – atorvastatin and simvastatin – have significantly improved efficacy in reducing low-density lipoproteins (LDL–C; the “bad” cholesterol) levels compared to the earlier statins [Kapur, 2008]. Rosuvastatin which according to IMS National Prescription Audit, IMS Health 2014 and pitavastatin are third generation statins and are considered the strongest statins [Kapur, 2008; Barrios, 2013]. But is stronger actually better? 
As you might guess, not all statins are the same. In a recent analysis of 135 studies, which included nearly 246,955 patients and all 7 of the statins currently on the market, researchers found that the drugs simvastatin and pravastatin had the fewest side effects of all the statins [Naci, 2013]. Researchers also found that lower doses produced fewer side effects in general. Other findings from this large analysis revealed: 
A slightly increased risk of type 2 diabetes was observed among people taking statins. However, researchers conclude that the benefits of statin on the cardiovascular system far outweigh the relatively small risk of diabetes.
Statins, particularly atorvastatin, were linked to an increase in liver enzyme irregularities. Patients who take any of the statins should have regular liver function tests to play it safe. 
In early 2014, the FDA released a recommendation on statin risk reporting that "statin benefit is indisputable, but they need to be taken with care and knowledge of their side effects"[FDA, 2014]. Thus, a variety of side effects, albeit rare, should be considered. Peripheral neuropathy (nerve pain in the lower extremities) can occur [Jacobs, 1994; Jeppersen, 1999; Giast, 2002]. This side effect can manifest several years after therapy begins and the risk increases with age [Beghi, 1998; Daglioglu, 2010]. A common complication is myopathy (muscle weakness), ranging from aggravating but clinically benign myalgia (muscle pain) to rare but life-threatening rhabdomyolysis, a breakdown of muscle tissue which releases various toxins into the bloodstream that can permanently damage the kidneys [Magni, 2015]. The risks associated with muscle problems include drug-drug interactions, female gender, advanced age, diabetes mellitus, hypothyroidism (low thyroid levels) and vitamin D deficiency. Recent evidence has implied that statin therapy can result in some degree of memory loss [Evans, 2009]. Memory loss may occur in those who are on the more potent statins at the higher doses. If you experience any of these side effects, contact your prescriber who will have several options to treat high cholesterol, including the use of a lower dose of the same statin, intermittent non-daily dosing of statin (e.g., every other day dosing), or initiation of a different statin, alone or in combination with non-statin lipid-lowering agent.
As the dose increases, side effects become more prevalent. As a consequence more people stop taking statins due to these side effects. Therefore, the initial dose should be as small as possible to assess whether the lower doses are effective. Simvastatin and pravastatin may have the most favorable side effect profiles, yet they tend to be the least potent statins. The statins that are the strongest –   rosuvastatin and pitavastatin – tend to have the most side effects, and, therefore should be reserved for patients whose cholesterol cannot be controlled with a less potent statin.
What about the auxiliary label on your pill vial that says “Do not take with grapefruit juice”? The current medical advice is to avoid grapefruit juice consumption while taking 3 widely used statins, simvastatin (Zocor), lovastatin (Mevacor) and atorvastatin (Lipitor). In simple terms, when these drugs are taken with grapefruit juice, they tend to stay in the bloodstream longer than they should and can cause serious muscle damage (rhabodmyolysis).
A 2016 study showed that one daily glass of grapefruit juice increases blood levels of simvastatin and lovastatin by about 260% if taken at the same time and about 90% if taken 12 hours apart [Lee, 2016]. One glass increases atorvastatin by about 80% no matter when they are taken. 
In terms of cholesterol, simvastatin 40 mg, lovastatin 40 mg, and atorvastatin 10 mg daily reduce low-density lipoprotein (LDL) cholesterol (bad cholesterol) levels in a 60-year-old man by 37%, reducing ischemic heart disease risk by 61%. When simvastatin or lovastatin are taken at the same time as grapefruit juice, the reduction in LDL cholesterol is 48%, and in heart disease is 70%. If the juice is taken 12 hours before these statins, the reductions are, respectively, 43% and 66%, and for atorvastatin, 42% and 66%. Hmmm – seems like the grapefruit juice is actually helping!
Risk vs. Benefit? The increased rhabdomyolysis risk from grapefruit juice consumption due to the increased effective statin dose is minimal compared with the greater effect in preventing heart disease. Bottom line: Grapefruit juice should not be contraindicated in people taking statins.
Impact of the drug on our culture: Heart disease has been the leading cause of death in the United States since 1921, and stroke has been the third leading cause since 1938 [CDC, 1999]; together they account for approximately 40% of all deaths. Since 1950, age-adjusted death rates from CVD have declined 60%, representing one of the most important public health achievements of the 20th century [NHLBI, 1998]. The use of statins has contributed greatly to this endeavor so much so that the current American College of Cardiology/American Heart Association Task Force on Practice Guidelines emphasize the use of statins to continue to drive down the rates of CVD [Stone, 2013]. 
However, the fact remains that statin therapy is of no use if patients are not adherent to treatment regimens and/or they do not make lifestyle modifications. A 2015 study looked at deaths from CVD in England from 2000 to 2007 [Guzman-Castillo, 2015]. The study revealed that overall deaths from heart disease were estimated to be down by over a third during the time period. However, the impact of statins has a societal imbalance, because the analysis showed that the use of statins benefitted the 20% richest people more than the 20% poorest people. Unlikely to be a result of any biological factor, the difference may instead arise due to a combination of socioeconomic and cultural reasons, such as people with chaotic lifestyles associated with poverty being less likely to stick to a treatment plan. The study also discovered that lifestyle changes – such as encouraging people to stop smoking, to eat healthily and to exercise regularly – have had a much bigger impact than medical approaches, like statins. In other words, you have to put some effort into getting your cholesterol down – a pill may not be enough. 
If only celebrities who died of heart attacks and high cholesterol knew then what we know now. Those who died prematurely from heart attacks and cardiovascular disease include:
Cass Elliot (singer) – age 32 
F. Scott Fitzgerald (author) – 44
James Gandolfini  (actor) – age 51
Warren G. Harding (US president) – age 57 
Paul Lynde (actor) – age 54 
Harry Nilsson (singer) – age 52
Roy Orbison (singer) – age 52
Elvis Presley (singer) – age 42
Fatty Arbuckle (actor) – age 46
John Candy (actor) – age 43
Where the drug is today: Thanks in part to Mevacor and the other statins – as well as lifestyle modifications – the Grim Reaper has more time on his hands with regard to CVD: there are about 425,000 deaths each year from heart disease compared to the 1.5 million lives that would have been lost if the statins did not exist. [NIH, 2010]. In addition, the death rate from stroke, the third most common cause of death, has declined by about 75% since the early 1960s. The gain in longevity in the United States has been extraordinary. Between 1970 and 2005, the life expectancy of the average American increased by over 6 years [NHLBI, 2010]. Of this increase, almost 5 of those 6 years can be attributed to a slowing of deaths from CVD. 
How many Americans take cholesterol-lowering drugs today? According to a report generated from the CDC, the use of cholesterol-lowering drugs increases with age — 17% of those ages 40 to 59 took such medications, while use increased to 48% among those 75 and older. In addition, approximately ¾ of adults with heart disease and over ½ of adults with high cholesterol were taking a cholesterol-lowering drug. While evidence supports and guidelines recommend statins for all those with established heart disease, about 3 in 10 of the patients who have high cholesterol are not being treated with statins. By 2011-12, 93% of adults who used a cholesterol-lowering medication used a statin, with the remaining using more or less inadequate therapies such as niacin and red yeast rice. 
Ron Gasbarro, PharmD is a registered pharmacist, medical writer, and principal at Rx-Press.com. Write him at ron@rx-press.com.  

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