(1)
Department of Urology, University of Michigan Medical Center, Ann Arbor, Michigan, USA
(2)
Jenkins/Pokempner Director of Complementary & Alternative Medicine, University of Michigan Medical Center (Dept of Urology), Ann Arbor, MI, USA
Introduction
The leading cause of death in the USA for women and men is cardiovascular disease (CVD) , and this has been the case for 116 of the last 117 years [1]. CVD causes more deaths than cancer and chronic lower respiratory diseases (CLRD) combined. CVD causes one death per minute among females in the USA or over 400,000 deaths, which is approximately the same number of female lives lost by cancer, CLRD, and Alzheimer disease combined. The most recent US statistics have recorded the following: approximately 41,000 deaths from breast cancer, 70,500 female deaths from lung cancer, one in 30 deaths are from breast cancer whereas 1 in 7 was from coronary heart disease (CHD), and 1 in 4.5 females died of cancer and 1 in 3.1 died of CVD. CVD is also still a disease of the young and old. Approximately 150,000 Americans died of CVD last year who were less than 65 years of age and over one third of CVD deaths occurred before the age of 75 years (life expectancy is 78.7 years). The number 1 cause of death in women and men from age 65 and older is CVD (number 2 is cancer). Thus, it could be argued that the overall impact of lipid lowering with statins or lifestyle changes should be of paramount importance in women treated for breast cancer, concerned about prevention and a reduction in all-cause mortality.
Statins and primary prevention
“When used for primary prevention, statins are associated with lower rates of all-cause mortality, major vascular events, and revascularizations compared with placebo. Statin therapy is not associated with increased rates of life-threatening adverse effects such as cancer [2, 3].” This was the conclusion of one of the largest and most current and extensive meta-analyses of statins and primary prevention. Is there another pill in medical history ever invented that in otherwise healthy individuals can make this claim? I am not aware of one, which is reason enough to discuss this finding with the appropriate patients. This extensive meta-analysis included the following [2, 3]:
Number of randomized trials: 18
Number of participants: 56,934
Men = 60 % of the participants and Women: 40 %
Mean age: 57 (range of 28–97 years)
Countries: 17 trials from the USA, Japan, and Europe; one trial from South America, Israel, South Africa, and Russia
Average LDL reduction versus placebo: 39 mg/dl (multiply by 0.0259 to convert to millimoles per liter)
All-cause mortality: 14 % Reduction (Number Need to Treat or NNT for 5-years of 138)
Fatal and Nonfatal CVD (combined): 25 % Reduction (NNT for 5-years of 49)
Fatal and Nonfatal Coronary Heart Disease (CHD) Events: 27 % Reduction (NNT 88)
Fatal and Nonfatal Stroke: 22 % Reduction (NNT 155)
Coronary Revascularization (Stents, Coronary Artery Bypass Grafting or CABG, …): 38 % Reduction (NNT 96)
Incidence of cancers, myalgia, rhabdomyolysis, liver enzyme increases, arthritis, or renal dysfunction: No difference between statin and placebo groups.
Increase diabetes was found in one of two trials (18 % increase, 95 % CI, 1.01–1.39, NNT 198)
The overall quality of the studies was high, and they were funded by pharmaceutical companies. A total of three trials, which comprised almost 50 % of the recruited group, were stopped early because of a significant reduction in the primary endpoint. The median control group CVD rate was 15 % over 10 years and NNT would be 25–75 over 5 years to reduce CVD rates to 10 % over 10 years. Hemorrhagic stroke could be increased by statins but none of the individual studies provided clarity on this issue. Overall, the result of this unique analysis suggests the benefits of statins outweigh the risk of life-threatening events. Another method of analyzing the full results for statins and the Primary Prevention of CVD are found in Table 4.1 [2, 3].
Outcome (# of trials) | Events Statins | Total in statin group | Events Placebo/control | Total in control group | Relative risk (95 % CI) | NNT—5 years (95 % CI) |
|---|---|---|---|---|---|---|
All-cause mortality (13) | 1077 | 24,408 | 1223 | 23,652 | 0.86 (0.79–0.094) | 138 |
Total CVD (9) | 1103 | 11,892 | 1444 | 11,913 | 0.75 (0.70–0.081) | 49 |
Total CHD (14) | 820 | 24,217 | 1114 | 23,832 | 0.73 (0.67–0.080) | 88 |
Total stroke events (10) | 345 | 20,302 | 442 | 19,993 | 0.78 (0.68–0.89) | 155 |
Revascularization (7) | 286 | 21,166 | 461 | 21,237 | 0.62 (0.54–0.72) | 96 |
Any adverse event (12) | 5748 | 20,718 | 5090 | 19,998 | 1.00 (0.97–1.03) | NA |
Type 2 diabetes (2) | 342 | 12,205 | 290 | 12,202 | 1.18 (1.01–1.39) | 99 |
Still, there are other issues that need to be resolved. For example, one recent 6-month primary prevention trial found reduced energy and fatigue with exertion [4], but more quality of life data is needed from long-term trials to address this and other issues such as changes in memory. Overall, in these trials individuals treated with statins were just as likely to discontinue treatment compared to placebo (12 %) [2, 3].
Interestingly, the most recent American College of Cardiology/American Heart Association (ACC/AHA ) guidelines on the treatment of cholesterol to reduce cardiovascular risk in adults recommends moderate- to high-intensity statin treatment for primary prevention (class I recommendations) for the following [5]:
LDL cholesterol of 190 mg/dl or higher
Aged 40–75 years with type 1 or 2 diabetes
Aged 40–75 years with LDL between 70 and 189 mg/dl and 7.5 % or higher estimated 10-year risk of CVD
The group also suggests it could be reasonable to offer statin therapy in those with a 10-year risk of 5 % to less than 7.5 % (class IIa recommendation). The cholesterol guideline cutoffs were derived from the placebo group of 3 notable primary prevention only trials:
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) [6],
Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study [7], and
Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) [8].
Statins, safety, and Type 2 diabetes
The sum of the recent data and meta-analyses provides a large source of evidence that should quench some of the overall controversy of utilizing statins in so-called “healthy individuals” (primary prevention) [2, 3, 9]. In the appropriate individuals statins reduce all-cause mortality, CVD events, especially costly cardiovascular procedures, and are of low cost (5 are now generic) and well-tolerated overall. Regardless, the primary issue that still needs to be resolved is whether or not statins significantly increase the risk of diabetes, and if so is that risk negligible or relevant? For example, it may be dose-related, or primarily in those with diabetes risk factors. In the notable JUPITER trial there were 2.5 CVD events or deaths avoided for each potential case of diabetes with rosuvastatin [10]. Thus, for most qualifying individuals the benefit appears to outweigh the risk, but more answers and clarity on this topic are desperately needed. The association of statins and type-2 diabetes is indeed a real finding from meta-analyses but causality has not been proven, but it appears women, the elderly, and those on higher dosages may be at higher risk [11, 12].
Recent laboratory evidence suggests a potential mechanism of action whereby statins increase the risk of diabetes [13]. Investigators from McMaster University in Ontario, Canada have found that these drugs may activate an immune response pathway that hinders insulin signaling. Multiple statins activate NLRP3/caspase-1 inflammasome, a multiprotein complex, which is known to encourage inflammation and insulin resistance. Interestingly, combining a statin with the drug glyburide (an inhibitor of NLRP3/caspase-1) suppressed these harmful effects in fat tissue of obese mice. These negative effects of statins were also not found in mice genetically engineered to lack expression of NLRP3/caspase-1 inflammasome . Thus, especially in high-risk patients there may be value in monitoring insulin sensitivity during statin use and using antidiabetes medications may further reduce risk. Ultimately, if the overall risk of type 2 diabetes becomes consistently clinically significant researchers may find a way to improve this drug class, for example CoQ10 supplementation is also being investigated for this purpose.
Still, one mantra of this drug class (and others) that now seems more relevant than ever is the need to encourage patients to be on the lowest dosage of a statin, along with moderate to aggressive lifestyle change to maintain small dosage needs (or no drug). In fact, there is also recent data to suggest that consistent lifestyle changes such as exercise may provide similar benefits to these and other preventive medications at least in a secondary prevention setting. For example, a total of four exercise and 12 drug meta-analyses and the addition of three recent exercise trials were utilized in a recent investigation for a total of 305 randomized control trials with over 339,000 participants [14]. A total of over 14,700 participants were randomized to exercise in 57 trials. Four conditions with evidence on the impact of exercise on mortality outcomes were the focus: secondary prevention of coronary heart disease, rehabilitation of stroke, treatment of heart failure, and the prevention of diabetes. No statistical differences were found between exercise and drug interventions in the secondary prevention of heart disease and pre-diabetes. Exercise was more effective compared to drug treatment among patients with stroke, and diuretics were more effective than exercise in heart failure. More studies are needed but current randomized data suggest the mortality benefits of exercise and prescription medications are similar in the secondary prevention of heart disease, rehabilitation after stroke, prevention of diabetes, and even provide unique benefits in heart failure. It will be of enormous interest in the future to determine the impact of exercise on a variety of other diverse and similar medical conditions. It is also interesting that after countless dollars and studies have been conducted in breast cancer, one of the only lifestyle modifications that may prevent or reduce the recurrence of this disease is exercise.
Statins and women
Interestingly, in the AFCAPS/TexCAPS study , the effect of lovastatin on the risk of first major coronary event was greater in woman versus men (−46 % versus −37 %), but the number of women having such an event was small (20 out of 997), so there was no treatment difference between genders [6, 15]. In the MEGA study , which used pravastatin, there was a 37 % reduction in men versus 29 % for women [7, 15]. Almost 70 % of the participants in MEGA were women, but interestingly the average BMI was 23–24, which is far below what is observed in US trials (BMI of 27–28) for men and women. In the JUPITER trial, which was stopped in 1.9 years because of its significant impact on reducing CVD events the average LDL reductions were 50 % and high-sensitivity C-reactive protein (hs-CRP) was reduced by 37 % [8, 15]. Positive impacts were observed in all subgroups evaluated and risk reduction in the rosuvastatin group was −46 % for women and −42 % for men. Women in JUPITER experienced a significant reduction in revascularization/unstable angina (−76 %, 95 % CI 0.11–0.51), and there was a nonsignificant reduction in nonfatal myocardial infarction (−44 %) or CHD death (−27 %). However, it needs to be reiterated that this trial was stopped in 1.9 years for already meeting its primary endpoint and other primary prevention trials also had short follow-up and smaller numbers of events. Thus, I find it striking in primary prevention that some “experts” make claims that the impact of statins in women is not known or of no benefit. Simply the potential dramatic reduction in the need of a revascularization procedure should be further explored and discussed with women at higher risk of a cardiovascular event (also see Chaps. 5, 6 and Reynolds Risk Score).
Table 4.2 is a summary of the statin data and primary prevention trial results for women.
Trial name | Statin treatment | Women (%) | Primary endpoint | Relative risk in women (95 % CI) |
|---|---|---|---|---|
AFCAPS/TexCAPS | Lovastatin 20–40 mg/day versus placebo | 997 (15) | Sudden cardiac death, MI, unstable angina | 0.54 (0.22–1.35) |
JUPITER | Rosuvastatin (Crestor)—20 mg/day versus placebo | 6801 (38) | MI, stroke, unstable angina, CHD death, revascularization | 0.54 (0.37–0.80) |
MEGA | Pravastatin 5–20 mg + diet versus diet alone | 5356 (69) | CHD, MI, sudden cardiac death, angina, revascularization | 0.71 (0.44–1.14) |
Statins and breast cancer (incidence versus recurrence)
Overall, there has been no lucid association between statins and breast cancer incidence [16]. Yet there is accumulating data that statins may impact cancer progression more than cancer incidence, including breast cancer [17–19]. Numerous prospective studies suggest a reduction in recurrence including:
A 2008 Kaiser Permanente US study of 1945 early stage breast cancer survivors and 210 recurrences were reported and primarily lovastatin or simvastatin (lipophilic statins) were utilized. An overall RR = 0.67 (0.39–1.14) [20] was observed. Mean duration of statin use was only 1.96 years and there was reduced risk of recurrence with increasing duration of statin use (p trend = 0.02). This study suggested post-diagnostic statin use was beneficial.
In the 2011 Danish Breast Cancer Cooperative Group registry (n = 18,769), simvastatin (highly lipophilic statin) was associated with a reduced risk of breast cancer recurrence with an RR = 0.70 (0.57–0.86) [21].
In an MD Anderson Cancer Center (Houston, TX) US study statins were associated with a significant (p < 0.001) reduction with an HR-0.40 (0.26–0.67) with the use of atorvastatin or simvastatin [22].
A 2013 study from Germany of 3024 patients at risk of recurrence (stage I–III) found nonsignificant reduction in recurrence and HR = 0.83 (0.54–1.24) and reduced breast cancer-specific mortality (HR = 0.89, 0.52–1.49) with the use of any statin [23].
A Seattle, WA USA 2014 study of 4216 women found a nonsignificant reduction in recurrence with lipophilic statins with an HR = 0.76 (0.55–1.06) [24].
A 2014 Finnish Cancer Registry cohort (31,236 cases) found the potential for a significant lower risk of breast cancer death especially with pre-diagnostic statin use with an HR = 0.54 (0.44–0.67) [25].
Pre-surgery and statins
Pre-surgical clinical trials have demonstrated reduced proliferation activity and enhanced apoptosis in high-grade breast cancer tissue only in patients randomized to high (80 mg/day) or low-dose (20 mg/day) fluvastatin for 3–6 weeks before mastectomy [26]. Antiproliferative effects were also demonstrated in another presurgical clinical study of atorvastatin (80 mg/day) on invasive breast cancer utilized for 2 weeks before mastectomy, primarily in tumors expressing the rate limiting enzyme for cholesterol in breast cancer tissue [27].
Mechanisms of action (not just cholesterol but pleiotropic effects)
It is well-known that statins block the rate-limiting enzyme in the cholesterol synthesis pathway, 3-hydroxy-methylglutaryl (HMG) CoA reductase. However, there are multiple diverse mechanisms (including lipid lowering) whereby statins my disrupt cancer growth and include the following [28–31]:
Decreased localized and systemic inflammation
Helps normalize cell signaling (intracellular lipid-rafts)
Inhibit thrombotic process (anticoagulant properties, enhance fibrinolysis, …)
Inhibit tumor cell proliferation
Induction of cell cycle arrest
Induction of apoptosis
Reversion of multidrug resistance
Inhibit cell-signaling pathways involved in invasion and metastasis
Induction of tumor differentiation
Modulate immune responses
Reduces cholesterol intermediates and by-products that assist in cell growth and tumor promoting effects of oncogenes
Reduces levels of estrone sulfate and estrogen mimic compounds
Improve vascular endothelium function
Reduce oxidative stress
Modulate smooth muscle cell proliferation
Stabilize plaques
Stimulate bone growth/repair
Upregulation of nitric oxide synthase
Differences and similarities in statins
Currently available statins (in alphabetical order), and the minimum doses needed to reduce LDL cholesterol by at least 30–40 % are found in Table 4.3 [32, 33].
Drug | Dosage (mg/day) | LDL reduction (%) |
|---|---|---|
Atorvastatin (generic) | 10 | 39 |
Fluvastatin (generic) | 40–80 | 25–35 |
Lovastatin (generic) | 40 | 31 |
Pitavastatin (Livalo®) | 2 mg | 35–40 |
Pravastatin (generic) | 40 | 34 |
Rosuvastatin (Crestor®) | 5 | 39–45 |
Simvastatin (generic) | 20–40 | 35–41 |
Other notable differences between FDA approved statins include the following [32, 33]:
Statin drugs that are NOT negatively impacted by grapefruit juice includes: fluvastatin, pitavastatin, pravastatin, and rosuvastatin.
Lovastatin, pravastatin and simvastatin are derived from fungal metabolites and have half-lives of 1–3 h, so daily compliance is critical for LDL reduction.
Atorvastatin, fluvastatin, pitavastatin, and rosuvastatin are synthetic compounds with half-lives that range from 1 h (fluvastatin) to 19 h (rosuvastatin).
Lipophilic statins include: Atorvastatin, fluvastatin, lovastatin, pitavastatin, and simvastatin (most lipophilic), which are more susceptible to undergo cytochrome P450 enzyme metabolism (except for pitavastatin). And passive diffusion through the hepatocyte membrane allows for their hepatic effects.
Relatively hydrophilic statins, which are not metabolized by P450 enzymes include pravastatin and rosuvastatin. An active-carrier mediated process allows hydrophilic statins to impact hepatic cells.
Bias of industry funded statin trials?
A systematic review and network meta-analysis included 183 randomized trials of statins. A total of 146 industry-sponsored trials were found and 64 were placebo controlled and no differences were found in outcomes (especially LDL changes) from non-industry funded studies [34, 35].
Statins—Discovered from a natural source
Patients and health care professionals should be reminded that statins are naturally derived drugs. The story of their discovery is fascinating and will allow a greater appreciation of this drug class and the dietary supplement “red yeast rice” (RYR) , which is a rguably one of the better options today for statin intolerant patients.
It took approximately 2 years and thousands of moldy broth samples for a researcher named “Akira Endo ” to identify something that actually lowered cholesterol [36, 37]. His discovery, taken from a mold like the one that grows on fruit turned out to be the very first in a class of drugs that in the past and also currently grosses billions a year for pharmaceutical companies. Dr. Endo is credited with discovering the first statin in 1973 from a natural source or one normally produced in nature. It was a fungal byproduct that shares the same basic chemical structure to three of the biggest selling statin drugs of all time: lovastatin (Mevacor®), pravastatin (Pravachol®), and simvastatin (Zocor®). All three drugs have now lost their patents by mid-2006 and are now also sold as generics. Some researchers hypothesize that it is three billion years of natural selection that helped Dr. Endo find this original product. This may be part of the recent ongoing trend in some small scientific circles to reexamine the possibility of finding compounds from nature.
Dr. Endo, now 81 years old was born on a farm in the snowy north of Japan [36, 37]. He remembers being taught by his grandfather about the fungi that grew in his geographic area. Dr. Endo was interested in one poisonous mushroom that killed flies but not people. He was fascinated by the fact that a natural compound could have such an impact. His original research came at a time when there was a general enthusiasm from natural products to treat infections. For example, penicillin is a compound produced by a mold to kill bacteria, and was accidentally discovered in 1928 by Alexander Fleming . Fleming had allowed his untidy lab with bacteria to sit during a vacation. He came back to find that mold had grown in one plate and the mold had a bacteria-free zone around it. Amazingly, penicillin was later mass produced during World War II and saved millions of lives. After the war a new discovery for tuberculosis occurred. The drug known as “streptomycin ” was developed by researchers at Rutgers University, who investigated microorganisms from the soil, and it eventually became the first antibiotic that could be utilized to cure tuberculosis.
Dr. Endo became employed after college by a Tokyo-based pharmaceutical company, Sankyo and his job was to research food ingredients [36, 37]. He investigated some 250 kinds of fungi to find just one that produced an enzyme to make fruit juice less pulpy. This product was a success, and in 1966 the company allowed Dr. Endo to travel to Albert Einstein College of Medicine in New York to pursue his real strong interest in cholesterol research. During this time, cholesterol was a popular topic in research circles because of some evidence that it might play a major role in heart disease. Dr. Endo was surprised to find such strong interest by Americans in diet and dieting. “I thought it was really strange that people would cut off the fat before eating their steak. This was a culture shock, something inconceivable in Japan.” Dr. Endo has stated.
Clofibrate was an anticholesterol drug already being used, but it came with notable side effects. Several companies recognized that inhibiting a vital enzyme in the body’s production of cholesterol known as “HMG-CoA reductase ” might be a better drug [36, 37]. However, researchers could not find a substance with this mechanism that actually worked in living animals. Dr. Endo, with his unique background had a different idea: find something in fungi that might block the enzyme. He already was well aware of the penicillin and streptomycin stories of discovery and in college he actually read a Japanese translation of a Fleming biography. Dr. Endo had realized that bacteria, like humans, needed cholesterol to maintain the integrity of their cell walls. He figured that some fungus most likely had evolved a compound that would block this HMG-CoA reductase enzyme as a way of keeping enemy bacteria from using cholesterol and eventually killing them. So, it was a matter of locating the right fungus. Dr. Endo convinced the Sankyo company to give him assistance. A chemist who had just joined the company named “Masao Kuroda ” and two lab assistants joined his team. In April 1971 they began brewing fungal broths and tested each of them for their ability to block the cholesterol enzyme, which they got from ground up rat livers. “It was a bet, just like the lottery,” said Dr. Endo. For more than 2 years, he and his team worked countless hours at their lab next to a train depot in southern Tokyo. “We were doing grunt work every day until we got sick of it,” he said. Some chemicals were successful at inhibiting the enzyme but were not accepted because they were too toxic.
After testing some 6000 fungal broths, they found the perfect one in August 1973 [36, 37]. A compound made by a mold called “ Penicillium citrinum ,” which was similar to a mold that grows on outdated oranges, and it produced a strong inhibitor of the enzyme that helps the body produce cholesterol. This was the first statin. However, Dr. Endo ran into a problem because the compound soon to be named “compactin ” hardly worked in rats. More research would later find that rats actually differ in how they make cholesterol. Dr. Endo was puzzled until he happened to meet a colleague at a local watering hole near the laboratories one evening. The colleague suggested he use some hens for research, because they were about to be destroyed, and later the substance worked in these animals.
However, there was disagreement with Dr. Endo and the company on whether or not this research should be further pursued because companies working with other compounds that also held some promise. Therefore, Dr. Endo embarked on a surreptitious experiment at Osaka University. Akira Yamamoto was treating patients at this university hospital that had very high levels of cholesterol because of a genetic defect. Dr. Endo remembers calling Dr. Yamamoto from home at night so colleagues would not learn of the experiment. Dr. Endo personally prepared the samples of the potential drug and brought them to Osaka. Today, this would not be allowed because a review board would have to approve the experiment but following this procedure was not needed at that time.
The first patient (patient zero) in the entire world to receive a statin was an 18-year old woman. She was also the first to experience a side effect that even today can occur with these drugs: muscle pain (myalgia). Dr. Yamamoto gave her such a high dose she was weak and unable to walk. Dr. Yamamoto was advised apparently by his boss to stop the testing, but insisted he should continue the research. He stopped the drug on the first patient and she recovered. He also tried compactin on other patients but in lower dosages. This procedure lowered cholesterol in nine patients by an average of 27 %, according to a paper he later published. The first patient apparently has since been treated with other drugs and lives today in Southern Japan and she even had a daughter.
The Sankyo company agreed to place Dr. Endo’s drug in clinical trials, and he felt he had done enough at this point and took a job as a professor at Tokyo Noko University. He apparently did not leave the job on friendly terms with the company. Dr. Endo still mentions that the company told the researchers in his lab not to even assist him with placing his boxes of papers on the moving truck. Sankyo apparently in a one-page agreement in 1976 with Merck allowed access to its data and procedures associated with Dr. Endo’s statin. Companies often do release such information when interested in partnering with another business group. However, Merck had also been working on its own cholesterol compound and did not have any official affiliation with Sankyo. In 1978, Merck found a different fungus with a compound that was essentially identical to Dr. Endo’s and called it “lovastatin.” Dr. Endo claims he also discovered this compound independently, during his first several months at Tokyo Noko University. Merck held the patent rights in the USA, and in 1987 began marketing this compound in the USA as “Mevacor®”—the very first FDA-approved statin drug.
Eventually, Sankyo no longer pursued compactin, but instead focused on another statin with a similar structure [36, 37]. It licensed this compound outside of Japan to Bristol-Myers Squibb Company, which began selling it in the USA in 1991 as “Pravachol® .” In the early to mid-1990s, with strong research behind them, statins became to gain enormous popularity and Merck even released another statin known as “Zocor® ” in 1992. Pfizer’s “Lipitor® ” is a statin with a structure different from Dr. Endo’s original discovery, and it became the world’s number 1 selling drug with approximately $12 billion in sales per year.
As the popularity of statins continued to grow Dr. Endo received little to no attention. For example, on the Sankyo website the discovery of compactin is mentioned but not Dr. Endo [36, 37]. However, some Sankyo spokesperson mentions Dr. Endo as a key figure in the discovery. Michael S. Brown and Joseph Goldstein won a Nobel Prize for their research in cholesterol and wrote in 2004: “The millions of people whose lives will be extended through statin therapy owe it all to Akira Endo.” Dr. Endo apparently never earned a penny from his statin discovery. He left Sankyo in December 1978 and was making less than $2000 a month. Later in his time at the University doing more research on fungal byproducts he found applications for some compounds for use in cosmetics, chewing gum, and other products. He is now retired from the University, and he maintains an office in a two-room apartment in western Tokyo, with closets full of files he has maintained for years. Interestingly, several years ago Dr. Endo had a daylong health exam and was found to have a slightly abnormal cholesterol level. He claims the doctor did not know him and told him, “We have good drugs for that.” Dr. Endo also claims he took Mevacor® for a while but discontinued the drug. At his physical in 2004, his LDL or “bad cholesterol” was 155 mg/dl, but instead of going on a statin he decided to first exercise more and brought his number down to 130 mg/dl. Dr. Endo used a Japanese proverb “The indigo dyer wears white trousers” to explain why he has not yet taken a drug that was partly from his own research and invention.
Thus, numerous statins and multiple other drugs have been derived from natural sources (approximately one third of current medications on the market), but Akira Endo’s is arguably one of the most notable. Again, the statins derived from natural sources as well as several other naturally derived drug examples are listed in Table 4.4 [36].
Drug name | Where it is used | Launch date | Where it comes from |
|---|---|---|---|
Aspirin | Painkiller | 1899 | Willow bark |
Penicillin | Antibiotic | 1940s | Fungus |
Mevacor | Cholesterol-statin | 1987 | Fungus |
Pravachol | Cholesterol-statin | 1991 | Fungus |
Zocor | Cholesterol-statin | 1992 | Fungus |
Taxol | Cancer | 1993 | Pacific yew tree |
Byetta | Diabetes | 2005 | Gila monster saliva |
Red Yeast Rice (RYR)
Lost in the overall story of Akira Endo was that he found another fungus that was able to block cholesterol synthesis that was also utilized as part of the statin discovery. Dr. Akira Endo also found that a Monascus yeast strain naturally produced a substance that inhibits cholesterol synthesis [37, 38]. He named it “monacolin K ” and it is found in the dietary supplement red yeast rice extract (RYR). This was later isolated and is now known to be of the same structure as lovastatin, the first marketed statin. Thus, RYR could also be considered one of the first statins used in medical history.
RYR favorably competes with lovastatin, pravastatin and simvastatin in terms of potency, and is now considered an alternative for statin intolerant patients [39–41]. RYR has demonstrated a significant reduction in cardiovascular events (primary endpoint) in a randomized controlled trial of almost 5000 participants followed for a median of 4.5 years (Chinese Coronary Secondary Prevention Group study) [42].
RYR is a traditional Chinese herbal medicine first mentioned in 800 AD in the Tang Dynasty for blood circulation [43, 44]. It is produced by the fermentation of the fungal strain Monascus purpureus Went (red yeast) over moist and sterile rice. RYR is also actually a common dietary compound and food colorant utilized in numerous Asian countries. In China, Japan, and several other countries it is utilized as an additive and preservative for fish and meat. It has a vibrant red color, flavor, and aroma, thus it is also utilized as a flavoring agent in a number of Chinese recipes and dishes, and it is even used for brewing red rice wine. RYR is also known by multiple synonyms as a food product including: Hong Qu, Hung-Chu, Ang-kak, Ankak rice, Red Mold Rice, and Beni-Koji.
It is now known that RYR contains ten different compounds known as “monacolins ” (statin-like compounds) that block the rate-limiting enzyme for cholesterol synthesis [45]. These are listed in Table 4.5. Of these, again monacolin K is likely most responsible for the primary LDL reduction associated with RYR.
Monacolin compounds in RYR |
|---|
Dihydromonacolin K |
Monacolin J |
Monacolin JA |
Monacolin K (lovastatin equivalent) |
Monacolin KA |
Monacolin L |
Monacolin LA |
Monacolin M |
Monacolin X |
Monacolin XA |
Total monacolin content (sum of the ten detectable monacolins) |
RYR overall lipid and clinical efficacy
A meta-analysis of over 9600 patients in 93 randomized trials involving three different commercial variants of RYR has summarized this extensive experience [46]. The mean reduction in total cholesterol, LDL, triglyceride, and increase in HDL was the following: −35 mg/dl (−0.91 mmol/L), −28 mg/dl (−0.73 mmol/L), −36 mg/dl (−0.41 mmol/L), and +6 mg/dl (+0.15 mmol/L).
Xuezhikang is a commercial RYR product evaluated in a large, randomized, placebo-controlled clinical trial with robust endpoints [42, 47]. The China Coronary Secondary Prevention Study (CCSPS) enrolled 4870 participants (3986 men, 884 women) with a previous myocardial infarction (MI), and a baseline mean total cholesterol, LDL, triglyceride, and HDL of approximately 208 mg/dl (5.38 mmol/L), 129 mg/dl (3.34 mmol/L), 165 mg/dl (1.85 mmol/L), and 46 mg/dl (1.19 mmol/L). Participants received RYR 600 mg twice daily (1200 mg total, monacolin K 2.5–3.2 mg/capsule) or matching placebo and followed for 4.5 years. The trial was conducted from May 1996 to December 2003 in 65 hospitals in China. The primary endpoint was nonfatal MI or death from coronary or cardiac causes. Secondary endpoints included total mortality from CV disease, total all-cause mortality, need for coronary revascularization procedure, and change in lipid levels. Fasting blood samples were drawn at baseline, 6–8 weeks after randomization, and at 6-month intervals. There were two interim analyses, and the second one demonstrated a significant difference for the primary endpoint. The study was stopped in June 2003. A total of 98 % of the participants completed the study and mean BMI was 24–25 (normal weight). It is of interest that a plethora of these endpoints were significantly reduced with the exception of a nonsignificant reduction in fatal MI. Cancer mortality and all-cause mortality were reduced. Lipids were also modestly and significantly reduced. No serious adverse events were observed during this trial. Total adverse events and treatment cessation numbers were similar for RYR and placebo. The number needed to treat (NNT) to prevent a primary end-point over the 4.5 year duration of the trial is 21, which favorably compares to the NNT range (19–56) observed in previous secondary prevention trials [48]. Subsequent subgroup evaluations from the CCSPS trial have found equivalent benefits with RYR among diabetics [49], elderly (mean age 69 years) [50], and hypertensive participants [51]. Potential anticancer benefits found in the overall trial with RYR were also found among the elderly (significant reduction in cancer deaths) [42, 50], and included a 51 % reduction in cancer incidence [50]. Thus, the data has been consistent that RYR reduces lipid parameters, especially LDL [52–54], and appears to have a favorable impact on clinical endpoints [42]. The summary of the lipid results compared to placebo and of the clinical endpoints results for the CCSPS are listed in Tables 4.6 and 4.7.
Lipid value | Change with RYR compared to placebo (%) | p Value |
|---|---|---|
Total cholesterol | −11 | <0.001 |
LDL cholesterol | −18 | <0.001 |
Triglycerides | −15 | <0.001 |
HDL cholesterol | +4.2 | <0.001 |
Table 4.7
Multiple clinical endpoint observations in the largest randomized trial (CCSPS) of RYR versus placebo [47]
Clinical endpoints | Risk reduction with RYR compared to placebo (%) | p Value |
|---|---|---|
Nonfatal myocardial infarction (MI) | −62 | <0.001 |
Coronary disease death | −31 | 0.005 |
Fatal MI | −33 | 0.19 |
Fatal stroke | −9 | 0.85 |
Revascularization | −36 | 0.004 |
CVD death | −30 | 0.005 |
Cancer death | −56 | 0.014 |
Total or overall deaths | −33 | 0.0003 |
Other clinical trials conducted continue to support the lipid lowering impacts and safety of RYR. A randomized trial of 74 dyslipidemia patients comparing 40 mg/day of simvastatin to a high potency RYR (2.53 mg monacolin K per capsule, total monacolins, 5.3 mg/capsule) and lifestyle changes with fish oil found that the LDL reductions between both groups were similar after 12 weeks (−40 % for simvastatin, −42 % for RYR) [45]. Participants consuming RYR needed to consume 4–6 capsules (2400–3600 mg RYR total) per day compared to one pill per day for the prescription drug group. No dropouts occurred, and there was no difference in adverse events reported. In the simvastatin arm three patients experienced musculoskeletal symptoms with one having elevated liver function tests (LFTs) . RYR group had one patient with elevated creatine kinase numbers. This abnormality may have been caused by excessive exercise.
Another trial (n = 62) by the same principal author utilized a less potent RYR (1.02 mg monacolin K per capsule, total monacolins, 2.16 mg/capsule) at a dose of six capsules (3600 mg total RYR) per day compared to placebo for statin-intolerant (myalgia induced) patients for 24 weeks and found a significant (p = 0.01) LDL reduction of −21.3 % [39]. It should also be of interest that 93 % of the subjects on RYR in this trial with a history of statin-intolerance were able to tolerate this supplement without myalgia.
Another group of 43 statin-intolerant adults with dyslipidemia were randomized in a separate trial to prescription pravastatin at 20 mg (40 mg total) or RYR 2400 mg twice daily (4800 mg total, monacolin K at 1.245 mg per capsule, eight capsules per day), and both groups were asked to adhere to weekly healthy lifestyle educational sessions [41]. After 12 weeks a 30 % reduction in LDL was observed for RYR and a 27 % reduction for pravastatin. Only one of 21 in the RYR (5 %) and two of 22 (9 %) participants in the pravastatin group discontinued because of myalgia recurrence. Mean pain severity, and muscle strength at week 4, 8, and 12 did not differ. Other recent publications report similar results [40, 55]. A recently published crossover study of children (aged 8–16 years) with heterozygous Familial hypercholesterolemia (n = 24), and Familial Combined Hyperlipidemia (n = 16) found that a RYR supplement significantly (p < 0.001) reduced LDL by 25 % [56]. There were no adverse events in terms of liver or muscle enzyme abnormalities over the 8-week treatment period.
Related posts:
S.A.M. and Breast Cancer—Focus on Aspirin and Other Integrative Aspirin-Like Medicines: The Real “Natural” Options
The Ideal 7-Step Breast Cancer Diet, Lifestyle, and Dietary Supplements Program for Prevention/Recurrence: Heart Healthy = Breast Healthy!
Supplements/Diet/Other Integrative Method Vernacular and Controversies from A to Z: What is the Latest or Greatest, or Not So Great?!
25+ Observations Over 25+ Years for Surviving and Thriving in the Dietary Supplement Quality Control and/or Perception Versus Reality World
Introduction
Rapid Review of Breast Cancer Treatment Side Effects and Dietary Supplement/Integrative Options from A to Z: What Helps, Harms, or Does Nothing?
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
