What the Heck Has Been Going on in My World?
By Mark A. Moyad, MD, MPH, University of Michigan
article #69 – Summer 2015
A total of 69 times in a row (and for 15+ years!) I have written and volunteered for this newsletter, and I have yet to receive any personal financial compensation or personalized classic timeless gift s such as: a PAACT complimentary concert tickets to see a Justin Bieber concert or a back stage pass to meet Miley Cyrus (wait I don’t even want those things), a package of Double-Stuff Oreo Cookies (amazing), McDonalds French Fries (doubly amazing), Five-Guys Junior Hamburger (triply amazing) or a Del Taco baby Burrito with extra green sauce (quadrupley amazing) and finally a free PAACT state-of-the-art elliptical or treadmill machine and church pew because after I eat all that stuff (aka junk food that tastes incredible) I will need a few hours to run it off and pray real hard that it does not stick to my belly, coronary or penile arteries forever!” YIKES!!!
FIRST AND FOREMOST I WANT TO THANK ALL OF YOU FOR MAKING “THE SUPPLEMENT HANDBOOK” – my new book a best seller in the winter and spring of 2015! AN AMAZON BEST SELLER!!! YEAH!! THANK YOU!!! Second, if you have not picked up a copy please get one on Amazon (the cheapest place to procure a copy) to support my beer fund! For less than 20 bucks you get 512 pages of material on over 100 medical conditions and when not using this amazingly big book it also functions as a beer coaster or a potato chip or pizza plate holder when you’re watching the big game on TV (or for those in my kids generation – watching the big game on your computer or phone (because 20 years from now someone is going to read this column and ask “What is a TV”?). NOT BAD!
314) If you cannot tolerate your statin/cholesterol lowering drug or need to go to a lower dosage of a statin drug because of side effects then Zetia (ezetimibe) is NOW an option and it’s also being studied as an anti-prostate cancer drug! How groovy/awesome is that!
(Reference: IMPROVE-IT Investigators. New England Journal of Medicine, published on June 3, 2015.)
LOWER IS BETTER! The combination of a statin drug with ezetimibe (also known as “Zetia”10 mg per day) resulted in a greater reduction of LDL (aka “bad cholesterol”) and reduced cardiovascular events greater than a statin alone. Side effects including muscle, gallbladder, and liver side effects and rates of cancer, over the course of the clinical trial, were the same in both groups (a good thing). It’s also being studied right now against prostate cancer but this is very preliminary.
WHAT ELSE DO I NEED TO KNOW?
Ezetimibe (Zetia) blocks the absorption of cholesterol from food/intestines and it’s a prescription drug. Someone can expect to get a 15-25% reduction in LDL with one pill of ezetimibe (not bad). However, here is the most recent, fabulous news! JUST PUBLISHED clinical trial data (called “IMPROVE-IT”) with statins have actually found a moderate positive impact on clinical endpoints and not just cholesterol values with ezetimibe. This should increase the use of ezetimibe immediately in those patients with problems taking statins or higher dosages of statins and reignite the discussion of a “lower is better” philosophy, because in high-risk patients ezetimibe and simvastatin lowered LDL to almost 53 mg/dl compared to approximately 70 mg/dl in simvastatin only participants. TELL ME MORE!!! (Okay, when you see all CAPS in texting it means you are YELLING – so I WILL STOP YELLING AND TELL YOU MORE!). The IMPROVE-IT trial was more specifically a double-blind, randomized trial of 18,144 patients from 1147 medical centers in 39 countries who had been hospitalized for an acute coronary syndrome (acute heart attack or high-risk unstable chest pain) within the previous 10 days. Th e combination of simvastatin (used to be known as Zocor-a statin drug) at 40 mg and ezetimibe (again Zetia) at 10 mg was compared to simvastatin (40 mg) by itself. The primary endpoint of this trial was the combined end point of cardiovascular death, nonfatal heart attack, unstable chest pain needing re-hospitalization, coronary revascularization (procedure like bypass or stent placed 30 or more days after randomized in the trial) or nonfatal stroke. The average age of the participants was 63-64 years of age (50 years or older to be eligible), 76% were male, 84% were Caucasian, 61% had hypertension, 27% had diabetes and 33% were current smokers! Additionally the mean BMI was 28, which is overweight, and the mean LDL was 84 mg/dl before they the trial started. YIKES!!! Apart from the fact that they already had a low LDL, these were not the healthiest group of boys and girls. In fact, I was really disappointed that the researchers and the editorial in this New England Journal of Medicine article point out that this group as a whole was very unhealthy. And, apart from the higher smoking rate this group is actually reflective of the U.S. population! DOUBLE YIKES!!! Okay, back to our story boys and girls and dog (my dog Chauncey is watching me while I’m typing this article probably, wondering why PAACT has never given him a free official PAACT bone, squeeze toy or squirrel look alike)!
The median follow-up in this clinical trial was 6 years and the LDL cholesterol average at the end of the trial was 54 mg/ dl in the combination statin-ezetimibe group and 69.5 mg/d in the statin only group. The rate of the primary endpoint at 7 years was 32.7% in the combination group and 34.7% in the statin only group, which is only an absolute difference of 2 percentage points but this was still significant (p=0.02). Muscle, gallbladder, and liver side effects and cancer were similar between the two groups. Discontinuation of the medication in either group because of side effects was approximately 10-11% (again no difference). However, in reality compliance was a big issue throughout the trial because 42% of the participants in IMPROVE-IT (combination or statin alone group) stopped their study medication prematurely (for any reason), which is about 7% per year, which actually closely resembles what has been observed in other trials! In other words, it’s not the side effects that are causing patients to stop these drugs but the lack of compliance (boredom, forget, don’t like it, would rather be watching Tiger baseball or Michigan football, travels a lot… blah, blah, blah). I make fun of this but with lifesaving drugs or even supplements that help it is hard to find folks that will take pills almost all the time. So, this is why I always say that I love it when someone does not qualify for taking any pills because they are so healthy because pill taking is a PAIN IN THE GLUTEUS MAXIMUS (aka “buttocks” as Forest Gump used to say…and “Life is Like a box of chocolates – you never know what you are going to get unless of course you see the one in the box with nuts in it before you bite it then you know it is going to taste great!” Sorry I digressed!
BACK TO THE STORY….Adding ezetimibe lowered LDL by 24%. Keep in mind that no differences between the groups were found for death from cardiovascular disease or death from any cause (cancer…), but significant reductions were found in the combination group for the rates of heart attack and ischemic stroke . This is a credible finding since the differences began to emerge after 1-year into the trial and it was only conducted for about 6 years (not a long time actually). Thus, overall it represents a moment where a non-statin therapy to reduce LDL can also reduce cardiovascular outcomes (something missing with niacin, and others). It appears that lower is better, and had these patients started with higher LDL levels arguably even better results would have been observed. It is also interesting that in the combination group the reduction in the inflammatory blood marker hs-CRP was also significantly reduced compared to the statin only group. This is part of the reason that I believe ezetimibe should continue to be studied against breast and prostate cancer marker.
Still, the IMPROVE-IT trial offers important new evidence for the “LDL Hypothesis” that lowering of this blood marker is the primary driver of what changes cardiovascular risk (after the first year of the study the LDL was 53 mg/dl in the combination group and 70 mg/dl in the statin only group. I know that there are many nice folk out there that want you to believe that cholesterol has nothing to do with heart disease and I think you know how I feel about that, which is similar to how I feel when Michigan State or Ohio State beats Michigan in any sport (it is just plain wrong). Despite just a 2% difference in the primary endpoint in favor of the combination group, this is almost identical to what would have been predicted from past trials based on the LDL difference!
Again, offering more evidence for the LDL hypothesis. Ezetimibe was being studied by Harvard researchers in their laboratory, and they found preliminary evidence years ago that it may have some anti-prostate cancer effects. Regardless, this drug represents new options or hope for those that cannot achieve their target LDL with diet, exercise and statins. This also offers hope for new medications in the pipeline such as “PCSK9 inhibitors” that reduce LDL via reducing/blocking LDL receptor removal to allow for more LDL to be cleared from the circulation, and these agents have the ability to lower LDL (bad cholesterol) as much as 60%. ZOWIE BATMAN! However, the problem with these drugs is that they are supposed to be given by subcutaneous injection once every 2-4 weeks, and with overall compliance in the IMPROVE-IT trial not being very good, this is not a good sign of future drug compliance if PCSK9 blockers work. Personally, I don’t get excited about sticking myself with a needle every few weeks unless of course it helps me with my…you know what down there…. in my pelvic region! I mean my wallet or helps to make me more money! What were you thinking I was thinking???????!
315) Statins don’t work in women? Hmm really? BREAKING NEWS!(Reference: Wang A, Aragaki AK, Tang JY, Kurian AW, Manson JE, Chlebowski RT, et al. Statin use and all-cancer mortality: prospective results from the Women’s Health Initiative. J Clin Oncol 2015;33 (suppl; abstr 1506). & THE SUPPLEMENT HANDBOOK by Dr. MOYAD (Hey I know that dude he is the one that I love to love…okay I made that part up…but my new bestselling book is real.)
Interestingly, at the time of this chapter’s submission, data from the noteworthy Women’s Health Initiative (WHI) clinical trial was released at the annual American Society of Clinical Oncology (ASCO) meeting (again the largest cancer meeting and it is held in Chicago – the place with the big tower and beautiful winters). The study enrolled women aged 50-79 from 1993-1998 at 40 U.S. clinical centers. There were a total of 146,326 participants with a median follow-up of 14.6 years. A total of 23,067 incident cancers and 3,152 cancer deaths were observed. Numerous confounding variables were adjusted for, and compared with those that never used statins, those that did use statins had a significant 22% reduction in cancer mortality. The reduction in cancer death was not associated with statin potency, duration or type of statin itself. Current statin use was associated with significantly reduced mortality of numerous cancer types, including breast, colorectal, ovarian, digestive, and bone/connective tissue cancer deaths. Interestingly, statin use was not associated with a decrease in cancer incidence despite its impact on mortality (THIS IS WHAT HAS ALSO BEEN OBSERVED IN PROSTATE CANCER BY THE WAY OR AS I LIKE TO TEXT “FYI”). The conclusion of the study was as follows: “In a cohort of postmenopausal women, regular use of statins or other lipid-lowering medications may decrease cancer mortality, regardless of the type, duration, or potency of statin medications used.” Thus, in the worst case scenario if cholesterol lowering does not alter the course of breast cancer and continues to only lower the risk of morbidity and mortality in women that is still a worst case scenario with ample merit don’t you agree? So, why wasn’t this headline news? Beats me! It doesn’t prove cause and effect but it’s one of the largest indirect looks ever conducted in women. Maybe the media was too obsessed with important stuff that day like whether or not Kim Kardashian was going to
– STATIN PRIMARY PREVENTION TRIALS ONLY AND IMPACT ON WOMEN (insert table here)
wear the blue or the black dress at a Hollywood party! COME ON PEOPLE WAKE UP! FYI – I think she should go with the black dress because like my wife she looks stunning in black and then for shoes I am thinking Jimmy Choo or Manolo Blahnik shoes which are actually on sale this week at Neiman Marcus…. sorry I digress again! Darn it!
STATIN PRIMARY PREVENTION TRIALS ONLY AND IMPACT ON WOMEN TRIAL
WHAT ELSE DO I NEED TO KNOW?
The leading cause of death in the U.S. for women and men is cardiovascular disease (CVD), and this has been the case for 116 of the last 117 years. CVD causes more deaths than cancer and chronic lower respiratory diseases (CLRD) combined. CVD causes 1 death per minute among females in the U.S. 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 U.S. statistics have recorded the following: approximately 41,000 deaths were 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.
BUT, DOC MOYAD I HEAR ALL THE TIME THAT STATINS HAVE NO EVIDENCE OF WORKING IN WOMEN! Well, that statement makes me as mad as at long-tailed cat stuck in a room full of rocking chairs or a mouse stuck in a room full of mouse traps or a hamster stuck in a room with a defective spinning wheel or….you get the idea! This is not accurate. Statins like any drug or supplement comes with benefits and catches and ideally I don’t want anyone taking any pills, but for the women (and men) that really need them it has changed lives so let’s review the trials with women that were healthy but at an increased risk of a cardiovascular events. Here we go…..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% vs -37%), but the number of women having such an event was small (20 out of 997), so there was no treatment difference between genders. In the MEGA study, which used pravastatin, there was a 37% reduction in men versus 29% for women. 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 U.S. 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%. 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%), and there was a non-significant reduction in nonfatal heart attacks (-44%) or heart disease 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. A -76% in revascularization procedures means that these women were NOT getting BYPASS SURGERY or STENTS placed in their arteries and this is one thing that ALWAYS gets missed when talking about cholesterol lowering. These medications have dramatically reduced the need for getting your chest cracked up and needing bypass surgery! (SEE CHART ABOVE)
Statins, Safety and Type 2 Diabetes…THIS STUFF IS REAL!
In the appropriate individuals statins reduce all-cause mortality, cardiovascular 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 cardiovascular events or deaths avoided for each potential case of diabetes with rosuvastatin (Crestor). 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. Recent laboratory evidence suggests a potential mechanism of action whereby statins increase the risk of diabetes. 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 (SAY WHAT?), 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. WHAT ALL THIS SCIENTIFIC MUMBO JUMBO (Hey that was an elephant! Oops – his name was Dumbo) MEANS IS THAT NO ONE SHOULD TAKE A STATIN WITHOUT REALIZING THAT YOU WANT TO BE ON NO PILL OR THE LOWEST DOSE POSSIBLE BECAUSE HIGHER DOSES PROBABLY DO INCREASE THE RISK OF DIABETES IN SOME FOLKS! Thus, especially in high-risk patients there may be value in monitoring insulin sensitivity during statin use and using anti-diabetes medications may even 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 or reduce diabetes risk with another pill, for example CoQ10 supplementation is also being investigated for this purpose. Still, one mantra of this drug class (and others) NEEDS TO BE REPEATED… It appears more relevant than ever that DOCTORS need to encourage patients to be on the lowest dosage of a statin, along with moderate to aggressive lifestyle changes to maintain small dosage needs (or no drug). PATIENTS NEED TO TRY TO BE ON THE LOWEST DOSE 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 4 exercises and 12 drug meta-analyses and the addition of 3 recent exercise trials were utilized in a recent investigation for a total of 305 randomized control trials with over 339,000 participants. A total of over 14,700 participants were randomized to exercise in 57 trials (Naci H, et al. BMJ 2013;347, published October 1, 2013). 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.
316) Statins and prostate cancer treatment. And the beat goes on….BREAKING NEWS AGAIN…JUST KEEP ON BREAKING…
(Reference: Harshman LC, J Clin Oncol 2015;33: Abstract 148 & Hamilton RJ, et al. J Clin Oncol 2015;33: Abstract 145.)
Recently, at ASCO (largest cancer meeting in the world, a large study from Harvard and Canada concluded with the following statement below (note: this does not prove cause and eff ect but
makes the lower cholesterol and statin theory against prostate cancer more interesting don’t you think? -“…statin use at the time of ADT initiation was associated with a significant increase in TTP on ADT even after adjusting for established prognostic factors.” (n=926 folks) Moyad comment – Patients appeared to have a better response to hormone therapy if they were also
taking a statin drug. -For ADT following primary or salvage radiation-“statin use was associated with improved overall and prostate cancer-specific survival and improved quality of life.” In terms of intermittent androgen deprivation (IAD)-“more off treatment intervals and longer off treatment.” (n=1364 folks studied) Moyad comment – Patients had a better response to IAD if they were on a statin drug.
WHAT ELSE DO I NEED TO KNOW?
I have nothing else to say except if men and women reduce their cholesterol while being treated for breast or prostate cancer and it doesn’t work in fighting cancer, then I apologize that all it might do is reduce the number 1 cause of death in men and women for 114 of the last 115 years. HEART HEALTHY = PROSTATE HEALTHY!!! (Moyad Trademark Circa 2003 in the medical literature and if you do not believe me look it up. So, if you use these terms at any point in your life you need to donate some money to PAACT and then donate some Money to the Moyad Beer fund, which is also known as MBF. T-shirts will be available soon!).
317) Metformin, breast cancer and a phase 3 trial! Why do I have to know about this? Please read on…AND TEACH ME ABOUT THIS DRUG and REMEMBER THAT EXERCISE AND DIET WORKED BETTER THAN THIS DRUG TO PREVENT TYPE 2 DIABETES (but you never get to hear about this!).
(Reference: Goodwin PJ, et al. Eff ect of metformin vs placebo on weight and metabolic factors in NCIC CTG MA.32. J Natl Cancer Inst 2015;107: epub ahead of print. & Diabetes Prevention Program or DPP in New England Journal of Medicine 2002.)
Metformin (generic “natural” drug derived from the French Lilac”) given to non-diabetic women in the hope of preventing breast cancer from returning at least appeared to make participants more heart healthy! So, should patients ask their doctors about it in order to lose a little weight, drop their blood sugar and prevent type II diabetes if they are at higher risk? Yes, but remember that exercise and weight loss via diet arguably worked better in preventing type 2 diabetes.
WHAT ELSE DO I NEED TO KNOW?
(THIS IS A LONG ARTICLE SO BUCKLE UP…IT’S INTERESING, BUT IT’S ABOUT AS LONG-WINDED AS My grandfather when he talks about the positives and negatives of his colon health and latest bowel movements just as I am about to take the first bite of my pizza…sorry Grandpa I suddenly lost my appetite!) Metformin has actually been available in Europe since the 1950s but was not approved by the U.S. FDA until December 30, 1994. An extended release (XR metformin) version was approved in October 2000. Metformin was actually first synthesized and found to lower blood sugar in rabbits in the 1920s and then put aside for decades because of an increase in insulin synthesizing/utilization research. A 1957 published clinical trial of diabetes (by French physician Jean Sterne – who coined the name of metformin as the glucose eater or “Glucophage”…REMEMBER THIS DRUG NAME) was then completed and the U.K introduced it in 1958 and Canada in 1972. Metformin is now considered a first-line drug treatment along with diet and exercise for adult and pediatric patients with type 2 mellitus because of its favorable overall profile (glucose control, weight loss and low risk of hypoglycemia). It is arguably the only drug proven to prevent pre-diabetes (high-risk diabetes patients) from becoming diabetes and is a primary treatment in patients with metabolic syndrome. Overall, few drugs in medicine cost less with such a long-term safety profile and even added potential heart health benefits. WOW and WOW SPELLED BACKWARDS!! Metformin works by reducing liver glucose production (“inhibiting gluconeogenesis”) and increasing skeletal muscle tissue uptake of glucose. Metformin essentially leads to a maximum 75% reduction in liver glucose production. It also reduces blood insulin levels (not directly), increases insulin sensitivity, suppresses synthesis of proteins, fatty acids and cholesterol, and increases the utilization of free fatty acids. Metformin has also demonstrated some evidence of reduced intestinal glucose absorption. Metformin increases insulin sensitivity by activating hepatic and muscle AMP-activated protein kinase (AMPK – “metabolic master switch”), which results in reduction of fatty acid synthesis and stimulation of fatty acid oxidation in the liver and increase in muscle glucose absorption. BLAH! BLAH! BLAH! Metformin is generally available in 500, 850, and 1000 mg tablets. The starting dose is 500 mg twice a day or 850 once a day, given with meals. The most common dosage utilized in the Diabetes Prevention Program (DPP) was 850 mg twice a day. In general, clinical experience suggests 500 mg once a day with a meal and increasing dose in 500 mg increments every 2-4 weeks until maximum dosage is achieved. Metformin XR can be prohibitively expensive and available in 500- and 750-mg tablets utilized with the evening meal. The half-life of metformin is on average 5-6-hours in plasma (longer retention in red blood cells or blood-up to 18 hours), which suggests 94% of the drug is removed by the body in 24 hours. This short half-life emphasizes the need for daily compliance whether it is for patients or when measuring glucose and other parameters in clinical trials. Metformin is limited by gastrointestinal complications (soft stool, diarrhea, gas, abdominal pain and more rarely nausea and vomiting) in up to 50% of patients, but these adverse effects are usually transient and resolve within days to weeks of initiating treatment. Additionally, gastrointestinal side effects are reduced greatly by again, titrating increasing dosages of the drug every 2-4 weeks (for example 500 or 850 once a day for 2 weeks and then 500 mg additional) and when it is consumed with food. Although food has been reported to reduce the rate and extent of metformin absorption by increasing the time to peak plasma concentration by approximately 40 minutes, but this appears to be a small issue especially compared to the overall importance of long-term compliance. Less than 5% of patients in clinical trials are not able to tolerate the drug due to side effects. Extended release (XR) metformin appears to improve gastrointestinal tolerability and can be given once a day, but is more expensive (no thanks!). Metformin can reduce vitamin B12 and/or potentially magnesium levels, so these values should be monitored by the doctor that you adore or love the most in your life (not a romantic love but a “hey let me buy you a cold beer” kind of love). It has been known that this drug interferes with B12 absorption in the last part of the small intestine and can lower B12 in 10-30% of patients. The reduction of B12 by metformin appears to be dose-dependent. Rarely, patients complain of a “metallic taste” with the drug, which has been more commonly found with similar medications. Regardless, “metallic taste” has been reported in clinical trials in approximately 3 to 11% of patients. It also appears to be self-limiting with only 0.5% of patients complaining of metallic taste after 3 months of treatment. Regardless, a reduction in dose or the passing of time appears to resolve this issue almost immediately in patients distressed by this issue. The most serious concerning adverse event with metformin is lactic acidosis, where a low pH in body tissues and blood (acidosis) along with increases in lactate is problematic. The overall incidence of lactic acidosis on metformin has been estimated to be less than 1 case per 1000 total patient years on the drug. In other words, it has become as rare as almost any other drug especially when working closer with your doctor. Still, metformin is contraindicated in some individuals because of impaired kidney function and the potential concerns of lactic acidosis (many doctors think this is overrated and metformin should be available over the counter, but that’s not going to happen. You should talk to your doc about these things and not a newsletter with a guy that likes to make funny jokes a lot for personal therapy who also happens to be a doctor). Iodinated contrast media administration given for some imaging tests could result in lactic acidosis in a patient utilizing metformin. However, this rare adverse effect occurs if the contrast causes renal failure. Metformin is excreted primarily by the kidneys so continued utilization of metformin after the initiation of kidney failure causes toxic concentrations of the drug and subsequent lactic acidosis. In order to avoid this complication metformin should be withheld after the administration of contrast agent for 48 hours, and if renal function is normal after 48 hours from receiving contrast then metformin can be reinitiated. However, despite what the package insert recommends, which is also to withhold metformin 48 hours before contrast medium is given, others have argued there is no justification for this before and then after procedure (for 48 hours). Still, it seems prudent to stop metformin two days before and after contrast in any person with a hint of kidney issues simply because the benefit exceeds the risk in my opinion THE TRIAL THAT SHOCKED THE WORLD (DPP = Diabetes Prevention Program)!!!
This landmark trial was published on February 7, 2002 in the New England Journal of Medicine. This trial consisted of 3234 non-diabetic individuals with elevated fasting blood glucose (mean of 106 mg/dl and hemoglobin A1c of 5.9% and 67% with a fasting glucose of 95-109 mg/dl and 33% with 110-125 mg/dl) were assigned to placebo, 850 mg metformin twice daily (850 mg for first month then 850 mg twice a day thereafter) or lifestyle changes with a goal of at least 7% weight loss (via low-fat low caloric diet) with 150 minutes of physical activity per week. Mean age and BMI was 51 years and 34, respectively, with 68% women, 45% members of a minority group and 20% 60 years of age or older. However, almost 33% of the participants had a baseline BMI of 22 to 29! Approximately 70% of the participants had a family history of diabetes and 16% of the women had a history of gestational diabetes. The average follow-up was only 2.8 years and compared to placebo the group utilizing metformin reduced the risk of diabetes by 31% (95% CI 17- 43) and the lifestyle intervention reduced the incidence by 58%. (LIFESTYLE CHANGES BEAT ONE OF THE BEST SELLING DRUGS OF ALL TIME…EXTRA, EXTRA, READ ALL ABOUT IT IN THE PAACT NEWSLETTER). In addition, one of the key findings of this landmark publication was the “lifestyle intervention was significantly more effective than metformin.” In fact, the number needed to treat (NNT) or to prevent one-case of diabetes over 3-years for metformin was 13.9 persons for metformin and 6.9 for lifestyle-intervention. Regardless of BMI group (22-<30, 30-35 or >35) metformin or lifestyle was beneficial in reducing the incidence of diabetes regardless of gender and race or ethnic group, but metformin appeared to have a greater impact in those with a BMI of 35 or more. Overall, treatment effects did not significantly differ by gender or race or ethnic group. Daily caloric intake was reduced by 249 kcal in the placebo group, 296 in the metformin group, and 450 kcal in the lifestyle group (p<0.001). The average weight loss was 0.1, 2.1 (4.6 pounds), and 5.6 kg (OVER 12.3 POUNDS) in the placebo, metformin, and lifestyle groups (p<0.001). Interestingly, side effects with metformin were significantly (p<0.02) greater than placebo in terms of gastrointestinal symptoms (diarrhea, flatulence, nausea, and vomiting), but were significantly (p<0.02) lower with lifestyle changes compared to placebo!!!!!! YEAH BABY!!! LIFESTYLE RULES!!! Anti-Cancer!? Now, perhaps, the most observed and truly landmark event is a phase 3 trial being conducted in North America, the United Kingdom, and Switzerland and it has already completed enrollment of 3649 non-diabetic women receiving conventional treatment for T1-3, N0-3, M0 breast cancer diagnosed during the previous 12 months. Interestingly, patients needed to have a fasting glucose of less than or equal to 126 mg/dl (7.0 mmol/L), which is the threshold for diabetes diagnosis, but essentially enrolls only pre diabetics or those with normal blood sugar. Women with a history of lactic acidosis, current use of diabetes drugs, previous or recurrent breast cancer, greater than moderate intake of alcohol or “marked” liver, kidney, or cardiac abnormalities were excluded. Subjects were randomized to metformin 850 mg oral caplet twice a day for 5 years, which included a 4-week initial metformin acclimatization period of 850 mg a day for 4 weeks and then the addition of another 850 mg per day. Interestingly, this study also included a metabolic substudy that has been completed!!! AND YOU ARE ABOUT TO GET THE BREAKING NEWS RESULTS!!! Th e first 492 individuals with fasting blood samples at baseline and after 6-months were included. Mean age, BMI, and glucose of participants in the substudy was 52 years, 27-28, and 95 mg/d or 5.3 mmol/L (range 88-101 mg/dl or 4.9-5.6 mmol/L), respectively. The results from this substudy were impressivem because the results below “did not vary by baseline BMI or fasting insulin” including the following:
• Weight reduced 1.7 kg (3.7 pounds) or -2.3% with metformin and increased 0.5 kg or +0.7% with placebo (p<0.001). BMI change vs placebo also was significant (p<0.001).
• Glucose reduced 1.9% with metformin and increased 1.9% with placebo (p=0.002).
• Insulin reduced 11.1% with metformin and did not change with placebo (p=0.002)
• hs-CRP was unchanged with metformin and increased 6.7% with placebo (p=0.002).
• Leptin (hormone that when it goes down is a symbol that the drug has positive/beneficial metabolic changes…
GOOD NEWS!!!) reduced 9.5% with metformin and increased 10.7% with placebo (p<0.001). Interestingly, members of this research group had found previously that higher insulin levels in breast cancer were associated with two times the risk of distant recurrence and three times the risk of death.
318) Adult vaccines may reduce your risk of a heart attack and have anti-cancer eff ects? Has Moyad lost it? (well yes, I never had “it” but I do believe this preliminary research!). VACCINES = HEART HEALTHY!!! (References: 1. Corrales-Medina VF, et al. JAMA 2015;313:264-274. 2. Mitchell DA, et al. Nature March 19 2015.).
If you qualify for any adult vaccine right now, please go get it because it may not only reduce your risk of cardiovascular disease (CVD) but it might also enhance the effects of your cancer treatment. This is preliminary research but who caresthis is a SIDE BENEFIT (get it….not a side effect) of some of these adult vaccines.
WHAT ELSE DO I NEED TO KNOW?
Vaccines are no longer helpful just for kids, they are incredibly helpful for adults! Adult men and women need to be more vigilant about getting them. People will not hesitate to take an unproven supplement to boost or support the immune system but they are probably not aware that there are vaccines that do a much better job of doing this than any other over the counter pill.
I have explained in the past how many adult vaccines like the fl u vaccine are heart-healthy and you need to get these vaccines for all the side benefits! And now comes the latest research that preventing pneumonia might fight heart disease and other vaccines could enhance the effects of cancer treatment! Okay, this is preliminary stuff but it’s quite groovy, cool, and hip! A recent study of over 5800 adults found that pneumonia might be an independent risk factor for cardiovascular disease (CVD)! Hospitalization for pneumonia was associated with an increased short- and long-term risk of CVD! Why? Infections can cause proinflammatory changes in the composition of heart disease plaques and make them more vulnerable to causing sudden cardiac events (heart attack, stroke…). And, in other research it seems when someone suff ers from a serious infection like pneumonia and recovers, the inflammation in the body continues for arguably months and months after the time the person has recovered. So, you feel better but the body is still dealing with all the effects of the infection. Not nice! Additionally, in a somewhat stunning recent small randomized human study with brain tumors researchers gave a small number of individuals a tetanus/Td shot (actually tetanus/ diphtheria toxoid) to enhance their immune response to an experimental dendritic cell immune therapy and for some of the patients it did appear to provide a “boost” or enhanced treatment effect! In fact, it appeared to significantly enhance survival in patients with glioblastoma. Among the 6 patients that received the Td shot, three lived between 20 and 24 months from diagnosis, and three lived longer than 3 years – including one patient that is still alive after 9 years. And, this data compares with a median survival of 18.5 months in the control group of this study. Researchers thought the Td shot would work by causing an immune response locally at the vaccine site but were surprised that it actually appeared to cause a systemic (body wide effect) immune response. This is only a small human study of brain cancer. However, I do think it is time to get excited about getting both pneumonia vaccines if you qualify. PCV13=Prevnar and PPSV23=Pneumovax since September 2014 are now both recommended just not at the same time, so talk to your doctor because if you are 65 years or older or in many other special circumstances you may qualify ASAP. Also, for all those adults that have let too much time go by since they had their tetanus shot or never had one – it is time to go in there and get it ASAP if you qualify!
319) Ginseng looks good again to battle cancer-related fatigue (CRF)!! This is really getting interesting! And, it should be an option now because many of the new drugs work very well, but fatigue is a big problem in some patients (for example with Xtandi, chemotherapy, hormone suppression or listening to your kid tell you the many reasons why they could not clean up there room over the past month – that is also exhausting after a while). BREAKING NEWS! YEAH!!!
(Reference: Yennurajalingam S, et al. Integrative Cancer Therapies 2015; and Barton DL, J Natl Cancer Inst 2013;105:1230-1238 and Moyad MA. Th e Supplement Handbook, 2014.)
If you are experiencing fatigue from cancer treatment or just trying to prevent it then 1000-2000 mg American ginseng (3- 5% ginsenosides) is a good option and/or 800 mg per day of Panax ginseng (Asian ginseng at 7% or more ginsenosides) may also soon be a good option. This research was done at two places you may never have heard of – Mayo Clinic and MD Anderson Cancer Center (sarcasm alert #546). Look at Ginseng Board of Wisconsin web site for the low cost brand that was tested in the Mayo clinic trial (www.ginsengboard.com). Also, several clinical trials of weight lift ing or resistance exercise just 2-3 times a week also reduces CRF.
WHAT ELSE DO I NEED TO KNOW?
It was already time to make ginseng an option for cancer related fatigue in 2013 when the Mayo clinic and 40 other medical centers completed the results of an 8-week study of American ginseng 2000 mg per day versus placebo to reduce fatigue and it worked! They used a ginseng from the Ginseng Board of Wisconsin (www.ginsengboard.com) so this is the one I recommend! The one from the big clinical trial is the one you can trust. The reason this needs to be an option soon is simply due to the LACK OF OPTIONS FOR CANCERRELATED FATIGUE (CRF) THAT ARE SAFE. How bad is CRF?! In clinical studies it can range as high as 60-90% and it’s also a limiting factor of one of the best prostate cancer drugs ever invented known as “Xtandi.” In this new MD Anderson Cancer Center study 30 patients with CRF (rated as 4 or more out of 10 on a scale) ingested 800 mg a day of Panax ginseng (Asian ginseng prepared from the root with 7% or more ginsenosides – the active ingredient) for 29 days. Median age of patients was 58 years and capsules were provided by Indena S.p.A. (Milan, Italy). It’s also interesting that 10 of the patients were being treated for genitourinary cancers. Feelings of well-being and score for appetite significantly improved as well as fatigue on ginseng. The median improvement was a nice 5 points on a scale! This is outstanding, but keep in mind that this is preliminary but past research really supports that this is a real impact! Th e results of this small study not only show efficacy that the product was safe and no side effects were associated with the supplement. It also suggests that again not just fatigue but appetite, quality of life and pain improved over 4 weeks. A total of 63% of the patients noted moderate to vast improvement in their CRF with ginseng treatment. Ginseng appears to be impacting or reducing the effects of pro-inflammatory compounds via some mechanism that is being studied now at Mayo Clinic and many other centers. Ultimately the study concluded in the following way “We conclude that high-dose Panax Ginseng is safe and tolerable and rapidly improves CRF. Our findings also suggest that PG can improve symptoms such as pain, appetite, sleep disturbances, and overall Quality of Life. Randomized, placebo-controlled trials of Panax Ginseng are justified.” BEAUTIFUL SENTENCE DON’T YOU THINK?! (of course it is!). THAT’S ALL FOLKS…. See you in FALL, when I will write about many other serious issues and give timeless advice in the next newsletter, such as why it is never good to wait more than 1.214 seconds to say “ABSOLUTELY NOT” if your spouse asks you if he or she “looks fat in this new summer outfit?” And why it is never smart to drink 5 glasses of water before renewing your driver’s license at the DMV with the no on-site bathroom (you are number 103 and they just called number 12 and now it is decision time folks).