I was considering starting off this installment of the Doc Gumshoe meanderings with a discussion of an article about why women in particular reject statin therapy. The thought then occurred to me that surely there is a constituency in Gumshoe Nation that would promptly reply that the reason is obvious: women have more sense than men, so they reject statins on the grounds that they might do more harm than good. So I would have to be prepared to defend statins, on the grounds (and I stand firmly on those grounds) that statins do a whole lot more good than harm. Of course, I have no idea whether my defense would have any impact on the doubters.

That little thought process, by the way, proves that I am not a chatbot powered by artificial intelligence. A chatbot would have no doubts, self or otherwise.

So let’s start out with the article that prompted that bit of self-doubt.

Why do more women than men reject statins?

This finding is based on a retrospective study conducted at Mass General Brigham and Women’s Hospital, which included more than 24,212 high-risk patients treated there between January 1, 2000 and December 31, 2018. (JAMA Network Open. 2023; 6(2):e231047)

The study focused on high-risk patients who either had coronary artery or vascular disease, diabetes, very high cholesterol, or had suffered a stroke. All were recommended statin medications by their physicians to reduce their risk of heart attack and stroke and reduce cholesterol levels. About a fifth of the total patient cohort did not accept the initial recommendation of statin therapy. A significantly higher percentage of women than men – 24.1% versus 19.7% – initially rejected statin therapy. It took three times as long for people in the study who initially said no and then consented to taking statin medications to reduce their LDL cholesterol levels to less than 100 mg/dL, compared to people who initially said yes – about 4.5 years compared with 1.5 years.

A LDL-cholesterol level below 100 mg/dL is strongly recommended for all patients, whether or not they are at risk of acute cardiac events, and has been shown to reduce their risk significantly. Bringing LDL-cholesterol levels below 100 mg/dL lowers the risk of all-cause mortality, cardiovascular mortality, stroke, heart attack, and the need for revascularization, all by significant percentages. The greatest reduction is in the risk of a heart attack, which shrinks by about one-third.

The study’s biggest surprise, however, was the much higher rate of refusal by women than men. The study authors wonder if this might be due in part to a misconception that heart disease impacts men more than women, and plan to further research the reasons underlying these results.

Dr Alexander Turchin of the Harvard Medical School, the study’s lead author said, “Our study highlights the alarming number of patients who refuse statins and signals that physicians must have discussions with patients about why. Even in this higher-risk patient population, so many people did not accept statin therapy. We need to better understand what our patients’ preferences are and to be able to provide more patient-centered care.”

A look across the gender aisle

Okay, so women (perhaps because they think that their risk of cardiac ailments is lower than men’s risk) are more apt to shun statin therapy than their y-chromosome counterparts. But what males shun is going to the doctor in the first place. A 2022 survey of American men found that 55% said that they didn’t get regular screenings with a doctor. Men of color were less likely to get regular checkups – about 63% reported that they did not routinely get checkups.

Another poll, conducted by Orlando Health, found that about a third of the men surveyed thought that they didn’t need checkups, and about 65% thought that they could skip visits with doctors because they are naturally healthier than most people. It has been pointed out that this statement is logically impossible – a majority (65%) of men cannot be healthier than a majority of men. No questioning that some guys are healthier than most, but the majority cannot enjoy that privileged status.

If a big fraction of the male population of the US just doesn’t go to the doctor unless they are really, really sick, then it follows that those doctor-shunners don’t get their cholesterol tested and therefore a sizable percentage of US males are going around with elevated LDL-C levels and not taking statins. Add that to the slice of the population that does get tested, does have high LDL-C, but either initially or ultimately refuse to take statins, and the sum total of males and females at risk for serious cardiac issues not protected by statins is enormous.

Permit me now to state clearly and unequivocally where Doc Gumshoe stands on this issue.

The risks of statin side effects are real, but the risks from cardiac events are far greater and much, much more severe.

The most common statin side effects are aches and pains in the muscles. Very rarely, statins can cause a life-threatening muscle ailment called rhabdomyolysis, which can bring severe muscle pain, liver damage, kidney failure and death. Rhabdomyolysis occurs in about 1.5 statin users per 100,000, or about 0.0015%.

The frequency of muscle aches and pains in statin users is fairly low, about 5%. However, in placebo-controlled trials, about 30% of subjects in the placebo arm report these muscle aches and pains, suggesting that in most cases the harm is not due to the statin itself, but to the anticipation that it could cause harm.

Other statin side effects include mild liver damage, a small increase in blood sugar which can cross the line defining type 2 diabetes, and neurological side effects, including some instances of memory loss or confusion. Conversely, there has also been evidence that statins may improve brain function in some people with dementia.

There are some risk factors that increase the likelihood of experiencing statin side effects:

• Taking multiple medications to lower your cholesterol
• Being female
• Having a smaller body frame
• Being age 80 or older
• Having kidney or liver disease
• Drinking too much alcohol
• Having certain conditions such as hypothyroidism or neuromuscular disorders including amyotrophic lateral sclerosis (ALS)

So, yes, there are side effects resulting from taking statins. But since statins have come into wide use, the decline in deaths due to cardiac issues has been nothing short of spectacular. If heart disease rates had remained at their 1996 peak, there would have been about 10 million more deaths attributable to heart disease since then. The decline in deaths due to strokes has been similar. Stroke mortality (per 100,000) plummeted from 88 to 31 for women and 112 to 39 for men between 1975 and 2019 in the US. Since then, progress in reducing stroke deaths has slowed, especially in Hispanics and people living in the southern parts of the US, perhaps because of the pandemic.

Are these death rate reductions mostly due to statins? No one can say for absolutely certain, but the overwhelming preponderance of the evidence is that statins do more good than harm, and trying to change the minds of the statin-deniers would be worth the effort.

No surprise – a Mediterranean diet reduces heart disease in women

The normal assumption would be that since we already know that the Mediterranean diet reduces heart disease overall, it has to reduce heart disease in women. But there are differences between the sexes, and this study, in the BMJ’s Heart (http://dx.doi.org/10.1136/heartjnl-2022-321930), is the first meta-analysis to show that it has a similar effect in women. Pooling 16 female-only studies with 22,495 participants, they found that women who most closely followed the diet, which emphasizes whole grains, vegetables, fruit, legumes, nuts, and extra-virgin olive oil, had a 25% lower risk of coronary heart disease, a 24% lower risk of cardiovascular disease and a 23% lower risk of dying over the study’s 12 years. Stroke incidence was 13% lower in the Mediterranean diet adherent women, but that result did not reach statistical significance.

A large review in Nutrients (2019 Mar; 11(3): 655) reported that sticking to the Mediterranean diet reduced the incidence of cardiovascular disease in high-risk individuals of both sexes by about 40%, and reduced mortality in high-risk individuals by about 34%. Note that the women in the study above were not specified as being at high risk for heart disease of any kind. In both reviews, adherence to the Mediterranean diet was by self-report only.

The authors note that it is not precisely known how the Mediterranean diet works, but its antioxidant and gut microbiome effects on inflammation and other risk factors may play a role. They call for more research on women, including the effects of premature menopause, preeclampsia, and gestational diabetes.

I have to point out that both of those studies are far from definitive. Perhaps, rather than stating boldly that the Mediterranean diet “reduces” mortality and cardiovascular disease, I should have said that it was “associated with a reduction” in those events. In both cases, other factors could have been involved in those effects. It is possible that the women who adhered to the Mediterranean diet had different life-styles than the non-adherent cadre. In addition to consuming those healthy foods, the adherents might have a higher proportion of non-smokers, and might be more physically active than those lazy non-adherents, who spend a lot of their time smoking cigarettes and watching TV while they gorge on unhealthy snacks.

3D printed hearts help cardiologists in treating aortic stenosis in some patients

Aortic stenosis is a common heart valve problem which can affect as many as one- fifth of persons over the age of 65. The aortic valve normally opens when the left ventricle contracts, permitting blood to pass into the upper chamber, then into the aorta and thence into the arterial system, supplying oxygen to the entire body. But the aortic valve can fail to open sufficiently. The heart strains to work harder and harder to overcome this impediment. The results can be deadly. Survival rates without treatment for severe symptomatic aortic stenosis are low –  50% at 2 years after symptom onset, and 20% at 5 years.

The only treatment for aortic stenosis is valve replacement. This procedure is employed when the width of the aortic valve goes below one square centimeter. The prosthetic valve has to be correct for the anatomy and pumping action of the patient’s heart. In many cases, the procedure is fairly straightforward. The defective valve is removed, and the prosthetic valve is inserted in its place. This surgery is minimally invasive, by which we mean that it is not necessary to cut open the patient’s chest and cut into the heart itself. The process is carried out by inserting the catheter (a long flexible tube that can be guided from one end) into the femoral artery, and snaking it through the arterial system until it reaches the site of the defective aortic valve. In this procedure, cardiologists place one of two FDA-approved prosthetics—Medtronic’s’ Evolut R or Edwards Lifesciences’ SAPIEN 3—into the aortic valve. The prosthetic expands and integrates with the tissue, allowing the heart to pump blood effectively again. This procedure is called transcatheter arterial valve replacement (TAVR).

TAVR procedures rely on very advanced and sophisticated surgical technology; however, despite the complex technology required, most are simple and straightforward, and most patients do not stay in the hospital more than overnight. (A good friend of mine had TAVR and went home the same day.) However, some cases, based on the patient’s specific anatomy, are considerably more complex, and the usual replacement valves are not a good fit.

In patients with a form called paradoxical low-flow, low-grade severe aortic stenosis, it would be very beneficial to understand the biomechanical aspect of that valve and how it behaves in different flow dynamics. To address this problem, bioengineers led by a team from Massachusetts Institute of Technology described how they used cardiovascular data from individual patients to print soft models of their hearts, complete with the ability to pump just as their hearts did.

To see if they could offer a solution by way of 3D printed hearts, the MIT team set out to create soft models that were anatomically and functionally representative of the hearts of individual patients. They compiled CT data from 15 aortic stenosis patients and then reconstructed digital 3D renderings. These were subsequently used to print physical 3D models from an elastic plastic resin, the stretchiness of which mimics the heart muscle.

The team got these printed hearts to pump by wrapping them in sleeves similar to blood pressure cuffs. Each sleeve had four inflatable pockets that were designed to match the shape of the individual’s heart. The pace of contraction for each pocket could be adjusted individually, allowing the researchers to fine-tune the pumping motion so that it mirrored the patient’s real-life heart.

With the models built and pumping, the researchers took echocardiograms of the printed hearts in action and compared them to echocardiograms from the patients themselves. They found that the models recreated the pressure and blood flow seen in the patients, including those whose hearts had unique pumping mechanisms due to tissue remodeling caused by aortic stenosis.

Next, the researchers wanted to assess if they could also recreate the effect of TAVR on patients’ hearts. They implanted either the Evolut R or SAPIEN 3 prosthetics into the models, then recorded their pumping action and compared it to post-implantation results from the actual patients. Once again, the models mapped to the patients’ improved flow dynamics.

The 3D printed hearts have yet to be used as a way of modeling the effects of a TAVR prosthetic device in a real patient prior to the actual TAVR procedure, but the expectations are high. There does not appear to be any obstacle to the use of these printed hearts, since their role is in aid of guiding the procedure, but not in the procedure itself. They provide the cardiologists with a useful working model of the patient’s heart that is outside of the patient. The MIT team expects that the printed hearts could be made from routine patient imaging in about one day. They anticipate that the method of making 3D printed anatomical models will be used to assist clinicians in a range of procedures. We can anticipate 3D printed lungs, livers, kidneys, and other parts of our anatomy as a way to model surgical procedures without actually submitting the patient to the scalpel.

One more low-evidence boost for curcumin

Back in early 2016, Doc Gumshoe took a look at curcumin and the many spiels promoting curcumin as a highly effective treatment option for many diseases and conditions. Here’s a bit of what I had to say back then:

“For Gumshoe denizens who have been paying attention to other perhaps more important matters, such as the fate of the nation and the world, curcumin is a yellow substance in the rhizomes of the turmeric plant, Curcuma longa. Those rhizomes, which are sort of root clumps like ginger, are cooked, dried, and used as spices in many Asian curries. Curcumin is used in cosmetics mostly because of its color, and has recently become one of the darlings of the supplements industry, as per the promotion we’re looking at.”

That particular promotion stated unequivocally that curcumin was “the ultimate no-side-effects pill for every disease.” And here’s a list of the diseases they specifically mention:

“It’s 400-times more potent than the diabetes drug Metformin” — reports Auburn University researchers (Journal of Biochemical and Biophysical Research Communications)

Performs better in memory tests than the drug Aricept (the most widely prescribed Alzheimer’s drug)— Salk Institute for Biological Studies

More effectively treats Major Depressive Disorder (MDD) than Prozac — without Prozac’s devastating side effects, according to a randomized, controlled study.

Lowers cholesterol and triglyceride levels better than the statin drug Lipitor (Journal of Drug Research and Development)

Treats chronic uveitis — a leading cause of blindness — better than corticosteroids… the only available prescription treatment (Journal of Phytotherapy Research)

Beats Celebrex for relieving knee arthritis pain (Journal of Alternative and Complementary Medicine)

Relieves rheumatoid arthritis pain better than Ibuprofen (Journal of Phytotherapy Research)

“Therapeutic effects are comparable to pharmaceutical NSAIDs… but with a major difference in that this compound is nontoxic and free of side effects.” – Vanderbilt and University of Pittsburgh researchers (Journal of Surgical Neurology International )

“Could enhance erectile function with more efficacy and more prolonged duration of action than Viagra” (International Journal of Impotence Research)

“More effective in stopping the protein fragments from forming than many other drugs being tested to treat Alzheimer’s” – UCLA Alzheimer’s Department and Veterans Affairs researchers (Journal of Biological Chemistry)

Destroys more colon cancer stem cells than FOLFOX (one of the most widely prescribed chemotherapy protocols) – Baylor University researchers”

And now, two PharmD candidates, Rebecca E. Matthews and Christine Philipose, post a short piece in Pharmacy Times (March 21, 2023) suggesting that curcumin may be useful as an addition to chemotherapy in the treatment of ovarian cancer. If this should happen to be true, it would be a very, very big deal, because ovarian cancer is very difficult to treat and seldom detected early enough for whatever treatment options exist to be effective. Ovarian cancer is not one of the more frequent cancers – the estimated annual number of new cases is about 20,000, while the estimated number of new breast cancer cases is close to 300,000. But the estimated number of ovarian cancer deaths is about 13,000 annually. The five-year survival rate is well below 50%.

Below I am quoting most of what they say in the Pharmacy Times paper:

“Although chemotherapy remains the primary approved therapeutic approach in the treatment of ovarian cancer, it is limited by AEs, reduced response rate, and a high prevalence of relapse.  Curcumin is a natural phenolic compound, used in Ayurveda and Chinese medicine.

This relative of turmeric possesses diverse therapeutic properties, such as anti-inflammatory, analgesic, antitumor, and antioxidant.  For the management of ovarian cancer, it has been observed in both cellular and animal models that curcumin suppresses cell proliferation and promotes apoptosis.

Furthermore, curcumin when combined with chemotherapy is more likely to enhance the synergistic effect of cancer cells to drug therapy.  The addition of this phytochemical to current ovarian cancer chemotherapeutics may enhance drug cytotoxicity, while reversing multiple drug resistance, with nano-formulations of curcumin developed to increase the bioavailability of this natural product.  The administration of cisplatin and nanocurcumin in a rat model resulted in a significant reduction in ovarian tumor volume and weight, while downregulating signaling pathways, and reducing cellular viability.

A more recent study investigated the synergistic effects of curcumin and paclitaxel at reducing proliferation and promoting apoptosis in ovarian cancer cells.  The cytotoxic effects of curcumin were reported to be a result of its regulation of miR-9 expression, with miR-9 known to regulate the gene expression of BRCA1.”

Their conclusion is as follows:

“Further studies are required to evaluate the use of curcumin as an adjunctive therapeutic option to currently approved chemotherapy.”

That conclusion is modest indeed. The authors indirectly refer to one important problem with using curcumin as a drug: it is very difficult to get enough of the active ingredient into the circulation to have any therapeutic effect whatever. They mention “nano-formulations of curcumin developed to increase the bioavailability of this natural product.” Curcumin is very poorly absorbed when taken orally, and it has a very short half-life, meaning that the duration of action is brief. It does appear to be quite safe, as one would suppose, being that it’s a major component of turmeric.

Based simply on the number of citations in PubMed (the National Library of Medicine), there should be at least some health benefits with curcumin. PubMed lists 71,433 papers that mention curcumin, and 15,128 clinical studies of which 5,905 were conducted in humans. The numbers of papers about curcumin’s effects on cancer were 53,266, and 51,051 addressed curcumin’s mechanism of action. For example, a detailed paper on the mechanism of curcumin’s anti-inflammatory action was published in PPar back in 2008. Here’s a little excerpt:

“Based on a number of clinical studies in carcinogenesis, a daily oral dose of 3.6 g curcumin has been efficacious for colorectal cancer and advocates its advancement into Phase II clinical studies. In addition to the anticancer effects, curcumin has been effective against a variety of disease conditions in both in vitro and in vivo preclinical studies.”

PPar (which I had never heard of) is a journal dedicated to peroxisome proliferator-activated receptors. It is published by Hindawi, a company founded in Egypt in 1991 but now located in the UK. In 2021, Clarivate, an analytics company that lists publications in the area of bibliometrics and scientometrics, de-listed 21 of Hindawi’s journals because of compromised articles which they had published.

What I have been able to find out about the potential usefulness of curcumin in treating diseases that affect us humans leaves me with the skepticism indicator blinking red. Yes, the advocates of Ayurvedic medicine and the proponents of supplements promote curcumin vigorously, but so far I have seen no Phase 3 clinical studies that support the inclusion of curcumin in list of drugs that are genuinely useful in health-care.

An asthma drug may reverse the progression of COPD

The drug is Dupixent (dupilimumab) from Sanofi and Regeneron. Dupixent already has several indications, including asthma, eczema, and chronic rhinosinusitis with nasal polyps. It’s not highly surprising that an asthma drug, which helps patients breathe, would also be effective in chronic obstructive pulmonary disease (COPD). Even though the fundamental causes of asthma and COPD are different, the effects of the two on lung function have many similarities.

A Phase 3 study compared Dupixent to placebo in 939 COPD patients with type 2 inflammation who were active or former smokers on maximal standard-of-care inhaled therapy. Trial subjects on Dupixent demonstrated a clinically significant 30% reduction in moderate or severe exacerbations over 52 weeks. The phase 3 study met its primary and secondary endpoints, setting Dupixent up to become the first biologic treatment for COPD. There have been few advancements in COPD treatment over the last decade. It is one of the world’s most common causes of death.

Dupixent not only limited the COPD-related exacerbations, but also demonstrated improvements in lung function, quality of life, and COPD respiratory symptoms. Other biologics targeting COPD, such as GSK’s Nucala and AstraZeneca’s Fasenra, have failed. While Nucala and Fasenra target IL-5 proteins, Dupixent targets the IL-4 and IL-13 pathways, which most likely accounts for its significantly superior efficacy. The IL (interleukin) proteins are cytokines; a class of agents that can cause inflammation.

Sanofi and Regeneron took the unusual step of moving directly to Phase 3 clinical trials, which will speed time to FDA approval of the COPD indication for Dupixent. COPD was the sixth leading cause of death in the US in 2020, before the COVID pandemic set in. About 15 million people in the US have COPD, and it was the cause of death in about 150,000 individuals. Dupixent therefore has the potential to improve the lives – and prevent the deaths! – of many, many people in the US and globally.

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Several of the comments/questions in response to the last Doc Gumshoe posting left me a bit puzzled. I am hereby requesting all denizens of Gumshoe planet to do a bit more than type in an abbreviation, assuming that I can figure out what it stands for. I try, but sometimes I’m totally stumped, so I’m left with no clue as to how to respond to your questions. Nonetheless, please do not let that request on my part prevent you all from making whatever comments and asking whatever questions you have in mind. I will put my noggin to the task and see what I can come up with.

Stay well and enjoy the coming Spring! (Is it really coming?) Best to all, Michael Jorrin (aka Doc Gumshoe)

[ed note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a longtime medical writer (not a doctor) and shares his commentary with Gumshoe readers once or twice a month. He does not generally write about the investment prospects of topics he covers, but has agreed to our trading restrictions.  Past Doc Gumshoe columns are available here.]