April 2025 Newsletter

The GLP-1 (Glucagon Like Peptide-1) agonists branded as Wegovy, Ozempic, Rybelsus, Mounjaro, Zepbound, Victoza, Saxenda, Trulicity, Byetta, Bydureon, Adlyxin have received much attention over the last several months for good reason.

Their utility not only in their original purpose – treatment of certain forms of diabetes – but more recently for weight loss and beneficial “side effects” including improved cardiovascular health and markers (lower blood pressure and reduced risk of stroke, heart attack and cardiovascular disease), reduced cravings for sweets and alcohol, improved lipid profiles (cholesterol and triglycerides), improved kidney health, neuroprotective benefits (reduced risk of Alzheimer’s Disease and other forms of dementia as well as improved neurocognition) and reduced risk of certain cancers. It’s an impressive list of benefits, and, despite the recent recognition, these drugs have been around in different iterations since 2005 and have an impressive track record of safety. In our practice at RSM, the only side effects witnessed have been nausea and vomiting that occur when either the starting dose is too high for the patient (very rare), or, the patient advances the dose more rapidly that recommended (not as rare ☺…”if one is good, 2 must be better!…”). A more recent iteration of the GLP-1 agonists that actually works additionally on GIP (Gastric Inhibitory Polypeptide) and GCG (Glucagon) agonism, and therefore, theoretically as well as practically, functions even more effectively to promote, among other benefits, fat loss is called retatrutide and may prove to be the most efficacious of all the current options (NB: retatrutide has yet to be released by Eli Lilly, but trials show the aforementioned efficacy). 

The question to be answered for many of us is whether these drugs can be used in small enough doses to avoid excess fat loss, but still provide the other aforementioned beneficial “side effects”. I and other patients are currently experimenting with retatrutide (available via compounding pharmacies) to evaluate the possibility and I will keep you posted.

At Duke University, researchers brought to light the mechanisms by which we observe that low testosterone leads to prostate cancer and higher levels of testosterone can prevent and actually be used to successfully treat (using “bipolar therapy”) prostate cancer. 

We have replaced the 80 year-old dogma that testosterone causes prostate cancer with an understanding that certain estrones (4-hydroxyestrone and 16 alpha-hydroxyestrone, eg) can initiate prostate cancer and that another metabolite of testosterone, dihydrotestosterone, can accelerate prostate cancer growth, while optimal higher testosterone actually protects against prostate cancer. (https://corporate.dukehealth.org/news/study-solves-testosterones-paradoxical-effects-prostate-cancer).

Testosterone Replacement Therapy does NOT create blood clots, nor does increased blood “thickness” necessarily lead to blood clots. 

Medical professionals often conflate blood viscosity with blood “stickiness”. First, blood stickiness refers to the propensity for – as the word “stickiness’ implies – blood coagulability (platelet adhesiveness and aggregation). Stickiness involves nonmechanical factors that increase coagulability such as inflammation (reflected in markers such as c-reactive protein (“CRP”), elevated thrombin, fibrinogen, and markers for oxidative stress, certain estrogens, cancers and genetic predispositions (e.g., Factor V Leiden gene mutations). At the risk of furthering the propagation of misinformation, the theory that blood viscosity equates with blood clotting coincides with part of Virchow’s triad which states that increased blood viscosity leads to slower flow which predisposes blood stasis, hypercoagulability, and endothelial injury. While there can be a theoretical connection between increased blood viscosity and clot formation (“thrombosis”), the body has many compensatory mechanisms that address this as evidenced by populations that live at altitude. These “high altitude populations” have increased hemoglobin and hematocrit (“viscosity”) but no increase in stroke or thrombosis. Why? Because the body compensates – as it does for the lack of oxygen available at altitude – for the increased viscosity through vascular remodeling such as increased capillary density and ability to produce nitric oxide which supports better blood flow. In addition, red blood cells become more flexible and their tendency to clump together (rouleaux formation) is reduced which allows them to flow through capillaries more easily. And lastly, even with an elevated hematocrit (increased number of red blood cells as a percentage of whole blood), plasma volume increases to lower relative viscosity. Bottom line: increased blood viscosity does NOT equal increased clotting. 

Relevant studies include the following:

https://www.ahajournals.org/doi/10.1161/JAHA.120.020562

https://academic.oup.com/jcem/article/109/12/3186/7667216

https://www.nejm.org/doi/full/10.1056/NEJMoa2215025

https://www.reuters.com/business/healthcare-pharmaceuticals/fda-issues-labeling-changes-testosterone-products-2025-02-28/

Exposure to testosterone therapy in the 15 days before the event/index date was not associated with an increased risk of VTE (“Venous Thromboembolism” or “blood clot”) (aOR, 0.90; 95% CI, 0.73-1.12). None of the specific routes of administration examined were associated with an increased risk of VTE (topical [aOR, 0.80; 95% CI, 0.61-10.41], transdermal [aOR, 0.91; 95% CI, 0.38-2.16], and intramuscular [aOR, 1.15; 95% CI, 0.80-1.64]). These findings persisted using exposure windows that extended to 30 and 60 days before the event/index date.

https://www.mayoclinicproceedings.org/article/S0025-6196(15)00428-0/fulltext

Medical Treatments for Hypogonadism do not Significantly Increase the Risk of Deep Vein Thrombosis Over General Population Risk

https://pubmed.ncbi.nlm.nih.gov/30447269

There is a low annual incidence of venous thromboembolism in the general population – 48 to 120 per 100 000 people.

Data suggest that testosterone therapy has effects that may counteract the potentially increased risk of venous thromboembolism. For example, testosterone therapy is one of the few treatments that reduces levels of lipoprotein(a) [Lp(a)] by the impressive range of 20-59%.^57–59 Lp(a) may be an indirect risk factor for blood clots.^60–66

1. Berglund L, Carlstrom K, Stege R, et al. Hormonal regulation of serum lipoprotein (a) levels: effects of parenteral administration of estrogen or testosterone in males. J Clin Endocrinol Metab. 1996;81(7):2633-2637.
2. Marcovina SM, Lippi G, Bagatell CJ, Bremner WJ. Testosterone-induced suppression of lipoprotein(a) in normal men; relation to basal lipoprotein(a) level. Atherosclerosis. 1996;122(1):89-95.
3. von Depka M, Nowak-Gottl U, Eisert R, et al. Increased lipoprotein (a) levels as an independent risk factor for venous thromboembolism. Blood. 2000;96(10):3364-3368.
4. Sofi F, Marcucci R, Abbate R, Gensini GF, Prisco D. Lipoprotein (a) and venous thromboembolism in adults: a meta-analysis. Am J Med. 2007;120(8):728-733.
5. Grifoni E, Marcucci R, Ciuti G, et al. The thrombophilic pattern of different clinical manifestations of venous thromboembolism: a survey of 443 cases of venous thromboembolism. Semin Thromb Hemost. 2012;38(2):230-234
6. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG. Genetic evidence that lipoprotein(a) associates with atherosclerotic stenosis rather than venous thrombosis. Arterioscler Thromb Vasc Biol. 2012;32(7):1732-1741.
7. Helgadottir A, Gretarsdottir S, Thorleifsson G, et al. Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism. J Am Coll Cardiol. 2012;60(8):722-729.
8. Young G, Albisetti M, Bonduel M, et al. Impact of inherited thrombophilia on venous thromboembolism in children: a systematic review and meta-analysis of observational studies. Circulation. 2008;118(13):1373-1382.
9. Tsimikas S. A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. J Am Coll Cardiol. 2017;69(6):692-711.

A second reason that elevations in hematocrit with testosterone treatment may not be inherently dangerous is that low testosterone levels are associated with higher levels of prothrombotic factors in men, regardless of age, obesity, body fat distribution, and related metabolic parameters.⁶⁷

1. De Pergola G, De Mitrio V, Sciaraffia M, et al. Lower androgenicity is associated with higher plasma levels of prothrombotic factors irrespective of age, obesity, body fat distribution, and related metabolic parameters in men. Metabolism. 1997;46(11):1287-1293.

Exercise, supplemental vitamin D3, and supplemental omega-3 fats can significantly positively affect aging.

A recent fairly well-designed study (https://www.nature.com/articles/s43587-024-00793-y) demonstrates that as little as 2,000IU of vitamin D3 daily, 1 gram of omega-3 fatty acids daily, and strength training for 30 minutes, 3 times per week slowed the pace of aging, and reduced infections, falls and cancer over 3 years. Interestingly, the study shows the effect of the supplementation of each separately as well as synergistically (so, it wasn’t, for example, just the exercise, and whether one was taking vitamin D3 or not, there would have been improvement, because it was all attributable to exercise alone). 

The evaluation of age was determined using measurements of DNA methylation (Horvath). At RSM, we recommend annual testing using DNA methylation in order to evaluate results of protocols and their effect on aging. We have arranged for discounted pricing through our association with TruAge – a company that not only provides DNA methylation testing to evaluate “biological age”, but DunedinPACE testing which reflects the estimated rate of aging. These two tests are considered the “gold standard” in the industry for evaluating age.

Studies we have to date demonstrate that it therefore makes sense to take your daily supplemental vitamin D3 and Omega-3 fatty acids, and to exercise to improve VO2max (maximum ability to utilize oxygen) and maintain or improve muscle mass while decreasing or maintaining minimal optimal fat.

For those who want to make taking their daily dose of these and other supplements, please ask about our “RSM Packs” – a customized daily and individually prepackaged supply of supplements designed for you.

An over-the-counter supplement of a naturally occurring substance, fisetin, can help slow aging.

Another way to reverse the biological aging clock is to rid the body of cells that are no longer functioning properly and recycle their contents. The use of fisetin, a polyphenol found in high concentration in apples, Japanese persimmons, onions, and particularly, strawberries, has been shown to do just that as well as provide an anti-inflammatory and antioxidant function. A dose of 20mg/kg for two consecutive days per month is the preferred protocol for administering it, and, some studies show even better benefit by combining it with quercetin (500 – 1,000mg). More is NOT better in this case, and this protocol should be used no more often than monthly. The research not only shows senolytic, anti-inflammatory and antioxidant properties, but neuroprotective effects that may include reducing accumulation of beta-amyloid plaques, anticarcinogenic properties (like many polyphenols) and improved insulin sensitivity and endothelial function.

Current research shows the benefits, and, arguably, the need for more protein consumption, particularly with age.

Most of us have heard about the need for protein in our diets, and, the various rules of thumb for determining the optimal amount to be consumed daily, especially if we exercise and want to maintain or build muscle. The old standard: “1 gram of protein per pound of body weight” has been touted as the base from which one can adjust upward or downward depending upon goals and daily exercise time and type. 

Protein is needed not just for body composition maintenance or adjustments, but for “protein-based” hormones such as thyroid and growth hormone that are made of combinations of amino acids mostly derived from consumption of proteins. While athletes do typically require more protein (actually, endurance athletes tend to require the most rather than even bodybuilders who are legendarily required to eat the most protein), as we age we require more protein to maintain muscle, a leaner body composition and to function better. Protein is a poor source of energy compared to carbohydrates and even fats, and actually requires more energy than ither fat of carbohydrate to be used as a source of energy. So, it can be helpful in modulating blood sugar for diabetics certainly but also for those of us who simply want to maintain a more even blood sugar level and avoid spikes in energy and insulin. 

Recent studies show that there really is no upper limit for protein consumption as previously thought. However, there is ample evidence that while a high protein diet has its advantages certainly, we may not want to eschew the consumption of vegetables and other carbohydrates and fats for their contribution to other nutrients the body needs.

The use of protein supplements to achieve the desired daily protein should be used as such: supplementally, rather than as a replacement for real food sources of protein for the simple reasons that one receives multiple benefits beyond the consumption of protein when eating foods considered “proteins” than with protein supplements. Other nutrients besides protein are food in real food sources of protein including vitamins, minerals, fats and carbohydrates.

For many patients taking medication to treat hypertension, one medication that deserves consideration to replace one’s current medication is an ARB (Angiotensin Receptor Blocker) called telmisartan. 

While it belongs to a class of hypertension medications that reduce blood pressure by blocking receptors of angiotensin II and thereby relaxing the walls of the arterial blood vessels and lowering blood pressure, unlike the others of this and a similar class (ACE inhibitors), telmisartan has some potentially very beneficial side effects. The result is that for those who may have borderline hypertension of acceptable blood pressure than could still be safely lowered, telmisartan may be an addition that improves healthspan. 

If interested, please inquire, but, in short, telmisartan has been shown to have a strong beneficial effect on metabolism as a PPAR-gamma agonist. It has been shown to strongly support mitochondrial and fat oxidation, strongly reduce inflammation and “inflammaging”, and strongly enhance cognition and neuroprotection though various mechanisms of action.

There is little argument now that a healthy lifespan (“healthspan”) is directly linked to the body’s ability to process oxygen as measured by VO2max. 

VO2max is a measure of one’s maximal aerobic capacity and is defined as the maximum volume of oxygen one’s body can consume per minute, per kilogram of bodyweight during maximal exertion. 

How does one improve VO2max? A French scientist, Veronica Billat, found that, essentially, the more time spent training at maximal output, the more of an effect on improving VO2max, and, that more time (approximately twice as much) in this range could be achieved through interval rather than steady state training. (https://pubmed.ncbi.nlm.nih.gov/10638376/)

The only interesting rub is that is order to achieve maximal output, the metabolism of the byproducts of maximal output (mainly lactic acid) is enhanced and optimized by the aerobic system which is improved by exercise in Zone 1 and Zone 2 (classically defined as the ability to hold a conversation comfortably while exercising). So, bottom line, one should exercise at both low (90%) and high (10%) intensity levels to achieve maximal VO2max.

Bacterial vaginosis (BV) can be a frequently occurring infection for some women, creating frustration for her as well as her partner. New research suggests that treating the partner – formerly ignored – may actually very significantly (by as much as 50%) improve outcomes. 

With male partners, the former theory was that the penis would not “carry” the microbes, and therefore did not need to be treated. And, the thought was not only that a monogamous relationship was protective, but that multiple partners was the source of BV. However, use of a topical antibiotic for the male or treatment in addition to treatment of the infected woman so significantly improved outcomes of treatment for BV, that the recent study (https://apple.news/AT8dZ0dVQSyK76bAAgXujaw) was stopped early. 

He circumnavigated Great Britain swimming 6 hours on and 6 hours off over 157 days setting a World Record for swimming…as well as an unofficial record for bananas consumed! Now, in May, he is swimming frigid waters while attempting yet another World Record circumnavigating Iceland.

Many of you have heard me speak of one of my friends and superheroes, Ross Edgley. Ross holds multiple World records and has performed countless feats of strength and endurance while contributing to conservation and cancer charities. He is also one of the nicest, good-natured and warm individuals you will meet. He is about to embark upon yet another record setting adventure; this time circumnavigating Iceland (in 2018, he swam 1,780 miles all the way around Great Britain in 157 days). Please give a look to his latest here: (https://drrandmcclain.com/ross-edgley/), and please consider contributing and at least following his adventure coming up soon.

As an avid bicyclist, one knows that possibly THE most important part of the sport is proper bike fit, and, that for proper bike fit, the saddle (bike seat) is essential. 

A challenging bike ride does not need to be made more so by an uncomfortable saddle and the possible if not likely side effects that include “saddle sores” and perineal injury if not properly fit and adjusted. Saddles range in their design, construction and materials, but the widths are usually limited to 135-155mm “off the shelf”. Many of us require either a larger or smaller width saddle to ride efficiently and comfortably and a custom-built saddle is the only viable option. I am happy to say that I have found a company that will provide just that through a fairly easy (and fun?) process. For those interested please check out Posedla (https://posedla.com/products/joyseat#judgeme_product_reviews) and use “JOYSEATLOYAL10” code for a 10% discount on your saddle purchase.