08:54 AM

523 - “Glutides” for CV Risk Reduction, Sodium and HTN, “Small Talk”?

From the Literature

1)  “Glutides” for Cardiovascular (CV) Risk Reduction

Glucagon-like receptor 1 agonists (GLP-1 or “-glutide” medications) have become incredibly population for the treatment of diabetes and, increasingly, obesity. So much so that there is now a national shortage of these medications. Because of its effect on obesity, researchers wanted to test its effect on cardiovascular (CV) risk reduction in people who had obesity without diabetes. As a first step, they have apparently decided to test semaglutide (vs. placebo) in people with obesity and pre-existing CV disease in the SELECT trial, funded by the makers of semaglutide (Novo Nordisk).

The trial, overall, was designed very well. The inclusion criteria included overweight and obesity (BMI 27 and above), but the mean BMI was 33 and 71% of subjects had a BMI of 30 or greater. The median age was 62, and 75% of subjects had had a previous myocardial infarction (MI). The researchers titrated semaglutide up over 16 weeks to a target dose of 2.4 mg (or matching placebo), and the trial continued for an average of 40 months. The study used a composite endpoint of death from CV causes, non-fatal MI, or non-fatal stroke (a reasonable composite outcome). 17,604 subjects started the trial and 17,061 completed it, and the results were analyzed using the intention-to-treat principle.

Semaglutide was associated with a 1.5% decreased absolute risk for the composite outcome (6.5% vs. 8.0%, hazard ratio (HR) 0.8, 95% confidence interval (CI) 0.72 to 0.90). This gives a rough number needed to treat (NNT) of 67 over almost 4 years of treatment. Of note, death from cardiovascular causes was also significantly reduced (HR 0.85, 95% CI 0.71 to 1.01), but no other dichotomous outcomes were significant. In the secondary outcomes using continuous data, there were significant reductions in weight, blood pressure, Hemoglobin A1c, high-sensitivity CRP, and cholesterol. Serious adverse events occurred in 33.4% of intervention subjects vs. 36.4% of controls (fewer in the intervention group!), but adverse events resulting in discontinuation of the medication occurred in 16.6% in the semaglutide group vs. 8.2% of control (NNH~12).

John’s Comments:

It won’t be surprising for readers of this newsletter to learn that the researchers are more loudly touting a “20% cardiovascular risk reduction” rather than a “NNT of 67.” First, remember that calculating precise NNTs from a longitudinal trial like this requires statistical adjustment, for which I would have to phone a statistical friend (and I did not). Second, it’s not that this NNT is particularly bad, but folks with CV disease are at highest risk. This intervention is likely to have even less impact in people without CV disease (i.e., for primary prevention). I worry that because the title of the study states, “in obesity without diabetes” and doesn’t mention the CV disease required to enter the trial, we will slide down the path toward primary prevention with this medication without sufficient data.

While the serious adverse event data is reassuring, it might be hard to keep people on this medication. For every subject spared a CV outcome, five people had to stop the medication due to adverse events and tolerability issues (mostly gastrointestinal- and gallbladder-related). And, as I’m sure we have all experienced recently, price and availability are two additional very limiting aspects to the usefulness of this medication.


·         Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. New England Journal of Medicine. 2023;0(0). Link

From the Literature

2)  The Impact of One Week of a Low Salt Diet on Blood Pressure

Sodium is a dietary component that substantially contributes to elevated blood pressure (BP) in certain individuals.  Estimated daily average sodium intake in middle-aged to elderly US adults is 3.5 g, far exceeding World Health Organization (< 2gm/d) and the American Heart Association (< 2.3gm/d and ideally < 1.5 gm/d) recommendations.   There is great individual variability with regard to the impact of sodium on BP, with estimates suggesting that approximately 50% of individuals with HTN and 25% of those without HTN exhibit salt sensitivity of BP (SSBP).  The within-individual BP response to variation in sodium intake has been used to define individuals who experience meaningful BP differences with sodium intake reduction. 

Most randomized trials testing dietary sodium reduction excluded individuals taking antihypertensive medications.  Thus, among individuals with treated hypertension, uncertainty persists regarding the extent to which dietary sodium reduction lowers BP.

A recently published study attempted to answer this question among a group of 213 community dwelling persons aged 50-75 which included the spectrum of individuals with normotension and treated and untreated hypertension. Using a prospectively allocated diet order crossover design of 1-week high-sodium and 1 week low-sodium diets, the researchers examined the distribution of within-individual BP responses to dietary sodium, the difference in BP between individuals allocated to consume a high- or low-sodium diet first, and whether these varied according to baseline BP and antihypertensive medication use.  Blood pressures were monitored using 24-hour ambulatory BP monitoring (ABPM) and 24-hour urine sodium excretion was also measured to approximate actual sodium intake.  

The high-sodium diet was achieved pragmatically by daily supplementation of each participant’s usual diet with 2 bullion packets, each containing 1100 mg of sodium. The low-sodium diet was standardized across sites through preparation in metabolic kitchens and provided at no cost to participants with instructions not to consume anything outside that provided.  The low-sodium diet was designed to provide daily averages of approximately 500 mg of sodium and approximately 4500 mg of potassium. 

The authors found that across the study group, the mean decrease in BP between the high-sodium and low-sodium diet groups was 7.5 mm Hg and median decrease in BP was 6 mm Hg (both P < .001).  This did not significantly differ by hypertension status or antihypertensive medication use and was generally consistent across subgroups.  The commonly used threshold of a 5–mm Hg or greater decline in mean arterial pressure from high- to low-sodium diets classified 46% of individuals as “salt sensitive”, consistent with previous studies.  Adverse events were mild, reported by 9.9% and 8.0% of individuals while consuming the high- and low-sodium diets, respectively.  Adverse events in the low sodium group were most frequently cramps and weakness. 

Mark’s Comments:

This was a wonderfully designed study in which the average decline in BP in the low sodium group was equivalent what one might expect by taking 12.5 mg of hydrochlorothiazide a day.  It was notable to see the impact of the decrease in sodium intake so quickly, and humbling to see how quickly the impact was reversed when intake increased again.  Previous studies have shown that there will likely not be additional improvement after a week on a lower sodium diet unless additional decreases in sodium intake occur.  

Unfortunately, it can be quite challenging given our present food supply to follow a low sodium diet and the food industry has been reluctant to lower the sodium content in food because high sodium products sell better since once someone has adapted to a higher sodium diet, low sodium foods don’t tend to taste as good.  The good news is that the reverse is also true, and if someone follows a low-sodium diet for a while, their taste buds will adapt and higher sodium foods will not taste as good.  This has certainly been my personal experience.  The additional good news is that there is likely a linear improvement in BP as sodium intake increases, so even going from the present daily intake to the present recommendations will show some decrease in bp.

Finally, there is presently no good way to determine who is “salt sensitive” other than observing blood pressures on low vs. high sodium diets for an individual, and 24-hour ambulatory monitoring is not commonplace and can be expensive.  As such, a goal of  lowering dietary sodium may be a “hard sell” for our patients.  


·         Gupta D, et al.  Effect of Dietary Sodium on Blood Pressure: A Crossover Trial. JAMA. Published online November 11, 2023.  Link

From PeerRxMed ( www.PeerRxMed.org )

3) Enlarging “Small Talk”


 “Gatherings consume our days and help determine the kind of world we live in.”  – Priya Parker, author of The Art of Gathering: How We Meet and Why It Matters 

This time of year tends to be a season for social gatherings, and while it is true we are a “connecting species”, there are many who find themselves uncomfortable at Holiday parties for a multitude of reasons, including a more introverted disposition, an aversion for “small talk”, and a fear the conversation will turn to topics for which they might experience discomfort or find emotionally draining, and therefore dread this time of year from a socializing perspective.   If that is the case for you, read on. 

Small talk has historically been my seasonal social aversion, but this year I’m finding myself surprisingly excited about attending upcoming festivities.  It’s not that I’m feeling a lack of social connection, but rather am experiencing a rekindled desire to get to know people I “know” in more meaningful ways.  And there is a specific reason why this shift has taken place for me.     

Recently while at the gym, I was talking with one of the other early morning regulars who I have become acquainted with over the past year.  He’s a retired career military veteran and while he talks little about that time in his life, I’ve probed enough to know he experienced some horrific things in combat during his time on active duty.  He has cancer now, and it is evident that he “soldiers through” his physical pain in the same way he has learned to soldier through his emotional pain all these years.  Yet whenever I speak with him, all he can talk about is what a fortunate man he is.   

On this particular day, he had a focused agenda.  “Doc,” he said (that’s how I’m known at the gym – he’s not a patient), “I would be quite honored if you and a guest would come to a Holiday party my wife and I are having.  I come from humble roots and yet find myself at this stage of my life surrounded by incredible people.  I count you among them.  It’s important for me that you wonderful people get to know each other, and since I’m not sure how much longer I’ll be around, I want to be sure to connect you now.” 

You can bet we’ll be there …

In these challenging times, we need all the meaningful connection we can get.  Like myself, you likely “know” some wonderful people who you really don’t know at all.  So over the next few weeks as I gather with others for our many seasonal celebrations, I plan to carry the Spirit of my gym friend with me – arriving with an open heart and prepared to meet some wonderful people, and invite you to do the same.  If you’re not sure where to start, these 36 questions have been shown to help even strangers feel more connected with each other. 

This year, let’s choose to intentionally create the kind of world we want to live in – one where we make the most of our limited time together, one gathering at a time.  Where connection is the intention, no talk is small talk. 

Feel free to forward Take 3 to your colleagues.  Glad to add them to the distribution list.

 Mark and John

 Carilion Clinic Department of Family and Community Medicine