11:47 AM

446 - GLP-1 Agonist Side-Effects, Statins in ASCVD, More Song and Dance

Take 3 – Practical Practice Pointers©

From the Department of Clarification

From the Department of Clarification

Our recent coverage of low FODMAP (Fermentable oligo-, di-, & monosaccharides, and polyols) diets in Take 3 #444 had one reader confused about part of Take 3 #424, when we first discussed the low FODMAP diet for irritable bowel syndrome. In the earlier piece, I wrote: “A low FODMAP diet is very difficult to follow as it includes many foods that are thought to be part of a healthy diet…”

What I meant, of course, is “the low FODMAP diet restricts many foods that are thought to be part of a healthy diet…,” which is one of the barriers that may prevent clinicians and patients from adopting this diet.

John’s Comments:

Sorry for the confusion. Diets can be thought of as restricting intake of certain poor-quality foods or as plans for users to eat more of the healthy foods. Either way, it’s best to specify exactly what is meant.

From the Literature

1)  Side Effects from GLP-1 Agonists for Diabetes and Weight Loss


GLP-1 (glucagon-like-peptide-1) agonists (“-glutide” medications like liraglutide and semaglutide) are very popular these days for diabetes control (with benefits for heart and kidney disease) as well as weight loss. The risk of pancreatitis with these medications was known from when they were first released, but recent reports have indicated a potential for gallbladder disease. A systematic review examines this question across all “-glutide” medications.

The researchers searched multiple databases and had clear inclusion/exclusion criteria for the review. The risk of bias for the outcomes was mostly low with some moderate risk of bias for the secondary outcomes.

Seventy-six studies (60 for diabetes, 13 for weight loss, plus a smattering of others) with ~ 103,000 patients were included in the review. GLP-1 agonists were associated with an increased risk of gallbladder or biliary disease (RR, 1.37; 95% CI, 1.23-1.52) compared with controls. The absolute risk difference was an additional 27 (17-38) events per 10,000 patients per year. Similar risks were found for the individual outcomes of cholelithiasis, cholecystitis, cholecystectomy, and “biliary disease,” but not biliary tract cancer. There was very little heterogeneity in the data (I-squared = 0% for the main outcome). Longer use at higher doses was associated with greater risk. The injectable agents (liraglutide, dulaglutide and exenatide, e.g.) seemed to be more associated with these outcomes than the other agents (including oral semaglutide) in this class.

Use of these agents for weight loss was more strongly associated with the gall bladder outcomes than use for diabetes.

Sensitivity analyses did not alter the results, and there was no evidence of publication bias.

John’s Comments:

There is a lot of enthusiasm for these agents, and they seem to be effective for diabetes with some positive additional benefits for associated heart and kidney disease. But new drugs are approved based on their efficacy and evidence of no significant common harms. Subtler harms can take a while to manifest themselves. These effects on gall bladder disease are concerning, but fortunately rare. It is best to advise our patients of these possible side effects so that they can contact us when they occur and to keep our eyes open for more data like this.


He L, Wang J, Ping F, et al. Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases: A Systematic Review and Meta-analysis of Randomized Clinical Trials. JAMA Intern Med. 2022;182(5):513. Link


From the Literature

2)  Statin Use in ASCVD – We Have a Long Way to Go


Almost 1 in 2 Americans will develop a clinical manifestation of atherosclerotic cardiovascular disease (ASCVD) in their lifetime.  Once established, the risk of sustaining a subsequent ASCVD event, such as a myocardial infarction, stroke, limb loss, or cardiovascular death, is at least 10% per year.  

In 2013, the American College of Cardiology and the American Heart Association published guidelines that included a Class I recommendation for high-intensity statin use among patients with established ASCVD who were younger than 75 years of age based on data that indicated such treatment could decrease the number of ASCVD events by approximately 30%, with additional gains with the use of high-intensity statins. Although the release of the guideline resulted in a demonstrable increase in the prescription of high-intensity statins, a number of studies showed that the rate of use had plateaued in 2017, with approximately 30%-50% of eligible patients ultimately being treated.  An update to these guidelines in 2019 broadened the high- intensity statin recommendation to Class II for those older than 75 years of age with ASCVD. 

To better understand statin use in this population, the authors of this retrospective cohort study performed a multicenter analysis of >600,000 patients with established ASCVD for statin use by querying pharmacy and medical claims data from a commercial health plan were between January 31, 2018, and January 31, 2019. Statin use as of January 31, 2019, was evaluated, as was 12-month adherence and discontinuation patterns.  For the purposes of this study, ASCVD was defined as those with a diagnosis or procedure code representative of coronary artery disease (CAD), peripheral arterial disease (PAD) or cerebrovascular disease (CVD). 

The authors found that overall: 1) statin therapy was prescribed in only one-half of the patients; 2) roughly 1 in 5 patients received high-intensity statins; 3) younger patients, female patients, and patients with atherosclerosis in noncoronary beds (peripheral arterial disease or cerebrovascular disease) were much less likely to receive guideline-concordant statins; and 4) statin adherence, as measured by prescription refill rates, remained low except in the high-intensity statin group, where more than 80% of patients achieved > 75% adherence based on days covered by medication; 5)  Among the no-statin cohort, almost two-thirds had seen a cardiologist in the prior 12 months, and among those with the lowest levels of adherence, >80% had seen their Primary Care Clinician or cardiologist in the prior 12 months.

Mark’s Comments: 

Despite more optimistic estimations of statin adherence in other studies, this study represents one of the largest analyses of statin prescribing and adherence patterns in the US.  The findings are sobering, particularly since we’re talking secondary prevention.  In an accompanying editorial, the authors suggest that key drivers of this non-guideline-concordant statin use occur at the level of 1) clinicians – therapeutic inertia, not understanding guidelines regarding management if a patient experiencing statin-associated side-effects (SASE); 2) patients – non-adherence, SASE, and 3) social influences – internet, media, other external influences.  Suggested interventions include making guideline more user friendly, leveraging team-based care, providing smart clinical decision support systems, and identifying trusted sources of information for the patients and clinicians. 


·         Nelson, A et al.  High-intensity Statin Use Among Patients with Atherosclerosis in the US.  J Am Coll Cardiol. 2022 May, 79 (18) 1802–1813. Abstract

·         Virani S, Ballantyne C, Peterson L.  Guideline-Concordant Statin Therapy Use in Secondary Prevention: Should the Medical Community Wait for Divine Intervention?  Editorial Comment.  J Am Coll Cardiol.  2022 May, 79 (18): 1814-1817.  Link

From PeerRxMed (sign up with a buddy at www.PeerRxMed.org )

3)  Time to Belt a Tune and Bust a Move


“You’ve gotta dance like there’s nobody watching … Sing like there’s nobody listening … “  William Purkey, Ed.D, Author and Educator

Think about the last time you danced – really danced, as in letting your body just move to the music with unself-conscious abandon.  What about the last time you sang – really sang, as in loud and from the heart and not really caring how you sounded.  I suspect you can recall such times, but perhaps they were quite long ago, and you may be tempted to add an immediate and self-conscious caveat that at that time you weren’t totally of “right mind.” 

What you may also recall is how doing so was great fun and made you feel energized.         That’s certainly the case for me.  I absolutely love to dance and sing, particularly with others, but it’s been a long time since I “really danced” and “really sang,” and doing both of them more regularly would have health benefits for my body and soul.  Yet I don’t.  When our children were younger we danced and sang together all the time, but somewhere along the line, that was lost.  So this past weekend, as I included a bit of singing and dancing in my birthday festivities (without perhaps the “really”) and felt that familiar sense of elation that doing so brings, I found myself wondering why I don’t do this more often.

It is speculated by anthropologists that some manner of song and dance are coded into our DNA.  The ability to produce musical tones appears to predate spoken language, while movement to rhythm is a natural impulse that likely accompanied our evolution to our present human form.  Indeed, the incorporation of music and dance into rituals and ceremonies is both universal and ancient across all cultures and recorded times, and archeological records indicate the existence of dance before the birth of the earliest human civilizations.  We can readily conclude that song and dance have been part of what connects and bonds us as humans since we became … human.


If that is the case, then why would such natural tendencies which function as an important form of connection and community and can provide both joy and solace be something that has become marginalized from the daily life of so many, including myself – or relegated to something that is primarily watched as a form of entertainment rather than participated in (guilty again)?  And why would so many of us find ourselves insisting we “can’t” do either one, even though it is part of our human coding? 

While there are many explanations, here’s what I know.  I greatly miss doing both more often than I do, and have made it an intention to change that, starting with car singing (caution, car-dancing can be hazardous) and a one-song daily dance time with some singing thrown in for good measure.  Perhaps you’ll consider joining me?  While doing so won’t immediately connect us with others (until you invite them to join in), it will connect you with your soul and lift your spirits.  And we could all use more of that right now … and then pass it on. 


Mark and John

Carilion Clinic Department of Family and Community Medicine

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

Email: mhgreenawald@carilionclinic.org