#560 - Cardiac Amyloidosis, Tirzepatide for OSA?, Prevent Physician Suicide

From the ACC/AHA

1)  Primary Care Recognition of Cardiac Amyloidosis

There are certain things that we learned in medical school that will always feel rare to me. Amyloidosis is one of them. There are lots of different amyloidoses, but cardiac amyloidosis has gained some recent notoriety because one type is recognized a lot more than people thought. How much more? Well, it’s hard to find specific numbers, and there is nothing as useful as a rate we can expect to see in primary care, but we can start with what we know from a recent American College of Cardiology/American Heart Association (ACC/AHA) 

ACC/AHA “Expert Consensus Decision Pathway” (so, unfortunately, not an evidence-based clinical guideline).

There are two types of cardiac amyloidosis – light-chain (AL) and transthyretin (ATTR). AL remains pretty rare – incidence is estimated at 1 in 75,000-100,000 thousand people. ATTR is “more common than we thought” – 16% of people having valve replacements for aortic stenosis, 13% of people diagnosed with heart failure with preserved ejection fraction (HFpEF).

The diagnostic algorithm for the cardiac amyloidoses is a little complicated. First, try to think of amyloid when your patients have left ventricular (LV) hypertrophy or increased LV mass – especially if they also have a low-voltage ECG despite the increased LV mass - or if they have atrial fibrillation or other conduction disorders.

Then look for extracardiac clues:

• In both AL and ATTR: polyneuropathy and autonomic dysfunction
• In AL only: macroglossia, periorbital purpura, easy bruising, proteinuria
• In ATTR only: carpal tunnel, biceps tendon rupture, trigger finger, spinal stenosis

An echo might show the increased LV mass, but cardiac magnetic resonance imaging (MRI) can differentiate amyloid from other causes but MUST be accompanied by testing for an AL-associated monoclonal protein – serum kappa/lambda free light chains and serum and urine immunofixation electrophoresis (IFE).

Then the algorithm splits:

• If there is a monoclonal protein detected – consult hematology for AL-cardiomyopathy (AL-CM). This has a relatively poor prognosis.
• If there is no monoclonal protein, then scintigraphy can evaluate for ATTR-CM.
  • Treatment for ATTR-CM is available (tafamidis, an extremely expensive oral medication that can stabilize the amyloid deposits)
  • Even if tafamidis is not an option, treatment of the heart failure associated with ATTR-CM should account for the frequent intolerance of much of the guideline-directed medical therapy recommended for other heart failure.

John’s Comments:

It behooves primary care clinicians to be aware of this disorder – especially of the extra-cardiac manifestations – since we would be in the best position to see the diagnostic forest for the trees. For heart failure diagnosis and management in primary care, it is becoming more important for us to think through etiologies and presentations, form an accurate diagnosis, and appropriately tailor therapy. I think if we are more careful about pursuing the definitive diagnoses for the usual heart failure causes, less common ones like cardiac amyloidosis will stand out.

References:

• Kittleson MM, Ruberg FL, Ambardekar AV, et al. 2023 ACC Expert Consensus Decision Pathway on Comprehensive Multidisciplinary Care for the Patient With Cardiac Amyloidosis. Journal of the American College of Cardiology. 2023;81(11):1076-1126. Link
• When Heart Failure Is Actually Cardiac Amyloidosis. Medscape. Accessed September 6, 2024. Link

From the Literature

2)  Tirzepatide and Obstructive Sleep Apnea (OSA)

Obstructive sleep apnea (OSA) has an estimated prevalence in the US of 15-30% in males and 10-15% in females when OSA is defined broadly as an apnea-hypopnea index (AHI) >5 events per hour of sleep.  When more stringent definitions are used (eg, AHI ≥5 events per hour plus symptoms or AHI ≥15 events per hour/“moderate OSA”), the estimated prevalence is approximately 15% in males and 5% in females. Evidence confirms that advancing age, male sex, and higher body-mass index (BMI) increase OSA prevalence with higher BMI being the strongest factor for both risk and severity.   

More than 2 decades ago, prospective observational studies reported that a 10% weight gain over 4 years is associated with a 32% increase in the apnea–hypopnea index (AHI) and, conversely, a 10% weight loss predicts a 26% decrease in AHI.  More recently, randomized controlled trials (RCTs) with up to 4-year follow-up indicated that weight loss is associated with decreased OSA severity with an average change in AHI of 0.78 events/h for every kilogram of weight lost, and that a small proportion of patients can achieve remission of OSA (AHI < 5 events/h).

A recently published paper of two phase-3, double-blind, randomized, controlled trials involving 269 adults with moderate-to-severe obstructive sleep apnea and obesity looked to see the impact of a maximally tolerated dose of tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonistGLP-1 agonist, vs. placebo for 52 weeks on their OSA.   Participants were assigned to trial 1 or trail 2 based on whether or not they were receiving CPAP.  The primary end point was the change in the AHI from baseline.  There were multiple secondary end points, including weight loss and sleep-related patient-reported symptoms.

At baseline, the mean AHI was 51.5 events per hour in trial 1 and 49.5 events per hour in trial 2, and the mean body-mass index (BMI) was 39.1 and 38.7, respectively.  The authors found that in trial 1, the mean change in AHI at week 52 was −25.3 events per hour (95% confidence interval [CI], −29.3 to −21.2) with tirzepatide and −5.3 events per hour (95% CI, −9.4 to −1.1) with placebo, for an estimated treatment difference of −20.0 events per hour (P<0.001).  In trial 2, the mean change in AHI at week 52 was −29.3 events per hour (95% CI, −33.2 to −25.4) with tirzepatide and −5.5 events per hour (95% CI, −9.9 to −1.2) with placebo, for an estimated treatment difference of −23.8 events per hour (P<0.001).  Averaging the two groups, the percent change in body weight was 18.7% (21.7 kg) in the tirzepatide group vs. 1.5% (1.7 kg) in the placebo group.

The authors concluded that for persons with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide significantly reduced AHI, body weight, and short-term (1 week) sleep-related outcomes (as well as some other secondary outcomes) over 1 year of intervention as compared with placebo.

Mark’s Comments:

Essentially, what the authors found was that weight loss with tirzepatide improved OSA in a predictable way, just like previous studies have found for other modalities that promote weight loss, which, while exciting, is not ground-breaking.  What was notable about this study from my perspective is that it was published in the NEJM, funded by Lilly (makers of tirzepatide), and the lead author is a paid consultant for Lilly.  While I respect the fact that getting FDA approval for new indications requires research, I’m not clear why this study was New England Journal of Medicine-worthy.  Learning that a drug that has been shown to be effective for weight loss can also improve the symptoms of OSA is really not news.  I’m not paranoid, but it does make me wonder ….

In an accompanying editorial, the author was also diplomatically skeptical, writing, “Whether tirzepatide improves patient-centered outcomes in obstructive sleep apnea remains unclear because a change in the AHI has not been validated as a surrogate marker of clinically relevant end points …. Additional analyses of the effects of tirzepatide on a broader range of patient-reported outcome measures by the SURMOUNT-OSA team will be eagerly awaited to evaluate the potential utility of tirzepatide as a sole treatment for obstructive sleep apnea.”

Reference:

• Malholtra A, et al.  Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity.  NEJM.  Published ahead of print 21 June 2024.  Link  

From PeerRxMed ( www.PeerRxMed.org )

3)  No One Should Struggle Alone

“We need to be better at helping each other.”  Physician colleague who came within minutes of committing suicide.

We know the work we do as physicians and other healthcare clinicians is challenging and can be incredibly emotionally taxing.  Each year at this time I’m reminded of the many conversations I’ve had over the years with colleagues who reached out for support due to their feeling that they were at their emotional “wits end”.  One that continues to stand out for me is a colleague who 7 years ago came within minutes of choosing to take her life through suicide.  Since then she has shared details with me of that painful time and her healing journey.    

When we last spoke, she was far enough away from that intensely dark and emotionally raw time to have gained deeper insight.  One of the things she told me (and has given me permission to share) speaks directly to why it is so essential to have a buddy (or buddies) who understands what it is like to travel this professional journey called healthcare:  “I’m not the kind of person who would ever consider something like suicide – so I thought.  But I broke, and the level of emotional pain I was feeling is difficult to describe.  It had to be quite obvious to others that something was wrong.  I believe they wanted to help, but none of them seemed comfortable in reaching out to me and when they did, it was easy to push them away.”  She concluded, “We need to be better at helping each other.” 

National Physician Suicide Awareness Day will be on Tuesday, September 17^th this year.  Started in 2018, the vision for this initiative is that this day will serve as a call to action for all of us to re-commit to breaking down stigma, opening the conversation, decreasing the fear of consequences, recognizing warning signs and learning to approach our colleagues who may be at risk for suicide or struggling emotionally.  Of course, it is a tragedy to think that we even need a day to raise awareness of physician suicide, but the statistics indicate that on average, one of our physician colleagues choses to take their life every day, and these statistics do not account for our NP, PA, PhD, PharmD, Allied health, and nursing teammates, all of whom, as we know, are struggling mightily as well.  Additionally, the 2023 Medscape Physician Suicide Report indicates 1 in 10 physicians have had thoughts of suicide, yet 40% told no one.    

According to Psychiatrist Michael Meyers, MD, author of the book The Physician as Patient, when a colleague shares that they are having suicidal thoughts, or even that they’re struggling emotionally, the first step is to thank them for sharing the information; “I’m sure that wasn’t easy, but I appreciate that you respect me enough to share with me.   Let’s talk more.”  Then ask what you can do to help.  If, on the other hand, you note that someone isn’t doing well, reach out and compassionately let them know of your concern and that you’d like to help, and don’t hesitate to ask directly if they’ve considered suicide. 

The pressures we face with the work we do are extraordinary.  Given this, the entire purpose of the PeerRxMed process is to ensure that “no one cares alone.”  It is vital that every one of us has someone we are certain we can reach out to in good times and bad and we know they will be there for us.  This is a person who knows us well enough that they would recognize when were weren’t doing well and would feel very comfortable and even insistent in ensuring we received the help we needed.   The stakes are too high to do otherwise.   Let’s all commit to becoming better at helping each other.  If you’re not signed up for PeerRx, get a buddy and do so (if you’re not sure how, e-mail me).  If you are, encourage others to sign up as well.  This is too important to leave to chance.  The life that we save could be someone close to us, or even our own.

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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