16:15 PM

491 - Statin Intolerance Option?, Preventing Frailty, Self-Compassion

Take 3 – Practical Practice Pointers©

From the Literature

1)  A New Option for CVD Risk Reduction for the Statin Intolerant?


Statin intolerance – usually muscle aches and pains occurring in between 7 and 29% of patients - often confounds our efforts to optimize cardiovascular risk reduction for our patients. A group of cardiology researchers has been studying bempedoic acid as a solution to this problem. Bempedoic acid is a prodrug that is converted to the active ingredient only in the liver, not in muscle tissue, where it could cause muscular side effects. It reduces the synthesis of cholesterol in the liver by affecting the same HMG-CoA reductase pathway, just earlier in the pathway than statins do. It has been shown to reduce LDL cholesterol by 17-28%, prompting its approval by the US Food and Drug Administration, but outcomes data has not been available until now.

The investigators compared bempedoic acid with placebo in a randomized, controlled trial of patients with coronary artery disease (~70%) or at high risk for it (~30%). They followed almost 14,000 patients (18-85 years, mean 65 years, 48% female, 90% white) for an average of ~40 months looking for a composite primary outcome of major adverse cardiovascular events (MACE) - death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.

The baseline LDL level was 139 mg/dl. The bempedoic acid group had a lower incidence of MACE than the placebo group - 11.7 vs. 13.3%, hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.79 to 0.96; absolute risk reduction (ARR) 1.6%, number needed to treat (NNT) 63. It did not reduce fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause, but did significantly reduce fatal/non-fatal myocardial infarction and coronary revascularization (NNT 91 and 71 respectively). Both gout and cholelithiasis were more common in the bempedoic acid group (NNH ~ 100 for each) and “small increases” in creatinine, uric acid and liver enzymes were noted. Withdrawals due to adverse events were the same between the groups.

The study was funded by the manufacturer of bempedoic acid (Esperion Therapeutics), and they were allowed to review and comment on the manuscript prior to publication, but “final decision on content was reserved for the academic authors with no restrictions on the right to publish.” Of note, the investigators allowed subjects to continue low-dose statins (22% in each group) and other cholesterol lowering medications (11% took ezetimibe in each group).

John’s Comments:

Despite these patients being labelled as high-risk, their baseline LDL levels were fairly low (compared to the first statin studies, where LDLs were ~190), which may account for the high NNTs seen in this study. This, of course, could be because both low-dose statins and ezetimibe were taken at reasonably high rates by the subjects (I guess the investigators were using a different definition of “statin intolerance” than I use). The benefit of reducing some CV outcomes must be balanced against gout and cholelithiasis outcomes. I would be interested to see a breakdown of the data between the patients with cardiovascular disease and those with just high-risk – it may be that bempedoic acid is worth its side effects mainly for CAD patients with statin intolerance.

Overall, while it does look like bempedoic acid may do something useful in CV risk reduction, the generalizability concerns make it hard to determine exactly the right place for this medication. Of note, goodrx.com has this medication (Nexletol) at $400+/month for a prescription without insurance, but a manufacturer-sponsored card will bring the cost to $10/month.


·         Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med. Published online March 4, 2023. Link

From the Literature


2)  Preventing and Reversing Frailty in the Elderly


Frailty in older people is a state of physical and physiological vulnerability to external stressors that is associated with increased risk of disability, dependency and mortality.  Its prevalence increases with age from 11% in over 65-year-olds to 50% in over 80-year-olds. Mortality risk is almost three times higher for frail compared with non-frail older people and an older person living with frailty may visit their primary care clinician up to four more occasions annually than a non-frail person.

The diagnosis is made when patients meet at least three of the following criteria: low grip strength, low energy, slow walking speed, low physical activity, and unintentional weight loss. A diagnosis of “pre-frailty” is just two of these criteria.  This definition has been adapted to provide a continuous score using the SHARE-Frailty Instrument (SHARE-FI), an open-access validated, gender-specific phenotypical frailty tool.    

There is evidence that frailty can be delayed and even reversed with appropriate interventions.  However, interventions remain underused in primary care.  This may in part be due to the absence of a standard approach to frailty intervention and partly due to both clinicians and older people believing it is inevitable or unmodifiable.

The authors of this study identified that the most effective and easiest to implement intervention may be a combination of exercises emphasizing weight-bearing for strength and sufficient dietary protein.  They co-designed an intervention, with public and patient input, of exercise and dietary protein education, and studied the effectiveness of this intervention in a randomized controlled trial (RCT) in six primary care practices in Ireland.

 The authors enrolled adults aged 65+ with Clinical Frailty Scale score ≤5 from December 2020 to May 2021.  Participants were randomized to intervention or usual care with allocation concealed until enrolment.  Intervention comprised a 3-month home-based exercise regime, emphasizing strength, and dietary protein guidance.  Effectiveness was measured at 3 months by comparing frailty levels, based on the SHARE-Frailty Instrument, on an intention-to-treat basis.  Secondary outcomes included bone mass, muscle mass and biological age measured by bioelectrical impedance analysis.  Ease of intervention and perceived health benefit were measured on Likert scales.

The resistance exercise regime consisted of 10 physical exercises, repeated 10 times, increased to 15 repetitions when comfortable (see figure S1 in 2nd reference).  Exercises were to be undertaken at least four times per week, up to once daily.  Participants were also asked to walk for 30 to 45 min, three to four times weekly and were advised to consume 1.2 g protein/kg body weight daily and provided nutritional education (see figures S2-S3 in 2nd reference).

Of the 359 adults screened, 197 were eligible and 168 enrolled; 156 (92.9%) attended follow-up (mean age 77.1; 67.3% women; 79 intervention, 77 control).  At baseline, 17.7% of intervention and 16.9% of control participants were frail by SHARE-FI.  At follow-up, 6.3 and 18.2% were frail, respectively.  The odds ratio of being frail between intervention and control groups post-intervention was 0.23 (95% confidence interval: 0.07–0.72; P = 0.011), adjusting for age, gender and site.  Absolute risk reduction was 11.9% with a number needed to treat (NNT) of 8.4.  Grip strength (P < 0.001) and bone mass (P = 0.040) improved significantly.  In a post-intervention survey, 66.2% found the intervention easy and 69.0% reported feeling better.

The authors concluded that over a 3-month intervention, a combination of exercises and dietary protein significantly reduced frailty and improved self-reported health.

 Mark’s Comments:

I chose to highlight this article based on the feasibility of the intervention in primary care practice and the potential positive impact across a population in both preventing and delaying frailty.  Often, I find my older patients (and their families) wanting clear instructions regarding what they can do to increase their “health span,” and this simple intervention provides that.  Though the study was performed in Ireland, I could see no reasons that it would not be translatable to our patient population, though access to adequate protein could be a limitation in some socioeconomically disadvantaged groups.


·         Travers J, Romero-Ortuno R, Langan J, et al. Building resilience and reversing frailty: a randomised controlled trial of a primary care intervention for older adults. Age Ageing. 2023 Feb 1;52(2):afad012. Link

·         Supplement with pictures of exercises and protein education – Figures S1-S3:  Link

From PeerRxMed ( www.PeerRxMed.org )

3)  You Deserve a Break Today:  Practicing Self-Compassion 

“If your compassion does not include yourself, it is incomplete.”  Jack Kornfield

“You’re such a bad ____!”   That inner critic doesn’t visit me as often anymore, but when it does, it piles on quickly … “physician, teacher, leader, writer, husband, father, friend, son” are a few of the “usual suspects” that show up when it rears its ugly head, with “citizen of the world” thrown in this time for good measure as it berated me for not being as civically involved as I “should” be.  It didn’t take me long to determine what the issue was – a “perfect storm” combination of deadlines, my often ridiculously high self-expectations and drive, grieving the loss of a loved one, a slowly healing physical injury, feeling disconnected from myself and those close to me, and the heaviness of all going on in the world was overwhelming my emotional circuits.  In other words, I was feeling quite human.

Studies have shown that although physicians in general have higher levels of personal resilience than others, our tendency to be intolerant of our imperfections can contribute to many forms of personal and professional distress.  While trying to talk us out of our deeply rooted high standards will not likely succeed, there are methods to lessen the impact of these thoughts on our psyche by reprogramming the ways in which we both view and “talk to” ourselves. This is the practice of self-compassion. 

According to Kristin Neff, PhD, self-compassion involves acting the same way towards yourself when you are having a difficult time, fail, or notice something you don’t like about yourself as you would with someone you loved dearly under the same circumstances.  When one is being self-compassionate, they are practicing the principle that you can’t give to others what you don’t have to give, so that the patience, kindness, and nonjudgement you show to yourself will ultimately be what you will bring to the world. 

The definitive action I took after noticing I had entered that self-berating vortex was pivotal, and not only saved me ongoing suffering, but also revealed that I am actually making progress (growth!) with the evolution of my emotional-management system.  Instead of entering my “default mode” of isolating myself with my thoughts and emotions, I acknowledged my struggles to myself (“you’re feeling overwhelmed”), reminded myself they were temporary (“this will pass”), and reached out and shared my struggles with those close to me (including my PeerRxMed partners).  All I need to say was, “I’m having a rough day emotionally” to both myself and to them, and they were there to listen.  Those conversations also opened the door for them to share some things they were struggling with, which likely would not have happened had I not shared my own.

So next time you notice you are “bad-thoughting” yourself (it will happen, with your own personal variation and preferred targets), give yourself a break and treat yourself like a person who is deserving of love and grace and patience … because you are.  And then do us all a favor, and pass it on. 

Further Resources: 

If you would like to create a life of greater self-compassion, here is a link to some self-compassion guided exercises and practices from Dr. Neff:  Self-Compassion Resources


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