#552 - SGLT-2 Inhibitors, Migraine Prevention, Being Positively Deviant

From the Literature

1)  How Much Difference Can SGLT-2 Inhibitors Make?

These days, as soon as we’ve had our fill of discussing glucagon-like-peptide-1 (GLP-1) agonists, we turn around and get hit with sodium–glucose co-transporter-2 inhibitors (SGLT-2i).  We’ve covered the rapid ascendancy of SGLT-2s in both diabetes and congestive heart failure (CHF, Take 3 #534 and #537). Most of the studies that are provided as evidence of their benefit include “composite outcomes” – usually Major Adverse Cardiac Events (or MACE) – which include any one of: myocardial infarction (MI), admission for CHF, revascularization or cardiovascular death.  One of the problems with using composite outcomes is that unless the outcomes included in the composite are all relatively equal in severity, the most common (and frequently less serious) outcome is usually the one that accounts for most of the benefit, which can produce a false impression of the drug’s effectiveness.  In addition, there is now enough accumulated evidence on these agents to look for patterns of effectiveness in patients with multiple conditions – CHF, atherosclerotic cardiovascular disease (ASCVD), history of diabetes (DM), or chronic kidney disease (CKD) – rather than the limited range conditions in any one primary study.

The authors of a recent Lancet systematic review wanted to analyze the largest studies of SGLT-2is to see if their effect on important individual outcomes held up across patient populations with a range of comorbidities. They looked for studies with > 1000 patients that had any one of: type 2 DM, CHF, CKD, and ASCVD, took an SGLT-2i or placebo, and who were evaluated for: “[1] a composite of first hospitalization for heart failure or cardiovascular death, [2] first hospitalization for heart failure, [3] total (i.e. first and recurrent) hospitalization for  heart failure, [4] cardiovascular death, and [5] all-cause mortality.” (I know…they used some smaller composite outcomes even in this study…).  The authors searched multiple databases, appraised each study for risk of bias, and assessed for heterogeneity across the data – all good quality points.

There was data from 15 separate studies (57 publications, including re-analyses) included in the analysis. Overall, the meta-analysis showed SGLT-2 inhibitors were associated with significant reductions in each of the five outcomes:  composite hospitalization or heart failure or cardiovascular death (HR 0·78 [95% CI 0·75–0·82]), first hospitalization for heart failure (HR 0·71 [0·67–0·75], cardiovascular death (HR 0·87 [0·83–0·92]), total hospitalization for heart failure (RR 0·70 [95% CI 0·66–0·75]), and all-cause mortality (HR 0·89 [95% CI 0·84–0·94]). Across a range of demographics, the effect of SGLT-2i therapy was consistent, except for a greater reduction in total hospitalization for heart failure in those of Asian race, and geographic location in Asia.

The effect of SGLT-2i therapy was also consistent across patients in patients with pre-existing CHF, DM, and ASCVD and various combinations of those conditions – although the effect was generally stronger for the hospitalization outcomes than for the mortality outcomes. In patients with a recent myocardial infarction, there was no significant effect on cardiovascular death (both alone, and in the composite outcome with first hospitalization for CHF). The authors found relatively low amounts of heterogeneity in the meta-analyses. They assessed all the studies to be of low risk of bias. There was possible publication bias in the hospitalization outcomes, but not for cardiovascular death (this could have been because the authors intentionally excluded small studies, which may have shown less effect).

John’s Comments:

While these types of studies aren’t themselves groundbreaking, they are helpful to reassure us that real world use of these agents (in patients with a variety of demographics and comorbidities) will produce results consistent with the individual trials. One important addition this study achieves is a better sense of overall reduction in cardiovascular mortality, since none of the trials were independently powered to examine this. Of note, there were no safety or tolerability outcomes included in this analysis, which is unfortunate.

Reference:

• Usman MS, Bhatt DL, Hameed I, et al. Effect of SGLT2 inhibitors on heart failure outcomes and cardiovascular death across the cardiometabolic disease spectrum: a systematic review and meta-analysis. The Lancet Diabetes & Endocrinology. 2024;12(7):447-461. Link

From the American Headache Society

2)  First Line Treatment for the Prevention of Migraine

It is estimated that migraine headaches (migraine) impacts about 12% of the US adult population, effecting 17% of women and 6% of men.  Those with migraine often experience reduced quality of life due to pain, nausea, sensitivity to light and sound, and other symptoms. These can severely impact daily activities, work, and social interactions.  Migraine is also often associated with other health conditions such as depression, anxiety, sleep disorders, and cardiovascular diseases.

Preventive therapy is a core goal in the treatment of migraine.  Preventive treatment is defined as an intervention to reduce migraine attack frequency, intensity, duration, and disability.  Successful preventive therapy should also improve responsiveness to acute treatments, reduce overall costs attributed to migraine and its treatment, and improve quality of life. Preventive therapy is indicated in ~40% of patients with migraine, although only a minority of such patients are using such treatments, in part because of limitations with efficacy and tolerability for more longstanding, established therapies.

The available evidence indicates traditional first-line treatments, particularly orally administered medications, may not be consistently effective, have concerns with tolerability and safety, and lack clear predictors of treatment response that guide clinical decisions about which to try first.  As these medications were all developed for indications other than migraine, the choice of which of these preventive treatments to implement is often based upon comorbidities, such as hypertension, insomnia, depression, and obesity, that may make a given treatment either indicated or contraindicated.  Multiple studies show that long-term adherence to these therapies is poor, based in part on unsatisfactory tolerability, and, in part, on lack of efficacy.

In 2021 the American Headache Society (AHS) published a consensus statement on migraine prevention and recommended, based on the available evidence at the time, that an individual try at least two classes of previous first-line migraine medications for ≥8 weeks before being considered for CGRP-targeting therapy.  In the case of chronic migraine, the recommendation was that a trial of onabotulinumtoxinA/Botox could be an alternative to a trial of two classes of medications.

Since the time of that statement, new evidence has been published regarding the efficacy, safety, and tolerability of calcitonin gene-related peptide (CGRP)-targeting therapies include the monoclonal antibodies (mAbs – erenumab/Aimovig, fremanezumab/Ajovy, galcanezumab/Emgality, and eptinezumab/Vyepti), and the small-molecule CGRP receptor antagonists (gepants – rimegepant/Nurtec and atogepant/Qulipta).  Given this new information, the AHS recently published an updated position statement for migraine preventive therapy specifically indicating that initiation of these newer therapies should not require trial and failure of non-specific migraine preventive medication approaches but rather should be considered first-line therapy.

Updated recommendations for treatments to consider include:

• For of episodic migraine with or without aura (4–14 monthly migraine days/MMDs) based upon International Classification of Headache Disorders (ICHD-3) with at least moderate disability ((Migraine Disability Assessment/MIDAS score ≥11 or Headache Impact Test/HIT-6 score >50)

OR

• For chronic migraine with or without aura (≥15 monthly headache days/MHDs) based upon ICHD-3. 
  • Topiramate
  • Divalproex sodium/valproate sodium
  • Beta-blocker: metoprolol, propranolol, timolol, atenolol, nadolol
  • Candesartan
  • Tricyclic antidepressant: amitriptyline, nortriptyline
  • Serotonin-norepinephrine reuptake inhibitor: venlafaxine, duloxetine
  • Other Level A or B treatments (established efficacy or probably effective) according to AAN scheme for classification of evidence
  • Monoclonal antibodies targeting CGRP or its receptor including erenumab, fremenezumab, galcanezumab, or eptinezumab
  • Small-molecules targeting the CGRP receptor (“gepants”) including atogepant and rimegepant

For chronic migraine, considerations can also include OnabotulinumtoxinA

Mark’s Comments:

Although it appears the older and newer preventive medications have similar efficacies, the CGRP-targeted therapies often have better tolerability and fewer side effects than the antidepressants, antihypertensives, and antiseizure medications but cost significantly more.  This is the trade-off we’ll need to balance as we determine where these medications “fit” into our treatment options.  As with other newer medications, this will unfortunately often come down to insurance coverage.  For example, the GoodRx price for a month of fremenezumab/Ajovy is $720 and for atogepant/Qulipta is $1,069.  The good news is, we have options.  Lots of them, so work with your patients to find the one that works for them.

Reference:

• Charles A, et al.  Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: An American Headache Society position statement update.  Headache. April 2024.  64(4): 333-341.  Link

From PeerRxMed ( www.PeerRxMed.org )

3)  Being Positively Deviant (and inviting others along for the ride)

"The reasonable man [sic] adapts himself to the world: the unreasonable one persists in trying to adapt the world to himself. Therefore all progress depends on the unreasonable man." — George Bernard Shaw

In my work helping to lead clinician well-being efforts, it has become a regular habit of mine to ask colleagues who are successfully navigating and even thriving in the midst of our demanding work, or what we might call “positive deviants,” if they have any “secrets” to their approach.  These are the colleagues who obviously love what they do and experience joy doing it while others struggle mightily.  They’re doing similar work, often in the same organization, but with a widely different outcome. 

Indeed, this question is quite relevant given the data regarding physician distress, where studies consistently (and persistently) indicate the majority of us continue to be “failing to thrive.”  Positive deviance encourages the adoption of often unconventional yet successful practices by those who, despite facing similar challenges, find ways to achieve more desirable outcomes.  These often simple practices deviate from what we have come to accept as the norm and can often include innovative approaches to time management, administrative efficiency, psychological reframing, prioritizing self-care, and fostering supportive professional relationships. 

While their answers vary based on context and personality, there are a few common themes that have emerged over the years of my inquiry and are supported by research.  The first is that almost without exception these positive professional deviants assign meaning to their work that elevates it beyond transaction to a sense of calling.  In doing so, they know their work matters and makes a difference, even in the midst of potential tedium and hassle.  They also are willing to try new things when their present process is not working, and are never content with the “status quo” when it is not achieving desired outcomes.  Additionally, they have all developed the habit of being able (and willing) to reframe situations to tap into “possibility thinking” even as I would not consider any of them to be “excessively” optimistic.

While some organizational cultures are threatened by such qualities (labeling them “Mavericks” or even “disruptive”), positive deviance can benefit healthcare organizations by creating a culture of collaborative experimentation and improvement. This can foster a more supportive and resilient healthcare environment even in the midst of organizational entropy.  

But perhaps the most telling insight from my query of my “positive deviant” network was how many of them shared with me that, “No one has ever asked me this before!”  It’s time that we do so more often.  By seeking out and learning from those who have found ways to maintain their well-being, we can adopt new strategies that enhance our own lives.  Take a moment this week to observe your colleagues and identify someone who seems to be thriving despite the challenges of our work. Initiate a conversation with them about their strategies for maintaining well-being and consider how you might incorporate some of their practices into your own life.  Share your findings with a peer and encourage them to do the same.  By fostering a culture of positive deviance, we can collectively improve our well-being and continue to provide the best care for our patients.  Now that does sound positively deviant!

______________

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