11:32 AM

#534 - New “CKM” Drugs, Onychomycosis Rx, Getting Angry?

Take 3 – Practical Practice Pointers©

From the Literature

1)  Estimating the Benefit of All the New “CKM” Drugs


As we read in Take 3 # 528, cardio-kidney-metabolic (CKM) syndrome is advocated to be a new major sphere of concern in practice. Because of drugs like glucagon-like peptide (GLP)-1 agonists, sodium glucose cotransporter (SGLT)-2 inhibitors, and non-steroidal mineralocorticoid receptor antagonists (ns-MRAs), the American Heart Association (AHA) and American College of Cardiology (ACC) guidelines have begun to shift to a more holistic view of risk – encompassing heart, kidney, and metabolic disease as a product of intersecting and somewhat synergistic risk factors.

But how effective are these new drugs in actually taming risk in these patients? A new statistical modeling study makes some educated guesses. This study uses individual patient data (which is great) from 2 large SGLT-2 trials (CREDENCE and CANVAS), study level data (which is good) from eight studies of GLP-1 agonists, and study level data from 2 trials of finerenone (an ns-MRA). The authors combined this data to project the likelihood of MACE (major adverse cardiac events – cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) when these drugs were used in various combinations (including all together) in patients with diabetes and albuminuria. The authors had to make a lot of assumptions to combine this data for analysis, but generally offered sound reasons for their methods or based them on previous studies in the field.

The absolute risk differences (which are more useful than relative statistics like hazard ratios) presented in this study were calculated over three years. For the combination of all three agents (plus renin-angiotensin system blockade with ACE inhibitors or ARBs) vs. “usual care” there was a decrease in the risk of MACE by 4.4% (95% confidence interval (CI) 3.0 to 5.7, number needed to treat 23). The authors also estimate an all-cause mortality reduction of 3.1% (NNT ~ 33).

There are lots of limitations to this kind of data analysis – using only select trial databases (even for logical reasons like they are from large, well-done studies, with individual patient data available) limits generalizability. The authors assumed that the effect of the medications would stay the same over time when that is not truly known. The authors did make adjustments for the difficulties with adherence that were seen in the trials. Finally, this study was not a test of these drugs actually tried together in patients – instead their predicted combination effects were assumed to be additive in the model, when this might not be true at all in real life.

John’s Comments:

There is a LOT of hype around these medications currently, and they seem to have a lot of promise, but an NNT of 23 over 3 years to prevent an additional MACE outcome, while good, is far from the miraculous effect we’d expect, given the hype. I mean, they used ALL the drugs and in a fairly high-risk population…I expected more. The difference in estimated life years gained with the combination of these medications in this artificial analysis is 3.2 years (from 17.9 to 21.1 years) – real life results may vary considerably. It will be difficult, but essential, for us to keep up with the actual study results from the trials of these drugs to avoid being swayed too far by all the enthusiasm.


  • Neuen BL, Heerspink HJL, Vart P, et al. Estimated Lifetime Cardiovascular, Kidney, and Mortality Benefits of Combination Treatment With SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Nonsteroidal MRA Compared With Conventional Care in Patients With Type 2 Diabetes and Albuminuria. Circulation. 2024;149(6):450-462. Link


Question from a Colleague

2)  Therapies for Onychomycosis


Question:  Anything new for the treatment of onychomycosis?

Answer:  Onychomycosis occurs in 10% of the general population, 20% of persons older than 60 years, and 50% of those older than 70 years.  In addition to its unappealing appearance, it can cause nail disfigurement, pain, and may increase risk for soft tissue bacterial infections. Dermatophytes are the most common causes, but yeast (eg, C. albicans) and nondermatophyte molds are other common causes.  Confirming the diagnosis with a fungal culture can be helpful as the diagnosis can commonly be confused with nail discoloration from other causes, such as trauma, lichen planus, and psoriasis. However, while a culture can have high specificity, it is time-consuming (three to six weeks) and dependent on an appropriate medium, the temperature conditions, and the existence of viable fungus. Contamination by bacteria and other opportunistic fungi may compromise the correct diagnosis.

Treatment can be difficult because of high failure rates and high recurrence rates, so establishing expectations prior to treatment is important.  Approximately 20% of patients who have successful treatment will have recurrence within 2 years of treatment. For most patients, oral treatments will be preferred when taking into consideration cost and outcomes. Terbinafine is considered the first line treatment, particularly if multiple nails and/or nail beds are involved.  Initial treatment of 250 mg/day for 6 weeks for fingernails and for 12 weeks for toenails is considered the present “gold standard.”  Cost is generally quite low ($10/month) and monitoring minimal.  Recommendations are to check liver function tests at baseline and if normal, no further monitoring is needed unless the patient has underlying known liver disease. 

A recently published network meta-analysis looked at the relative efficacy of monotherapies for dermatophyte toenail onychomycosis.  The authors looked at 21 studies and used a statistical calculation method of surface under the cumulative ranking curve (SUCRA) which measures the likelihood that a regimen was more likely to be effective or to cause harm for each regimen.  Their findings confirm terbinafine as the overall standard but with some potential refinements.  Using the definition of “complete cure rate” as having attained both mycological and clinical cure, they found that terbinafine “booster therapy” with 250 mg daily for 12 weeks followed by 12 weeks off followed by 4 additional weeks was more effective in complete cure at 1 year (83% vs. 46%) and terbinafine given continuously for 24 and 16 weeks had better mycological cure rate at 1 year than other terbinafine regimens but not as good as the booster therapy for complete cure (59% for 24 week therapy and 51% for 16 week therapy). 

Mark’s Comments:

I found this most recent study to be helpful in terms of confirming terbinafine as our “gold standard” for treatment but also in terms of considering other potential regimens for patients.  Given their findings, I’ll likely consider the “booster option” with more patients after discussing the pros and cons.  Remind patients that good foot hygiene can be helpful to prevent recurrence, including keeping feet dry, wearing clean socks, keeping nails trimmed, avoiding going barefoot at the pool or in the locker room, and using an antifungal product for feet and shoes.   


  • Gupta A et al.  Relative impact of traditional vs. newer oral antifungals for dermatophyte toenail onychomycosis: a network meta-analysis study.  British Journal of Dermatology, Volume 189, Issue 1, July 2023, Pages 12–22. Link

From PeerRxMed ( www.PeerRxMed.org )


3) Perhaps It’s Time to Get Angry


“Anybody can become angry - that is easy, but to be angry with the right person,  to the right degree, at the right time, for the right purpose, and in the right way - that is not within everybody's power and is not easy.”   Aristotle

My outburst caught me completely off guard.  After a seemingly trivial episode in which I realized I had forgotten something at home while traveling to work, I screamed a series of expletives to no one in particular.  Afterwards I felt both surprised and strangely a little better, but at the same time disturbed by the force of my reaction when I am usually pretty even keeled.  I was left wondering where all of that emotion might have come from.  

Most of us who work in healthcare have been led to believe the experience of anger or frustration or a myriad of other strongly “negatively charged”  emotions is very “unprofessional.”  We therefore may find ourselves often denying or suppressing them.   This does not, of course,  make them go away, but rather more often has them leak or burst out at inopportune or inappropriate times or cause us internal “emotional corrosion.”   And while certainly the way one expresses their anger can be inappropriate and/or destructive, the experience of anger itself is quite natural and very understandable given the present challenges of practicing medicine and our past few years as a country.

Wondering what the professionals have to say about “anger management” these days,  I visited the website of our colleagues at Mental Health America (MHA) and was relieved to find that perhaps my private vocal outburst was not so inappropriate after all.  Some of their suggestions for outlets for emotions such as anger include consciously pausing and breathing, exercising, journaling, dancing, singing, going to a different room or outside, verbalizing the anger in an appropriate setting (aka “venting”), asking for help, and even screaming (in private).  They emphasized the importance of gaining a better understanding of the cause or causes of your anger for you and managing both yourself and that circumstance. 

Later that day I took a few minutes to process this episode with one of my PeerRxMed buddies.  In doing so, I was able to see how a stressor from a health-related issue may have been the real source of my outburst, with my forgetfulness being a catalyst for the anger that was apparently lurking just under the surface.  We also checked in with each other as to how we were processing our numerous present challenges and whether we were regularly accessing the outlets that we know are helpful for us.  Finally, we agreed that it would be wise for us to check in more frequently to specifically ask how each of us was doing emotionally, while not accepting “I’m fine” for an answer.

So, if you’ve experienced feelings of anger lately (or whatever you call your “anger-like emotions”), please know you’re not abnormal and you’re not alone.  Remember that your PeerRxMed partner is standing by to help support you, since I’m confident that you are no longer foolish enough to think you can or should manage your challenges and distress on your own.  Indeed, we all need to leave those days behind us.  After all, no one should care alone … ever. 

For more suggestions and details from Mental Health America, here are some links:

  • Dealing with anger and frustration:  Link
  • Healthy ways to release rage:  Link


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