Digest 62: Groundhog Day No More?

February 21, 2025 | By Nora Taranto

Welcome Back to The Curbsiders Digest!

In this issue, we discuss a new non-opioid on the block, very low LDL and cognitive outcomes, cannabis and mental health, and brief anticoagulation pauses. Effortlessly absorb important medical news, with our twice monthly newsletter featuring easily digestible analysis of the latest practice-changing articles, and of course…bad puns. 

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Issue 62

02/21/2025

Appetizers (to whet your appetite) 

Palate Cleanser (aka the melon part of the meal) 

The Main Course

A Digestif or two

Appetizers

Brought to you hot off the stove, from a variety of specialties. Delivered in super tasty, bite-sized morsels. 
-Jennifer DeSalvo MD; Laura Glick MD; Alyssa Mancini MD

• Comparing Glucose-Lowering Agents in Peripheral Artery Disease. A large retrospective cohort study just published in Diabetes Care followed U.S veterans with diabetes who were initiated on SGLT-2 inhibitors or DPP-4 inhibitors (in addition to metformin, sulfonylureas, insulin, or some combination), comparing the risk of peripheral artery disease(PAD)-related surgeries including revascularization and amputation. The weighted cohorts included >76,000 patients on SGLT-2 inhibitors (94% on empagliflozin) and >75,000 patients on DPP-4 inhibitors, with a median age of 69 and a median time since diabetes diagnosis of ~10 years.  SGLT-2 use was associated with an increased risk of PAD-related surgery compared to DPP-4 inhibitor use (event rate of 11.2 vs. 10.0 per 1000 person-years, aHR 1.18). SGLT-2 inhibitors were also associated with a higher risk of the individual outcomes of amputation (aHR 1.15) and revascularization (aHR 1.25).  Notably, median follow-up in both groups was short (~0.7 years).  (LG)
• Perils of PRN anti-hypertensive medications. JAMA Intern. Med recently published a retrospective cohort study of 133,760 veterans hospitalized on medical and surgical units at VA hospitals who received >1 scheduled anti-hypertensive medication within 24 hours of admission with >1 systolic blood pressure (BP) >140 mmHg during hospitalization. The authors compared adverse event rates in those who received as-needed anti-hypertensive medications during hospitalization and those who did not. 28,526 patients (21%) received as needed anti-hypertensive medications. As-needed users appeared to have a 1.2x increased risk of acute kidney injury (95% CI 1.18-1.29) particularly with IV medication use, 1.5x greater risk of rapid BP reduction (95% CI 1.39-1.62), and 1.7x higher risk of a composite of myocardial infarction, stroke, or death during hospitalization (95% CI 1.49-1.92) compared to non-users. This study used target trial emulation, which reduces but does not eliminate the risk of confounding in observational studies (including confounding by indication). (JD)
• How low can your LDL go? In a study just published in NEJM Evidence, a cohort of patients from FOURIER (an RCT demonstrating the cardiovascular and LDL-lowering benefit of evolocumab, a PCSK9 inhibitor) who participated in a neurocognitive substudy and were eligible for open-label extension (EBBINGHAUS-OLE) with evolocumab were followed for long-term neurocognitive outcomes. Study endpoints were assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) that can assess cognitive changes in multiple domains over time.  473 patients (median age 62, 30% female) continued evolocumab for a median of 5.1 years after FOURIER, and had a median LDL cholesterol level of 35 mg/dL twelve weeks into the extension period. There were no significant changes over time in executive function (primary endpoint) or working memory on CANTAB. There were no significant differences in any cognitive scores based on initial FOURIER treatment assignment (evolocumab vs placebo). (JD)
• A new non-opioid medication to treat acute pain. The FDA recently approved suzetrigine (Journavx), a first-in-class non-opioid analgesic that works by targeting a pain-signaling pathway involving sodium channels in the peripheral nervous system. Suzetrigine was approved to treat moderate to severe acute pain in adults. The efficacy of suzetrigine for acute pain management following abdominoplasty and bunionectomy was assessed in two phase 2 randomized, double-blind, placebo-controlled trials, the results of which were published in 2023 in NEJM. In these trials, 577 participants were randomly assigned to receive the study drug at varying doses vs. hydrocodone bitartrate-acetaminophen vs. placebo.  Compared with placebo, the study drug at the highest dose (100 mg load, followed by 50 mg every 12 hours) reduced acute pain over a 48-hour period. The most common adverse reactions with Journavx are itching, muscle spasms, increased CPK levels, and rash. It is contraindicated for use alongside strong CYP3A inhibitors, and users should also avoid drinking grapefruit juice while taking. (AM)
• New data on perioperative anticoagulation management. JAMA Network Open recently published the results of a prospective, multicenter, single-arm cohort study that included 1902 patients (mean age 70.4 years, 59.7% male, mean CHA₂DS₂-Vasc score 2.8, mean HAS-BLED score 1.6) with atrial fibrillation who planned to undergo a procedure with minimal to low bleeding risk (i.e. endoscopy, dental procedure, ocular surgery).  48% were receiving apixaban, 32% were receiving edoxaban, and 19% were receiving rivaroxaban–and the majority of patients underwent endoscopy (50%), followed by dental procedures (43%) and ocular procedures (6%). These patients followed the PERIXa protocol (eFigure 1a), where they were given the last dose of a factor Xa inhibitor 24 hours before the procedure and restarted it the next day after the procedure. The 30-day event rate of major bleeding was only 0.1% (and 2.6% for clinically relevant nonmajor bleeding), and there were no thromboembolic events. (AM)

Palate Cleanser

The melon part. To get rid of the taste of those pesky apps.  And to fill your brain with some fun facts.

How do you integrate artificial intelligence (AI) into your clinical practice? Dr. Peter Kim’s blog post, “Three essential ChatGPT habits every doctor should master,” provides practical, effective tips to help you unlock the power of AI in your clinical practice. He highlights the need to be clear and specific by providing a framework to structure your ChatGPT prompts: “acting as a [role] perform [task] in [format].” He also emphasizes the importance of frequently using ChatGPT to hone your ability to ask the right questions to obtain optimal answers. Furthermore, he encourages experimenting with a diversity of prompts to learn AI’s versatility and creativity. Check out his article for more details to elevate your practice with AI!

– Jennifer DeSalvo MD

The Main Course

Alexander Chaitoff, MD, MPH

Cannabis Use and Mental Health
Cannabis use is growing across nearly all segments of the United States (US) population, for multiple reasons. One study reported that there was a 15-fold increase in cannabis use over the last 30 years, and in 2022 there were more daily users of cannabis than daily users of alcohol in the US. Cannabis has been legalized for medical or recreational purposes in over 50% of states, though data are mixed on how much this increases cannabis use. There also appears to be a growing perception of cannabis as a potentially healthier alternative to other substances, with several research groups finding that Americans view substances like alcohol/tobacco as more harmful than cannabis.  There is no doubt that opioids, tobacco, and alcohol are all associated with negative health outcomes – but is cannabis really a benign alternative?

Cannabis use and risk of psychosis

In medical reports dating back to at least the 1930s, risk of developing psychosis has been one of the primary adverse health outcomes linked with cannabis use. Yet as of 2019, there was still only inconclusive evidence that cannabis use actually caused schizophrenia or other psychotic disorders. Most studies can’t disentangle whether cannabis use leads to subsequent psychosis (a true causal relationship) or whether one of two confounded associations might exist: 1) those using cannabis are more likely to have undiagnosed psychosis at the time of use or 2) those using cannabis self-select and are more likely to be diagnosed with other psychiatric disorders, regardless of cannabis use. It’s unlikely we’ll ever randomize people to take cannabis or placebo and follow for psychosis, so other study designs are needed.

Enter a 2025 study by Myran et al., published in JAMA Network Open. This study investigated the impact of cannabis legalization policy changes in Canada, looking at the effect of cannabis liberalization laws (beginning in 2015) on cannabis use and schizophrenia diagnoses from 2006 – 2022. In doing so, they were hoping to study a “natural event” (i.e. the policy change), which can help mitigate some of the confounding present in observational studies comparing users of a drug to non-users. The authors looked at the prevalence of cannabis use disorder and the rate of incident schizophrenia diagnosis, defined via ICD codes in claims data, in the period before and after laws liberalizing cannabis. They calculated the change in population attributable risk fraction for cannabis use disorder associated with schizophrenia in the pre-period and post-periods. The population attributable risk fraction quantifies the impact of a risk factor on likelihood of developing a disease, at the population level–a.k.a. the proportion of schizophrenia cases attributable to cannabis use disorder.  Among 13,588,681 Ontario residents (aged 14-65), the adjusted incidence rate of cannabis use disorder rose by nearly 5 times during the study period. The adjusted rates of schizophrenia diagnoses, meanwhile, fell by 27%. The proportion of new schizophrenia cases associated with cannabis use disorder increased from 1.6% in 2006 to 9.6% in 2022.

So did the study prove cannabis use causes schizophrenia? Not really. Sometimes, descriptive trends tell the story better than any statistical analysis. Here, cannabis use went up but overall rates of schizophrenia did not increase. If a factor is strongly linked with an outcome, you expect them to track together (e.g. as smoking has decreased, incident lung cancer has decreased). While the authors report that rates of “psychosis not otherwise specified” increased during the study period, it was not nearly to the degree that cannabis use increased, and there were other reasons to expect such non-specific psychosis diagnoses to increase (e.g. a significant spike in 2020, which is expected given evidence that social isolation worsens psychotic symptoms). There is also reason to pause with this population attributable risk factor approach, which is valid only if all potential variables that could contribute to risk of an outcome are accounted for.  This study was missing numerous important potential risk factors for schizophrenia – such as a family history of mental health disorder.

Studying cannabis moving forward

Dozens of news outlets reported on this study and overwhelmingly characterized the results as evidence of the poor health effects of cannabis. But the health effects of cannabis remain unclear. While there continues to be a lack of strong evidence that cannabis leads to psychotic disorders, there are new studies linking cannabis to other poor health outcomes, including suicide and cardiovascular disease.  To what degree cannabis causes outcomes or is just correlated remains less obvious. In the meantime, there is bioplausibility for cannabis’ negative health effects and reason to counsel patients on limiting use, just as we would for many other substances.

Read The Study Here!

Digestifs

Before you go….
we’ve got a few nibbles!

Consolidate your learning with a Quiz!  

This week on The Curbsiders: In Episode #471, Dr. Tom DeLoughery effortlessly walks us through the workup and management of iron deficiency anemia. He covers when to think about oral versus IV supplementation, how to think through the different IV iron formulations available today, and reactions to IV iron.

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Until next time, keep that brain hole digesting! 

The Curbsiders Digest

Issue 62

Editor in Chief: Nora Taranto MD

Banner: Kate Grant  MBChB, DipGUMed

Alexander Chaitoff, Jennifer DeSalvo,  Laura Glick, Alyssa Mancini, and Nora Taranto report no disclosures.

Kate Grant reports no disclosures.  

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