#477 Hotcakes: Suzetrigine for acute pain, SGLT2i and PAD, Safety of Lowering LDL, Restrictive vs Liberal Transfusion Strategy in MI revisited

March 31, 2025 | By Rahul Ganatra

Audio

Video

Join us as we review recent practice-changing articles on suzetrigine for acute pain, the risk of PAD events from SGLT2 inhibitors, the safety of very low LDL, and the benefits of restrictive vs liberal transfusion strategies in acute MI with anemia. Fill your brain hole with a delicious stack of hotcakes! Featuring Rahul Ganatra (@rbganatra), Matt Watto (@doctorwatto), and special guest Molly Brett (Paul Williams got a break and took a much-needed vacation this week!).

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Show Segments

• Intro, guest introduction, disclaimer
• Cognitive safety of very low LDL Cholesterol
• Suzetrigine for acute pain
• Risk for amputation associated with SGLT2 inhibitors
• Transfusion strategies in acute MI with anemia revisited
• Outro

Hotcake #1: Cognitive Safety of Very Low LDL (Watto)

Zimerman A, O’Donoghue ML, Ran X, et al. Long-term cognitive safety of achieving very low ldl cholesterol with evolocumab. NEJM Evidence. 2025;4(1).

What was the research question? What are the long-term cognitive effects of lipid-lowering to extremely low LDL values with evolocumab? 

Why is this study important? When I discuss statins with patients, most express their concerns about muscle symptoms, and the next most common question I get is about cognitive impairment. The FDA says cognitive symptoms are uncommon and transient, generally resolving within 3 weeks of discontinuation. To date, no adverse cognitive events were apparent from short-term studies of PCSK9 inhibitors including a systematic review and meta-analysis (Raccah, 2021). 

How was the study done? This open-label extension study included 473 patients with atherosclerotic cardiovascular disease who had previously completed the EBBINGHAUS cognitive substudy of the FOURIER trial of evolocumab. Patients were followed for a median of 5.1 years (maximum follow-up of 7.2 years). Cognitive function was assessed annually using the Cambridge Neuropsychological Test Automated Battery (CANTAB), with executive function as the primary endpoint.

Who were the patients? The parent FOURIER trial was a randomized, double-blind, multinational, phase 3 clinical trial of evolocumab versus placebo in 27,564 patients between 40 and 85 years of age with atherosclerotic cardiovascular disease and an LDL-C level >70 mg/dl or a non–high-density lipoprotein (HDL) cholesterol level of >100 mg/dl while on optimal statin therapy. Patients in EBBINGHAUS could not have baseline cognitive impairment. 

Top-line results: This was a negative study: the authors did not detect any difference in the primary outcome of worsening executive function measured annually for 5 years among patients with a median LDL of 35 mg/dL on a PCSK9 inhibitor. Cognitive scores remained stable, and there was no apparent association between achieved LDL-C levels and changes in cognitive performance. 

Learning points & limitations: Patients in this study were relatively young, highly educated, and free of cognitive impairment at baseline. As such, they may have been at low baseline risk for cognitive impairment, raising our concern for selection bias and uncertainty about whether these results generalize to other groups. Also, it is unknown if 5 years is a sufficiently long duration of follow-up and could explain a false-negative finding if it takes more time for cognitive impairment attributable to very low LDL to develop. The manufacturer of evolocumab funded this study, but the 2017 protocol for the EBBINGHAUS trial confirms the primary outcome was unchanged, increasing our confidence in these results.

Bottom line: These findings align with previous short-term studies and reinforce that very low LDL-C levels do not cause cognitive impairment.

Hotcakes rating: 2.5 / 5 because this was an open-label extension study with a highly selected population

Further reading:

• Hermann Ebbinghaus – Wikipedia
• FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs
• Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the risk for neurocognitive adverse events: A systematic review, meta-analysis and meta-regression – PubMed    

Hotcake #2: Suzetrigine for acute pain relief (Rahul) 

Jones J, Correll DJ, Lechner SM, et al. Selective Inhibition of Na V 1.8 with VX-548 for Acute Pain. N Engl J Med. 2023;389(5):393-405. 

What was the research question? What is the efficacy and safety of suzetrigine, a novel non-opioid oral pain medication, for treating postoperative soft tissue and bony pain?

Why is this study important? Suzetrigine is the first member of a new class of medications approved by the FDA in January 2025 for the treatment of acute pain. Suzetrigine was developed as a non-addictive alternative to opioids and works by blocking transmission of nociceptive pain through selective inhibition of a subtype of sodium channel that is only expressed in peripheral sensory neurons. 

How was the study done? This paper reports results of two phase 2 randomized trials. In one trial, patients undergoing abdominoplasty (a “tummy tuck”) were randomized in a 1:1:1:1 ratio to one of four groups: high-dose suzetrigine, moderate-dose suzetrigine, hydrocodone-APAP, or placebo. In the other trial, patients undergoing bunionectomy were randomized in a 2:2:1:2:2 ratio to one of five groups: high-, mod-, or low-dose suzetrigine, hydrocodone-APAP, or placebo. In both trials, pain was assessed on a 0/10 scale at baseline and then another 19 times over 48 hours. The primary outcome was the time-weighted average of these measurements, with later measurements weighted more than earlier measurements.  

Who were the patients? Both trials included about 300 patients who were mostly white women in their 40s. Patients were eligible if they requested pain relief within a few hours of surgery and reported pain of >4/10. Patients on chronic opioids or NSAIDS were excluded, as were patients if they had “any sensory abnormality or painful physical condition that in the opinion of the investigator could confound the patient’s ability to assess postoperative pain.” 

Top-line results: This was a positive study: among patients undergoing abdominoplasty, high-dose suzetrigine led to better pain relief at 48 hours after surgery than low-dose suzetrigine, low-dose hydrocodone-acetaminophen, or placebo: a baseline pain score of ~7.5 was reduced to 4 with suzetrigine vs 5 with placebo. Among patients undergoing bunionectomy, the numbers were similar: a baseline pain score of ~7 was reduced to 2.5 with suzetrigine and 3.5 with placebo. Regarding adverse effects, constipation occurred in 10% and headache in 15% of patients on suzetrigine, both more often than with placebo (5% for each). No AEs were severe.  

Learning points & limitations: We should consider a few sources of bias toward a benefit of suzetrigine. First, the dose of hydrocodone was low, achieving similar relief as placebo. Second, no consort diagram is provided, limiting our ability to assess for the impact of vague selection criteria on creating selection bias towards a benefit of suzetrigine. In addition, the time-weighted primary outcome (“SPID48”) is difficult to interpret and the minimum clinically important difference has not been established. Finally, no data is presented on rescue medication use (patients could receive ibuprofen if needed but nothing else), a conspicuous omission that has no inherent direction of bias, but makes me wonder if those data weren’t supportive.   

Bottom line: I’m excited, but need more data before having an informed opinion on its use.

Hotcakes rating: 3 / 5 

Further reading:

• FDA Highlights of Prescribing Information: Journavx (Suzetrigine)

• Full abdominoplasty trial: NAVIGATE-1 (NCT05558410) 
• Full bunionectomy trial: NAVIGATE-2: (NCT05553366)
• Safety of suzetrigine: single-arm open-label cohort study (NCT05661734)
• Suizetrigine for painful diabetic neuropathy (NCT05660538)

Hotcake #3: SGLT2 inhibitors and risk of PAD (Molly) 

Griffin KE, Snyder K, Javid AH, et al. Use of sglt2i versus dpp-4i as an add-on therapy and the risk of pad-related surgical events (Amputation, stent placement, or vascular surgery): a cohort study in veterans with diabetes. Diabetes Care. 2025;48(3):361-370.

What was the research question? Is SGLT2 inhibitor use associated with excess adverse PAD events (amputation, peripheral artery revascularization, or stenting) compared with DPP4 inhibitor use? 

Why is this study important? When SGLT2 inhibitors were first approved, two randomized trials showed a ~twofold increased risk of lower limb amputation in patients taking canagliflozin, prompting a black box warning from the FDA in 2017. Since then, pharmacovigilance studies and other trials have shown mixed results on the association between other SGLT2 inhibitors and amputations. The FDA dropped the black box warning in 2020 but left warnings about amputation risk in the prescribing information. 

How was the study done? This was a retrospective cohort study comparing 76,000 US veterans with diabetes who started an SGLT-2 inhibitor (added to other diabetes medications) with 76,000 propensity-matched veterans who started a DPP-4 inhibitor during the study period. Most of the SGLT2 group received empagliflozin (94%), and most of the DPP4 group received saxagliptin or alogliptin. The primary outcome was the time to the first PAD-related surgical event, identified by billing codes. The median duration of follow up was about 8 months.

Who were the patients? The median age was 69 years, hemoglobin A1c was 8.4%, and the average duration of diabetes was about 10 years. Half of patients smoked, a third had CAD, and 8% had a preexisting diagnosis of PAD. Overall, this was a relatively high-risk group of patients.

Top-line results:  This was a positive study. In adjusted analyses, over a median follow-up of 8 months, SGLT2 inhibitors were associated with ~1 excess PAD event (amputation, revascularization, or stenting) per 1,000 patient-years compared with DPP4 inhibitors. Expressed as a cumulative probability, the absolute risk of a PAD event at 4 years was 4% for SGLT2 inhibitors and 2.8% for DPP4 inhibitors, or an absolute risk difference of 1.2%. The cumulative probability of death was lower among patients on SGLT2 inhibitors compared with those on DPP4 inhibitors.

Learning Points & Limitations: Evidence of confounding by indication is abundant in the unweighted dataset: SGLT2s were prescribed to generally sicker patients. However, this well-done study used an active-comparator, new-user design and propensity score matching to limit the impact of confounding by indication on the results. While the mechanism of increased amputation risk from SGLT2 inhibitors remains unknown, these results are persuasive that SGLT2 inhibitors as a class (not just canagliflozin) probably have some small association with PAD events. 

Bottom line: Multiple randomized controlled trials support the cardiometabolic benefits of SGLT2 inhibitors, which outweigh this small but real increase in risk for PAD events. Given this, I will still prescribe SGLT2 inhibitors, even in patients at high risk for PAD. In patients with active, untreated, or progressive PAD with indications for SGLT2 inhibitors, I might hold off until the patient is stabilized.

Hotcakes rating: 3.5 / 5

Hot take #1 Transfusion thresholds in MI revisited (Rahul)

Carson JL, Fergusson DA, Noveck H, et al. Restrictive versus liberal transfusion in myocardial infarction — a patient-level meta-analysis. NEJM Evidence. 2025;4(2). 

Summary: A meta-analysis from the authors of the MINT trial of restrictive vs liberal transfusion strategies in acute MI with anemia (see episode #424 for a refresher) updates our understanding of the benefits of red blood cell transfusion in this population. The MINT trial, which dominated this meta-analysis (contributing 80% of the patients and almost 90% of the outcomes), randomized patients with acute MI and anemia to transfusion when hemoglobin had fallen below 7 g/dL, or below 10 g/dL. That study was inconclusive with respect to the primary outcome of death or MI at 30 days, but the authors did find that among patients with type I MI, transfusion for hgb < 10 led to a 4.4% absolute reduction in death and MI at 30 days (NNT = 23). In this meta-analysis combining data from 4 trials comparing liberal and restrictive transfusion strategies, the authors again found that liberal transfusion was NOT associated with improved survival or reduced MI at 30 days, but there was a survival advantage at 6 months, driven by a reduction in cardiac deaths at 30 days. 

Bottom line: A liberal transfusion strategy is resource-intensive and probably doesn’t benefit unselected patients, but there could still be a subset of patients who benefit. Rather than transfusing all patients with MI and anemia for hgb <10, these results make me more likely to transfuse patients with ongoing ischemia or ongoing blood loss who haven’t yet been revascularized, and less likely to transfuse patients with higher hemoglobins and who are otherwise stable.

Links

Links are included in the show notes above.

Goals

Listeners will review recent practice-changing articles and medical news.

Learning objectives

After listening to this episode listeners will…

1. Determine the cognitive safety of evolocumab for achieving very low LDL
2. Describe the use of suzetrigine for treatment of acute pain
3. Evaluate the risk of peripheral arterial disease events attributable to SGLT2 inhibitors

Disclosures

The Curbsiders report no relevant financial disclosures. 

Citation

Ganatra RB, Brett MS, Watto MF. “#477 Hotcakes: Suzetrigine for acute pain, SGLT2i and PAD, Safety of Lowering LDL, Restrictive vs Liberal Transfusion Strategy in MI revisited”. The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list Final publishing date, March 31, 2025.