March Madness – DIGEST 75

March 28, 2026 | By Nora Taranto

Welcome Back to The Curbsiders Digest!

In this issue we discuss March Madness, plus lipids, GLP-1s, and DOAC Comparisons oh my! Effortlessly absorb important medical news, with our monthly newsletter featuring easily digestible analysis of the latest practice-changing articles, and of course…bad puns. 

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Issue 75

03/27/2026

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, Joshua Gilman MD, Laura Glick MD, Alyssa Mancini MD

• A new (oral) PCSK9 on the block. NEJM recently published a randomized, placebo-controlled trial (CORALreef Lipids) evaluating the efficacy and safety of the oral PCSK9 inhibitor Enlicitide in a large cohort of patients with either ASCVD and an LDL > 55 or LDL >70 and an intermediate-to-high cardiovascular risk.  Patients had to be receiving guideline-directed background lipid-lowering therapy (e.g. statins, ezetimibe) already for at least 30 days (unless they had documented intolerance to statins). Mean percent change in LDL in the enlicitide arm at week 24 was 56% greater than with placebo. Outcomes with enlicitide were sustained over the treatment period, as were improvements in multiple secondary biomarkers of interest (non-HDL percent change, apoB levels, lipoprotein(a)). There were no significant new adverse events with this agent.  This oral agent–with an effect size similar to that of currently available PCSK9 injectables–may ultimately offer an important alternative to injectable medications in patients who need additional LDL lowering agents beyond statins and/or ezetimibe. (LG) 
• Prescribing precision in depression management. JAMA recently published the results of a multi-center, randomized trial that utilized the PETRUSHKA (Personalizing Antidepressant Treatment for Unipolar Depression Combining Individual Choices, Risks, and Big Data) decision-support system as a tool to personalize anti-depressant treatment in patients with major depressive disorder. The study randomized nearly 500 adults (in Brazil, Canada, and the UK) with major depressive disorder to use this tool versus usual care with their clinician, and evaluated treatment discontinuation at 8 weeks as well as changes in PHQ-9 and GAD-7 scores. Of 493 participants (median age 35, 58% female) those who received a personalized antidepressant using the PETRUSHKA tool had a lower rate of discontinuation due to any reason compared to the usual care group at 8 weeks (17% vs. 27%, aRR 0.62, P =.007). Additionally, use of the PETRUSHKA tool led to greater improvements in depression and anxiety symptoms at 24 weeks, compared to usual care. (JD) 
• DOAC Comparisons. In the first head to head comparison of two direct oral anticoagulants, the international, open-label COBRRA trial (just published in NEJM) randomized 2760 patients with acute venous thromboembolism (VTE) to apixaban or rivaroxaban. Patients were randomized to receive 3 months of either anticoagulant (AC) with a primary outcome of clinically relevant bleeding, a composite of major bleeding and clinically relevant non-major bleeding. Secondary outcomes included the individual components of the primary outcome, recurrent symptomatic VTE, and death from any cause. Patients were excluded if they had been on AC for >72 hours immediately prior to enrollment, had an indication for long-term AC use, a creatinine clearance <30ml/min, or any contraindication to either medication as determined by a local treating clinician. At the 3 month follow up there was less bleeding in the apixaban group, with clinically relevant bleeding occurring in 3.3% of patients compared to 7.1% (RR 0.46, 0.33-0.65, p<0.001). Apixaban use was associated with a reduction in both major bleeding (0.4% vs 2.4%) and clinically relevant non-major bleeding (2.9% vs 4.9%). There was no difference in rates of recurrent VTE or death, and there were no bleeding or recurrent VTE related deaths. (JG) 
• Are GLP-1 RAs more efficacious in certain patient populations? JAMA Internal Medicine recently published a systematic review and meta-analysis looking at whether the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) varies by certain patient characteristics. The meta-analysis included 41 articles representing 64 RCTs–with 48 trials that could be individually assessed. These studies–which were assessing semaglutide, liraglutide, exenatide, lixisenatide, and dulaglutide–looked at change in body weight by age, baseline BMI, and baseline HbA1c, or percentage change in body weight from baseline by sex, race and ethnicity. Within 6 trials analyzed by sex (including 19,906 patients), weight loss was greater among women (10.9%) than men (6.8%). There was no significant difference in efficacy by age (7 trials including 4,314 patients), race (9 trials including 25,229 patients), ethnicity (7 trials including 8,328 patients), baseline BMI (15 trials including 9,473 patients), or baseline HbA1c (4 trials including 1,886 patients). (AM) 
• Improved kidney outcomes with SGLT2i vs. GLP-1 RA initiation. JAMA Internal Medicine recently published the results of a comparative effectiveness study that used nationwide, population-based data from Denmark to look at kidney outcomes in individuals with type 2 diabetes on metformin who initiated treatment with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) or glucagon-like peptide-1 receptor agonist (GLP-1 RA). The study included 36,279 individuals (mean age 63) who initiated an SGLT2i and 18,782 individuals (mean age 61) who initiated a GLP-1 RA. Individuals in both groups had comparable diabetes duration, eGFR, and urine albumin-creatinine ratios. Compared with GLP-1 RAs, SGLT2i initiation was associated with a lower 5-year risk of chronic kidney disease (6.7% vs 8.2%, risk difference -1.5%), and a lower 5-year mean cumulative count (MCC) of acute kidney injury per 100 individuals (25.2 for SGLT2i and 28.7 for GLP-1 RA, with an MCC ratio of 0.88). These findings were consistent across subgroups, but were most pronounced among individuals without preexisting kidney disease. Of note, secondary outcomes of albuminuria and mortality were slightly reduced in GLP-1 RA initiators. (AM) 

Palate Cleanser

As physicians, few of us are taught how to give bad news – the words we choose, the way we position our bodies, the silence we may or may not allow. Unfortunately, sometimes it takes receiving bad news to help inform how we can best deliver this news, as Julia Michie Bruckner details in a recent self-reflection published in JAMA. 

She recounts joining her father’s neurology visit via Zoom as he was diagnosed with frontotemporal dementia. Later, as a patient herself, she receives her own cancer diagnosis in a part of the hospital undergoing noisy construction. She then reflects on giving bad news in the Emergency Department, from giving results concerning for cancer to preparing a family for impending intubation of a loved one, for which she describes small, deliberate acts—dimming the lights, sitting down, softening her voice, allowing for silence—as a way to ignore her surroundings and meet patients where they are. It’s a reminder that while we can’t change the news, we can shape the moment it lands – check out her moving article here. 

– Jennifer DeSalvo MD

The Main Course

Joshua Gilman MD

Big Updates in Dyslipidemia Management
The wait is over! The recently published 2026 American College of Cardiology / American Heart Association guidelines on the management of dyslipidemia represent a significant update to the 2018 cholesterol guidelines, incorporating new evidence from major cardiovascular outcomes trials and introducing important changes to risk assessment and lipid lowering therapy (LLT). Here, we’ll review some of the major updates that will likely impact daily practice.

The PREVENT Equation Takes Center Stage (Section 4.2.3.2)
The new guidelines now recommend using the PREVENT (Predicting Risk of Cardiovascular Disease Events) equation for cardiovascular risk assessment in lieu of the Pooled Cohort Equations (PCE). PREVENT offers several advantages –it’s race neutral, includes kidney function (eGFR), extends the age range down to 30 years old, and provides both 10- and 30-year risk assessments. The PREVENT equation notably provides a more accurate risk assessment compared to the PCE. The updated guidelines recommend using the “CPR” Framework: Calculate 10-year ASCVD risk using PREVENT; Personalize estimated risk by considering specific patient risk enhancers not included in PREVENT, and Reclassify risk with selective use of coronary artery calcium (CAC) scores/Reassess treatment recommendations.

Risk Threshold Updates and Indications for Lipid-Lowering Therapy (LLT) (Section 4.2)
For primary prevention in adults 30-79 with low-density lipoprotein cholesterol (LDL-C) levels of 70-189mg/dL, the guidelines recommend estimating the 10-year ASCVD risk with PREVENT and categorizing patients as low (<3%), borderline (3% to 5%), intermediate (5% to 10%), and high risk (≥10%). LLT is recommended in intermediate/high risk groups and can be considered in borderline-risk patients based on risk enhancers and/or an elevated high sensitivity CRP. Coronary Artery Calcium (CAC) scores can be used if the decision to initiate LLT remains uncertain in those with borderline or intermediate risk. Other primary prevention groups recommended for LLT include patients with severe hypercholesterolemia (LDL-C ≥190mg/dL), patients 40-75 years old with type 2 diabetes, patients with CKD stage >3 with LDL-C 70-189mg/dL, patients with HIV on antiretroviral therapy, and patients with coronary atherosclerosis incidentally found on non-cardiac CT scans. Lastly, patients with an LDL-C ≥160mg/dL should be considered for LLT regardless of their 10-year ASCVD risk estimate. 

New LDL-C and Non-HDL-C Targets (Section 4.2.3.7 & Section 4.2.6)
The new guidelines also bring back specific LDL-C and non high-density lipoprotein cholesterol (non-HDL-C) targets for both primary and secondary prevention groups. These dual targets acknowledge that non-HDL-C captures all atherogenic lipoproteins and can be particularly useful in patients with hypertriglyceridemia. In primary prevention, adults at borderline (3 to 5%) or intermediate risk (5 to 10%) should aim for an LDL-C <100mg/dL/non-HDL-C <130mg/dL when LLT is initiated. Those athigh risk (≥10%) should aim for an LDL-C <70mg/dL/non-HDL-C <100mg/dL. For secondary prevention, patients with established ASCVD but not at very high risk should target LDL-C <70mg/dL/non-HDL-C <100mg/dL. Very high risk secondary prevention patients should target an LDL-C of <55mg/dL/non-HDL-C <85mg/dL. 

Childhood Screening (Section 3.1)
The guidelines also emphasize earlier identification of dyslipidemia across a patient’s lifespan. Universal lipid screening is now recommended starting at age 19 and at least every 5 years thereafter.  Screening is also recommended for children aged 9-11 years. For children and adolescents ≥8 years old with an LDL-C >160mg/dL despite lifestyle modification, LLT is recommended to reduce LDL-C. 

Universal Lipoprotein(a) (Lp(a)) Screening (Section 4.2.10)
A new 2026 recommendation is that all adults should have Lp(a) measured at least once for ASCVD risk assessment. An elevated Lp(a) >50mg/dL is found in ~20% of patients which confers a 40% higher relative risk of ASCVD, and risk further increases with increasing Lp(a) levels. Because Lp(a) is genetically determined and largely unaffected by lifestyle, cascade testing of first-degree relatives is recommended when elevated levels are identified. For patients with elevated Lp(a), optimal early control of modifiable risk factors is essential. In individuals with clinical ASCVD and an elevated Lp(a) who have not achieved their LDL-C/non-HDL-C goals on maximally tolerated statin, a PCSK9 monoclonal antibody is recommended as these agents have been shown to lower both LDL-C by ~60% and Lp(a) by ~15-30%.

Expanded Role for Non-Statin Therapies (Section 4.2.4.4 & Section 4.2.6)
The guidelines also provide stronger recommendations for adding non-statin therapies to achieve treatment goals, reflecting evidence from recent cardiovascular outcomes trials such as FOURIER, ODYSSEY OUTCOMES, CLEAR OUTCOMES, and REDUCE-IT. For patients without clinical ASCVD who have severe hypercholesterolemia (LDL-C ≥190mg/dL) and are on maximally tolerated statin therapy, the guidelines recommend adding ezetimibe, a PCSK9 monoclonal antibody and/or bempedoic acid – with targets of LDL-C <100mg/dL/non-HDL-C <130mg/dL. Additionally, PCSK9 monoclonal antibodies ± ezetimibe are recommended as second line therapy for secondary prevention in both very high risk patients and non-high risk patients on maximally tolerated statins who have not achieved target goals. The guidelines also recognize the role of icosapent ethyl in patients with established ASCVD and triglycerides ≥150mg/dL on maximally tolerated statins. 

These updates reflect a more personalized, target-driven approach to lipid management that emphasizes earlier identification, more accurate risk assessment, and aggressive treatment to specific goals using combination therapy when needed.
Read the full guidelines here!

Hyperlipidemia 2026 Guideline Updates Summary
Chris “The Chiu Man” Chiu, MD & Sarah Leupold, PharmD

Digestifs

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This week on The Curbsiders: We have the hot topic of hot topics–longevity (in the context of cardiology!)! Dr. Greg Katz walks us through primary prevention from a longevity perspective in Episode #518 – filled with pearls for your patients and family members. 

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The Curbsiders Digest

Issue 75
Editor in Chief: Nora Taranto MD
Banner: Kate Grant  MBChB, DipGUMed

Jennifer DeSalvo,  Joshua Gilman,  Laura Glick, Alyssa Mancini, Chris Chiu, Sarah Leupold,  and Nora Taranto report no disclosures

Kate Grant reports no disclosures.  

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