👆Just published in @ATHjournal — from our #EAS 2026 Oral Presentation DOUBLE-HIT GENETIC DYSLIPIDEMIA: when two lifelong genetic drivers converge. 👉LDL-C 272 mg/dL 👉Lp(a) 766.4 nmol/L 👉apoB 198 mg/dL 🤔 Possible-to-probable familial hypercholesterolemia + extreme Lp(a) 👉The result: An extraordinary lifelong cumulative apoB burden, with diffuse coronary, carotid, subclavian, aortic and peripheral atherosclerosis — plus calcific aortic valve disease. 👆The message is simple: Atherosclerosis is about the magnitude × duration of exposure to apoB-containing particles. When FH and extreme Lp(a) coexist, the vascular system faces a true genetic “double hit.” With @alavallecobo & @natinardelli_ @society_eas #Atherosclerosis #LpA #FamilialHypercholesterolemia #ApoB #LDL #ASCVD #EAS2026

I read Gonzalez et al. with great interest, especially alongside the newly published RISSCI-2 study in Atherosclerosis doi.org/10.1016/j.atheroscle… The observation of a median 53% LDL-C reduction with ezetimibe is certainly intriguing. But we should be very careful about what this study actually demonstrates. The 14 patients were retrospectively selected because they had already shown a marked LDL-C response to ezetimibe. They were not consecutive, there was no control group, and the prevalence of this response among unselected patients with ketogenic diet-associated hypercholesterolemia is unknown. Again the same problem! Therefore, 53% is not an estimate of the expected effect of ezetimibe in ketogenic hypercholesterolemia. It is the response observed in a selected group of hyperresponders. That distinction is fundamental. The mechanistic interpretation is even less certain. The authors propose increased dependence on intestinal cholesterol absorption, yet sterol-balance markers did not show a uniform hyperabsorption phenotype. Negative testing for monogenic FH or sitosterolemia does not establish that the LDL elevation was caused by the ketogenic diet, particularly when pre-diet lipid values were frequently unavailable and formal clinical FH criteria were not systematically applied. This becomes especially relevant in light of the new RISSCI-2 study in Atherosclerosis. In a prospective dietary intervention using stable-isotope tracing, differences in saturated-fat absorption did not explain interindividual LDL-C responsiveness, and changes in markers of cholesterol absorption and synthesis were remarkably similar between high and low responders. RISSCI-2 does not directly refute Gonzalez et al. The populations and hypotheses differ. But it provides an important reminder: A striking pharmacological response does not prove the mechanism responsible for the underlying hypercholesterolemia. Even more importantly, a retrospective case series of 14 selected responders cannot be used to ask why clinicians should prescribe statins or PCSK9-targeting therapies instead of a “$10 drug.” That comparison confuses hypothesis-generating evidence with randomized cardiovascular-outcomes evidence. Selecting patients because they had an exceptional response and subsequently presenting that exceptional response as evidence for treatment selection is not precision medicine; it is selection bias until prospectively validated. Ezetimibe is an excellent, inexpensive, evidence-based drug. That does not require inflating what this study demonstrates. The correct conclusion is actually the one contained in the paper itself: this is an interesting hypothesis-generating observation deserving prospective confirmation. Precision medicine starts with phenotype. But rigorous science starts with knowing what the study design allows us to claim.

🇦🇷 Proud to share our latest publication in @ATHjournal from the GAELp(a) Registry. Another important contribution from Argentina and Latin America to the global understanding of Lp(a) and cardiovascular risk. 👉 1,861 patients from a nationwide multicenter Argentine registry 👉 Risk-weighted apoB reclassified 60% of participants by ≥10 percentiles 👉 As Lp(a) increased, conventional apoB progressively underestimated atherogenic burden 👉 At Lp(a) ≥300 nmol/L, RW-apoB was 1.91× measured apoB — an 86% underestimation of weighted atherogenic burden 👉 The discordance was driven primarily by Lp(a), not triglyceride-rich lipoproteins 🙌 Beyond the findings, this is another milestone for the GAELp(a) collaborative network: high-quality, multicenter real-world evidence generated in Argentina and contributing to the international lipid field. 🇦🇷 💪 Proud of this team. Proud of Argentine science. 🪢sciencedirect.com/science/ar… @society_eas @magabrielama83 @lschreier1 @alavallecobo @JSoumoulou @nicolasrennamd @lynchsantiago @natinardelli_ @sebagz1

👉The “low cholesterol increases mortality” argument just took another hit. ☝️A new Danish population study spanning nearly 30 years found: 📍Median LDL-C fell from 142 to 124 mg/dL 📍Median non-HDL-C fell from 174 to 150 mg/dL 📍The LDL-C level associated with the lowest mortality shifted downward from 155 to 135 mg/dL 📍The non-HDL-C level associated with the lowest mortality shifted downward from 186 to 162 mg/dL 📍At the same time, overall mortality declined 📍Cardiovascular mortality declined substantially 👉Key takeaways 1️⃣ Lower population LDL-C did not lead to higher mortality. 2️⃣ The “optimal” LDL-C observed in epidemiological mortality curves is not a fixed biological constant. 3️⃣ Mortality nadirs move as populations become healthier, cardiovascular prevention improves, and LDL-C levels decline. 4️⃣ The well-known U-shaped association between LDL-C and mortality is likely driven, at least in part, by reverse causation and residual confounding at the low end. 5️⃣ These findings are fully consistent with the extensive genetic, epidemiological, and randomized trial evidence supporting LDL-C lowering for ASCVD prevention. 👉Bottom line 📍The question is not whether lowering LDL-C increases mortality. 📍This study suggests the opposite concern may have been misplaced all along: 📍As population LDL-C levels fell, mortality did not rise—it fell too. 🔓🔗 atherosclerosis-journal.com/… @society_eas @ATHjournal @BNordestgaard