A Cape Cod physician and author says the failure of the most advanced Lipoprotein (a) drug points to a problem with the strategy, not the science
The most closely watched cardiovascular trial of the year returned a negative result on September 4, and the reaction inside cardiology has been something close to disbelief. Novartis announced that pelacarsen, an injectable antisense therapy designed to silence the gene behind Lipoprotein (a), did not reduce cardiovascular events in Lp(a)HORIZON, a Phase III outcomes study of 8,323 patients with established cardiovascular disease. The drug lowered the target it was built to attack. The composite primary endpoint of cardiovascular death, non-fatal heart attack, non-fatal stroke and urgent coronary revascularisation requiring hospitalization did not improve against placebo.
“These are not the results we hoped for,” Shreeram Aradhye, president of development and chief medical officer at Novartis, said in the company’s statement, adding that the findings still advance scientific understanding of the relationship between Lipoprotein (a) lowering and cardiovascular outcomes. The company has not published a hazard ratio or the magnitude of the reduction it achieved, and says full data will come at a medical congress it has not yet named. The industry response came quickly. Amgen, which is running an outcomes trial of a rival Lipoprotein (a) drug, saw its own program come under fresh scrutiny in the days after the readout.
The particle at the centre of the disappointment has one of the strongest evidence bases in preventive cardiology. Lipoprotein (a) is a fat-carrying protein molecule whose levels are largely inherited, and roughly one in five people worldwide carry elevated levels. Levels above about 125 nmol/L raise the risk of heart attack and stroke across genders, rise for women in the perimenopausal years, and climb temporarily during pregnancy. Nothing in the standard toolkit lowers it, and no targeted therapy has been approved. Genetic and epidemiological studies had made the case for causality so consistently that pelacarsen was widely treated as the vanguard of a new era in prevention.
Kumara Sidhartha, a physician and author who has spent his career on nutrition as a clinical intervention, reads the result differently from the analysts. In his view, the target was never the problem. The problem is that a trial can only test what its design asks, and this one asked a single molecule to carry the weight of a whole disease process.
That argument is the subject of the opening chapter of his book, in which he describes the pattern of thinking he believes produced this outcome. “This is the same reductionist problem in viewing health and chronic diseases,” he writes. “If we don’t see that inflammation is part of a whole sequence of changes with common root causes of poor nutrition, then we will be targeting each individual problem with individual solutions.”
The mechanism, as Sidhartha describes it, offers one explanation for why the number can fall without the outcomes following. Lipoprotein (a) does its damage through a chain rather than a switch. The particle becomes hazardous when it oxidizes in circulation, activating NF-kappaB signaling that inflames the vessel wall, and the damage compounds when the endothelial lining is already weak enough to give plaque somewhere to take hold. Reducing the concentration of the particle while leaving that oxidative and inflammatory environment intact removes only one contributor from a list that otherwise stays in place.
The design of Lp(a)HORIZON makes that reading harder to dismiss than it would otherwise be. Every participant was already receiving guideline-directed care, including lipid-lowering and blood pressure treatment, which means the trial was measuring the risk for heart attacks and cardiac deaths that remains after conventional levers have been pulled. In that population, at that dose, lowering Lipoprotein (a) did not reduce it. What the leftover risk is actually made of is now the open question, and Sidhartha’s answer is the accumulated effect of diet, chronic inflammation, oxidative stress and the condition of the gut microbiome over decades.
He is careful about where that leaves medication. Statins, blood pressure control and revascularisation remain part of his practice philosophy, and his position is that dietary change belongs alongside as standard care rather than in place of it. The distinction matters commercially as well as clinically, because the intervention he points to has no approval pathway and no sponsor.
The published research on diet and Lipoprotein (a) is still small. A defined whole-food, plant-based diet lowered Lipoprotein (a), inflammatory markers, and other atherogenic particles within four weeks in a study published in Clinical Cardiology in 2018. Larger observational work, including an analysis of middle-aged adults in the Journal of the American Heart Association and a systematic review in Nutrients, has associated plant-based dietary patterns with lower incident cardiovascular disease, lower cardiovascular mortality, and lower all-cause mortality. Those findings are associations rather than trial results, but they concern the same kinds of outcomes Lp(a)HORIZON set out to measure.
The practical guidance Sidhartha gives patients with a high Lipoprotein (a) result is unglamorous and immediate. He encourages more berries, citrus, leafy greens and cruciferous vegetables, along with turmeric, ginger, garlic and cinnamon. Walnuts, flaxseeds, beans, whole grains and fermented foods such as kimchi or tempeh also feature, while processed foods, refined sugar, excess oils and trans fats get pared back. The pattern is rich in antioxidants, polyphenols, omega-3 fats and fiber, and its focus is on the whole chain of oxidation, inflammation and vessel health rather than on any single number.
Whether the pharmaceutical hypothesis survives will not be settled for years. Amgen’s olpasiran and Eli Lilly’s lepodisiran, both small interfering RNA therapies that have produced deeper reductions in Lipoprotein (a) than pelacarsen managed, are still in outcomes trials, with results expected over the next few years. Neither result changes the genetic evidence that elevated Lipoprotein (a) is causally linked to cardiovascular disease. What the September announcement did establish is a much smaller point than a verdict on the particle itself, and for patients that smaller point is the more pressing one. Millions of people carry an inherited risk factor that raises their chance of a heart attack or stroke, and as of this month there is still no approved drug that treats it.
One drug, at one dose, in one already well-treated population, lowered the Lipoprotein (a) number and yet did not prevent cardiac events. Sidhartha sees two possible readings. Either Lipoprotein (a) may be a marker of cardiac events rather than a cause, or the downstream effects of its oxidized form, along with endothelial health, matter more than its levels before oxidation. In either case, his view is that an evidence-based, whole-diet approach aimed at endothelial health, oxidative stress, and inflammation is a reasonable course while the olpasiran and lepodisiran trials run to completion.
References
- Najjar RS, Moore CE, Montgomery BD. Consumption of a defined, plant-based diet reduces lipoprotein(a), inflammation, and other atherogenic lipoproteins and particles within 4 weeks. Clin Cardiol. 2018 Aug;41(8):1062-1068.
- Kim H, Caulfield LE, Garcia-Larsen V, Steffen LM, Coresh J, Rebholz CM. Plant-Based diets are associated with a lower risk of incident cardiovascular disease, cardiovascular disease mortality, and all-cause mortality in a general population of middle-aged adults. Journal of the American Heart Association. 2019;8(16).
- Gan ZH, Cheong HC, Tu Y, Kuo P. Association between plant-based dietary patterns and risk of cardiovascular disease: a systematic review and meta-analysis of prospective cohort studies. Nutrients. 2021;13(11):3952.
- Patel H, Chandra S, Alexander S, Soble JS, Williams KA. Plant-based nutrition: an essential component of cardiovascular disease prevention and management. Current Cardiology Reports. 2017;19(10).
- Erlinge D, Tsimikas S, Maeng M, et al. Lipoprotein(a), cholesterol, triglyceride levels, and vulnerable coronary plaques: a PROSPECT II substudy. JACC. 2025 Jun;85(21):2011-2024.
- Barkas F, Brandts J, De Bacquer D, et al. Global variation in lipoprotein(a) levels among patients with coronary heart disease: insights from the INTERASPIRE study and implications for emerging Lp(a)-lowering therapies. JACC. 2025 Jun;85(21):2028-2042.
Disclaimer: This article is for informational and educational purposes only and does not constitute medical advice, diagnosis, or treatment. The research, clinical findings, dietary approaches, and opinions discussed may not apply to every individual. Readers should consult a qualified healthcare professional before making changes to their medications, diet, treatment plan, or cardiovascular care. References to specific drugs, therapies, foods, or dietary patterns should not be interpreted as endorsements or as substitutes for individualized medical guidance.
