People with type 1 diabetes continue to face an elevated risk of cardiovascular disease even when they maintain good glycemic control and apparently normal cholesterol levels. This phenomenon, known as residual cardiovascular risk, calls into question the ability of routine blood tests to reflect actual risk and points to the existence of more complex alterations in the types of particles that transport cholesterol in the bloodstream. A study led by researchers from the Institut de Recerca Sant Pau (IR Sant Pau), Hospital de Sant Pau, and CIBERDEM, published in the journal Frontiers in Endocrinology, shows that these patients have increased levels of small dense low-density lipoproteins (sdLDL), a type of LDL cholesterol made up of smaller particles that accumulate more easily within arterial walls. This finding provides a mechanistic explanation for this residual cardiovascular risk and reinforces the need to go beyond standard cholesterol measurements.
“What is relevant is not only that there is more sdLDL, but that it appears in patients with apparently normal lipid profiles. This indicates that mechanisms different from the classic ones are contributing to cardiovascular risk in type 1 diabetes,” explains Dr. Helena Sardà, first author of the study and researcher in the Endocrinology, Diabetes, and Nutrition research group at IR Sant Pau.
To further investigate this issue, the study analyzed the lipid profile of 69 patients with long-standing type 1 diabetes—with more than two decades of disease and good glycemic control—and compared it with that of a group of people without diabetes. At first glance, the results might have seemed reassuring, since patients with type 1 diabetes had lower total LDL cholesterol levels.
However, a more detailed analysis revealed a different reality. These patients had a higher concentration of sdLDL and a greater proportion of these particles within the overall LDL fraction, as well as a smaller average particle size. These particles more easily penetrate the arterial wall, remain in circulation longer, and undergo modifications that promote fat accumulation in the arteries, making them especially relevant from a cardiovascular perspective.
In addition, the study used several complementary techniques to analyze these particles more precisely, allowing researchers to detect alterations that do not appear in conventional tests. Overall, the results showed that although the total number of LDL particles could be lower, their composition was less favorable, reinforcing the idea that the quality of these particles may be just as important as their quantity.
“These findings indicate that the conventional lipid profile may provide a false sense of security in some patients with type 1 diabetes. Even when the numbers appear normal, the composition of the particles may still be unfavorable,” notes Dr. Sardà.
The study described these differences and provided clues about the mechanisms that could explain them. Researchers identified changes in various key proteins that regulate lipid metabolism in the body, helping explain how these smaller, denser particles are generated.
Specifically, they observed increased levels of apolipoprotein C3 (ApoC3) and higher hepatic lipase activity, together with reduced activity of the cholesteryl ester transfer protein (CETP). This combination of alterations promotes the formation of sdLDL and points to a remodeling of the lipoprotein profile that does not follow the classic mechanisms associated with insulin resistance or elevated triglycerides.
ApoC3, in particular, showed a very close relationship with sdLDL levels, suggesting that it plays a central role in their formation. Meanwhile, hepatic lipase contributes to transforming particles into smaller forms, whereas lower CETP activity alters the balance among different lipoprotein types, reinforcing this less favorable profile.
The study also pointed to a possible additional factor related to type 1 diabetes treatment. Subcutaneous insulin administration generates a distribution pattern different from the physiological one, with a lower direct effect on the liver, which could alter the way lipoproteins are produced and transformed and promote the appearance of these smaller particles.
“The importance of the study lies not only in describing an alteration but in providing a coherent explanation for why it occurs. This helps us better understand why cardiovascular risk persists in people with well-controlled type 1 diabetes,” adds Dr. Sardà.
Overall, these findings reinforce the idea that type 1 diabetes is associated with changes in lipoprotein quality that may go unnoticed in routine clinical practice and are key to explaining its residual cardiovascular risk. The researchers emphasize that direct measurement of sdLDL cholesterol could improve cardiovascular risk assessment in these patients beyond conventional lipid parameters.
In addition, the study identifies proteins such as ApoC3, CETP, and hepatic lipase as potential therapeutic targets. Modulating these pathways could help reduce the burden of sdLDL and potentially the associated cardiovascular risk. Although this was a cross-sectional study, it provides a solid foundation for future research aimed at confirming these mechanisms and evaluating their clinical impact.
Sardà H, Solé A, Colom C, Borràs C, Carreras G, Benítez S, Miñambres I, Escolà-Gil JC, Sánchez-Quesada JL, Pérez A. Altered small dense LDL profiles in long-standing controlled type 1 diabetes. Front Endocrinol (Lausanne) 2026;17. https://doi.org/10.3389/fendo.2026.1804987.
Last update: 22 de May de 2026
