Saturated fat impact on LDL tied to genes

Clinical takeaway: Expect heterogeneous LDL responses to low-carb diets and follow lipids accordingly, especially in patients already at higher cardiovascular risk.

Low-carb diets help some patients lose weight and control blood sugar. But their effect on LDL is famously inconsistent, with some patients' cholesterol levels climbing while others hold steady. A new analysis points to genetics as part of the reason. Those patients already genetically prone to high LDL had the largest cholesterol increases on a low-carb diet, and the effect tracked how much saturated fat they ate.

On a low-carb diet, saturated fat's effect on LDL got stronger the higher a patient's genetic risk. In the third of patients with the lowest genetic risk, eating more saturated fat had no clear effect on LDL at all. In the middle third, LDL rose modestly as saturated fat went up. In the highest-risk third, the same increase in saturated fat pushed LDL up about twice as much, roughly 10 mg/dL for each step up in intake.

In genetically susceptible patients on low-carb diets, saturated fat hit LDL hardest. Still, individual responses spanned an enormous range, from a 36% drop in LDL to a 126% jump over 6 months. Genetic risk and saturated fat each nudged LDL on their own too, by about 6 and 5 mg/dL per step. But that amplifying pattern, where genetic risk magnified saturated fat's effect, showed up only with low-carb diets, not low-fat.

Researchers ran a secondary analysis of DIETFITS, a randomized trial in which 609 adults with overweight or obesity followed a healthy low-carb or low-fat diet. Among the 431 with genetic data, they built a polygenic score from thousands of LDL-related variants and tested how it interacted with saturated fat intake to shape 6-month LDL change, independent of how much weight patients lost.

If validated, a polygenic score like this one could help clinicians predict who will see LDL climb on a high-saturated-fat, low-carb diet before they even start. But this approach would need testing and development in more diverse populations first.

"These findings highlight that there is real heterogeneity in how people respond to diet. Dietary conversations can sometimes become overly simplified. One person may say, 'Low-carb diets always raise LDL cholesterol,' while another says, 'My LDL cholesterol did not change at all.' Our findings suggest that both experiences can be true, depending, at least in part, on the individual's genetic makeup," said Alexa Barad, PhD, RDN, a postdoctoral scholar at Stanford University School of Medicine.

Source: Barad A, et al. NUTRITION 2026. 2026 Jul 27. Genetic Modification of LDL-C Response to Change in Saturated Fat Intake: A Secondary Analysis of the DIETFITS Trial