Researchers from the Department of Advanced Biomedical Sciences at Federico II University in Naples have discovered a significant association between low levels of plasma LDL cholesterol and an increased risk of developing type 2 diabetes. This relationship appears to be independent of statin use, a class of drugs commonly prescribed to lower cholesterol levels. The findings, detailed in the study “A six-year longitudinal study identifies a statin-independent association between low LDL-cholesterol and risk of type 2 diabetes,” have been published in Cardiovascular Diabetology.
The study addresses a long-standing clinical conundrum regarding the effects of statins on diabetes risk. While statin therapy has been linked to a dose-dependent increase in the incidence of type 2 diabetes, the underlying mechanisms remain poorly understood. Genetic research has provided additional insights, suggesting that genetic variations in cholesterol-lowering pathways may be associated with a higher risk of diabetes.
Researchers focused on specific genetic variants in the HMGCR and NPC1L1 genes, which are known to lower LDL cholesterol. These variants appear to correlate with an increased risk of diabetes. Conversely, individuals with familial hypercholesterolemia, a genetic disorder characterized by very high LDL cholesterol and elevated coronary artery disease risk, seem less prone to developing type 2 diabetes.
This study involved a cohort of 13,674 adults aged between 19 and 90 years, recruited from 140 general practitioners who contributed to a shared electronic medical record system. This system tracked patient visits, diagnoses, laboratory results, and treatment outcomes. The cohort included slightly more than half who were prescribed statins at baseline. Notably, the mean age of statin users was 70 years, compared to 54 years for non-users.
Over a median follow-up period of 71.6 months, researchers found that 1,819 participants, or 13% of the cohort, developed incident type 2 diabetes. Among those treated with statins, 1,424 participants (or 20%) were diagnosed with diabetes, while 395 participants (or 6%) without statin therapy received the same diagnosis.
The analysis revealed a clear trend: for every 10 mg/dl increase in LDL cholesterol, there was a 10% reduction in the hazard of developing diabetes, reflected by an adjusted hazard ratio of 0.90. The incidence rates of type 2 diabetes varied significantly across LDL cholesterol quartiles, with rates of 27.6, 17.4, 13.5, and 8.4 cases per 1,000 person-years in the low (<84 mg/dl), medium (84–<107 mg/dl), high (107–<131 mg/dl), and very high (≥131 mg/dl) groups, respectively. Statin therapy was associated with an increased diabetes risk across all LDL cholesterol categories. The relative risk was most pronounced among those starting with very high LDL cholesterol, with an adjusted hazard ratio of 2.41. Researchers concluded that lower LDL cholesterol levels were linked to a higher risk of type 2 diabetes, largely independent of statin use, while higher LDL levels (≥131 mg/dl) were associated with the lowest observed diabetes risk.
These findings could have significant implications for clinical practice, as they highlight the potential risks associated with lowering LDL cholesterol too aggressively. As more individuals are treated with statins and other cholesterol-lowering interventions, understanding the broader metabolic implications becomes increasingly crucial.
The research underscores the complexity of cholesterol metabolism and its intricate relationship with diabetes risk, inviting further investigation into how best to balance cardiovascular health with metabolic outcomes.
For more information, refer to the study by Maria Lembo et al., published in Cardiovascular Diabetology in 2025.
