Researchers at the Department of Advanced Biomedical Sciences at “Federico II” University in Naples report that lower plasma LDL cholesterol is associated with a higher risk of incident type 2 diabetes in adults followed in primary care, independent of statin use.

Genetic clues and clinical puzzles

Statin therapy has a reputation for raising the rate of new type 2 diabetes diagnoses in a dose-dependent fashion, with no clear understanding of why. Genetic work adds another layer, linking LDL cholesterol-lowering alleles in HMGCR and NPC1L1 to higher diabetes risk and suggesting that LDL-C lowering across multiple pathways may share a connection with diabetes risk.

Familial hypercholesterolemia illustrates that pattern in the opposite direction. Individuals with this monogenic condition, marked by strikingly high LDL-C and increased coronary artery disease risk, appear less likely to develop type 2 diabetes, whereas LDL-C-lowering genetic variants tend to raise diabetes risk.

Large prospective analyses have shown that LDL-C-related genetic factors and type 2 diabetes move in opposite directions across mechanisms that alter LDL-C. Work with HMGCR, PCSK9, and NPC1L1 genes has tied genetically proxied HMGCR inhibition to lower blood pressure and higher fasting glucose, with PCSK9 and NPC1L1 inhibition showing no effect on blood pressure or fasting glucose.

Those observations raise a straightforward question. If LDL-C-lowering alleles track with more diabetes, and very high LDL-C often tracks with less, how does actual plasma LDL-C, measured in everyday clinical care, relate to new type 2 diabetes over many years in the general population, and how much of that pattern belongs to statins versus LDL-C itself?

In the study, “A six-year longitudinal study identifies a statin-independent association between low LDL-cholesterol and risk of type 2 diabetes,” published in Cardiovascular Diabetology, investigators asked whether plasma LDL-C predicted incident type 2 diabetes during long follow-up and examined whether statin therapy altered that relationship.

A cooperative of 140 general practitioners provided the data collection. Each doctor contributes to a shared electronic medical record that follows patients across visits and tracks diagnoses, prescriptions, hospital admissions, emergency care, laboratory results, vital signs, and deaths.

More than 200,000 adults appear in the system, with age and geographic distributions that naturally mirror the city of Naples. A cohort of 13,674 adults between 19 and 90 years of age remained after applying all inclusion and exclusion criteria. Slightly more than half the cohort received statin therapy at baseline.

Baseline differences between statin users and nonusers followed expected patterns. Statin recipients, 7,140 people in the cohort, had a mean age of 70 years compared with 54 years among 6,534 nonusers.

During follow-up (median 71.6 months), 1,819 participants (13%) developed incident type 2 diabetes, 1,424 (20%) statin-treated participants compared with 395 (6%) nonusers.

Observable correlations

Each 10 mg/dl higher LDL-C was associated with a 10% lower hazard of diabetes (adjusted HR 0.90), so that lower LDL-C corresponded to higher risk. Incidence rates across LDL-C quartiles were 27.6, 17.4, 13.5, and 8.4 cases per 1,000 person-years in the low (

Statin therapy was associated with greater diabetes risk in every LDL-C category (1.75 in the low group, 1.63 in the medium group, 1.54 in the high group). The largest relative increase was seen in those starting at very high, with an adjusted hazard ratio of 2.41.

Researchers conclude that statin use increases diabetes risk within every LDL category and shows its greatest relative impact among individuals starting from very high LDL-C levels.

Still, the overall picture links low LDL values to greater diabetes risk, with lower LDL-C levels coinciding with higher diabetes incidence, largely independent of statin use, while LDL-C at or above 131 mg/dl coincided with the lowest observed risk.

More information:
Maria Lembo et al, A six-year longitudinal study identifies a statin-independent association between low LDL-cholesterol and risk of type 2 diabetes, Cardiovascular Diabetology (2025). DOI: 10.1186/s12933-025-02964-6