Large Naples study finds lower LDL cholesterol linked to higher diabetes risk, independent of statins
A major study from the Department of Advanced Biomedical Sciences at Federico II University in Naples has found that lower plasma LDL cholesterol is linked to a higher risk of developing type 2 diabetes, even when statin use is taken into account. The findings add new clarity to a long-running debate over whether LDL cholesterol itself influences diabetes risk or whether the increase is driven mainly by statin treatment.
For years, clinicians have observed a pattern in which people taking statins appear more likely to receive a diagnosis of type 2 diabetes. This effect has been shown to rise in line with dosage, but the biological reason has remained uncertain. Genetic studies have added further complexity by indicating that people who carry LDL-lowering alleles in the HMGCR and NPC1L1 genes are more likely to develop diabetes. These observations have suggested that cholesterol lowering through several biological pathways may share a connection with rising diabetes risk.
In contrast, people with familial hypercholesterolaemia provide an opposing pattern. The condition is marked by very high LDL cholesterol and a well-known increase in the risk of coronary artery disease. Yet individuals with familial hypercholesterolaemia appear less likely to develop type 2 diabetes. The contrast between high LDL cholesterol with lower diabetes rates and low LDL cholesterol with higher rates has prompted questions about the underlying biology and whether statins simply accelerate a broader relationship.
Previous large-scale analyses have also suggested that LDL-related genetic factors and type 2 diabetes risk move in opposing directions. Genetic work involving HMGCR, PCSK9 and NPC1L1 genes has indicated that proxies for HMGCR inhibition are associated with lower blood pressure and higher fasting glucose, while genetic inhibition of PCSK9 and NPC1L1 showed no similar influence on those measures.
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The Naples study sought to examine how plasma LDL cholesterol levels measured in routine primary care relate to new onset type 2 diabetes over several years and to separate the influence of statin therapy from the influence of LDL cholesterol itself. The research is published in Cardiovascular Diabetology under the title A six-year longitudinal study identifies a statin-independent association between low LDL cholesterol and risk of type 2 diabetes.
A group of 140 general practitioners contributed data from a shared electronic medical record system that documents diagnoses, prescriptions, hospital admissions, emergency treatments, laboratory findings, vital signs and deaths. More than 200,000 adults are recorded in the system, and the final study cohort included 13,674 adults aged between 19 and 90 years after all inclusion and exclusion criteria were applied. Slightly more than half of these patients were using statins at baseline.
As expected, statin users differed from nonusers at the start of the study. The 7,140 participants taking statins had a mean age of 70 years, compared with 54 years in the 6,534 participants not receiving statin therapy. During a median follow-up of 71.6 months, 1,819 people, representing 13 per cent of the cohort, developed type 2 diabetes. Among these, 1,424 were taking statins, and 395 were not.
The analysis showed a clear relationship between LDL cholesterol levels and diabetes incidence. Every 10 milligrams per decilitre increase in LDL cholesterol was associated with a 10 per cent lower hazard of developing diabetes. Incidence rates across LDL cholesterol quartiles demonstrated the same pattern, with the lowest LDL cholesterol group experiencing the highest diabetes incidence and the highest LDL cholesterol group experiencing the lowest incidence.
Statin therapy increased diabetes risk within every LDL cholesterol category. The relative increase was most pronounced in individuals whose LDL cholesterol was at the very high end of the spectrum, with an adjusted hazard ratio of 2.41. Even so the overall pattern demonstrated that lower LDL cholesterol itself coincided with higher diabetes risk, largely independent of statin therapy.
Researchers concluded that statins increase diabetes risk consistently, but that lower LDL cholesterol appears to carry an intrinsic association with higher diabetes incidence. LDL cholesterol at or above 131 milligrams per decilitre corresponded to the lowest observed diabetes risk in the population studied.