Genetic High Cholesterol Condition Poses Diabetes Risk

A new review found that a genetic condition that puts people at a risk for high cholesterol is not protective against type 2 diabetes (T2D), despite previous studies suggesting the opposite.

Data from the European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (EAS FHSC) registry indicate that most individuals with heterozygous familial hypercholesterolemia are at a risk for T2D. Risk was highest in those who have overweight or obesity, used statins, and were older, said the authors, whose work was published in The Lancet Diabetes & Endocrinology.

That is similar to the risk factors for T2D in the general population, wrote the authors, all of whom were members of the EAS FHSC.

To manage that risk, it is essential to identify individuals with the condition early and to prescribe statins as soon as possible, wrote the authors. In addition, “helping patients to maintain control of lifestyle factors related to obesity might help to avoid the development of type 2 diabetes in those at already substantially elevated risk of atherosclerotic cardiovascular disease,” they wrote.

Heterozygous familial hypercholesterolemia is a common autosomal dominant condition that causes reduced clearance of low-density lipoprotein (LDL) cholesterol, leading to a higher risk for atherosclerotic cardiovascular disease (CVD). About 1 in 311 people worldwide have the condition, according to the EAS authors.

Previous studies in the Netherlands, Spain, and Canada suggested that having the genetic condition might protect against T2D.

To assess this, the authors examined registry data for 46,683 adults from 44 countries, of whom 24,784 had heterozygous familial hypercholesterolemia. Overall, 5.7% of the 24,784 adults had T2D.

The authors found that the incidence of T2D was highest in individuals from the Eastern Mediterranean (at almost 30.0%), Southeast Asia and Western Pacific (12.0%), and the Americas (8.5%).

The incidence of T2D in individuals with heterozygous familial hypercholesterolemia was lowest in the Netherlands at 3.2%, but the protective effect of the genetic condition might have been misunderstood, according to the authors.

A long-standing two-decade-long screening program in that country identified many non-index cases, most of which were younger, with lower LDL cholesterol and lower prevalence of atherosclerotic CVD, wrote the authors. “This finding suggests that lifestyle factors could have been addressed early in life in the Netherlands, hence the low prevalence of type 2 diabetes, rather than a true effect of heterozygous familial hypercholesterolemia protection,” they wrote.

The authors found the risk for T2D was higher with obesity than with statin use. But statins should not be discontinued, wrote the authors. The decrease in the risk for CVD with statins outweighed the risk for T2D in both the general population and those with heterozygous familial hypercholesterolemia, they wrote.

‘Welcomed Insights’

In an editorial accompanying the study, Marina Cuchel, MD, PhD, and Archna Bajaj, MD, of the Division of Translational Medicine and Human Genetics at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, wrote that the study “provides welcomed insights.”

The idea that the genetic condition is “protective against statin-induced type 2 diabetes has persisted” despite questions as to whether the earlier cohort studies showing such an effect could be replicated across broad patient groups, they wrote.

The study had limitations, including unequal numbers of people enrolled from each nation and region of the world, noted Cuchel and Bajaj.

However, they wrote that the study had important clinical implications. “The small, dose-dependent risk of type 2 diabetes associated with statin use was minor when compared with the risk associated with obesity,” they wrote.

Clinicians should manage not just LDL but also T2D risk, they said.

And given that statins may be too expensive for some populations, there should be a renewed focus on the early diagnosis of heterozygous familial hypercholesterolemia, wrote Cuchel and Bajaj.

The EAS FHSC was funded by investigator-initiated research grants to Imperial College London from Pfizer, Amgen, MSD, Sanofi-Aventis, Daiichi Sankyo, and Regeneron. Disclosures for the authors are listed with the original article. Cuchel declared receiving grant support for clinical trials on homozygous familial hypercholesterolemia from Regeneron Pharmaceuticals and Regenxbio and consulting and lecture fees from Ultragenyx and Chiesi. Bajaj declared receiving grant support for clinical trials on lipoprotein(a) and other forms of dyslipidemia from Alexion, Amgen, Eli Lilly, Ionis, Kaneka Medical, NewAmsterdam Pharma, Novartis, and Regeneron and consulting and lecture fees from Kaneka Medical, Ionis, Novartis, and Regeneron.

Alicia Ault is a Saint Petersburg, Florida-based freelance journalist whose work has appeared in publications including JAMA and Smithsonian.com. You can find her on X: @aliciaault.