Obesity increases risk of T2D in patients with HeFH

In a global cross-sectional study among adult patients with heterozygous familial hypercholesterolemia (HeFH), the overall risk of T2D was primarily increased with obesity, but also with advancing age or statin use.

This summary is based on the publication of European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration - Association of BMI, lipid-lowering medication, and age with prevalence of type 2 diabetes in adults with heterozygous familial hypercholesterolaemia: a worldwide cross-sectional study. Lancet Diabetes Endocrinol. 2024 Nov;12(11):811-823. doi: 10.1016/S2213-8587(24)00221-3

Introduction and methods

Background

In the general population, statin therapy is associated with increased risk of T2D, possibly due to increased LDL uptake via the LDL receptor resulting in pancreatic lipotoxicity. However, several cohort studies have reported low T2D prevalence in patients with heterozygous familial hypercholesterolemia (HeFH) [1-3], who are commonly treated with statins. This suggests these patients may be protected from T2D.

Aim of the study

The study aim was to investigate the associations of known key determinants of T2D, including statin use and BMI, with its prevalence in patients with HeFH.

Methods

In a cross-sectional study, individual-level data from 24,784 adults >18 years with a clinical and/or genetic diagnosis of HeFH from 44 countries were extracted from the European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration registry. Patients with known or suspected homozygous FH or T1D were excluded. Of the included participants, 19,818 (80%) had a genetically confirmed diagnosis of HeFH.

Outcomes

The main endpoint was the prevalence of T2D overall and by WHO region, and in relation to obesity (BMI ≥30.0 kg/m²) and lipid-lowering medication as predictors.

Main results

•  In the entire study population, the prevalence of T2D was 5.7% (1415/24,784). In the cohort with a genetic diagnosis, it was 4.1% (817/19,818).
• A lower T2D prevalence was observed in the Netherlands (3.2%) and the rest of Europe (8.0%), whereas the Eastern Mediterranean Region (29.9%), South-East Asia and Western Pacific Regions (12.0%), and the Americas (8.5%) exhibited higher prevalences.
• In a multivariable logistic regression model adjusted for age, sex, and lipid-lowering medication, the risk of T2D was higher in patients with overweight (OR: 1.67; 95%CI: 1.44–1.93; P<0.0001) and those with obesity (OR: 4.78; 95%CI: 4.14–5.53; P<0.0001) compared with participants with a healthy body weight (BMI 18.5–24.9 kg/m²).
• Other factors independently associated with a higher T2D risk were advancing age and use of lipid-lowering medication.
• When the study population was split into 12 risk categories (based on age tertiles, presence or absence of obesity, and statin use), the probability of developing T2D was most increased in patients in the highest risk category (age 55–98 years, obesity, receiving statin therapy) compared with the reference group (age 18–38 years, no obesity, no statin therapy) (OR: 74.42; 95%CI: 47.04–117.73).
• Patients in the upper age tertile who were taking statins but did not have obesity had a lower T2D risk relative to the reference group (OR: 24.42; 95%CI: 15.57–38.31).
• Among patients in the genetically diagnosed cohort, the OR in the highest risk category was 65.04 (95%CI: 40.67–104.02) for those with obesity and 20.07 (95%CI: 12.73–31.65) for those with no obesity.

Conclusion

In this large, worldwide cross-sectional study among adult patients with HeFH, the prevalence of T2D was 6% but varied greatly across WHO regions, with the highest prevalence in the Eastern Mediterranean and South-East Asia and Western Pacific Regions and the lowest in Europe. The overall risk of T2D was primarily increased with obesity, but also with advancing age or statin use. Based on reported prevalence rates in the general population, the authors conclude HeFH does not seem to protect against the development of T2D. “Our observations underscore that although statins might increase the risk of diabetes, this effect is trivial compared with the risk seen in people who are obese.”

Find this article online at Lancet Diabetes Endocrinol.

References

1. Besseling J, Kastelein JJ, Defesche JC, Hutten BA, Hovingh GK. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA 2015; 313: 1029–36.
2. Fuentes F, Alcala-Diaz JF, Watts GF, et al. Statins do not increase the risk of developing type 2 diabetes in familial hypercholesterolemia: The SAFEHEART study. Int J Cardiol 2015; 201: 79–84.
3. Brunham LR, Cermakova L, Lee T, et al. Contemporary trends in the management and outcomes of patients with familial hypercholesterolemia in Canada: a prospective observational study. Can J Cardiol 2017; 33: 385–92.