Overweight in Heterozygous FH Tied to Even Higher CAD Risk

MANNHEIM, Germany — Contrary to expectations, individuals with familial hypercholesterolemia (FH) have rates of overweight and obesity that mirror the general population ― rates that appear to have a substantial impact on these patients’ already increased risk of coronary artery disease, a registry analysis suggests.

Data on almost 36,000 individuals with FH were collated from an international registry, revealing that 55% of adults and 25% of children and adolescents with the homozygous form of FH had overweight or obesity. The figures for heterozygous FH were 52% and 27%, respectively.

Crucially, overweight or obesity was associated with substantially increased rates of coronary artery disease, particularly in persons with heterozygous FH, among whom adults with obesity faced a twofold increased risk, rising to more than sixfold in children and adolescents.

Moreover, “obesity is associated with a worse lipid profile, even from childhood, regardless of whether a patient is on medication,” said study presenter Amany Elshorbagy, DPhil, Cardiovascular Epidemiologist, Department of Primary Care and Public Health, Imperial College London, London, United Kingdom.

She added that, with the increased risk of coronary artery disease associated with heterozygous FH, the results showed that “together with lipid-lowering medication, weight management is needed.”

The research was presented at the European Atherosclerosis Society (EAS) 2023 on May 23.

Tended to Be Thin

Alberico L. Catapano, MD, PhD, director of cardiovascular research and of the Lipoproteins and Atherosclerosis Laboratory of IRCCS Multimedica, Milan, Italy, and past president of the EAS, told theheart.org | Medscape Cardiology that, historically, few FH patients were overweight or obese; rather, they tended to be thin.

However, there is now “a trend for people with FH to show more diabetes and obesity,” with the “bottom line” being that, as they are already at increased risk of coronary artery disease, it pushes their risk up even further.

In other words, if a risk factor such as obesity is added “on top of the strongest risk factor, that is LDL cholesterol, it is not one plus one makes two, it is one plus one makes three,” he said.

As such, Catapano believes that the study is “very interesting,” because it further underlines the importance of weight management for individuals with increased LDL cholesterol, “especially when you have genetic forms, like FH.”

Catapano’s comments were echoed by session co-chair Ulrike Schatz, MD, leader of the Lipidology Specialty Department at the University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany.

Indeed, she told Elshorbagy before her presentation that she finds “a lot of my FH patients have a tendency towards anorexia.”

Speaking to theheart.org | Medscape Cardiology, Elshorbagy said that that reaction was typical of “most of the clinicians” she had spoken to. Upon seeing her data, especially for homozygous FH patients, they say, “They are on the lean side.”

Consequently, the research team went into the study “with the expectation that they might have a lower prevalence of obesity and overweight than the general population,” but “that’s not what we’re seeing.”

Elshorbagy noted that it would be helpful to have longitudinal data to determine whether, 50 years ago, patients with HF “were leaner, along with the rest of the population.”

The registry data are cross-sectional, and the team is now reaching out to the respective national lead investigators to submit follow-up data on their patients, with the aim of looking at changes in body weight and the impact on outcomes over time.

Another key question for the researchers is in regard to fat distribution, as body mass index (BMI), “is not the best predictor of heart disease,” Elshorbagy said, but is rather central obesity.

Although they have also asked investigators to share waist circumference data, she conceded that it is a measurement that “is a lot harder to standardize across centers and countries; it’s not like putting patients on a scale.”

Overall, Elshorbagy believes that her findings indicate that clinicians should take a broader, more holistic approach toward their patients ― in other words, an approach in which lipid lowering medication is “key but is just one of several things we need to do to make sure the coronary event rate goes down.”

More With Than Without

Elshorbagy began her presentation by highlighting that the prevalence of overweight and obesity ranges from 50% to 70% and that it is “the only health condition where you’ve got more people worldwide with the condition than without.”

Crucially, overweight increases the risk of coronary artery disease by approximately 20%. Among patients with obesity, the risk rises to 50%.

Given that FH patients “already have a very high risk of cardiovascular disease from their high cholesterol levels,” the team set out to determine rates of obesity and overweight in this population and their impact on coronary artery disease risk.

They used cross-sectional data from the EAS FH Studies Collaboration Global Registry, which involves 29,262 adults aged ≥18 years and 6275 children and adolescents aged 5 to 17 years with heterozygous FH, and 325 adults and 57 children with homozygous FH.

Dividing the adults into standard BMI categories, they found that 16% of heterozygous and 23% of homozygous FH patients had obesity, while 52% and 55%, respectively, had overweight or obese.

For children, the team used World Health Organization Z-score cutoffs, which indicated that 9% of patients with heterozygous FH and 7% of patients with homozygous FH had obesity. Rates of overweight or obesity were 27% and 25%, respectively.

Among patients with heterozygous FH, rates of overweight or obesity among adults were 50% in high-income countries and 63% in other countries; among children, the rates were and 27% and 29%, respectively.

Stratified by region, the team found that the lowest rate of overweight or obesity among adult patients with heterozygous FH was in Eastern Asia, at 27%, while the highest was in Northern Africa/Western Asia (the Middle East), at 82%.

In North America, 56% of adult patients had overweight or obesity. The prevalence of coronary artery disease rose with increasing BMI.

Among adult patients with heterozygous FH, 11.3% of those with normal weight had coronary artery disease; the percentage rose to 22.9% among those with overweight, and 30.9% among those with obesity. Among children, the corresponding figures were 0.1%, 0.2%, and 0.7%.

Putting adults and children with homozygous FH together, the researchers found that 29.0% of patients with normal weight had coronary artery disease, compared with 31.3% of those with overweight and 49.3% of those with obesity.

Moreover, the results showed that levels of LDL and remnant cholesterol were significantly associated with BMI in adults and children with heterozygous FH, even after adjusting for age, sex, and lipid-lowering medication (P < .001 for all).

Multivariate analysis that took into account age, sex, lipid-lowering medication, and LDL cholesterol revealed that having obesity compared to not having obesity was associated with a substantial increase in the risk of coronary artery disease among patients with heterozygous FH.

Among adults with the condition, the odds ratio was 2.16 (95% CI, 1.97 –2.36), while among children and adolescents, it was 6.87 (95% CI, 1.55 – 30.46).

The results remained similar after further adjustment for the presence of diabetes and when considering peripheral artery disease and stroke.

No funding for the study was declared. Elshorbagy has relationships with Amgen, Daii chi Sankyo, and Regeneron.

European Atherosclerosis Society (EAS) 2023: Abstract O135/81. Presented May 23, 2023.

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