Risk of cardiovascular disease may rise for adults using Kaftrio/Trikafta
Changes seen in blood levels of fat-like molecules with 6 months of treatment
In adults with cystic fibrosis (CF), six of months treatment with Kaftrio (elexacaftor/tezacaftor/ivacaftor) led to lower levels of biomarkers of inflammation, but higher blood levels of fat-like molecules considered to be cardiovascular risk factors, according to a recent study in Italy.
While highly effective, the triple-combination therapy — available in the U.S. and Canada under the brand name Trikafta — highlights “the need for increased attention to potential long-term health issues,” its investigators wrote.
“This study paves the way for a deeper understanding of the complex interactions between inflammation, metabolic status and cardiovascular health in [adults with CF] after [Kaftrio] initiation,” they added.
The study, “Cardiometabolic risk factors in adults with cystic fibrosis undergoing elexacaftor/tezacaftor/ivacaftor therapy,” was published in the Journal of Cystic Fibrosis.
Study into cardiometabolic risks with Kaftrio (Trikafta) use
CF is caused by mutations in the CFTR gene that lead to dysfunctional or missing CFTR, a protein that normally helps regulate the flow of salt and water in and out of cells. As a result, thick and sticky mucus accumulates in the lungs and other organs, driving most disease symptoms.
Kaftrio has contributed to a better life expectancy in people with CF. But while its effects on CFTR reduce bodywide inflammation, a known risk factor for cardiovascular disease, the therapy’s use might also raise a person’s cholesterol and triglyceride levels, and lead to high blood pressure and to diabetes through a poorer response to insulin, the scientists noted.
“Given the increasing prevalence of cardiovascular diseases in the ageing population and the presence of cardiovascular risk factors associated with CF, understanding the impact of [Kaftrio] on cardiometabolic risk factors is a crucial clinical concern,” they wrote.
To explore early changes in cardiac and metabolic biomarkers, researchers at a CF center in Milan, Italy, collected data on 58 adults with CF being treated with Kaftrio. Most were men (62.1%), with a median age of 41. More than half (55.2%) had pancreatic insufficiency — when mucus blocks the release of enzymes needed to properly digest food, particularly fats — and 25.9% had CF-related diabetes. Another 10.6% were underweight, defined as having a body mass index (BMI, a measure of body fat based on height and weight) less than 18.5 kg/square meters (kg/m2).
After six months of treatment, patients experienced a median increase of 2 kg (about 4.4 pounds) and of 0.7 kg/m2 in BMI, compared to pretreatment weight and body fat.
Higher blood levels of cholesterol and triglycerides seen with treatment
Blood levels of cardiac and metabolic biomarkers, namely cholesterol, triglycerides (the most common type of fat, or lipid, in the body), apolipoprotein-B, and adipokines (leptin and adiponectin) also rose. Blood sugar levels and those of insulin remained unchanged.
Apolipoprotein-B is a type of protein that helps to assess the risk of heart and blood vessel disease; adipokines are proteins with multiple functions, including energy expenditure, insulin sensitivity and secretion, and fat distribution.
Results also showed a significant decrease in the levels of high-sensitivity C-reactive protein and a nonsignificant reduction in the levels of interleukin-6 (IL-6). Both C-reactive protein and interleukin-6 are markers of inflammation.
A lifetime risk of cardiovascular events then was calculated for patients 35 and older, using a tool provided by the European Society of Cardiology. Results indicated a significantly higher risk after six months of treatment.
The calculated score “aligns well with the clinical characteristics of [adults with CF], allowing for risk assessment in young populations with no history of cardiovascular disease,” the scientists wrote.
Before starting treatment, a higher BMI correlated with changes in the levels of adiponectin, HDL cholesterol (known as “good” cholesterol), and total cholesterol, among other markers.
With six months of treatment, a higher BMI associated with higher levels of leptin and lower levels of IL-6. The effect on both leptin and adiponectin suggests a disruption in the normal mechanisms that regulate these hormones, which may result in metabolic imbalances and increase the risk for obesity and cardiovascular events, the researchers noted.
Regular monitoring of fatty molecules and efforts to control body weight and blood pressure may allow patients, working with their healthcare teams, to balance the benefits of better nutritional status with cardiovascular risks, they added.
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