Trikafta medication use linked to weight gain in CF-related diabetes

New study findings may lead to 'paradigm shift' in CFRD treatment: Scientists

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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The use of the approved medication Trikafta (elexacaftor/tezacaftor/ivacaftor) was shown to significantly increase weight in people with cystic fibrosis-related diabetes (CFRD) and a low body mass index, or BMI, a measure of body fat, in a new study.

The researchers say the study’s findings, which also showed that non-insulin therapies may be safe and effective for cystic fibrosis (CF) patients who also have diabetes, could change the standard of care in CFRD.

“Until now, insulin has been the only recommended treatment of CFRD. In our three-year study, physicians were able to use alternate, non-insulin anti-glycemic therapies without any significant side effects,” the team wrote.

This suggests a paradigm shift in the treatment of CFRD [CF-related diabetes] in patients who are also treated with CFTR modulators,” the researchers wrote.

Their study, “The changing landscape of treatment for cystic fibrosis related diabetes,” was published in the Journal of Clinical and Translational Endocrinology.

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About half of CF patients will develop disease-related diabetes

CF is caused by mutations in the gene that provides instruction for making the protein CFTR. Disrupted or no CFTR activity leads to the production of abnormally thick, sticky mucus, which drives most disease symptoms.

People with CF are at risk for malnutrition due to inadequate calorie intake, increased energy expenditure, and impaired absorption. Additionally, CF-related diabetes, or CFRD, affects approximately half of those with the disease.

Among the biological mechanisms underlying CFRD are damage to cells in the pancreas that produce insulin, a hormone that controls blood sugar levels, and the impaired pancreatic release of enzymes needed for digestion.

For many years, insulin therapies were the mainstay treatment for CFRD. In recent decades, however, many new treatments have become available for treating CF and its related conditions.

Trikafta (sold as Kaftrio in the European Union) contains a combination of three CFTR modulators, which are medications that help improve the functionality of the defective CFTR protein in people with specific CF-causing mutations. It was approved in the U.S. in 2019.

While Trikafta has been proven effective at improving lung function in CF patients with eligible mutations, there is scant data on its long-term efficacy in CFRD. That lack of evidence led scientists at Saint Louis University School of Medicine, in Missouri, to review the records of 27 people with CFRD taking Trikafta medication. The patients had a mean age of 30.6, and 25 were non-Hispanic white individuals.

All had pancreatic insufficiency with at least one F508del mutations in the CFTR gene. The analysis followed the patients for a mean of 2.7 years after they started on Trikafta.

Insulin was used by 18 patients. The remaining nine were on modified diets alone.

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Use of Trikafta medication linked to 11-pound gain in CFRD patients

The researchers divided patients according to their body mass index, known as BMI, which is a ratio of weight to height. A total of 15 patients had low BMI — mean 19.5 kg per square meter (kg/m2) — while 12 had a BMI within the target range (mean 26 kg/m2).

In the low BMI group, Trikafta was associated with a significant weight increase, specifically an average gain of 5 kg (11 pounds) after one year of treatment compared with baseline, or the study’s start. Weight gain was sustained after two years, increasing by a mean of 6.8 kg (about 15 pounds) after three years. This weight gain was accompanied by significant improvements in BMI.

Four patients in the low BMI group reached a normal BMI by the end of follow-up. In contrast, no change in weight or BMI was seen in the so-called at-target BMI group over the entire study duration.

In conclusion, we found that CFTR modulator therapy with [Trikafta] led to an increase in weight in adult CFRD patients with low BMI [body mass index], but not in those whose BMI was already at target.

These results were not linked with differences in the use of medications that lower glucose (sugar), the team noted.

Insulin has long been the only recommended treatment for CFRD, but five patients — three in the low BMI and two in the at-target group — received non-insulin therapies to lower blood sugar without any significant side effects. Non-insulin therapies included glucagon-like peptide 1 receptor agonists and metformin.

No increases in obesity or basal insulin requirements were noted during the study. Likewise, levels of HbA1c, a measure of blood sugar, remained unchanged in both groups. HbA1c levels reflect the amount of glucose attached to hemoglobin, the protein that carries oxygen in red blood cells.

Overall, according to the researchers, these findings showed that non-insulin anti-glycemic therapies could be used without significant side effects.

“In conclusion, we found that CFTR modulator therapy with [Trikafta] led to an increase in weight in adult CFRD patients with low BMI, but not in those whose BMI was already at target,” the team wrote.

“Therapy for CFRD may change to be more in line with that of type 2 diabetes,” the scientists further stated, adding that more research will be needed to “explore the cardiovascular and renal effects of non-insulin therapies … in the management of CFRD.”