Trikafta Found to Improve Insulin Secretion, Body Weight in CF

But therapy did not lead to consistent improvement in CF-related diabetes

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by Steve Bryson, PhD |

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Treatment with Trikafta improved insulin secretion and body weight within one year in people with cystic fibrosis (CF), according to a small analysis.

Despite these findings, there were no consistent treatment-related improvements in measures relating to CF-related diabetes, or CFRD, a common complication among children and adults with CF.

“This is the first report, to our knowledge, examining measures of insulin secretion and resistance in pediatric and adult patients, before and after initiation of the highly effective CFTR modulator [Trikafta],” the researchers wrote.

The team added that while such CFTR modulator therapies “hold promise for improving insulin secretion, an alternate narrative is that rising BMIs [body-mass index scores] may lead to insulin resistance,” and an increased demand on cells, that ultimately result in outcomes such as diabetes.

The new data highlight the need for future studies investigating the effects of treatments like Trikafta on weight gain and changes in insulin sensitivity and secretion over time, they noted. Such future findings could inform treatment strategies.

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Investigating insulin secretion, body weight with Trikafta

Published in the Journal of Clinical & Translational Endocrinology, the study was titled “Glycemia and β-cell function before and after elexacaftor/tezacaftor/ivacaftor in youth and adults with cystic fibrosis.”

In addition to well-known lung symptoms associated with CF, up to 20% of adolescents and nearly half of affected adults will develop CFRD. Diabetes occurs when glucose levels in the blood become too high.

The thick mucus in CF leads to insufficient release of insulin from the pancreas, which contains the glands that control blood sugar. Insulin is the hormone that stimulates glucose uptake into cells.

Trikafta is an approved CF therapy containing three oral medications: elexacaftor, tezacaftor, and ivacaftor. Known as a CFTR modulator, the combination medicine helps correct defects in the production and function of CFTR protein, the underlying cause of CF.

Although Trikafta’s ability to improve lung function and other CF signs is well-established, its effects on insulin secretion in CF are still unknown.

To find out, the team analyzed data from participants in the EnVision CF Multicenter Study of Glucose Tolerance (NCT03650712), an examination in four CF centers of insulin and blood glucose levels in more than 400 children and adults with CF.

Participants undergo frequent oral glucose tolerance tests (OGTT) to measure the body’s response to glucose, which can reflect resistance to insulin or responsiveness, called insulin sensitivity.

During an OGTT, blood samples are withdrawn regularly after consuming glucose (dextrose) under fasting conditions, which involves no food for at least eight hours. Based on the resulting blood glucose levels over time, participants are classified as having normal glucose tolerance, abnormal glucose tolerance, or CFRD.

This analysis focused on 20 CF patients whose OGTTs were performed before and within a year of Trikafta initiation. The ages of the selected participants ranged from 11.3 to 58.9 years, and 75% were male. Nearly all (90%) were pancreatic insufficient. Just over half — 11 individuals or 55 % — had been on a different CFTR modulator before Trikafta.

Compared with before Trikafta, five patients demonstrated improvement in glucose tolerance after starting the combo medication. This means they had a shift from CFRD to abnormal glucose tolerance or from abnormal glucose tolerance to normal glucose tolerance. However, six individuals worsened, and nine had no change in glucose tolerance.

Overall, body weight and body fat content, as measured by body mass index (BMI), increased significantly after starting Trikafta. Lung function also significantly improved. Fasting blood glucose levels, as well as those taken one- and two-hours after dextrose ingestion, did not significantly change with Trikafta, nor did glucose levels in the blood over time.

Insulin secretion significantly increased with Trikafta, as indicated by the C-peptide index — the ratio of C-peptide to glucose levels in the blood, which is used to evaluate the function of cells in the pancreas that produce and secrete insulin, called beta cells.

Insulin resistance increased while insulin sensitivity (response) with treatment. Overall, beta cell function accounting for insulin sensitivity did not change.

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Investigating the impact of age

Because younger people can experience short-lived drops in insulin sensitivity during puberty, the team examined eight youths — patients ages 18 and younger — and 12 adults separately. In both groups, weight increased with Trikafta, but only adults saw a significant BMI increase. Likewise, all patients showed a decrease in insulin sensitivity with treatment, but only adults’ C-peptide index increased.

Among the 11 participants who had previously received a different CFTR modulator, Trikafta further improved lung function and increased body weight, insulin secretion, and insulin resistance.

Statistical calculations based on these data found a change in body weight correlated significantly with a change in the C-peptide index for insulin secretion but not with changes in fasting C-peptide, insulin resistance, or other measures of insulin secretion or sensitivity.

Trikafta also led to a significant decrease in median HbA1c levels, from 5.5 to 5.4%, which reflects the average blood glucose level over the prior 2–3 months. No significant differences were detected in continuous glucose monitoring data collected from a subset of nine patients, although there were trends toward lower glucose levels after treatment.

“Taken together, results from studies to date, including the findings from this report, suggest heterogeneity [variability] in glycemic response to CFTR modulators, with modest improvements at best in short term [beta]-cell function in response to highly-effective modulator therapies,” the researchers wrote. “No consistent improvements in glycemic measures have been seen across studies.”

“The variability in outcomes reported may relate to differences in age groups studied,” the researchers added. “Our findings highlight the need for future studies to better understand the effects of CFTR modulator-related weight gain, and anticipated changes in insulin sensitivity and secretion over time, to inform treatment and management strategies in the CFTR modulator era.”

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