Trikafta Boosts Glucose Tolerance in CF Adults in Small Study

Early treatment could have ability to prevent CF-related diabetes

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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At least three months of using the triple combination therapy Trikafta (elexacaftor/tezacaftor/ivacaftor) significantly increased glucose tolerance — reflecting better control of blood sugar levels — in adults with cystic fibrosis (CF), a small study found.

Production of insulin, the hormone that helps clear glucose from the bloodstream, wasn’t affected.

Researchers noted that impaired control of blood glucose — or blood sugar — levels is a hallmark feature of CF-related diabetes (CFRD). The findings suggest that if started soon enough, an ability to prevent CFRD may be among Trikafta’s benefits in CF.

“Early initiation of treatment as assessed through long-term prospective trials is mandatory to demonstrate if decreased glucose control is preventable or even reversible,” the team wrote.

The study, “Improved glucose tolerance after initiation of Elexacaftor / Tezacaftor / Ivacaftor in adults with cystic fibrosis,” was published in the Journal of Cystic Fibrosis

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Poor glucose tolerance tied to CFRD in patients

The buildup of thick, sticky mucus that characterizes CF can affect insulin production in the pancreas, which plays a role in digestion. Insulin is a hormone that prompts cells to absorb glucose — the main type of sugar in the blood — in the bloodstream as a source of energy. Patients also may develop insulin resistance, in which the body’s cells don’t respond properly to insulin.

Consequently, blood sugar levels are too high, also known as hyperglycemia or glucose intolerance. Abnormal glucose tolerance, even before a CF-related diabetes (CFRD) diagnosis, can be a major contributor to nutritional problems and lung function declines for CF patients.

Thus, it is an important target for CF therapies, according to the researchers.

Trikafta, the approved triple combo CFTR modulator therapy from Vertex Pharmaceuticals, has demonstrated a number of benefits for eligible CF patients, including improvements in lung function and nutritional status and gains in life quality.

While one previous study found that Trikafta led to increases in insulin secretion, it did not show consistent improvements in glucose tolerance among CF patients. As such, the potential relationship between Trikafta and CFRD has not been well-established.

To learn more, researchers in Switzerland now examined glucose tolerance before and after starting Trikafta treatment among 33 adult CF patients. All were seen at the team’s clinic between December 2019 and November 2021.

The 24 men and nine women in the study each had at at least one copy of F508del, the most common CF-causing mutation, and all had established pancreatic insufficiency. The patients’ mean age was 27.8.

Glucose tolerance was evaluated with an oral glucose tolerance test (OGTT) before starting treatment and again after at least three months — a median of 184 days — on Trikafta.

Essentially, this test monitors blood sugar levels on a time course after a person drinks a very sugary drink. The two-hour test is performed after the patient has fasted for at least eight hours.

Based on the findings, patients are classified as having normal glucose tolerance, indeterminate tolerance, glucose intolerance, or CFRD.

The results showed that patients’ glucose levels throughout the two hour test were significantly lower during the OGTT taken at least three months after starting Trikafta compared with the test taken before treatment.

In other words, glucose tolerance was significantly improved with Trikafta use.

A total of 16 patients (48.5%) saw an improvement in their glucose tolerance category (for example, impaired glucose tolerance, CFRD or indeterminate tolerance to normal) after at least three months of Trikafta. In contrast, four participants showed a deterioration of glucose tolerance.

Further results from an HbA1C test, which assesses a person’s average blood sugar levels over the previous 2–3 months, also indicated significant declines in blood sugar with Trikafta.

Treatment with the triple CFTR modulator [Trikafta] was associated with possible improvement of glucose tolerance without increases of insulin secretion.

In contrast to the prior study, no signs of increased insulin secretion were observed and no changes in the body’s sensitivity to insulin occurred.

Lung function also was significantly improved with treatment, and sweat chloride levels among patients were reduced. A sweat test, which measures the amount of salt in a person’s sweat, is considered the gold standard for diagnosing cystic fibrosis.

Healthy body weight increases also were observed, while levels of inflammatory markers were significantly decreased.

The findings overall indicate that “treatment with the triple CFTR modulator [Trikafta] was associated with possible improvement of glucose tolerance without increases of insulin secretion,” the team wrote.

Due to the small sample size from this single study site, “these results need to be interpreted with caution,” the researchers noted, adding that “longer studies are needed to determine if this improvement of OGTT is long lasting.”

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