Drop in blood sugar levels seen within months of starting Kaftrio
But for CF patients with diabetes, need for insulin goes unchanged
Blood levels of an indicator of diabetes, glycated hemoglobin (HbA1c), fell within the first year that cystic fibrosis (CF) patients were treated with Kaftrio, the triple combination therapy marketed as Trikafta in North America, according to a study of patients in Denmark.
But among those with CF-related diabetes (CFRD), no changes were seen with Kaftrio in the use of insulin — the hormone that helps cells obtain glucose from the blood — and in blood glucose levels. Glycated hemoglobin measures the average level of blood sugar or glucose, which sticks to hemoglobin in red blood cells, over two to three months.
This finding “indicates that the change in HbA1c after [Kaftrio] initiation might be independent of blood glucose levels,” the researchers wrote.
The study, “Decline in HbA1c during the first year of elexacaftor/tezacaftor/ivacaftor treatment in the Danish cystic fibrosis cohort, ” was published in the Journal of Cystic Fibrosis.
Diabetes common with CF, due to damage to pancreas and insulin production
CF is caused by mutations in the gene coding for the CFTR protein, which regulates the flow of chloride ions across the cell membrane. These mutations result in the accumulation of thick and sticky mucus in various organs, particularly the lungs and pancreas.
Up to half of all CF patients develop CFRD, due to damage to the pancreas that leads to insufficient insulin production. People with CF also are often insulin resistant, meaning their cells don’t respond normally to insulin.
CFRD is associated with a higher frequency of pulmonary exacerbations, or periods of acute symptom worsening, and poorer lung function. It has been suggested that this treatment may improve pancreatic function, allowing for better glucose metabolism by cells.
Kaftrio/Trikafta is a combination of three CFTR modulators (elexacaftor/tezacaftor/ivacaftor) that bind to the defective CFTR and promote its functionality. Whether the therapy helps to address patients’ CFRD and diabetes risk, the researchers noted, could be determined through continuous glucose monitoring to detect changes with treatment in glucose metabolism.
“The use of insulin could potentially also be influenced by [Kaftrio] but, to our knowledge, no previous studies have so far addressed this question,” they wrote.
Scientists with CF centers in Copenhagen and Aarhus analyzed changes in HbA1c and CFRD in 321 adolescents and adults, all followed at those centers, across a first year of Kaftrio treatment. Data was collected from January 2019 through December 2022.
Participants’ median age was 27 (study’s range, 12 to 80 years old), and 51% were male. The majority (75%) had F508del mutations in both CFTR gene copies, and pancreatic insufficiency was reported in 96% of the entire group. Around one-third (34%) had CFRD, and 13% had anemia, as indicated by low levels of hemoglobin, the protein in red blood cells that carries oxygen.
Most patients, 63%, had been treated with other CFTR modulators before starting on Kaftrio, and slightly more than one-quarter (27%) were using insulin therapy.
Lower HbA1c blood levels don’t lead to lesser dependence on insulin
All were evaluated for HbA1c levels before Kaftrio treatment started (baseline), and again at three, six, nine months, and 12 months later. The median time between baseline and Kaftrio initiation was seven days.
HbA1c levels across patients declined by 2.1 mmol/mol at three months and by 2.3 mmol/mol at one year of treatment, showing an initial drop and then stability. This effect was independent of a patient’s age, sex, glucose tolerance — typically measured by evaluating how well the body processes sugar within a few hours of it being ingested — or previous CFTR modulator use or nonuse.
The decrease in overall HbA1c levels also did not differ when adjusting for hemoglobin, or between patients with or without anemia. The study noted the iron deficiency that is common with anemia can falsely increase HbA1c levels.
Among the 26 people who entered the study with insulin-dependent CFRD (median age, 38), the mean decline in HbA1c levels at one year was 3.6 mmol/mol. However, no differences with Kaftrio treatment were seen in self-reported insulin use, the number of symptomatic events due to low blood glucose levels, or in continuously monitored glucose levels (available for 15 patients).
“This might suggest that the decline in HbA1c cannot solely be explained by an improvement in glucose metabolism,” the scientists wrote.
While study findings “align with previous studies suggesting a decline in HbA1″ with the triple combination therapy, “the implications of a decline in HbA1c remains to be elucidated,” the researchers concluded, “and only continuous follow-up will show potential beneficial long-term effects of [Kaftrio/Trikafta] on complications in CFRD.”
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