CFTR modulators effective at lowering insulin needs in CFRD

Treatment wasn't tied to blood sugar alterations in patients without diabetes

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Being treated with Kaftrio or Symveki led to a reduced need for insulin in people with cystic fibrosis-related diabetes (CFRD), a small study found.

The treatment wasn’t associated with alterations in blood sugar and associated factors in CF patients without diabetes.

The findings add to a growing and increasingly complex body of studies that seek to understand how combined CFTR modulator therapies might influence CFRD, the researchers said in “Combined CFTR modulator therapies are linked with anabolic benefits and insulin-sparing in cystic fibrosis-related diabetes,” which was published in the Journal of Clinical & Translational Endocrinology.

CFRD is one of the most common CF symptoms outside the lungs and is linked to worse lung function and a risk of severe outcomes. Like other forms of diabetes, it’s marked by high blood sugar, or glucose intolerance, but the mechanisms that bring it about are unique.

Particularly, the thick, sticky mucus that builds up in CF damages the pancreas, leading to the insufficient production of the hormone insulin, which helps absorb glucose from the bloodstream. Patients are also often insulin-resistant, meaning they don’t respond normally to it. Dysfunction of pancreatic beta cells have been implicated in this process.

Patients are usually treated with insulin injections to keep blood sugar levels in check.

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Exploring CFTR modulators’ effect on CFRD-related insulin needs

The emergence of combined CFTR modulator therapies such as Trikafta (elexacaftor/tezacaftor/ivacaftor), Symdeko (tezacaftor/ivacaftor), or Orkambi (ivacaftor/lumacaftor) has dramatically changed the treatment landscape for CF, leading to substantial improvements in lung function and a better prognosis for many patients. Trikafta is sold in Europe under the name Kaftrio.

These therapies’ effects on CFRD are still being investigated and studies have yielded conflicting results, leading researchers here to see how CFTR modulator therapies affect CFRD patients’ need for insulin treatment.

To evaluate this, the researchers retrospectively analyzed clinical data from 17 CFRD patients (12 men, five women) who were started on Kaftrio or Symveki at a clinic in Belgium. The patients had been living with diabetes for an average of 15 years, with insulin treatment having begun immediately after their diagnosis.

Thirteen patients received Symveki, but nine were later switched to Kaftrio. Four were only given Kaftrio. The median treatment time was 16 months, but all the patients were treated for at least a month.

Overall, 15 of the 17 patients (88%) required less insulin with CFTR modulators than they previously needed. Usage declined significantly from an average 50 units a day to 44 units.

Insulin requirements decreased for two patients who’d only been using a CFTR modulator for a month.

The patients’ blood sugar levels also tended to decrease with treatment, but this finding was not statistically significant. Some patients reported improvements in appetite and physical activity.

“These results could indicate, in line with recent literature, a potential benefit of new generation CFTR modulators in CF patients with diabetes,” the researchers wrote, noting the improvements in insulin sensitivity could be secondary to increased physical activity.

CFTR modulator effects on blood sugar

To learn more about CFTR modulators’ effects on blood sugar, the researchers examined data from 15 adult CF patients without CFRD treated with the modulators at their clinic.

These patients (10 men, five women) had a median age of 22 and three had impaired glucose tolerance, meaning their blood sugar levels were elevated, but not high enough to be considered diabetes. All but one patient was on Symveki, and the mean treatment time was 10 months.

A mathematical model called the Homeostasis Model Assessment (HOMA) was used to estimate their sensitivity to insulin as well as their beta cell function before and after starting the CFTR modulator.

In general, their blood sugar levels were stable over time and those with impaired glucose tolerance tended to remain stable, except for one person who became glucose intolerant. Neither insulin sensitivity nor beta cell function were significantly altered by CFTR modulator treatment, the HOMA analysis indicated.

Patients in both the CFRD and non-CFRD groups saw significant body mass index increases and lung function improvements on the therapy.

The researchers said the patients’ age could significantly influence both CF and diabetes, but subgroup analyses by age couldn’t be performed due to the small sample size, which might have also blunted their ability to see significant effects of modulator therapy in the non-CFRD group.

“Further data collection and prospective analyses are needed for in-depth assessment of the benefits of CFTR modulators on glucose homeostasis in CF patients,” they said.