GLP-1 Receptor Agonist Therapy in Cystic Fibrosis-Related Diabetes: A Case Report

To the Editor,

Cystic fibrosis (CF) is a multisystem disease caused by mutations in the CF transmembrane conductance regulator gene (CFTR), leading to pancreatic insufficiency and an increased risk of CF-related diabetes (CFRD). CFRD is characterized by relative insulin deficiency, with histopathological studies revealing partial loss of beta-cell mass. ¹ Insulin resistance can also contribute to hyperglycemia, especially during periods of disease exacerbation. ¹

Insulin is the primary treatment for CFRD. While non-insulin antidiabetic agents are not currently recommended due to insufficient clinical data, emerging research suggests that glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 inhibitors may offer promising alternatives to insulin therapy. ¹

Advances in CF care, particularly with highly effective modulator therapies (HEMT), have improved health outcomes. Small studies suggest possible short-term improvements in insulin secretion and glucose tolerance with certain HEMT combinations. ¹ However, it remains unclear whether HEMT directly influences insulin secretion in pancreatic beta cells or indirectly affects glucose tolerance by reducing systemic inflammation. ¹

In vitro studies have yielded conflicting results regarding the expression of CFTR in beta cells and its role in insulin secretion. ¹ Some research suggests that CFTR may directly influence islet cells, as evidenced by impaired GLP-1-augmented glucose-potentiated insulin secretion in both mice and human islet studies following CFTR inhibition. ² However, factors beyond the pancreas, such as impaired incretin secretion, may also affect beta-cell function. ³ Furthermore, evidence suggests that GLP-1 can improve glucose-dependent insulin secretion in individuals with CF and abnormal glucose tolerance, without affecting maximal beta-cell secretory capacity. ⁴ These observations make GLP-1 receptor agonists an intriguing option for the treatment of CFRD.

A previous case report demonstrated the successful use of semaglutide, a GLP-1 receptor agonist, in replacing prandial insulin in a 21-year-old man with CFRD. The treatment approach, which combined a low dose of semaglutide (0.13 mg weekly) with basal insulin, led to effective glycemic control. ⁵

In keeping with these previous results, we present a case demonstrating the efficacy of a higher dose of semaglutide (1 mg weekly) in a patient with CFRD, leading to significant improvement in glycemic control.

The patient, a 51-year-old woman, was diagnosed with CF (homozygous F508del) in infancy and diagnosed with CFRD at age 45. She had no family history of type 2 diabetes.

She had been receiving elexacaftor–tezacaftor–ivacaftor (HEMT) therapy for 3 years, along with dornase alfa, pancreatic enzymes, and fat-soluble vitamin supplements. Her lung disease was stable (forced expiratory volume in 1 s 71%).

Her CFRD insulin treatment regimen included pre-meal insulin aspart (dosed using a carbohydrate ratio of 1 unit/7.5 g and a correction factor of 1 unit/50 mg/dL blood glucose elevation above 120 mg/dL) and basal insulin degludec (8 units daily). No other non-insulin antihyperglycemic medications were previously used.

Continuous glucose monitoring (CGM) showed a time in range (TIR) of 79%, with some postprandial hyperglycemia episodes (Fig. 1A). Her HbA1c was 6.3%, kidney function was normal (estimated glomerular filtration rate 111 mL/[min·1.73 m²]), and serum albumin and total protein were normal (4.1 g/dL and 6.4 g/dL, respectively). The stimulated C-peptide level 2 h after a 50 g mixed meal was 520 pmol/L. She had experienced a weight gain of 5 kg over the past year (weight 63 kg; body mass index [BMI] 26.9 kg/m²).

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FIG. 1.

(A) Continuous glucose monitoring (CGM) data for 2 weeks immediately preceding the initiation of semaglutide treatment. (B) CGM data for 2 weeks, collected 2.5 months after the initiation of semaglutide treatment.

Subcutaneous semaglutide was initiated at 0.25 mg weekly and gradually titrated to 1 mg over 2 months. Concurrently, basal insulin was discontinued, and prandial insulin was reduced by 50%. Upon increasing the semaglutide dose to 0.5 mg weekly, prandial insulin was completely discontinued.

At a 3-month follow-up visit after semaglutide initiation, CGM data showed improved glycemic control (TIR 97%) with reduced postprandial glucose (Fig. 1B). During this time the patient lost 4.5 kg (weight 58.5 kg; BMI 24.3 kg/m²) and maintained stable lung function. HbA1c decreased to 5.9%. The stimulated C-peptide level after a 50 g mixed meal at this visit was 828 pmol/L. The patient tolerated the medication well, with no reported side effects.

In conclusion, this case adds to the growing evidence supporting the potential of GLP-1 receptor agonists, such as semaglutide, as effective and safe alternatives for managing CFRD. Significant improvement in glycemic control and weight loss were observed in this patient, leading to complete discontinuation of insulin therapy.

While these findings are promising, larger clinical trials are needed to confirm the long-term safety and efficacy of GLP-1 receptor agonists for CFRD and to identify the ideal patient profile for this therapy.