. 2026 Apr 16;43(7):2820–2835. doi: 10.1007/s12325-026-03599-z

Table 1.

Experimental studies on the effect of GLP-1RAs in CF

Study	Experimental model and study design	Major outcomes	Conclusions
Gharib et al. (2024) [21]	Formalin-fixed paraffin-embedded pancreas specimens 10 pwCF without CFRD 9 pwCF with CFRD 9 subjects without CF	Mean islet area was similar between groups, while glucagon per islet area was elevated in CFRD (Control 15.1 ± 2.3, CF 20.8 ± 3.1 and CFRD 29.5 ± 3.1%; p = 0.53 Control vs. CF, p = 0.01 Control vs. CFRD) Reduced GLP-1R by 77% area per islet area in pancreas from CFRD compared with control arm Significantly reduced insulin per islet area in CFRD compared with control arm (Control 52.5 ± 3.9 vs. CFRD 36.2 ± 4.9%, p = 0.03) Significantly reduced GLP-1R expression per insulin-positive islet area in CFRD (Control 36.2 ± 2.7 vs. CFRD 13.5 ± 3.3%, p = 0.004) GLP-1 from α-cells enhanced insulin secretion through binding to GLP-1R on β-cells 216 genes were significantly differentially expressed in α-cells (114 up, 102 down, p < 0.01) and 272 genes were significantly differentially expressed in β-cells (119 up, 153 down, p < 0.01) in CFRD In pwCFRD, upregulation of α-cell PCSK1N enzyme PC1/3 responsible for GLP-1 production and downregulation of PCSK1N	GLP-1R restoration may be beneficial for CFRD
Khan et al. (2019) [22]	C57BL/6 mice	CFTR inhibition was associated with non-significant weight gain for mice on CFTRi, but weight gain was significantly lower compared with control mice (60.3 ± 31.17% reduction, p < 0.01) Treatment with CFTRi and STZ significantly reduced fat mass, without significant effect on bone mineral density or lean mass No impact on glucose tolerance was found with CFTRi administration CFTRi administration reduced plasma insulin (36.40 ± 9.62% reduction, p < 0.01) and pancreatic insulin content (39.42 ± 9.74% reduction, p < 0.01), without any effect on glucagon and GLP-1 CFTRi administration was significantly correlated with islet area (69 ± 20% reduction, p < 0.001), β-cell area (72 ± 20% reduction, p < 0.001), and non-β-cell area (56 ± 23% reduction, p < 0.001) Endocrine/exocrine ratio was significantly lower compared with control arm (3.4 ± 0.6% vs. 7.7 ± 0.8%, p < 0.001) Histology: reduction (p < 0.001) in islet size and increase (p < 0.01) in ductal area	Islet cell number is maintained and treatment in CF should address β-cell mass preservation
Voetmann et al. (2025) [23]	C57BL/6 mice GLP-1R KO mice	682 genes and 1212 were affected by treatment with liraglutide at 2 h and 4 h, respectively A twofold upregulation of CFTR and fivefold upregulation of MUC5B was observed following liraglutide treatment Ren1, Vldlr and Il33 were upregulated Malat1 silencing was found in Brunner’s gland as a target of GLP-1 conjugated antisense oligonucleotide	Increased mucus response was found with GLP-1

Study

Experimental model and study design

Major outcomes

Conclusions

Gharib et al. (2024) [21]

Formalin-fixed paraffin-embedded pancreas specimens

10 pwCF without CFRD

9 pwCF with CFRD

9 subjects without CF

Mean islet area was similar between groups, while glucagon per islet area was elevated in CFRD (Control 15.1 ± 2.3, CF 20.8 ± 3.1 and CFRD 29.5 ± 3.1%; p = 0.53 Control vs. CF, p = 0.01 Control vs. CFRD)

Reduced GLP-1R by 77% area per islet area in pancreas from CFRD compared with control arm

Significantly reduced insulin per islet area in CFRD compared with control arm (Control 52.5 ± 3.9 vs. CFRD 36.2 ± 4.9%, p = 0.03)

Significantly reduced GLP-1R expression per insulin-positive islet area in CFRD (Control 36.2 ± 2.7 vs. CFRD 13.5 ± 3.3%, p = 0.004)

GLP-1 from α-cells enhanced insulin secretion through binding to GLP-1R on β-cells

216 genes were significantly differentially expressed in α-cells (114 up, 102 down, p < 0.01) and 272 genes were significantly differentially expressed in β-cells (119 up, 153 down, p < 0.01) in CFRD

In pwCFRD, upregulation of α-cell PCSK1N enzyme PC1/3 responsible for GLP-1 production and downregulation of PCSK1N

GLP-1R restoration may be beneficial for CFRD

Khan et al. (2019) [22]

C57BL/6 mice

CFTR inhibition was associated with non-significant weight gain for mice on CFTRi, but weight gain was significantly lower compared with control mice (60.3 ± 31.17% reduction, p < 0.01)

Treatment with CFTRi and STZ significantly reduced fat mass, without significant effect on bone mineral density or lean mass

No impact on glucose tolerance was found with CFTRi administration

CFTRi administration reduced plasma insulin (36.40 ± 9.62% reduction, p < 0.01) and pancreatic insulin content (39.42 ± 9.74% reduction, p < 0.01), without any effect on glucagon and GLP-1

CFTRi administration was significantly correlated with islet area (69 ± 20% reduction, p < 0.001), β-cell area (72 ± 20% reduction, p < 0.001), and non-β-cell area (56 ± 23% reduction, p < 0.001)

Endocrine/exocrine ratio was significantly lower compared with control arm (3.4 ± 0.6% vs. 7.7 ± 0.8%, p < 0.001)

Histology: reduction (p < 0.001) in islet size and increase (p < 0.01) in ductal area

Islet cell number is maintained and treatment in CF should address β-cell mass preservation

Voetmann et al. (2025) [23]

C57BL/6 mice

GLP-1R KO mice

682 genes and 1212 were affected by treatment with liraglutide at 2 h and 4 h, respectively

A twofold upregulation of CFTR and fivefold upregulation of MUC5B was observed following liraglutide treatment

Ren1, Vldlr and Il33 were upregulated

Malat1 silencing was found in Brunner’s gland as a target of GLP-1 conjugated antisense oligonucleotide

Increased mucus response was found with GLP-1

CF cystic fibrosis, CFRD cystic fibrosis-related diabetes, GLP-1R glucagon-like peptide-1 receptor, GLP-1 glucagon-like peptide-1, PCSK1N proprotein convertase subtilisin/kexin type 1 inhibitor, PC1/3 proprotein convertase 1, CFTR cystic fibrosis transmembrane conductance regulator, CFTRi cystic fibrosis transmembrane conductance regulator inhibitor, STZ streptozocin, KO knockout