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. 2021 Dec 23;14(1):69.
doi: 10.3390/cancers14010069.

Impact of Diabetes and Metformin Use on Enteropancreatic Neuroendocrine Tumors: Post Hoc Analysis of the CLARINET Study

Sara Pusceddu  1 , Claudio Vernieri  1   2 , Massimo Di Maio  3 , Natalie Prinzi  1 , Martina Torchio  1 , Francesca Corti  1 , Jorgelina Coppa  4 , Roberto Buzzoni  5 , Maria Di Bartolomeo  1 , Massimo Milione  1   6 , Benjamin Regnault  7 , Xuan-Mai Truong Thanh  8 , Vincenzo Mazzaferro  9   10 , Filippo de Braud  1   10
Affiliations

Impact of Diabetes and Metformin Use on Enteropancreatic Neuroendocrine Tumors: Post Hoc Analysis of the CLARINET Study

Sara Pusceddu et al. Cancers (Basel). .

Abstract

The prognostic role of diabetes mellitus (DM) in advanced enteropancreatic neuroendocrine tumors (NETs) is unclear. Progression free survival (PFS) was assessed in post-hoc analyses of the 96-week, phase III, double-blind, placebo-controlled CLARINET study of lanreotide 120 mg in patients with advanced non-functional enteropancreatic NETs with DM (with/without metformin) and without DM. Of 204 patients, there were 79 with DM (lanreotide, n = 42 {metformin, n = 14}; placebo, n = 37 {metformin, n = 10}) and 125 without DM (lanreotide, n = 59; placebo, n = 66). Median PFS was 96.0 and 98.0 weeks with and without DM, respectively (hazard ratio 1.20 {95% confidence interval 0.79 to 1.82}; p = 0.380). No difference in PFS was observed in lanreotide-treated patients with/without DM (p = 0.8476). In the placebo group, median PFS was numerically shorter with versus without DM (p = 0.052) and was significantly longer in patients with DM and metformin (85.7 weeks) versus without metformin (38.7 weeks; p = 0.009). Multivariable Cox analyses showed that DM at baseline was not associated with PFS (p = 0.079); lanreotide was significantly associated with lower disease progression risk (p = 0.017). Lanreotide efficacy was confirmed in patients with advanced enteropancreatic NETs, regardless of diabetic status; DM was not a negative prognostic factor. A potential antitumor effect of metformin was observed in patients receiving placebo.

Keywords: diabetes mellitus; lanreotide; progression-free survival.

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Conflict of interest statement

S.P. received: grants and research funding from Ipsen and Pfizer; honoraria from Ipsen and Novartis; acted in a consulting/advisory role for Ipsen, Novartis, Pfizer and Advanced Accelerator Applications, Mylan, Merck. C.V. received research funding by Roche and acted in an advisory role for Novartis. M.D.M. received: research funding from Tesaro-GlaxoSmithKline; acted in a consulting/advisory role for Novartis, Pfizer, Eisai, Takeda, Janssen, Astellas, Roche, AstraZeneca. M.T. has nothing to disclose. N.P. and V.M. received honoraria from Ipsen. F.C. has nothing to disclose. J.C. has nothing to disclose. R.B. received: research funding and honoraria from Ipsen; acted in a consulting/advisory role for Ipsen. M.D.B. has nothing to disclose. M.M. has nothing to disclose. B.R. and X.-M.T.T. are employees of Ipsen. F.d.B. received: grants, research funding and honoraria from Ipsen; acted in a consulting/advisory role for Ipsen.

Figures

Figure 1
Figure 1
Patient flow diagram. Further details of patient disposition from the CLARINET study are reported in Caplin et al., 2014 [19]. DM, diabetes mellitus.
Figure 2
Figure 2
PFS by DM status in (a) all patients and (b) excluding patients diagnosed with DM after study treatment initiation. CI, confidence interval; DM, diabetes mellitus; NR, not reached; PFS, progression-free survival.
Figure 3
Figure 3
PFS by DM status in patients receiving (a) lanreotide 120 mg and (b) placebo. CI, confidence interval; DM, diabetes mellitus; NR, not reached; PFS, progression-free survival.
Figure 4
Figure 4
PFS by metformin treatment in patients with DM who developed DM prior to study treatment in patients receiving (a) lanreotide 120 mg and (b) placebo (additional analysis). The additional analysis included patients without disease progression at three months after treatment initiation. Based on this criterion, four patients were excluded from this analysis (lanreotide group, n = 3; placebo group, n = 1). CI, confidence interval; DM, diabetes mellitus; NR, not reached; PFS, progression-free survival.
Figure 5
Figure 5
PFS by DM status and metformin treatment in (a) all patients receiving lanreotide 120 mg, (b) patients receiving lanreotide 120 mg, excluding those who developed DM after the start of treatment, (c) all patients receiving placebo and (d) patients receiving placebo, excluding those who developed DM after the start of treatment. HR: (a) DM with metformin compared with without DM: 0.94 {95%CI = 0.32; 2.77}; DM with metformin compared with DM without metformin: 1.22 {95%CI = 0.38; 3.87}; DM without metformin compared with without DM: 0.77 {95%CI = 0.33; 1.80}; (b) DM with metformin compared with without DM: 0.59 {95%CI = 0.18; 1.97}; DM with metformin compared with DM without metformin: 0.24 {95%CI = 0.07; 0.80}; DM without metformin compared with without DM: 2.50 {95%CI = 1.41; 4.44}; (c) DM with metformin compared with without DM: 1.23 {95%CI = 0.37; 4.05}; DM with metformin compared with DM without metformin: 1.81 {95%CI = 0.43; 7.71}; DM without metformin compared with without DM: 0.68 {95%CI = 0.22; 2.05}; (d) DM with metformin compared with without DM: 0.66 {95%CI = 0.20; 2.19}; DM with metformin compared with DM without metformin: 0.31 {95%CI = 0.09; 1.05}; DM without metformin compared with without DM: 2.15 {95%CI = 1.18; 3.92}. CI, confidence interval; DM, diabetes mellitus; HR, hazard ratio; NR, not reached; PFS, progression-free survival.
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