Effect of fenofibrate on residual beta cell function in adults and adolescents with newly diagnosed type 1 diabetes: a randomised clinical trial

Abstract

Aims/hypothesis: Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, shows some promise in alleviating beta cell stress and preserving beta cell function in preclinical studies of type 1 diabetes. The aim of this phase 2, placebo-controlled, double-blinded, randomised clinical trial was to investigate the efficacy and safety of fenofibrate in adults and adolescents with newly diagnosed type 1 diabetes.

Methods: We enrolled 58 individuals (aged 16 to 40 years old) with newly diagnosed type 1 diabetes and randomised them to daily oral treatment with fenofibrate 160 mg or placebo for 52 weeks (in a block design with a block size of 4, assigned in a 1:1 ratio). Our primary outcome was change in beta cell function after 52 weeks of treatment, assessed by AUC for C-peptide levels following a 2 h mixed-meal tolerance test. Secondary outcomes included glycaemic control (assessed by HbA_1c and continuous glucose monitoring), daily insulin use, and proinsulin/C-peptide (PI/C) ratio as a marker of beta cell stress. We assessed outcome measures before and after 4, 12, 26 and 52 weeks of treatment. Blinding was maintained for participants, their healthcare providers and all staff involved in handling outcome samples and assessment.

Results: The statistical analyses for the primary outcome included 56 participants (n=27 in the fenofibrate group, after two withdrawals, and n=29 in the placebo group). We found no significant differences between the groups in either 2 h C-peptide levels (mean difference of 0.08 nmol/l [95% CI -0.05, 0.23]), insulin use or glycaemic control after 52 weeks of treatment. On the contrary, the fenofibrate group showed a higher PI/C ratio at week 52 compared with placebo (mean difference of 0.024 [95% CI 0.000, 0.048], p<0.05). Blood lipidome analysis revealed that fenofibrate repressed pathways involved in sphingolipid metabolism and signalling at week 52 compared with placebo. The 52 week intervention evoked few adverse events and no serious adverse events. Follow-up in vitro experiments in human pancreatic islets demonstrated a stress-inducing effect of fenofibrate.

Conclusions/interpretation: Contrary to the beneficial effects of fenofibrate found in preclinical studies, this longitudinal, randomised, placebo-controlled trial does not support the use of fenofibrate for preserving beta cell function in individuals with newly diagnosed type 1 diabetes.

Trial registration: EudraCT number: 2019-004434-41 FUNDING: This study was funded by the Sehested Hansens Foundation.

Keywords: Beta cell function; Beta cell stress; Clinical trial; Fenofibrate; Newly diagnosed type 1 diabetes; Peroxisome proliferator-activated receptor alpha (PPARα); Type 1 diabetes.

Fig. 1

Fifty-eight participants were randomised to 52 weeks of treatment with either fenofibrate 160 mg/day or placebo in a 1:1 ratio. Two participants in the fenofibrate group dropped out after randomisation, but before receiving any trial treatment, and therefore were not included in the statistical analyses. During the 52 weeks of intervention, six participants in the fenofibrate group and two in the placebo group dropped out. T1D, type 1 diabetes

Fig. 2

Data are presented as observed mean change from baseline, with 95% CIs, in C-peptide concentrations during a 2 h MMTT over 52 weeks. C-peptide measurements were collected from plasma at the time points 0, 15, 30, 60, 90 and 120 min after ingestion of a standardised meal. (a) AUC values calculated from each MMTT using the trapezoid approach. (b) Highest C-peptide value obtained during each MMTT. For both (a) and (b) there were no between-group differences during the 52 weeks of intervention

Fig. 3

(a) HbA_1c values for 52 weeks. The dashed line marks the target HbA_1c at 53 mmol/mol (7%) for this study population. (b) Percentage time spent with a normal blood glucose level (3.9–10.0 mmol/ml), obtained from a CGM device worn continuously for 52 weeks. (c) Daily insulin use calculated from self-reported insulin dosage and the participant’s weight on the specific trial visit day during 52 weeks. The dashed line marks an insulin use of 0.4 U kg⁻¹ day⁻¹. (a–c) Observed mean values and 95% CIs. (d) Percentage of participants in remission at each visit defined as having an HbA_1c <53 mmol/mol (7%) and an insulin use ≤0.4 U kg⁻¹ day⁻¹. (a–d) No between-group effects during the 52 weeks of intervention

Fig. 4

Beta cell stress assessed by the PI/C ratio over 52 weeks. Data represent observed mean values and 95% CIs. Both proinsulin and C-peptide values were obtained from plasma samples collected on trial visit days in the morning after an overnight fast. At week 52, there was a 0.024 (95% CI 0.000, 0.048, p<0.05) higher PI/C ratio in the fenofibrate group compared with placebo. *p<0.05

Fig. 5

Lipid classes that differed between the fenofibrate group and placebo after 52 weeks of intervention (n=27 in the placebo group and n=23 in the fenofibrate group). Each dot represents the unadjusted p value for a unique lipid species on a −log₁₀ scale. The black dashed line marks the FDR-adjusted significance level and the grey dashed line marks a significance level of −log₁₀ (0.05). In total 511 unique lipid species were detected, of which 31 reached a p value above the FDR-adjusted significance level. Lipid species from the following lipid classes were identified: cholesteryl esters (CE), ceramides (Cer), diglycerides (DG), dimethyl-phosphatidylethanolamines (dMePE), fatty acids (FA), hexosylceramides (HexCer), lactosylceramides (LacCer), lysodimethyl-phosphatidylethanolamines (LdMePE), lysophosphatidylcholines (LPC), lysophosphatidylethanolamines (LPE), phosphatidic acids (PA), phosphatidylcholines (PC), phosphatidylethanolamines (PE), phosphatidylglycerols (PG), phosphatidylinositols (PI), phosphatidylserines (PS), sulfatides (SHexCer), sphingomyelins (SM) and triacylglycerols (TG)

Fig. 6

Human pancreatic islets isolated from seven healthy donors, incubated with vehicle (Ctrl), fenofibrate (Feno), proinflammatory cytokines (Cyt) or fenofibrate and proinflammatory cytokines (Cyt+Feno). Data are presented on a Log₁₀ (1+x) scale with individual points, representing subpopulations of islets as described in the Methods, together with means and SD. (a) GSIS at 20 mmol/l glucose was induced by proinflammatory cytokines (blue) compared with control (white). This effect was diminished in islets co-incubated with fenofibrate and proinflammatory cytokines (purple). (b) Cell death was induced by proinflammatory cytokines (blue) at low glucose (LG: 6.1 mmol/l) and high glucose (HG: 16.7 mmol/l), with no effect of fenofibrate alone (red). However, at HG, fenofibrate potentiated the toxic effect of proinflammatory cytokines (purple). *p<0.05, **p<0.01