7360 An Overlooked Cause of Hypoglycemia and Weight Loss: Phosphodiesterase-4 Inhibitors

Abstract Disclosure: J. Aurora: None. K. Cappetta: None. R.M. Lechan: None. Background: Phosphodiesterase-4 (PDE-4) inhibitors, apremilast and roflumilast, are anti-inflammatory agents used to treat psoriasis, psoriatic arthritis, and COPD. These agents are commonly associated with gastrointestinal intolerance. However, patients may also experience profound weight loss (>10%). We present a case of a patient with T2DM who developed significant hypoglycemia and weight loss on apremilast. Clinical Case: A 57-year-old female with T2DM, obesity, psoriasis, and postsurgical hypothyroidism due to papillary thyroid cancer developed symptoms of hypoglycemia and weight loss over 1 month. Prior to this, her A1c was 7.8% and weight 104 kg on stable doses of metformin, repaglinide, and insulin glargine. Insulin glargine and repaglinide were both discontinued given her symptoms, yet hypoglycemia persisted, and she continued to lose weight. Further investigations into the cause of this sudden change were carried out. Initial fasting labs: BG 53 mg/dL, C-peptide 4.48 ng/mL (RR 0.8-3.85 ng/mL), insulin 12.8 uIU/mL (RR <18.4 uIU/mL), proinsulin 29.8 pmol/L (RR <18.8 pmol/L), A1c 6.8%, cortisol 24.9 mcg/dL (RR 4-22 mcg/dL), IGF-1 95 ng/mL (Z-score -0.7), and IGF-2 434 ng/mL (RR 267-616 ng/mL). 1 month later, hypoglycemia symptoms improved but she continued to lose weight. Fasting labs were repeated: BG 84 mg/dL, C-peptide 5.62 ng/mL, insulin 24.3 uIU/mL, proinsulin 35 pmol/L, and beta-hydroxybutyrate (BHB) 0.17 mmol/L (RR <0.28 mmol/L); metformin was subsequently stopped. A MR abdomen revealed a 2 cm cystic pancreatic lesion that showed atypical mucinous epithelium by biopsy under endoscopic ultrasound guidance. Gallium-68 DOTATATE-PET scan was unremarkable for an insulin-producing tumor. Two months off metformin, she had no further episodes of hypoglycemia, but her weight loss continued. Fasting labs were repeated: BG 129 mg/dL, C-peptide 5.15 ng/mL, insulin 18.2 uIU/mL, proinsulin 40.5 pmol/L, and BHB 0.27 mmol/L. Review of her medications identified apremilast as a potential culprit contributing to both her hypoglycemia and weight loss, as her symptoms started 1 month after starting apremilast. Over 9 months using apremilast, her A1c decreased by 1% and weight decreased by 27%. Hypoglycemia resolved off all glucose-lowering agents. Conclusion: Significant weight loss with apremilast may be explained by PDE-4 inhibition increasing cyclic AMP, which triggers the release of GLP-1 with subsequent effects on pancreatic beta cells. Apremilast has also been shown to significantly increase fasting insulin levels in patients without insulin resistance, as seen in our patient (1). Given these effects, patients may be at higher risk of hypoglycemia with concurrent glucose-lowering agents, particularly secretagogues. BG and weight need careful monitoring for patients with T2DM using PDE-4 inhibitors. Reference: 1. Ikumi K, et al. J Dermatol. 2022;49(4):e125-e126. Presentation: 6/3/2024