The Drug Whisperer (Sept-Oct 2023)

1. Should Verapamil be Prescribed for Recently Diagnosed Type 1 Diabetics?

ABSTRACT: Verapamil promotes functional β-cell mass and improves glucose homeostasis in diabetic mice and humans with type 1 diabetes (T1D). Now, our global proteomics analysis of serum from subjects with T1D at baseline and after 1 year of receiving verapamil or placebo revealed IGF-I as a protein with significantly changed abundance over time. IGF-I, which promotes β-cell survival and insulin secretion, decreased during disease progression, and this decline was blunted by verapamil. In addition, we found that verapamil reduces β-cell expression of IGF-binding protein 3 (IGFBP3), whereas IGFBP3 was increased in human islets exposed to T1D-associated cytokines and in diabetic NOD mouse islets. IGFBP3 binds IGF-I and blocks its downstream signaling, which has been associated with increased β-cell apoptosis and impaired glucose homeostasis. Consistent with the downregulation of IGFBP3, we have now discovered that verapamil increases β-cell IGF-I signaling and phosphorylation/activation of the IGF-I receptor (IGF1R). Moreover, we found that thioredoxin-interacting protein (TXNIP), a proapoptotic factor downregulated by verapamil, promotes IGFBP3 expression and inhibits the phosphorylation/activation of IGF1R. Thus, our results reveal IGF-I signaling as yet another previously unappreciated pathway affected by verapamil and TXNIP that may contribute to the beneficial verapamil effects in the context of T1D.

Xu GL, et al. Verapamil Prevents Decline of IGF-I in Subjects With Type 1 Diabetes and Promotes β-Cell IGF-I Signaling. Diabetes. 2023 Oct 1;72(10):1460-1469. doi: 10.2337/db23-0256.

2. With the Exploding Patient Demand for GLP-1 Agonists, Make Sure You are Aware of These Potential GI Side-Effects

BACKGROUND: Glucagon-like peptide 1 (GLP-1) agonists are medications approved for treatment of diabetes that recently have also been used off label for weight loss. Studies have found increased risks of gastrointestinal adverse events (biliary disease,pancreatitis, bowel obstruction, and gastroparesis in patients with diabetes. Because such patients have higher baseline risk for gastrointestinal adverse events, risk in patients taking these drugs for other indications may differ. Randomized trials examining efficacy of GLP-1 agonists for weight loss were not designed to capture these events due to small sample sizes and short follow-up. We examined gastrointestinal adverse events associated with GLP-1 agonists used for weight loss in a clinical setting.

METHODS: We used a random sample of 16 million patients (2006-2020) from the PharMetrics Plus database (IQVIA), a large health claims database that captures 93% of all outpatient prescriptions and physician diagnoses in the US through the International Classification of Diseases, Ninth Revision (ICD-9) or ICD-10. In our cohort study, we included new users of semaglutide or liraglutide, 2 main GLP-1 agonists, and the active comparator bupropion-naltrexone, a weight loss agent unrelated to GLP-1 agonists.

Because semaglutide was marketed for weight loss after the study period (2021), we ensured all GLP-1 agonist and bupropion-naltrexone users had an obesity code in the 90 days prior or up to 30 days after cohort entry, excluding those with a diabetes or antidiabetic drug code.  Patients were observed from first prescription of a study drug to first mutually exclusive incidence (defined as first ICD-9 or ICD-10 code) of biliary disease (including cholecystitis, cholelithiasis, and choledocholithiasis), pancreatitis (including gallstone pancreatitis), bowel obstruction, or gastroparesis (defined as use of a code or a promotility agent). They were followed up to the end of the study period (June 2020) or censored during a switch.

Hazard ratios (HRs) from a Cox model were adjusted for age, sex, alcohol use, smoking, hyperlipidemia, abdominal surgery in the previous 30 days, and geographic location, which were identified as common cause variables or risk factors.6 Two sensitivity analyses were undertaken, one excluding hyperlipidemia (because more semaglutide users had hyperlipidemia) and another including patients without diabetes regardless of having an obesity code. Due to absence of data on body mass index (BMI), the E-value was used to examine how strong unmeasured confounding would need to be to negate observed results, with E-value HRs of at least 2 indicating BMI is unlikely to change study results. Statistical significance was defined as 2-sided 95% CI that did not cross 1. Analyses were performed using SAS version 9.4. Ethics approval was obtained by the University of British Columbia’s clinical research ethics board with a waiver of informed consent.

RESULTS: Our cohort included 4144 liraglutide, 613 semaglutide, and 654 bupropion-naltrexone users. Incidence rates for the 4 outcomes were elevated among GLP-1 agonists compared with bupropion-naltrexone users . For example, incidence of biliary disease (per 1000 person-years) was 11.7 for semaglutide, 18.6 for liraglutide, and 12.6 for bupropion-naltrexone and 4.6, 7.9, and 1.0, respectively, for pancreatitis.

Use of GLP-1 agonists compared with bupropion-naltrexone was associated with increased risk of pancreatitis (adjusted HR, 9.09 [95% CI, 1.25-66.00]), bowel obstruction (HR, 4.22 [95% CI, 1.02-17.40]), and gastroparesis (HR, 3.67 [95% CI, 1.15-11.90) but not biliary disease (HR, 1.50 [95% CI, 0.89-2.53]). Exclusion of hyperlipidemia from the analysis did not change the results (. Inclusion of GLP-1 agonists regardless of history of obesity reduced HRs and narrowed CIs but did not change the significance of the results . E-value HRs did not suggest potential confounding by BMI.

DISCUSSION: This study found that use of GLP-1 agonists for weight loss compared with use of bupropion-naltrexone was associated with increased risk of pancreatitis, gastroparesis, and bowel obstruction but not biliary disease.

Given the wide use of these drugs, these adverse events, although rare, must be considered by patients who are contemplating using the drugs for weight loss because the risk-benefit calculus for this group might differ from that of those who use them for diabetes. Limitations include that although all GLP-1 agonist users had a record for obesity without diabetes, whether GLP-1 agonists were all used for weight loss is uncertain.

Sodhi M, et al. Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss.  JAMA. 2023 Oct 5:e2319574. doi: 10.1001/jama.2023.19574. Online ahead of print.