Malderen, Kathleen Van

AbstractBackgroundWeight loss in response to the long‐acting GLP‐1 receptor (GLP1R) analog, liraglutide, is correlated with delay in gastric‐emptying (GE). The aim of this pilot study was to assess whether specific genetic variants in GLP1R or TCF7L2 are associated with delayed GE and weight loss in obese patients treated with liraglutide or the short‐acting GLP‐1 agonist, exenatide.MethodsWe evaluated in obese individuals the associations of genetic variations of GLP1R (rs6923761) and TCF7L2 (rs7903146) on GE T1/2 and weight from two trials that evaluated separately exenatide, 5 μg BID for 30 days, or liraglutide, 3 mg daily for 5 weeks. Data were analyzed using the dominant genetic model and intention‐to‐treat analysis.Key ResultsThere was a significant correlation between changes in weight and GE T1/2 (rs = −.382, P = .004). GLP1R rs6923761 minor allele A (AA_AG) carriers who received either exenatide or liraglutide had greater delay in GE T1/2 relative to baseline (117.9 ± 27.5 [SEM] minutes and 128.9 ± 38.32 minutes) compared to GG genotype (95.8 ± 30.4 minutes and 61.4 ± 21.4 minutes, respectively; P = .11). There was a non‐significant difference in weight loss based on GLP1R rs6923761 genotype after 5 weeks of treatment. There were no significant correlations with TCF7L2 (rs7903146) genotype.Conclusions & InferencesThe minor A allele of GLP1R (rs6923761) is associated with greater delay in GE T1/2 in response to liraglutide and exenatide. These studies provide data to plan pharmacogenetics testing of the hypothesis that GLP1R (rs6923761) influences weight loss in response to GLP1R agonists.

Background Meckel's diverticulum is present in about 2% of the population. The literature reports 3.2% incidence of tumors within Meckel's diverticulum; the tumors are predominantly benign. Objective and methods The purpose of this study was to evaluate malignant tumors in Meckel's diverticulum through systematic review of the literature and review of electronic medical records including pathology reports over 14 years at the Mayo Clinic, Rochester, USA. Results A literature review over the last 10 years identified 37 citations with 402 patients (median age: 58 years; 68.9% males). The predominant malignancy reported was neuroendocrine tumor 84.6%, followed by gastrointestinal stromal tumor 8.2%, and adenocarcinoma 6%. At the time of diagnosis, 29.5% of patients had metastases. In the Mayo Clinic electronic medical records review, there were 19 patients (5.1% of them surgically removed Meckel's diverticulum) who had a malignancy associated with Meckel's diverticulum: 63.2% neuroendocrine tumor, 10.5% gastrointestinal stromal tumor, 5.3% adenocarcinoma, 5.3% pancreatic epithelial neoplasia, and 15.8% metastases from secondary location. Median size of the malignancy was 7 mm, and 17/19 malignancies were coincidental findings. Most neuroendocrine tumors infiltrated the submucosa, while gastrointestinal stromal tumor and adenocarcinoma invaded the serosa. At the time of diagnosis, 33.3% of patients had metastases. Conclusion About 5% of Meckel's diverticulums resected were associated with malignant tumors, most commonly neuroendocrine tumor, and a significant portion of Meckel's diverticulum malignancy was metastatic at the time of discovery.

AbstractBackgroundOpioid‐induced constipation (OIC) is a major side effect of opioid use. Centrally acting antagonists result in opioid withdrawal or worsening of pain and lead to use of peripherally acting mu‐opioid receptor antagonists (PAMORAs). The required doses of the PAMORAs, methylnaltrexone and naloxegol, in the treatment of OIC are well established in chronic opioid users. OIC may occur after short duration of opioid treatment; the required doses of naloxone, naltrexone, and PAMORAs in opioid‐naïve subjects (with no opioid use for at least 3 months) are unclear. The aim of this review was to evaluate the PAMORA dose required for opioid‐naïve subjects to achieve similar beneficial effects on symptoms or valid surrogates to those observed in chronic opioid users.MethodsA PubMed search of μ‐opioid antagonists to counter μ‐opioid effects included terms: naloxone, naltrexone, methylnaltrexone, alvimopan, and naloxegol, as well as OIC and colonic transit.Key ResultsThe approved dose of methylnaltrexone in chronic opioid users, 0.3 mg/kg subcutaneous (SQ), did not affect motility in opioid‐naïve subjects. Trials investigating the required dose of alvimopan showed 0.5‐1 mg dose was efficacious in treating OIC; a 10‐fold higher dose (12 mg) of alvimopan is needed to block effects of codeine on small bowel and colonic transit in opioid‐naïve subjects compared to chronic opioid users. Opioid‐naïve users need 125 mg of naloxegol to reverse the effects of opioids on transit; this is in contrast to the 12.5 to 25 mg needed to treat OIC in chronic opioid users.Conclusions & InferencesOpioid‐naïve subjects require a higher dose of PAMORA than chronic opioid users to achieve μ‐opioid antagonist effect.