RESUMO
INTRODUCTION: Injectable semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) that was previously shown to be superior to liraglutide and dulaglutide in head-to-head comparisons in GLP-1 RA-naïve individuals. It is hypothesized that semaglutide will cause further reductions in glycated hemoglobin A1c (HbA1c) and weight in type 2 diabetes mellitus (T2DM) patients previously treated with liraglutide or dulaglutide. The REALISE-DM study provides the first real-world evidence of the effectiveness and tolerability of semaglutide in patients switching from another GLP-1 RA. METHODS: This retrospective real-world effectiveness analysis included T2DM adults who were on a stable dose of liraglutide or dulaglutide prior to switching to semaglutide. The primary outcome was change in HbA1c. Secondary outcomes were the changes in weight and body mass index (BMI), the occurrence of gastrointestinal side effects (GSEs), and discontinuations. Linear mixed models were used to estimate changes in HbA1c, weight, and BMI, and logistic regression was employed to analyze GSEs and discontinuations. RESULTS: Six months after the 164 patients in this study had switched to semaglutide, their mean HbA1c had decreased by 0.65% (7.1 mmol/mol) (95% prediction interval [PI]: 0.48, 0.81% [5.2, 8.9 mmol/mol]) from a baseline of 7.9% (interquartile range [IQR]: 7.3, 8.8) (62.8 mmol/mol [IQR: 56.3, 72.7]), while their weight and BMI had reduced by 1.69 kg (95% PI: 1.01, 2.37) and 0.59 kg/m2 (95% PI: 0.34, 0.84), respectively. Nineteen patients (11.6%) developed GSEs after switching. CONCLUSIONS: This study supports switching T2DM patients on liraglutide or dulaglutide to injectable semaglutide to achieve further reductions in HbA1c and weight. Although a small number of GSEs occurred, semaglutide was well tolerated by the majority of the patients.
RESUMO
Upon release into circulation, the potent insulin secretagogues glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are rapidly cleaved and inactivated by the enzyme dipeptidyl peptidase IV (DP IV). Long-term administration of specific DP IV inhibitors, so as to enhance circulating active GIP and GLP-1 levels, has been shown to improve glucose tolerance and beta-cell glucose responsiveness and to reduce hyperinsulinemia in the Vancouver diabetic fatty (VDF) rat model of type 2 diabetes. Using the VDF model, the current study was undertaken to examine the effects of long-term DP IV inhibitor treatment on insulin sensitivity. Euglycemic-hyperinsulinemic clamps were performed on two sets of conscious VDF rats treated with or without the DP IV inhibitor P32/98 (20 mg. kg(-1). day(-1) for 12 weeks). The protocol consisted of three sequential 90-min periods with insulin infusion rates of 0, 5, and 15 mU. kg(-1). min(-1) and included a constant infusion of [ (3)H]glucose for measure of hepatic and peripheral insulin sensitivity. Relative to untreated littermates, the treated animals showed a left shift in the sensitivity of hepatic glucose output to insulin (average reduction approximately 6 micro mol. kg(-1). min(-1)) and a marked gain in peripheral responsiveness to insulin, with glucose disposal rates increasing 105 and 216% in response to the two insulin steps (versus 2 and 46% in controls). These results provide the first demonstration of improved hepatic and peripheral insulin sensitivity after DP IV inhibitor therapy, and coupled with apparent improvements in beta-cell function, they offer strong support for the utility of these compounds in the treatment of diabetes.
