Glucagon-like peptide-1 (GLP-1) is a 30-amino acid incretin hormone produced in the intestine with beneficial effects on glucose metabolism and appetite regulation. Its action stems from the stimulation of insulin secretion, the suppression of glucagon secretion, and the slowing of gastric emptying. Current therapeutic options to enhance incretin effects are the use of dipeptidyl peptidase-4 (DPP4) inhibitors (iDPP4) and GLP-1 receptor agonists (GLP-1 RAs). The latter are an established therapeutic option in the treatment of hyperglycemia in people with type 2 diabetes mellitus (T2DM) and obesity. They act by mimicking the effect of GLP-1 to stimulate glucose-dependent insulin secretion, decrease postprandial glucagon secretion, and slow gastric emptying. All of this produces an anti-hyperglycemic effect, with a very low intrinsic risk of hypoglycemia.1, 2, 3 They also act on the central nervous system (CNS) by promoting satiety and reducing caloric intake, thereby contributing to weight loss.4, 5, 6, 7 In addition, some GLP-1 RAs have demonstrated a reduction in cardiovascular morbidity and mortality in patients with T2DM, both in primary and secondary prevention, thus becoming the cornerstone of treatment along with sodium-glucose cotransporter-2 (SGLT2) inhibitors (iSGLT2).8, 9, 10 Recently, we have achieved more evidence on the beneficial effect of GLP-1 RAs in non-alcoholic fatty liver disease (NAFLD) through a multifactorial mechanism of action that is not yet fully understood but appears to improve liver damage by promoting a reduction in steatosis and inflammation. This new line of action is significant, as up to 70% of patients with T2DM suffer from NAFLD, and we do not have specific treatments to fight it.11

In patients with T2DM and obesity, weekly administered GLP-1 RAs (exenatide LAR, dulaglutide, and semaglutide) achieve greater reductions in HbA1c and more weight loss vs daily administered GLP-1 RAs with a shorter half-life (exenatide, liraglutide, lixisenatide). In comparative and randomized clinical trials, semaglutide has proven to be more effective than other GLP-1 RAs in reducing HbA1c, with dulaglutide being the second most potent in anti-hyperglycemic efficacy.12, 13, 14, 15

The greater efficacy profile of semaglutide vs other GLP-1 RAs could be related to the structural characteristics of the molecule.16 It is a GLP-1 RA with 94% homology in the amino acid sequence with endogenous GLP-1, with 3 modifications in its structure that allow for a more prolonged binding to GLP-1 receptors and extend the half-life to approximately 1 week.17 Furthermore, being a small molecule, it can reach regions of the CNS involved in the control of food intake. This characteristic is attributed to the fact that weight loss with semaglutide is greater than that of other larger GLP-1 RAs such as dulaglutide, whose entry into the CNS is more limited.18

Although randomized clinical trials provide the greatest scientific evidence, they are limited on their external validity, since these studies often include selected patient populations that may not reflect real-world prescribing conditions,19 particularly with respect to changes between different GLP-1 RAs. There is limited real-world evidence on the effectiveness and possible adverse effects after switching from one GLP-1 RA to another. Published studies compared the transfer of daily or weekly administered GLP-1 RAs to weekly administered GLP-1 RAs20, 21, 22 demonstrating superiority in both HbA1c reduction and weight loss after switching from a daily or weekly GLP-1 RA to subcutaneous (SC) semaglutide.20, 21, 22, 23 However, the studies found included a small number of patients previously on dulaglutide, the second most potent weekly administered GLP-1 RA in anti-hyperglycemic efficacy.

Therefore, the SEMA-SWITCH study was designed to evaluate the safety and efficacy profile, in real-world ions, of switching from weekly SC dulaglutide to weekly SC semaglutide. When collecting and analyzing the data, oral semaglutide was not marketed in Spain, and therefore was not included for comparisons in the study.