Semaglutide: a review
Semaglutide is a molecule designed by the Danish laboratory Novo Nordisk. It is a peptide analogue of the GLP-1 (Glucagon Like Peptide-1) receptor. This peptide generates different effects:
Stimulates the release of insulin by the pancreas, in the presence of glucose
Slows gastric emptying
At the level of the central nervous system, it stimulates the satiety center and inhibits the appetite center.
In addition, anti-inflammatory effects are attributed to it. Helps better glycemic control in people with diabetes mellitus. It was also seen that it produces substantial weight loss in overweight and obese people. Its injectable formulations showed, in different patient populations, to reduce the risk of developing major adverse cardiovascular events, of dying, and also to reduce the progression of chronic kidney disease.
The Danish laboratory that invented it markets it as a weekly injectable (Ozempic) and daily oral capsules (Rybelsus) for the treatment of type 2 diabetes mellitus, and as a weekly injection (Wegovy), in a higher dose than Ozempic, for the treatment of obesity or overweight associated with a comorbidity secondary to excess weight.
In off-label use, when Wegovy is not available, many use Ozempic or Rybelsus with the goal of weight loss, in the absence of type 2 diabetes mellitus.
This drug is used as a complement to what is the cornerstone of metabolic and body weight control, which is a healthy diet and physical exercise.
Reviewing the original oral semaglutide, Rybelsus
Oral semaglutide is administered once daily, and is approved for use in 3 doses: 3 mg, 7 mg, and 14 mg. It is marketed under the brand Rybelsus, from the Novo Nordisk laboratory.
It is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus, to improve glycemic control as a complement to diet and exercise.
In the European Union, a new formulation of 1.5 mg, 4 mg and 9 mg doses of Rybelsus is approved, which is bioequivalent to the original formulation of Rybelsus️. It is not yet approved for the control of body weight exclusively. There are different clinical trials underway.
What’s new: the SOUL essay
In the SOUL trial, oral semaglutide showed a 14% reduction in the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes mellitus.
This is a randomized, double-blind study comparing oral semaglutide with placebo, as an adjunct to standard care (i.e., healthy diet, physical activity, and pharmacotherapy), for the prevention of major adverse cardiovascular events.
9,650 people with type 2 diabetes mellitus and established cardiovascular disease (CVD) and/or chronic kidney disease (CKD) participated in the trial. That is, the population already had a high cardiovascular risk when enrolling (approximately 1 in 3 adults with type 2 diabetes mellitus also has cardiovascular diseases).
As part of standard care, 49% of patients received SGLT2i (canagliflozin, dapagliflozin, or empagliflozin) at some point during the trial.
The trial achieved its primary objective by demonstrating a statistically significant and superior reduction in MACE of 14% for people treated with oral semaglutide compared to placebo.
The primary endpoint of the study was a composite outcome of first-occurrence MACE, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
In the trial, oral semaglutide had a safe and well-tolerated profile.
It comes to add
SOUL demonstrates that oral semaglutide reduces the risk of cardiovascular events, and that its benefits are additive to standard treatment.
Novo Nordisk expects to seek regulatory approval for a label extension for Rybelsus in both the United States and the European Union by the end of the year. Detailed results from SOUL will be presented at a scientific conference in 2025.
About the SOUL trial
SOUL was a multicenter, international, randomized, double-blind, parallel-group, placebo-controlled, phase 3 cardiovascular outcomes trial with 9,650 participants.
It was conducted to evaluate the effect of oral semaglutide versus placebo on cardiovascular outcomes in people with type 2 diabetes and established CVD and/or CKD. It was initiated in 2019, and its key objective was to demonstrate that oral semaglutide reduces the risk of major adverse cardiovascular events (a composite endpoint consisting of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) compared to placebo, both added to the standard of care in patients with type 2 diabetes and established CVD and/or CKD.
