First oral GLP-1 agonist launched for type II diabetes

Prescribers can now consider a GLP-1 agonist as an option for patients with type II diabetes who are hesitant to use injectable treatments.

The starting dose of Rybelsus is 3mg once daily. After one month, the dose should be increased to 7mg once daily; if needed, it can be further increased to 14mg once daily. | GETTY IMAGES
The starting dose of Rybelsus is 3mg once daily. After one month, the dose should be increased to 7mg once daily; if needed, it can be further increased to 14mg once daily. | GETTY IMAGES

Rybelsus is an oral formulation of the GLP-1 receptor agonist semaglutide, indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type II diabetes. It is taken once daily and is available in three tablet strengths, 3mg (for initial dose titration), 7mg and 14mg.

Rybelsus can be given as monotherapy when metformin is inappropriate, or in combination with other antidiabetic agents.

Oral semaglutide works in the same way as subcutaneous semaglutide (Ozempic). As an analogue of GLP-1, semaglutide reduces blood glucose in a glucose-dependent manner by stimulating insulin secretion and lowering glucagon secretion when blood glucose is high. It also slightly delays gastric emptying in the early postprandial phase.

'The availability of oral semaglutide may help to broaden treatment choice and facilitate adoption of earlier GLP-1 receptor agonist treatment in the paradigm of type II diabetes management,' say researchers.

Glycaemic control

The safety and efficacy of oral semaglutide were studied in eight clinical trials that included patients with type II diabetes of duration ranging from 3.5 to 15 years (n=8842).

In seven trials, the primary objective was assessment of glycaemic efficacy in settings ranging from monotherapy through to insulin add-on:

  • PIONEER 1 - monotherapy vs placebo in early diabetes
  • PIONEER 2 - with metformin vs the SGLT2 inhibitor empagliflozin in established diabetes
  • PIONEER 3 - with metformin (with or without a sulfonylurea) vs the DPP4 inhibitor sitagliptin in established diabetes
  • PIONEER 4 - with metformin (with or without an SGLT2 inhibitor) vs the injectable GLP-1 agonist liraglutide and placebo in established diabetes
  • PIONEER 5 - with basal insulin (with or without metformin), or metformin and/or a sulfonylurea, vs placebo in patients with advanced diabetes and moderate renal impairment
  • PIONEER 7 - flexibly dosed, with one or two other oral antidiabetic agents vs sitagliptin in established diabetes
  • PIONEER 8 - with insulin (with or without metformin) vs placebo in advanced diabetes

Over periods of treatment up to 78 weeks, oral semaglutide 7mg and 14mg once daily reduced HbA1c and improved other diabetes-related endpoints, such as fasting plasma glucose, across the spectrum of type II diabetes.

Depending on the dose, oral semaglutide lowered HbA1c by between 0.6 and 1.4 percentage points. The results compared favourably with those seen with empagliflozin, sitagliptin or liraglutide, which led to reductions of 0.9, 0.8 and 0.9 percentage points, respectively. Oral semaglutide was also more effective than placebo.

In addition, patients receiving oral semaglutide achieved weight loss of 2.0–4.3kg by the end of treatment. Like all GLP-1 agonists, semaglutide reduces body weight and body fat mass by reducing appetite and food intake, and lessening the preference for high-fat foods.

The most common side-effects of oral semaglutide were gastrointestinal, such as nausea and diarrhoea. Hypoglycaemia can occur when oral semaglutide is used in combination with insulin or a sulfonylurea; a reduction in the dose of insulin or sulfonylurea should be considered to reduce the risk.

Cardiovascular events

The PIONEER 6 trial confirmed that the cardiovascular safety of oral semaglutide was non-inferior to that of placebo. The results also suggested that oral semaglutide may reduce the risk of adverse cardiovascular events compared with placebo, but the difference was not statistically significant.

The trial compared oral semaglutide with placebo in addition to standard care in patients with type II diabetes at high cardiovascular risk (n=3183).

Over a median observation period of 16 months, major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) occurred in 61 patients in the semaglutide group (3.8%) and 76 (4.8%) of those in the placebo group (hazard ratio 0.79 [95% CI 0.57–1.11]).

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