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Oral semaglutide trumps sitagliptin in reducing HbA1c, weight in uncontrolled T2D

Roshini Claire Anthony
17 Apr 2019

Individuals with poorly controlled type 2 diabetes (T2D) had greater HbA1c reductions and weight loss when a 7 or 14 mg/day dose of the GLP-1* receptor agonist semaglutide rather than sitagliptin was added to their background diabetic medications, results of the phase IIIa PIONEER 3** trial showed.

A total of 1,864 patients from 14 countries (mean age 58 years, 47.2 percent female, mean baseline HbA1c and BMI 8.3 percent and 32.5 kg/m2, respectively) with T2D uncontrolled with metformin with or without sulfonylureas (HbA1c 7.0–10.5 percent) were randomized to add on once-daily oral semaglutide at doses of 3, 7, or 14 mg (n=466, 466, and 465, respectively) or sitagliptin 100 mg (n=467) for 78 weeks. Recipients of semaglutide 7 or 14 mg/day had their dose initiated at 3 mg/day and escalated every 4 weeks until randomized dose.

At week 26, patients who received the two higher doses of semaglutide experienced greater reductions from baseline in HbA1c compared with sitagliptin recipients (estimated treatment difference [ETD], -0.3 percent, 95 percent confidence interval [CI], -0.4 to -0.1 percent [7 mg/day] and -0.5 percent, 95 percent CI, -0.6 to -0.4 percent [14 mg/day]; p<0.001 for both). [ENDO 2019, abstract SAT-139; JAMA 2019;doi:10.1001/jama.2019.2942]

Noninferiority of semaglutide 3 mg/day compared with sitagliptin with regard to HbA1c reduction was not established at 26 weeks (ETD, 0.2 percent; p=0.09), with results appearing to favour sitagliptin (p=0.008).

Semaglutide 7 and 14 mg/day recipients also experienced greater weight loss than sitagliptin recipients (ETD, -1.6 and -2.5 kg, respectively; p<0.001 for both).

Similarly, semaglutide 7 and 14 mg/day recipients had greater reductions in HbA1c levels at week 78 compared with sitagliptin recipients (ETD, -0.1; p=0.06 and -0.4; p<0.001, respectively), while reductions in body weight were superior with all semaglutide doses compared with sitagliptin (ETD, -0.8 kg; p=0.02 [3 mg/day], -1.7 kg; p<0.001 [7 mg/day], and -2.1 kg; p<0.001 [14 mg/day]).

Patients on semaglutide 14 mg/day had greater reductions in fasting plasma glucose levels at weeks 26 and 78 than those on sitagliptin (p<0.001 for both), while more patients on semaglutide 7 and 14 mg/day achieved HbA1c <7.0 percent or 5.0 percent weight loss than those on sitagliptin.

Adverse event (AE) incidence was comparable among semaglutide 3, 7, and 14 mg/day, and sitagliptin recipients (79.4, 78.2, 79.6, and 83.3 percent, respectively), as was incidence of serious AEs (13.7, 10.1, 9.5, and 12.4 percent, respectively). Gastrointestinal (GI) disorders were the most common AE among semaglutide 14 mg/day recipients, while infections and infestations were the most common among semaglutide 3 and 7 mg/day and sitagliptin recipients.

A total of 298 patients discontinued treatment early. AE-related discontinuations, mainly GI events, occurred in 5.6, 5.8, 11.6, and 5.2 percent of semaglutide 3, 7, and 14 mg/day, and sitagliptin recipients, respectively.

The majority of AE-related discontinuations occurred during semaglutide dose escalation and as such, may differ in clinical practice where dose escalation is “based on individualized efficacy and tolerability”, said the researchers.

Severe or whole-blood glucose-confirmed symptomatic hypoglycaemia incidents occurred in 4.9, 5.2, and 7.7 percent of semaglutide 3, 7, and 14 mg/day recipients, and 8.4 percent of sitagliptin recipients, primarily in patients on both metformin and sulfonylureas.

By treatment end, 52.1, 64.6, 72, and 60.6 percent of semaglutide 3, 7, or 14 mg/day and sitagliptin recipients had not used rescue medications.


Clinical implications

“The results achieved with oral semaglutide may be of clinical relevance, as improved glycaemic control is associated with better diabetes-related outcomes, and because some patients may prefer oral medications to achieve this improved glycaemic control,” said the researchers.

“Furthermore, clinically meaningful weight loss contributes to greater glycaemic control and reduces cardiovascular risk factors, which is particularly beneficial in a population that frequently has comorbid obesity,” they added.

According to the researchers, the results are in line with other trials that demonstrated superiority of GLP-1 receptor agonists over DPP-4*** inhibitors in improving glucose control and weight loss. [Lancet 2010;376:431-439; Lancet Diabetes Endocrinol 2017;5:341-354; Diabetes Care 2014;37:2149-2158]

“[G]reater glucose lowering and weight loss compared with sitagliptin is not surprising given that this effect has been reported for other GLP-1 receptor agonists, including subcutaneous semaglutide,” said Professor Irl Hirsch from the University of Washington School of Medicine, Seattle, Washington, US, in an editorial. [JAMA 2019;doi:10.1001/jama.2019.2941]

“However, the comparable rates of AEs and overall safety, at least with the 7 mg/day dosage, are notable because sitagliptin is one of the better-tolerated drugs available to treat diabetes,” he said. Despite the favourable safety profile, cost may be the main factor limiting access to oral semaglutide, he added.


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