Aroda VR, Rosenstock J, Terauchi Y, et al. PIONEER 1: Randomized Clinical Trial Comparing the Efficacy and Safety of Oral Semaglutide Monotherapy with Placebo in Patients with Type 2 Diabetes. Diabetes Care. 2019 Jun 11. pii: dc19-0749. doi: 10.2337/dc19-0749. (Original study)

OBJECTIVE: This trial compared the efficacy and safety of the first oral glucagon-like peptide 1 (GLP-1) receptor agonist, oral semaglutide, as monotherapy with placebo in patients with type 2 diabetes managed by diet and exercise alone. Two estimands addressed two efficacy-related questions: a treatment policy estimand (regardless of trial product discontinuation or rescue medication use) and a trial product estimand (on trial product without rescue medication use) in all randomized patients.

RESEARCH DESIGN AND METHODS: This was a 26-week, phase 3a, randomized, double-blind, placebo-controlled, parallel-group trial conducted in 93 sites in nine countries. Adults with type 2 diabetes insufficiently controlled with diet and exercise were randomized (1:1:1:1) to once-daily oral semaglutide 3 mg, 7 mg, 14 mg, or placebo. The primary end point was change from baseline to week 26 in HbA1c. The confirmatory secondary end point was change from baseline to week 26 in body weight.

RESULTS: In the 703 patients randomized (mean age 55 years, 50.8% male, and mean baseline HbA1c 8.0% [64 mmol/mol]), oral semaglutide reduced HbA1c (placebo-adjusted treatment differences at week 26: treatment policy estimand, -0.6% [3 mg], -0.9% [7 mg], and -1.1% [14 mg]; trial product estimand, -0.7% [3 mg], -1.2% [7 mg], and -1.4% [14 mg]; P < 0.001 for all) and body weight (treatment policy, -0.1 kg [3 mg], -0.9 kg [7 mg], and -2.3 kg [14 mg, P < 0.001]; trial product, -0.2 kg [3 mg], -1.0 kg [7 mg, P = 0.01], and -2.6 kg [14 mg, P < 0.001]). Mild-to-moderate transient gastrointestinal events were the most common adverse events with oral semaglutide. Trial product discontinuations occurred in 2.3-7.4% with oral semaglutide and 2.2% with placebo.

CONCLUSIONS: In patients with type 2 diabetes, oral semaglutide monotherapy demonstrated superior and clinically relevant improvements in HbA1c (all doses) and body weight loss (14 mg dose) versus placebo, with a safety profile consistent with other GLP-1 receptor agonists.

Discipline Area Score
Endocrine 7 / 7
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Internal Medicine 5 / 7
Comments from MORE raters

Endocrine rater

As a diabetic endocrinologist, I find these are superb results from a first oral GLP-1 agonist that provide significant A1c and weight decreases equivalent to those given subcutaneously.

Family Medicine (FM)/General Practice (GP) rater

I am a Family Physician who frequently sees overweight individuals with DM2. GLP-1 receptor agonists appear helpful for lowering A1C and body weight in overweight individuals with DM2. However, the need for injections has limited their use. One of these medications, Semaglutide, is now formulated in an oral form. This was a very well conducted RCT with a placebo group and 3 dosages of Semaglutide finding that oral Semaglutide lowered A1C in a dose-dependent fashion. If repeated using researchers without ties to the company that produces the medication and if sold at a reasonable cost, this medication may have a large benefit to those treating DM2.

General Internal Medicine-Primary Care(US) rater

This is a potentially promising new therapy. HOwever, it is difficult to evaluate its real world effectiveness in a placebo trial and in patients who are pretty well controlled with diet/exercise who would generally be starting metformin rather than a new, brand medication. Price considerations will come into effect as well with so many other meds out there for T2D.

Internal Medicine rater

As a clinician, I am disappointed to read of new drugs for diabetes that compare with placebo in a group of patients not controlled with existing therapy (in this case not already controlled with diet and exercise). Oral Semeglutide may be novel and first in class but now comparisons with metformin should start and then the role in diabetic care should be determined. Perhaps not now!
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