Efficacy, Safety, and Tolerability of Oral Semaglutide Versus Placebo Added to Insulin With or Without Metformin in Patients With Type 2 Diabetes: The PIONEER 8 Trial

Abstract

Objective: To investigate the efficacy, safety, and tolerability of oral semaglutide added to insulin with or without metformin.

Research design and methods: Patients with type 2 diabetes uncontrolled on insulin with or without metformin were randomized to oral semaglutide 3 mg (N = 184), 7 mg (N = 182), or 14 mg (N = 181) or to placebo (N = 184) in a 52-week, double-blind trial. End points were change from baseline to week 26 in HbA_1c (primary) and body weight (confirmatory secondary). Two estimands were defined: treatment policy (effect regardless of trial product discontinuation or rescue medication) and trial product (effect assuming trial product continuation without rescue medication) in randomized patients.

Results: Oral semaglutide was superior to placebo in reducing HbA_1c (estimated treatment difference [ETD] -0.5% [95% CI -0.7, -0.3], -0.9% [-1.1, -0.7], and -1.2% [-1.4, -1.0] for 3, 7, and 14 mg, respectively; P < 0.001) and body weight (ETD -0.9 kg [95% CI -1.8, -0.0], -2.0 kg [-3.0, -1.0], and -3.3 kg [-4.2, -2.3]; P = 0.0392 for 3 mg, P ≤ 0.0001 for 7 and 14 mg) at week 26 (treatment policy estimand). Significantly greater dose-dependent HbA_1c and body weight reductions versus placebo were achieved with oral semaglutide at weeks 26 and 52 (both estimands). The most frequent adverse event with oral semaglutide was nausea (11.4-23.2% of patients vs. 7.1% with placebo; mostly mild to moderate).

Conclusions: Oral semaglutide was superior to placebo in reducing HbA_1c and body weight when added to insulin with or without metformin in patients with type 2 diabetes. The safety profile was consistent with other glucagon-like peptide 1 receptor agonists.

Trial registration: ClinicalTrials.gov NCT03021187.

Figure 1

Glycemic control–related efficacy end points. A: Observed absolute HbA_1c over time. ▼, placebo; ▴, oral semaglutide 3 mg; ♦, oral semaglutide 7 mg; ▪, oral semaglutide 14 mg. B: Estimated changes from baseline in HbA_1c. C: Estimated changes from baseline in FPG. D: Estimated changes from baseline in total daily insulin dosage. Treatment policy estimand: ANCOVA for continuous end points and logistic regression for binary end points, using data irrespective of discontinuation of trial product or initiation of rescue medication. Missing values were imputed by a pattern mixture model using multiple imputation. Pattern was defined by randomized trial product and treatment status. Trial product estimand: mixed model for repeated measurements for continuous end points and logistic regression for binary end points. Data collected after discontinuation of trial product or initiation of rescue medication were excluded. For binary end points, missing values were imputed from patients randomized to the same trial product using sequential multiple imputation. *Statistically significant ETD versus placebo in favor of oral semaglutide. P values are unadjusted two-sided P values for the test of no difference.

Figure 2

Body weight–related efficacy end points. A: Observed changes from baseline in body weight over time. ▼, placebo; ▴, oral semaglutide 3 mg; ♦, oral semaglutide 7 mg; ▪, oral semaglutide 14 mg. B: Estimated changes from baseline in body weight. C: Observed proportions of patients achieving ≥5% weight loss. D: Observed proportions of patients achieving HbA_1c <7.0% without hypoglycemia and without body weight gain. Treatment policy estimand: ANCOVA for continuous end points and logistic regression for binary end points, using data irrespective of discontinuation of trial product or initiation of rescue medication. Missing values were imputed by a pattern mixture model using multiple imputation. Pattern was defined by randomized trial product and treatment status. Trial product estimand: mixed model for repeated measurements for continuous end points and logistic regression for binary end points. Data collected after discontinuation of trial product or initiation of rescue medication were excluded. For binary end points, missing values were imputed from patients randomized to the same trial product using sequential multiple imputation. *Statistically significant ETD or estimated odds ratio (EOR) versus placebo in favor of oral semaglutide. P values are unadjusted two-sided P values for the test of no difference. †Severe or blood glucose–confirmed (<3.1 mmol/L [<56 mg/dL]) symptomatic hypoglycemic episode.