# Effectiveness of oral semaglutide versus empagliflozin for the management of type 2 diabetes. PIONEER‐2 trial emulation with real‐world data

## TL;DR

This study compares oral semaglutide and empagliflozin for managing type 2 diabetes in real-world settings, finding better blood sugar control with semaglutide but lower treatment persistence.

## Contribution

The study emulates the PIONEER-2 trial using real-world data to compare two diabetes drugs in a real-world setting.

## Key findings

- Oral semaglutide showed significantly greater HbA1c reduction compared to empagliflozin.
- Weight loss was similar between the two drugs, with a modest advantage for semaglutide at 18 months.
- Treatment persistence was lower for semaglutide, with a higher discontinuation rate.

## Abstract

Oral semaglutide and empagliflozin are commonly used for the management of type 2 diabetes (T2D), but head‐to‐head comparisons in real‐world settings are limited. We aimed to emulate the PIONEER‐2 trial using electronic health records to compare the effectiveness and persistence of oral semaglutide versus empagliflozin.

This was a retrospective multicentre study using electronic health records from Italian diabetes clinics. New users of oral semaglutide or empagliflozin were matched 1:2 and followed for up to 18 months. The primary outcome was HbA1c change; secondary outcomes included weight change and treatment persistence. Analyses used mixed models for repeated measures under both treatment policy and trial product estimands.

After matching, we included new users of oral semaglutide (n = 105) or empagliflozin (n = 207). Mean age was 65 years, diabetes duration 10 years, baseline HbA1c 7.6%, BMI 29 kg/m2, and 94% were on metformin. Only 28.6% of new users of oral semaglutide reached the 14 mg dose and 31.4% of empagliflozin new users reached the 25 mg dose. HbA1c reduction was significantly greater with oral semaglutide than with empagliflozin (mean difference − 0.35%, p <0.001). Weight loss over time was similar, with oral semaglutide showing a modest advantage at 18 months among persistent patients. Persistence was lower for semaglutide (HR for discontinuation 1.47, p = 0.007).

Under routine care, new users of oral semaglutide achieved better glycaemic control compared with empagliflozin new users, with similar weight loss but lower treatment persistence. These findings support the results of PIONEER‐2 and its transferability to clinical practice.