Abstract

Aims: The REALISED study assessed the clinical outcomes associated with oral semaglutide use in Thai patients with type 2 diabetes (T2D) in real-world clinical settings.

Materials and Methods: This retrospective, multi-centre cohort study included 195 patients with T2D initiating oral semaglutide between April 2022 and December 2023. Eligible participants had no prior injectable therapy and completed at least 26 weeks of treatment. The primary endpoint was the change in HbA1c from baseline to the end-of-study (EoS, Week 26); Week 52 outcomes were exploratory. Secondary endpoints included changes in body weight and the proportion achieving HbA1c less than 7%. Severe hypoglycaemia was the safety endpoint. A post hoc composite endpoint combined HbA1c less than 7% with at least 3% weight loss. Analyses used a mixed model for repeated measures and descriptive statistics.

Results: Oral semaglutide was predominantly used as add-on therapy (190/195 [97.4%]). Mean HbA1c decreased by -0.7% (95% CI: -0.9 to -0.5; p<0.0001), and mean body weight decreased by -4.3 kg (95% CI: -5.5 to -3.2; p<0.0001). At EoS, 75.9% (117/154) achieved HbA1c less than 7%, and 57.7% (71/123) met the composite endpoint. No severe hypoglycaemia occurred. Dose escalation from 3 mg to 14 mg was observed in 53.2% by Week 26 and 70.4% by Week 52.

Conclusions: The REALISED study provides the first real-world evidence of oral semaglutide use in Thai patients with T2D, demonstrating significant improvements in glycaemic control and weight reduction across routine care settings.

Study at a Glance

Study Snapshot: Key Statistics

Full Study Facts

What Researchers Actually Did

Between April 2022 and December 2023, investigators at four Thai university hospitals identified adult patients with confirmed type 2 diabetes who had initiated oral semaglutide and had no prior exposure to injectable glucose-lowering agents (insulin or GLP-1 receptor agonists). From 222 screened patients, 27 were excluded for missing baseline HbA1c, treatment interruptions exceeding two weeks, prior injectable use, or other protocol deviations, leaving 195 in the full analysis set. Baseline HbA1c was the most recent value within 12 weeks before initiation. The primary assessment was defined as the HbA1c measurement closest to Week 26 (within a plus-or-minus six-week window), consistent with standard six-month clinical follow-up. An optional extended observation period extended to Week 52 for patients who continued routine care; 72 patients had HbA1c data available at that time point.

Changes in HbA1c and body weight were estimated using a three-level mixed model for repeated measures (MMRM), incorporating linear and quadratic time since initiation, time-varying semaglutide dose (3, 7, or 14 mg), baseline HbA1c or weight, and random intercepts for both site and patient, with random slopes for time. Missing post-baseline data were handled under the missing-at-random assumption. Sensitivity analyses assessed EoS completers, patients with baseline HbA1c at or above 7%, those with baseline BMI at or above 25 kg/m2, and patients with stable background antidiabetic regimens. A post hoc composite endpoint, defined as HbA1c below 7% combined with at least 3% reduction in body weight, was applied to 123 participants with complete data for both measures.

Key Findings: Primary Outcomes

• HbA1c reduction (model-based, FAS, n=195): Estimated mean change from baseline to Week 26 was -0.7 percentage points (95% CI: -0.9 to -0.5; p<0.0001); relative change was -9.8% (95% CI: -12.0 to -7.5; p<0.0001).
• Observed HbA1c change in completers: Mean observed reduction was -1.0 percentage points (SD 1.2) among the 154 participants with EoS data, which is numerically larger than the model-based estimate, reflecting the difference between observed data and MMRM-adjusted estimates across all time points.
• Consistency across sensitivity analyses: Comparable HbA1c reductions were observed in EoS completers (n=154), participants with baseline HbA1c at or above 7% (n=123), and those with stable background antidiabetic medications (n=70).
• On-treatment analysis: Estimated change was -0.7 percentage points (95% CI: -0.9 to -0.5; p<0.0001), consistent with the in-study result.

Key Findings: Secondary Outcomes and Subgroup Analyses

Body Weight

• Estimated mean body weight reduction (FAS, n=194) at EoS: -4.4 kg (95% CI: -5.5 to -3.3; p<0.0001), corresponding to -5.3% relative decrease (95% CI: -6.5% to -4.0%; p<0.0001).
• On-treatment analysis: -4.6 kg (95% CI: -5.7 to -3.5; p<0.0001); relative decrease -5.5% (95% CI: -6.8% to -4.2%; p<0.0001).
• Results were consistent across EoS completers (n=141), patients with BMI at or above 25 kg/m2 (n=159), and those with stable background regimens (n=70).
• At Week 52 (exploratory, n=72), observed body weight reduction was approximately -4.7 kg, within the range reported in PIONEER REAL studies.

HbA1c Target Achievement

• Of 154 EoS completers, 117 (75.9%) achieved HbA1c below 7%; 44.4% (52/117) of those had baseline HbA1c at or above 7%, indicating meaningful glycaemic improvement even among those starting above target.

Composite Endpoint (Post Hoc)

• Among 123 participants with complete HbA1c and weight data at baseline and EoS, 71 (57.7%) met the composite of HbA1c below 7% and at least 3% body weight reduction.
• Among participants with baseline HbA1c at or above 7% and BMI at or above 25 kg/m2 (n=61), 30 (49.2%) met the composite target.
• Among obese participants (BMI at or above 25 kg/m2) with already-adequate glycaemic control (HbA1c below 7%) at baseline (n=43), 32 (74.4%) achieved the composite endpoint at EoS.

CKD Subgroup (Exploratory)

• Participants with normal or mildly decreased kidney function (eGFR at or above 60 mL/min/1.73m2; n=163): HbA1c reduction -0.9 percentage points (95% CI: -1.0 to -0.8; p<0.0001); weight reduction -4.3 kg (95% CI: -5.2 to -3.5; p<0.0001).
• Participants with CKD Stage 3 or higher (n=25): HbA1c reduction -0.8 percentage points (95% CI: -1.1 to -0.6; p<0.0001); weight reduction -3.7 kg (95% CI: -6.9 to -0.5; p=0.024). The CKD subgroup analysis is underpowered and should be interpreted with caution, as the authors themselves note.

Dose Titration Patterns

• 92.3% of participants (180/195) initiated at 3 mg; by Week 26, 59.6% of those initiating at 3 mg had escalated to 14 mg; by Week 52, 70.4% of the overall cohort were on 14 mg; no participants continued on 3 mg at Week 52.

Concomitant Medication Changes

• Sulphonylurea use declined from 35.4% at baseline to approximately 22% by EoS; thiazolidinedione use declined from 26.7% to approximately 18%. The authors suggest this may have contributed to observed weight loss, though no formal analysis quantified this contribution.

Adverse Events and Safety Profile

The safety endpoint was defined narrowly as severe hypoglycaemia. No severe hypoglycaemia events were recorded from treatment initiation through Week 52, despite approximately 55% of participants concurrently using sulphonylureas or other insulin secretagogues at baseline. The authors attribute this to the glucose-dependent mechanism of GLP-1 receptor agonists, which attenuates insulin secretion at euglycaemia.

Overall, 8 of 195 participants (4.1%) discontinued oral semaglutide by EoS. Among those who discontinued, three were transitioned to subcutaneous semaglutide, one was attributed to GI intolerability, three were due to change in treatment strategy, and four were for unspecified other reasons. The subsequent treatment status of the remaining five was unknown. This low discontinuation rate compares favourably to the 7% to 12% reported in Japanese and Italian real-world cohorts cited by the authors. The study did not systematically capture non-severe GI adverse events, weight loss-related symptoms, or other tolerability data, which limits the completeness of the safety picture.

Statistical Approach and Rigor

The primary analysis used a three-level MMRM with restricted maximum likelihood estimation. The model incorporated hierarchical clustering (site as a second-level random intercept, patient as a third-level random intercept), random slopes for time, and fixed effects for linear and quadratic time, time-varying semaglutide dose, and baseline values of the respective outcome. An unstructured covariance matrix was applied at the patient level. This approach is appropriate for longitudinal observational data with irregular visit intervals and is consistent with the methods used in the PIONEER clinical trial program.

The sample size was powered to detect a mean HbA1c reduction of 0.46 percentage points (SD 1.7) with 90% power, requiring 146 patients with EoS Hb

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