Background: Type 2 diabetes (T2D) is a chronic and progressive metabolic disorder that poses a major global health challenge. With over 530 million people affected worldwide in 2021 and projections estimating this number will rise to 780 million by 2045, there is an urgent need for therapies that go beyond glycaemic control to address weight management, cardiovascular risk, and patient adherence. To summarize evidence from clinical trials and real-world studies evaluating the efficacy, safety, and broader clinical impact of oral and injectable semaglutide in diverse T2D populations.
Methodology: A review of findings from multiple studies, including randomized controlled trials (PIONEER 11, Aroda et al., Bonora et al.) and real-world data (PIONEER REAL UK), assessing semaglutide’s impact on HbA1c, body weight, insulin use, and treatment satisfaction.
Results: In a predominantly Chinese cohort, oral semaglutide (14 mg) led to significant reductions in glycosylated hemoglobin (HbA1c) and weight. High-dose subcutaneous semaglutide (up to 16 mg/week) showed superior glycaemic and weight loss outcomes in overweight/obese patients versus lower doses. In real-world settings, oral semaglutide was effective and well-tolerated, with nearly 50% of patients achieving HbA1c targets and reporting improved treatment satisfaction. Once-weekly semaglutide facilitated glycaemic improvement and insulin discontinuation in insulin-dependent patients. Gastrointestinal side effects were the most common adverse events, but were generally mild and manageable.
Conclusion: Semaglutide, in both oral and injectable formulations, is a versatile, effective, and well-tolerated option for T2D management. It improves glycaemic control, supports weight loss, simplifies treatment regimens, and may reduce the need for insulin, making it particularly beneficial for patients with comorbid obesity and cardiovascular risk.

Semaglutide, Type 2 diabetes, Glycemic control, Weight loss, Insulin discontinuation, Real-world evidence, Cardiovascular risk.

T2D presents a major and growing global health concern. In the year 2021, an estimated 530 million people were affected, and this number is expected to rise to approximately 780 million by the year 2045. In China, about 140 million individuals had diabetes in 2021, and this is projected to increase to 174 million by 2045. Most of these cases are due to type 2 diabetes, which highlights the urgent need for more effective treatment strategies.[1-5]

Achieving and maintaining good blood glucose control and promoting weight loss are crucial in managing type 2 diabetes and in preventing long-term complications. Diabetes and obesity are closely connected by shared biological mechanisms. Recent research also suggests that East Asian populations, including those in China, show distinct clinical patterns compared to Western populations. These differences may influence treatment effectiveness and indicate the need for region-specific approaches.[6-10]

Glucagon-like peptide 1 receptor agonists (GLP-1 receptor agonists) are recommended by both international and Chinese guidelines for their ability to reduce blood sugar levels and body weight and, in some cases, lower the risk of heart disease. However, the use of injectable forms of these medications remains limited in some regions, like China and the United Kingdom. The reluctance to use injections has created a demand for effective oral treatment options.[11-15]

Oral semaglutide is the first GLP-1 receptor agonist available in tablet form. It combines the semaglutide molecule with an absorption enhancer known as sodium N eight two hydroxybenzoyl amino caprylate. Its safety and effectiveness have been demonstrated through a global clinical research program known as PIONEER. While the PIONEER 9 and 10 trials included mainly Japanese participants, the PIONEER 11 study focuses specifically on Chinese individuals with type 2 diabetes that is not well controlled by diet and exercise alone.[16-20]

In the United Kingdom, type 2 diabetes affects about 3.9 million people, with an additional one million undiagnosed and more than 2.4 million considered at risk. Early treatment involving lifestyle changes and medications is essential to reduce complications. While metformin remains the first choice according to the National Institute for Health and Care Excellence (NICE), GLP-1 receptor agonists are introduced when additional drugs fail. The arrival of oral semaglutide in 2020 offered a more convenient alternative to injectable options. The PIONEER REAL United Kingdom study evaluated its real-world use in patients who had not previously used injectable therapy, showing meaningful improvements in blood sugar levels and weight. NICE supports incorporating real-world evidence into treatment decisions.[21,22]

Further research has examined the use of higher doses of injectable semaglutide. Although gastrointestinal side effects were a concern at first, later studies found that patients tolerated larger doses over time. The SUSTAIN FORTE trial showed that a dose of two milligrams per week was more effective than one milligram per week and had a similar safety profile. Current studies are exploring weekly doses up to sixteen milligrams in individuals with a body mass index of twenty-seven or higher to assess potential benefits in weight loss and glycaemic control.[23]

Despite the availability of many medications that lower blood sugar, many patients still require insulin therapy, which may cause weight gain, low blood sugar episodes, and reduce long-term treatment adherence. Even with insulin, many individuals do not reach their blood sugar targets. Clinical guidelines now recommend GLP-1 receptor agonists as the preferred initial injectable therapy because of their ability to lower blood sugar and weight while also improving heart and kidney outcomes. These agents have proven more effective than insulin in both clinical trials and real-world practice, and they also allow for the simplification of complex treatment regimens.[24]

The GLIMPLES study conducted in Italy evaluated once weekly semaglutide use in patients already on insulin. It found significant improvements in blood sugar and body weight. Notably, about one-third of patients were able to stop insulin while maintaining good glycaemic control. Success in discontinuing insulin was more likely in those with a shorter history of diabetes, lower initial HbA1c levels, and fewer complications.[25]

Semaglutide in both oral and injectable forms offers a promising treatment for individuals with type 2 diabetes. Its demonstrated effectiveness, convenient oral formulation, and role in simplifying therapy make it an important option in current diabetes care.[26]

Efficacy and safety of oral semaglutide in a predominantly Chinese population with type 2 diabetes
PIONEER 11 was a 26-week, randomised, double-blind, placebo-controlled Phase IIIa trial (NCT04109547) conducted at 52 sites across China, Taiwan, Hungary, Serbia, and Ukraine. Adults aged ≥18 years (≥20 in Taiwan) with type 2 diabetes, baseline HbA1c 53–86 mmol/mol (7.0-10.0%), and no prior glucose-lowering therapy were randomised (1:1:1:1) to oral semaglutide 3 mg, 7 mg, 14 mg, or placebo after a 4-week run-in.

Participants took the study drug once daily in a fasting state with up to 120 mL of water, ≥30 minutes before food. The 7 mg and 14 mg groups underwent a 4-week dose escalation. The primary endpoint was change in HbA1c at week 26; the confirmatory secondary endpoint was change in body weight. Additional endpoints included HbA1c targets, weight loss (≥5%, ≥10%), and changes in fasting plasma glucose, 7-point SMPG, BMI, blood pressure, and lipids.

In a study by wang et al., a total of 774 participants were enrolled between October 2019 and October 2021, and 521 were randomised: 3 mg (n=130), 7 mg (n=130), 14 mg (n=130), and placebo (n=131). The cohort had a mean age of 52 years, baseline HbA1c 63 mmol/mol (8.0%), body weight 79.6 kg, and was 63.7% male.

At week 26, HbA1c reductions vs placebo were –12 mmol/mol (3 mg), –16 mmol/mol (7 mg), and –17 mmol/mol (14 mg) (p<0.001 for all). Weight reductions were significant with 7 mg (–2.2 kg) and 14 mg (–3.0 kg), but not with 3 mg.

More semaglutide users met HbA1c and weight loss targets. The 14 mg dose also reduced LDL-cholesterol and triglycerides. Adverse events occurred in 65.4%-72.3% of semaglutide groups vs 57.3% with placebo, mainly mild gastrointestinal symptoms. Serious adverse events were rare, with no deaths. Hypoglycaemia was infrequent.[27]

Efficacy and safety of high-dose semaglutide in type 2 diabetes with overweight or obesity
This multicenter, randomized, double-blind, placebo-controlled phase 2 trial was conducted at 75 sites in Greece, Hungary, Poland, and the U.S. Adults aged 18–64 years with type 2 diabetes (diagnosed ≥180 days), HbA1c 7.0–10.5%, BMI ≥27 kg/m², and stable metformin use were eligible. Key exclusions included recent use of diabetes/obesity medications, major comorbidities, or lifestyle changes.

Participants were randomized (3:1:3:1:3:1) to receive weekly subcutaneous semaglutide (2 mg, 8 mg, or 16 mg) or placebo, stratified by baseline HbA1c (<8.5% or ≥8.5%). Dosing began at 0.29 mg, escalating every 4 weeks to reach target doses over 12–24 weeks, followed by a 16–28-week maintenance phase. Total treatment duration was up to 40 weeks, with 9 weeks of follow-up. Dose reductions were not permitted; intolerant participants were discontinued. Injections were delivered via NovoPen 4.

The primary endpoint was the change in HbA1c at week 40. Secondary endpoints included changes in body weight, adverse events, and other metabolic/cardiovascular markers up to week 49. Rescue medication was allowed from week 12 for HbA1c >8.5%.

In a study by Aroda et al., out of 359 screened, 245 were randomized: semaglutide 2 mg (n=61), 8 mg (n=62), 16 mg (n=62), or placebo (n=60). A total of 219 (89.4%) completed the trial, and 181 (73.9%) completed treatment. Completion was highest in the 2 mg group (85%). Most discontinuations were due to GI adverse events.

Rescue medication use was 13.1%, mainly among those with baseline HbA1c >8.5%. Among completers, 94% (2 mg), 83% (8 mg), 98% (16 mg), and 61% (placebo) avoided rescue therapy.

HbA1c reductions at week 40 were −1.8%, −1.8%, −2.1%, and −1.0%, respectively. Weight reductions were −7.3%, −8.3%, −10.8%, and −2.0%. Dysesthesia occurred more in the 8 mg (8%) and 16 mg (18%) groups. Nine serious AEs were reported. No severe hypoglycemia or deaths occurred.[28]

Study Outcomes: Efficacy, safety, and treatment experience with oral semaglutide in routine clinical practice
PIONEER REAL UK was a 34–44-week, phase 4, non-interventional, prospective, single-arm study evaluating oral semaglutide in adults with type 2 diabetes (T2D) in routine UK clinical care. Participants (≥18 years) were injectable-naïve with recent HbA1c data. Semaglutide was prescribed independently of the study. The primary endpoint was change in HbA1c; secondary endpoints included weight change, treatment satisfaction, and achieving HbA1c <7%.

In a study, Saravanan et al., among 356 consenting participants (May 2021–August 2023), 333 began semaglutide; 299 completed the study, and 227 remained on treatment. Discontinuations (n=106) were mostly due to GI intolerance (51), supply issues (11), or other factors. Mean age was 58.5 years, 61.3% male, mean BMI 35.5 kg/m², weight 102.8 kg, and baseline HbA1c 8.6%. Most (70.6%) were treated in primary care.

Semaglutide was initiated primarily for glycaemic control (94%) and weight loss (73.6%). HbA1c dropped by 1.1% (95% CI –1.27 to –0.96; P < 0.0001) or 12.2 mmol/mol (CI –13.87 to –10.47). At EOS, 46.3% achieved HbA1c <7%, with greater reductions in those with higher baseline HbA1c and shorter diabetes duration.

Weight reduction (n=276) averaged 4.8 kg (CI –5.47 to –4.12; P < 0.0001) or 4.6% (CI –5.24 to –3.99). Composite outcomes: 36.4% had ≥1%-point HbA1c and ≥3% weight loss; 27.1% had ≥1%-point HbA1c and ≥5% weight loss. Treatment satisfaction improved: DTSQs score rose by 2.0 points; DTSQc at EOS was 13.6.

At EOS, 68.2% were on semaglutide: 73.1% on 14 mg, 21.6% on 7 mg, 5.3% on 3 mg. Additional meds were added in 25.2%, reduced in 17.4%. Clinical success was achieved in 72.6%. Waist circumference decreased by 5.0 cm.

Adverse events were reported in 57.4%, mostly mild/moderate. Serious AEs occurred in 5.4%. GI events were most common (41.1%). No related deaths, severe hypoglycaemia, or pregnancies occurred.[29]

Key clinical outcomes with once-weekly semaglutide in insulin-treated patients with type 2 diabetes
This multicentre retrospective real-world study (GLIMPLES) was conducted at 18 diabetes specialist centres in Italy using anonymised electronic records from MetaClinic. Adults (≥18 years) with T2D diagnosed ≥1 year before the index date, receiving any insulin regimen, and initiating once-weekly (OW) semaglutide without prior GLP-1RA exposure were included. Patients with other diabetes types or missing follow-up were excluded. The study was ethically approved per the Declaration of Helsinki.

The primary objective was to evaluate OW semaglutide’s effect on HbA1c; secondary objectives included changes in body weight, insulin dose, and insulin discontinuation. The index date was the first semaglutide prescription. Repeated prescriptions were used to define persistence. Data included demographics, BMI, blood pressure, diabetes duration, fasting glucose, HbA1c, lipid profile, kidney function, albuminuria, complications, and cardiovascular history. Follow-up semaglutide doses were also recorded.

Mixed models for repeated measures adjusted for baseline HbA1c, time, and persistence were used. Student’s t-test and chi-squared test were used for group comparisons. Logistic regression assessed predictors of achieving HbA1c <7%, while Cox regression evaluated predictors of insulin discontinuation. Analyses were performed using SPSS v28 with p < 0.05 as the significance threshold.

In Bonora et al.’s analysis (n = 674), mean age was 61.7 years, diabetes duration 11.5 years, and baseline HbA1c 8.2%. At initiation, 23.6% discontinued insulin; 81% used metformin, and 75.4% basal insulin. Over 18 months, HbA1c decreased by −0.8% (p < 0.001); greater reductions were seen in semaglutide continuers (−0.6%; p < 0.001), metformin users (−0.3%; p = 0.049), and non-SGLT2 inhibitor users (−0.3%; p = 0.045). Among continuers with baseline HbA1c >7%, 60% achieved <7% versus 24% of discontinuers. Weight loss averaged −3.5 kg (p < 0.001); 58% lost ≥5% weight, with greater reductions in women (−1.8 kg; p < 0.001) and those who stopped bolus insulin (+1.3 kg; p = 0.006). Insulin was stopped in 32.8%, 72.5% of whom achieved HbA1c <7%. Mean insulin dose declined by 10.0 UI (p < 0.001). Discontinuation predictors included shorter diabetes duration, lower baseline HbA1c and insulin dose, and absence of microangiopathy.[30]

Table 1:  Comparative table of semaglutide clinical and real-world studies

Recent clinical trials and real-world studies have consistently demonstrated the effectiveness and safety of semaglutide, both in oral and injectable forms, for managing type 2 diabetes (T2D). In the PIONEER 11 trial by Wang et al., oral semaglutide led to significant improvements in glycaemic control and body weight among a predominantly Chinese population with T2D inadequately managed with lifestyle interventions. Over 26 weeks, patients receiving 14 mg of oral semaglutide experienced a reduction in HbA1c by 1.6 percent and lost an average of 3.0 kilograms. The findings were consistent with prior global studies and confirmed the efficacy of oral semaglutide in East Asian populations, who often present with distinct pathophysiological features compared to Western populations.[27]

Aroda et al. evaluated higher doses of subcutaneous semaglutide, up to 16 milligrams weekly, in overweight or obese individuals with T2D. The 16 mg dose group showed the greatest reductions in HbA1c by 2.1 percent and in body weight by 10.8 percent at week 40. Gastrointestinal side effects were more common at higher doses but were generally manageable. This study supports the value of individualized dose escalation to achieve optimal results.[28]

In the United Kingdom, Saravanan et al. conducted the PIONEER REAL study in routine clinical practice. Patients experienced an average HbA1c reduction of 1.1 percent and weight loss of 4.8 kilograms over approximately nine months. Nearly half of the participants achieved an HbA1c below seven percent. Most patients continued treatment at the 14 milligram dose, and satisfaction scores significantly improved. These findings underline the real-world applicability and tolerability of oral semaglutide in primary care settings.[29]

Bonora et al. examined once-weekly injectable semaglutide in insulin-treated T2D patients across 18 centers in Italy. The study revealed a mean HbA1c reduction of 0.8 percent and weight loss of 3.5 kilograms. Notably, one-third of participants were able to discontinue insulin therapy while still achieving glycaemic targets. Those with shorter diabetes duration, lower baseline HbA1c, and absence of microvascular complications were more likely to stop insulin.[30]

Together, these studies highlight semaglutide’s capacity to improve glycaemic control, reduce body weight, and potentially simplify treatment regimens. It proves effective across different populations and healthcare settings. The benefits extend beyond glucose control to include reduced cardiovascular risk and better patient adherence, especially when individualized dosing strategies are applied for tolerability and sustained results.

Limitations
This review draws on both clinical trials and real-world data, which differ in design, population characteristics, and treatment settings, potentially limiting comparability. Real-world studies included in the review were observational, introducing risks of selection bias, incomplete data capture, and confounding variables. Many trials had relatively short durations, which may not fully reflect long-term efficacy, adherence, or safety outcomes. Additionally, regional variations in healthcare systems, prescribing practices, and population genetics may influence generalizability, particularly for data drawn predominantly from Chinese or European cohorts. The limited availability of head-to-head comparisons with other antidiabetic agents also restricts broader therapeutic positioning.

T2D remains a significant and growing public health concern worldwide, demanding effective and sustainable treatment strategies. Semaglutide, a GLP receptor agonist, has emerged as a transformative therapy due to its dual benefits of glycaemic control and weight reduction. This review of clinical trials and real-world studies demonstrates that semaglutide, in both oral and subcutaneous formulations, offers substantial advantages for diverse patient populations. Oral semaglutide has shown robust efficacy, particularly in Asian populations, by significantly lowering HbA1c and body weight, while improving overall treatment satisfaction. The availability of a convenient oral formulation has addressed long-standing barriers related to injectable therapies, especially in regions with cultural or logistical hesitations toward injections.

Injectable semaglutide, particularly at higher doses, has proven effective in managing overweight and obese individuals with T2D. It has also enabled insulin-treated patients to reduce or even discontinue insulin use, simplifying their treatment regimens and enhancing adherence. The favorable safety profile, with gastrointestinal side effects being the most common but generally mild and self-limiting, further supports its use in long-term management. Real-world evidence from studies such as PIONEER REAL UK and GLIMPLES Italy reinforces the clinical trial findings, confirming semaglutide’s impact on key outcomes in routine clinical settings. Importantly, semaglutide’s cardiovascular and renal benefits position it as a comprehensive therapeutic option beyond glycaemic control.

Overall, semaglutide represents a valuable addition to the diabetes treatment landscape, offering flexibility, effectiveness, and improved patient-centric outcomes in the management of type 2 diabetes.

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No funding

Corresponding Author:
Samatha Ampeti, PhD
Department of Pharmacology
Kakatiya University, University College of Pharmaceutical Sciences, Warangal, TS, India
Email: ampetisamatha9@gmail.com

Co-Authors:
Mansi Srivastava, Sonam Shashikala BV, Raziya Begum Sheikh, Patel Nirali Kirankumar, Shubham Ravindra Sali
Independent Researcher
Department of Content, medtigo India Pvt Ltd, Pune, India

All authors contributed to the conceptualization, investigation, and data curation by acquiring and critically reviewing the selected articles. They were collectively involved in the writing – original draft preparation and writing – review & editing to refine the manuscript. Additionally, all authors participated in the supervision of the work, ensuring accuracy and completeness. The final manuscript was approved by all named authors for submission to the journal.

Not applicable

None

None

https://doi.org/10.63096/medtigo3061238

Mansi S, Samatha A, Sonam SBV, Raziya BS, Patel NK, Shubham RS.  Advancing Type 2 Diabetes Management with Semaglutide: Clinical and Real-World Insights. medtigo J Pharmacol. 2025;2(3):e3061238. doi:10.63096/medtigo3061238 Crossref