Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown a significant reduction in glycated hemoglobin (HbA1c) and body weight in people with type 2 diabetes (T2D). In addition, some of the injectable GLP-1RAs such as liraglutide, semaglutide, and dulaglutide have shown a significant reduction in major adverse cardiovascular events (MACE). Among the injected GLP-1RAs, semaglutide deserves special mention at least for two reasons. A higher strength of injectable semaglutide (2.4 mg) is also approved for obesity. Secondly, injectable semaglutide (1.0 mg) has shown superior HbA1C and weight lowering in T2D over several active comparators in the Phase 3 Clinical Development Programme named SUSTAIN (Semaglutide Unabated Sustainability In Treatment of Type 2 Diabetes). This includes the superiority of injectable semaglutide 1.0 mg in both HbA1c and weight lowering over sitagliptin 100 mg (SUSTAIN 2, Global), canagliflozin 300 mg (SUSTAIN 8, Global), liraglutide 1.2 mg (SUSTAIN 10, European), dulaglutide 1.5 mg (SUSTAIN 7, Global), exenatide extended-release 2.0 (SUSTAIN 3, Global), and basal insulin glargine (SUSTAIN 4, Global) [1,2,3,4,5,6]. However, injectable semaglutide is not yet available in India. Currently, only two injectable GLP-1RAs such as liraglutide and dulaglutide are available in India. Among these two GLP-1RAs, liraglutide has shown a small but significantly higher weight loss compared to dulaglutide despite similar HbA1c control in AWARD 6 (Assessment of Weekly AdministRation of LY2189265 [dulaglutide] in Diabetes-6) [7].

Orally administered semaglutide is the first oral GLP-1RA approved in 2020 by the United States (US) Food and Drug Administration, the European Medicines Agency, and the Drug Controller General of India (DCGI) for the treatment of T2D, based on extensive Phase 3 Clinical Development Programme named PIONEER (Peptide InnOvatioN for Early diabEtes tReatment). Interestingly, like injectable semaglutide (1.0 mg), oral semaglutide (14 mg) daily has also shown superior HbA1c and weight lowering compared to several active comparators that include empagliflozin 25 mg (PIONEER 2, Global), sitagliptin 100 mg (PIONEER 3 and PIONEER 7, Global), injectable liraglutide 0.9 mg (PIONEER 9, Japanese) and 1.8 mg (PIONEER 4, Global), and injectable dulaglutide 0.75 mg (PIONEER 10, Japanese) [8,9,10,11,12,13]. These findings suggest that both formulations of semaglutide are seemingly effective HbA1c and weight-lowering agents in people with T2D. Interestingly, there are no Phase 3 head-to-head randomized controlled trials (RCTs) that compared these two formulations of semaglutide in people with T2D. However, an indirect comparison of PIONEER 1 and SUSTAIN 1 trial with oral vs. injectable semaglutide, respectively, (against placebo) showed similar proportions of patients with T2D achieved ≥ 5% (44% vs. 45%, respectively) and ≥ 10% (14% vs. 13%) weight loss despite a higher baseline mean body weight in SUSTAIN 1 (96.8 kg) compared with PIONEER 1 (88.1 kg) [14]. These observations concur with the findings from a study that showed a similar circulating level of semaglutide exposure with two different formulations of oral (14 mg) vs. injectable semaglutide (1.0 mg) [15].

Recently, a few observational studies have compared the safety and efficacy of oral vs. injectable semaglutide in people with T2D. A retrospective, single-center study (n = 103) from the UK [16] studied the comparative effectiveness of oral (n = 53) vs. injectable semaglutide (n = 50) in T2D. There was no significant difference in mean HbA1c (−1.77% vs. −1.90%), mean body weight (−9.0 kg vs. −7.2 kg), and mean body mass index (BMI −3.3 kg/m2 vs. −2.5 kg/m2) lowering with oral vs. injectable semaglutide, respectively, at 6-month (p = not significant, for all parameters). Concerning adverse events, gastrointestinal (GI) side effects were similar with both formulations (47% vs. 52% with oral vs. injectable semaglutide, respectively), and 17% of oral and 10% of injectable semaglutide receivers discontinued the treatment for various reasons. Another single-center retrospective study (n = 106) from Croatia [17] compared the effectiveness of oral vs. injectable semaglutide in people with T2D, who are naïve to GLP-1RA. This study showed no significant difference in median HbA1c (−1.4% vs. −1.1%, p = 0.13) and median body weight (−5.9 kg vs. −6.5 kg, p = 0.71)) reduction between oral vs. injectable semaglutide, respectively, at 6 months. Notably, while baseline median HbA1c was significantly higher in the oral semaglutide arm (8.8% vs. 8.0%, oral vs. injectable semaglutide, respectively, p = 0.04), body weight was insignificantly higher in the injectable semaglutide arm (97.3 kg vs. 102 kg, oral vs. injectable semaglutide, respectively, p = 0.08). A weight loss of > 10% was achieved in similar proportions of patients with T2D on both formulations (15.1% vs. 20.7%, oral vs. injectable semaglutide, respectively, p > 0.05). Concerning safety, nausea, the most common GI side effect was seen in similar proportions of patients with both formulations (20% vs. 22%, oral vs. injectable semaglutide, respectively) and none discontinued the treatment in both arms. Similarly, a propensity-matched, retrospective study (n = 214) from Italy [18] comparatively assessed the effectiveness of oral (n = 107) vs. injectable (n = 107) semaglutide in people with T2D for 18 months. Both formulations of semaglutide reduced HbA1c (−0.9% in each arm) and body weight (−3.3 kg vs. −3.7 kg, oral vs. semaglutide, respectively) similarly at 18 months. However, a higher proportion of patients have ≥ 5% weight loss (52% vs. 36%) and persistently continued (70% vs. 60%) on injectable vs. oral semaglutide, respectively.

Collectively, the HbA1c and weight-lowering potential of oral semaglutide (7–14 mg) appear to be nearly similar to injectable semaglutide (0.5–1.0 mg) and larger than other GLP-1RAs, currently approved in people with T2D. Table 1 summarizes the findings of results from the head-to-head RCTs of GLP-1RAs conducted to date and Figure 1 graphically represents the efficacy outcome. Table 2 summarizes the baseline characteristics and findings of results from the observational studies conducted to date that compared oral vs. injectable semaglutide, and Figure 2 graphically represents the efficacy outcome. Notwithstanding, unlike injectable semaglutide which has shown a significant reduction in MACE (SUSTAIN 6) and has an additional label for cardiovascular (CV) risk reduction, oral semaglutide is yet to show CV superiority over placebo (PIONEER 6) [19, 20]. Since PIONEER 6 was not powered to assess the CV superiority of oral semaglutide over placebo, the SOUL (Semaglutide cardiOvascular oUtcomes triaL, NCT03914326) has been specifically designed for this purpose and is estimated to be complete by July 2024 [21].

Table 1 Head-to-head randomized controlled trials of GLP-1RAs in people with type 2 diabetes
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Fig. 1
figure 1

HbA1c and body weight lowering with GLP-1RAs (head-to-head) in people with type 2 diabetes in RCTs

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Table 2 Comparative retrospective studies with oral vs. injectable semaglutide in type 2 diabetes
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Fig. 2
figure 2

HbA1c and body weight lowering with oral vs. injectable semaglutide in people with type 2 diabetes in real-world studies

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