The prevalence of type 2 diabetes (T2D) is rising globally, along with other chronic pathophysiologically and epidemiologically related diseases, including overweight and obesity, arterial hypertension, liver steatosis, and dyslipidemia, all conditions fostered by a sedentary lifestyle and diets high in hydrogenated fats and high glycemic load (1). Concordantly, the importance of a multifactorial approach in T2D has been emphasized by some authors (2, 3). The management of T2D has changed dramatically in the last decade due to the availability of new molecules with proven glycemic and extra-glycemic effects, targeting some specifically diabetes-related chronic comorbidities such as obesity and liver steatosis (4, 5). As an example, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are potent antidiabetic drugs with a favorable safety profile, also allowing a significant weight loss and protective cardiovascular (CV) effects (6, 7)

The use of peptides as oral therapeutic drugs is a long-standing challenge that poses significant technical, physiological and interindividual variability-related obstacles. Oral semaglutide is the first GLP1-RA available for oral administration. For the first time, a peptide-based molecule has been designed to undergo gastric absorption, avoiding the pH-dependent degradation and demolition operated by peptic enzymes (8). More precisely, oral semaglutide has been developed in coformulation with sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC), which acts as an absorption enhancer. SNAC is a hydrophobic molecule that binds to semaglutide, inducing an increased transcellular lipophilicity and enhanced mucosal absorption, without the need for a protective enteric coating (9). The activity of SNAC is transient and reversible, so it separates from the medication soon after it enters the bloodstream. Oral semaglutide is available in three doses: 3, 7, and 14 mg. It needs to be carefully titrated to avoid gastrointestinal discomfort, with a starting dose of 3 mg/day for the first 30 days, followed by 7 mg/day and then, if necessary, 14 mg. During the Peptide Innovation for Early Diabetes Treatment (PIONEER) program (10–15), oral semaglutide (14 mg) reduced HbA1c levels by 1.0-1.4%, significantly more than sitagliptin or empagliflozin did, and to a similar extent to liraglutide after 26 weeks. It also reduced body weight (BW) more than sitagliptin and liraglutide, and to a similar extent to empagliflozin. Lastly, it showed superiority in terms of both HbA1c, and BW reduction compared to dulaglutide (16). Although studies directly comparing the efficacy and safety of oral and subcutaneous semaglutide have never been conducted, a recently published systematic review and network meta-analysis showed that oral semaglutide was slightly less effective than subcutaneous semaglutide in improving glucose control and BW, with a comparable safety profile (17).

Weight loss is essential to improve the management of T2D and related comorbidities and complications, especially fat mass loss while preserving lean mass. In fact, weight loss due to a major decline in lean body mass is normally associated with a decline in skeletal muscle mass and strength, resulting in an increased risk of sarcopenia, impaired glucose sensitivity, and poor glucose control (18). Coexisting obesity and sarcopenia, also called sarcopenic obesity, is one of the leading causes of long-term worsening of glucose control, and should be considered another crucial therapeutic target, especially in elderly patients with T2D (19, 20).

The liver plays a central role in the regulation of lipid metabolism as it is the foremost site of lipid uptake, synthesis, oxidation, and distribution to peripheral tissues. Non Alcoholic Fatty Liver Disease (NAFLD) consists of excessive lipid accumulation in the liver, lipotoxicity, inflammation, and potential progression to Non Alcoholic SteatoHepatitis (NASH), liver fibrosis, and hepatocellular carcinoma (21). Evidence suggests a bidirectional relationship between the progression of NAFLD and T2D (22). An up-to-date approach to T2D should include appropriate assessment of body composition and biomarkers of NAFLD, both for clinical and research purposes, due to the metabolic role of new antihyperglycemic drugs, whose effect on weight, body composition, and metabolic parameters is now well established and documented (23–27).

In this context, early improvement in body composition, assessed by segmental multifrequency bioelectrical impedance analysis (SMF-BIA) (27), and in biochemical and ultrasound (US) characteristics of Non-Alcoholic Fatty Liver Disease (NAFLD) (28) has recently been found in T2D patients treated with once-weekly semaglutide for 26 and 52 weeks. On this basis, the aim of this study was to evaluate the effects of oral semaglutide on body composition and surrogate markers of NAFLD in a cohort of patients with T2D followed up for 26 consecutive weeks in a real-life setting.

To assess whether the available sample was sufficient to obtain reliable results, the first step was to evaluate the power analysis, using G*power, for the variable Fat Mass, which is one of the primary outcomes. Assuming an explained variability of at least 15% (η²), setting α=0.05, an effect size of 0.4 corresponding to a test power of 0.9 was estimated, based on a real sample of 30 patients (35).

Patient characteristics at baseline were expressed as mean, standard deviation, median, range, frequency, and percentage, as appropriate. Changes over time (T0, T3 and T6) for each variable were analyzed with repeated-measures Mixed Models, and changes in the means were estimated by the least-squares method; pre-planned contrasts between times were inserted in the model. To assess potential predictive factors, baseline characteristics were compared between Responder and Non-Responder patients by unpaired Student t test. Statistical analysis was performed with SAS 9.4 software (SAS Institute Inc., Cary, NC, USA), and graphs were made with Microsoft excel for Mac (vers.16.16.27, ©Microsoft 2018).

The results of this 26-weeks prospective, real-life study show that the oral formulation of semaglutide, in addition to improving glucose control and body weight, exerts beneficial effects on body composition by reducing fat mass and preserving muscle mass, with better overall body fluid distribution.

Since 2005, GLP-1RAs have been a treatment option for T2D, providing a significant reduction in HbA1c and body weight with a low risk of hypoglycemia. They have also been shown to provide cardio- and nephron-protection, especially in patients with cardiovascular and chronic kidney disease (37–39). Currently, semaglutide is the first GLP-1RA designed for both oral and injective administration. The oral formulation is an appealing option for patients with T2D who prefer oral to injectable therapies. By increasing patient compliance and adherence, oral semaglutide could promote earlier use of GLP1-RAs, allowing them to act as disease modifiers. It also provides a viable alternative during the current period of international shortage of the subcutaneous formulation of semaglutide (40).

Our study population also included newly diagnosed patients (disease duration 0 years). The short median duration of T2D, less than 10 years, indicates full implementation of recent guidelines prescribing GLP1-RAs as one of the main classes to be used in the first instance. At the same time, patients with long-lasting disease (maximum duration 35 years) were not excluded from the study, suggesting that oral semaglutide may also be a therapeutic choice in patients with longer disease evolution. Normal BMI was not a barrier to prescribing oral semaglutide, as normal-weight patients were also treated, as previously suggested (6). It should be considered, in fact, that the link between CVR and BMI is complex and related not only to the amount of body weight, but rather to fat distribution and body composition. Thus, normal weight patients may have a CVR similar to that of overweight individuals if their fat mass is predominantly visceral and/or they have a small amount of muscle mass (sarcopenia).

The reduced oral bioavailability (0.4-1%) and complex pharmacokinetics of oral semaglutide make appropriate counseling and patient adherence to the administration instructions crucial, and are potential obstacles to the success of this treatment regimen. The absorption of oral semaglutide, in fact, largely depends on several factors, including a fasting state and no pharmacological interference. It should be taken fasting, swallowing the tablets with about 120 ml of water, and then fasting for at least another 30 minutes post-administration (41). Hence, the bioavailability could be affected leading to a larger patient-to-patient variability when compared to subcutaneously injectable semaglutide (42). In this context, our evaluation of the effects of a 26-week course of oral semaglutide therapy confirmed, in a real-life setting, the effectiveness of this new drug formulation in achieving an early and significant decrease in HbA1c, body weight and waist circumference in treated patients. With reference to the body weight parameter, the average body weight loss was about 4 kg after 6 months. The result agrees with data from the main PIONEER studies (10, 14), with a response rate of 50%, which should be considered a satisfactory endpoint in this population. Indeed, in enrolled patients who were normal or underweight, excessive body weight loss was not desirable. A good drug manageability emerged from its negligible effects on heart rate, eGFR, and pancreatic enzymes. Furthermore, the significant reduction in ALT and FLI suggests that oral semaglutide improves liver lipotoxicity due to NAFLD, as previously reported for injectable GLP1-RAs (43) and, recently, for oral semaglutide as well (44). The significant change in FLI and not HSI in our study population, which had no signs of NASH (normal liver enzyme levels) at baseline, would reflect the predominant effect of the drug more on waist circumference, which enters the calculation of FLI alone and is more related to visceral fat, than on liver enzymes. Finally, also the finding of unchanged values of APRI and FIB4 scores under semaglutide therapy was not surprising. Indeed, both scores are validated tools for delineating the risk and severity of liver fibrosis and cirrhosis even in patients with NAFLD. In our sample, median values were normal at baseline, indicating that the study population was at low risk for liver fibrosis. Therefore, the absence of deterioration of these clinical data was what was expected over such a short observation period.

Considering the significant effects of GLP-1RAs on body weight reduction, it has become essential to assess their impact on different body compartments, and especially metabolically active components. In people who are overweight or obese, the decrease in fat-free mass (FFM), which includes the total mass of bone, muscle, connective tissue, and fluids within the body, contributes about 20-30% of the total diet-induced weight loss (45). Strategies to preserve muscle mass and function in patients with T2D receiving a dietary or therapeutic regimen that may induce weight loss are therefore crucial in the management of the disease (46), especially considering that T2D patients are prone to sarcopenia (20). Studies focusing on GLP1-RA effects on body composition have been concordant in demonstrating the effectiveness of this drug class in reducing fat mass while preserving lean mass (26–28, 47). Few studies have yet addressed this issue with reference to oral semaglutide. A 12-week randomized controlled trial (RCT) on T2D patients recently described a reduction in food craving, preference for sweet foods, and improved dietary control with oral semaglutide compared with placebo, resulting in a decrease in body fat mass analyzed by plethysmography, without impairment of whole lean mass (48).

In our study, during therapy we observed a significant and early decrease in both total fat mass and the fat mass index (FMI), which latter is a more reliable parameter for inter-individual comparisons because it normalizes measurements to height. Visceral adipose tissue also decreased during follow-up, although the reduction was not statistically significant. This finding is not surprising considering the baseline characteristics of the enrolled patients, which initially had pathological but highly variable average values of visceral adipose tissue, with minimum values as low as 0.6 liters, within normal range. The loss of visceral adipose tissue, regardless of magnitude, still has beneficial effects on glucose metabolism and is accompanied by a decrease in circulating cytokines involved in low-grade inflammation, insulin sensitivity, and cardiovascular risk (49).

Undoubtedly, the most interesting data concern the impact of oral semaglutide on lean mass. Throughout the observation period, despite the significant weight loss, patients had a beneficial and significant increase in Fat-Free Mass as early as the third month of treatment that persisted until the end of follow-up. Notably, this effect was attributable in part to the preservation of skeletal muscle mass and improved distribution of body fluids. This is in line with studies showing that GLP-1 increases vascular blood flow and activates glucose delivery into skeletal muscle via AMP-activated protein kinase (AMPK), thereby promoting muscle synthesis, reducing muscle breakdown (50, 51) and improving muscle microvascular recruitment (MVR) through increased endothelial surface area (52). Skeletal muscle mass enhancement positively affects insulin sensibility and fat metabolism through different molecular mechanisms (53), ultimately leading to clinically relevant benefits.

The finding of higher values of the SMM/VAT ratio after therapy than at baseline, suggests that oral semaglutide could prevent a potential state of sarcopenic visceral obesity in T2D patients. This is an important therapeutic goal because the risk of sarcopenic obesity increases with aging and is associated with worse glucose and blood pressure control, higher insulin resistance, higher prevalence of dyslipidemia, T2D, cardiovascular diseases, NAFLD, and higher mortality than sarcopenia or obesity alone (54, 55). In addition, the condition characterized by poor skeletal muscle mass and visceral adipose tissue accumulation (the so-called “sarcopenic visceral obesity”), is associated with a further increased insulin resistance and impaired metabolism, worsening the overall clinical picture (55).

Finally, special attention should be paid to the analysis of impedance data on body water distribution. The ECW/TBW ratio is strongly indicative of the body nutritional and metabolic qualities (56). Our data suggest that patients had a better hydration, as indicated by significant increase in total body water, and more beneficial fluid distribution (no increase in the ECW/TBW ratio) at the end of follow-up, indicating an overall improvement in the body’s nutritional status as a result of therapy.

To our knowledge, this is the first prospective real-world study to evaluate the impact of oral semaglutide on body composition and metabolic parameters in overweight and normal-weight patients with T2D. The main limitations of the study are the lack of a control group, the single-center design, and the low sample size, which, although statistically adequate, does not allow for a more in-depth analysis of muscle mass stratified by patient gender. Another limitation is the lack of instrumental evaluation of the liver, which did not allow us to confirm the diagnosis of NAFLD and its related liver complications. Finally, in light of the short duration of follow-up, it should be pointed out that long-term studies are needed to evaluate the duration of the effects of oral semaglutide over time.

Our data confirm the effectiveness of oral semaglutide, showing early benefits on glucose control, body weight, and fat mass. Oral semaglutide was also found to be a useful option for approaching normal-weight T2D patients, who are often excluded from GLP1-RA treatment. Of particular interest were the unexpected effects on lean mass. Improvement of muscle mass is highly desirable in patients with diabetes, who are more prone to sarcopenia conditions. This field of action is increasingly emerging as an interesting challenge that opens new promising perspectives in the multiparametric and personalized management of diabetic disease.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Ethics Committee of the Bari Polyclinic University Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

GP, SV, and DR contributed to conception and design of the study. VC, VL, DT, LC, and GL organized the database. GP, GL, VC, and VL contributed to the clinical follow-up of patients. MF performed the statistical analysis. SV, GL, and GP wrote the first draft of the manuscript. GP, SV, GL, DR, VT, CS, and GDP contributed to review and editing the final version of the manuscript. All authors contributed to the article and approved the submitted version.