Introduction

It is known that throughout the world that approximately 40% of adults are overweight and more than 15% of subjects are living with obesity. Obesity is a complex condition linked to chronic inflammation leading to the development of comorbidities such as metabolic syndrome, cardiovascular disease, type 2 diabetes (T2DM), non-alcoholic steatohepatitis or different types of tumors [1].

In the last years there has been a significant increase in knowledge of the use of glucagon-like peptide 1 receptor agonist (GLP1-RA) agonists in the treatment of T2DM and obesity or overweight. Since 2005, several GLP1-RA agonists have been approved for the treatment of T2DM, but only liraglutide and semaglutide have been approved for the treatment of obesity. Semaglutide is a long-acting GLP1-RA, indicated for the management of adults with T2DM and overweight or obesity as an adjunct to diet and exercise as shown by the SUSTAIN trial program [2]. GLP1-RA have demonstrated effectiveness in lowering glycated hemoglobin (HbA1C), decreasing weight, and reducing the risk of major cardiovascular events in patients with T2DM.

Since 2021, Semaglutide 2.4 mg has been approved by the European Medicines Agency (EMA) for the long-term treatment of both non-diabetic adult and adolescent subjects with obesity or overweight [3]. Currently, Semaglutide is the only GLP-1-RA available in both injectable and oral form for the treatment of T2DM subjects [4]. The STEP 2 study has shown that the once weekly Semaglutide therapy at a dose of 2.4 mg in T2DM subjects with overweight or obesity was more effective in weight loss (WL) compared to Semaglutide at dose of 1.0 mg or placebo [5]. The effectiveness of Semaglutide treatment at a dose of 2.4 mg on WL maintenance in subjects with overweight or obesity was also reported in the STEP 4 and STEP 5 studies respectively over the 48 and 104 weeks of therapy [6, 7]. Oral Semaglutide 50 mg also induced a significant WL compared to placebo (15.1% versus 2.4%) [8], however the use in clinical practice of oral Semaglutide 50 mg is not yet approved.

Here, we report the efficacy and safety of semaglutide therapy on glycemic control, the effectiveness on WL maintenance of Semaglutide therapy, and the comparison of efficacy between injectable (IS) and oral Semaglutide (OS) treatment alone or in combination with other antidiabetic drugs in T2DM subjects with obesity or overweight. Preliminary data from this article were reported at the 31st European Congress on Obesity (ECO 2024) [9, 10].

Patients and methods

One hundred and seventy-five subjects with obesity or overweight and recent diagnosis of (< 6 months) T2DM were retrospectively evaluated for WL and glycemic control with Semaglutide therapy at the Sant’Anna Hospital of Como. Baseline patient characteristics are reported in Table 1. At baseline, 35 patients had arterial hypertension in the IS group and 11 in the OS group. At the time of the first visit, no patient had other known comorbidities.

Table 1 Baseline characteristics of patients treated with injectable and oral Semaglutide
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All patients were aged more than 18 years old and examined every 6 months from the beginning of the treatment. Of these, 129 subjects (75 Female and 54 Male; mean age 61.2 ± 9.8 years) were treated with IS and 46 (24 Female and 22 Male; mean age 65.7 ± 12.8 years) with OS therapy for WL and glycemic control.

Semaglutide therapy was administered as monotherapy or in combination with metformin. The patients were no taking other antidiabetic drugs. IS treatment was administered once weekly subcutaneously. The starting IS dose was of 0.25 mg and with monthly increases up to 1.0 mg. OS therapy was administered once daily at the starting dose of 3 mg and with monthly increases up to 14 mg in all patients. Data on semaglutide effectiveness and safety was recorded up to 24 months for IS treatment group and up to 12 months for OS treatment group from baseline.

The percentage of WL and the mean body mass index m(BMI) changes in all patients and subgroups according to the degree of obesity were calculated to assess the effectiveness of both IS and OS group therapies. Percentage changes in glycated hemoglobin (HBA1C) were also calculated from baseline in both subject groups of treatment.

All patients were required to adhere to dietary and behavioral advice (as 200 min of walking per week) and any concomitant drug treatment. Patients received the total daily energy requirement calculated by using Harris-Benedict formula. The aim was to receive the target energy per day as a 500-kcal subtraction from the total energy requirement. The diet regime included approximately 50% carbohydrates, 30% lipids and 20% proteins. Patient consents were not required due to the retrospective nature of this study.

Statistical analysis was performed with GraphPad Prism software (version 9, GraphPad Software Inc., La Jolla, CA) and as also reported elsewhere [11]. Data were expressed as mean ± standard deviation (SD) and p-value was considered significant if < 0.05. The Kolmogorov–Smirnov test was used to evaluate data distribution. The comparison of data on weight and BMI changes was performed using the two-tailed paired student’s t or Wilcoxon test, Pearson correlation or Spearman tests.

Results

Effectiveness assessment of weight loss and weight loss maintenance after IS and/or OS

At the first visit, mean weight m(W) was 101.8 ± 24.6 and kg 95.2 ± 15.0 kg; mBMI was 36.7 ± 8.7 kg/m2 and 34.3 ± 5.3 kg/m2 respectively for IS and OS group of subjects. At baseline there were no statistical differences mW (p = 0.089) and mBMI (p = 0.39) between the two groups.

After 6 months from the beginning of therapy, 127/129 patients treated with IS (2 patients have not yet reached 6 months of treatment) achieved a mW of 95.4 ± 24.1 kg and mBMI of 34.2 ± 9.4 kg/m2, with a mW and mBMI reduction respectively of − 10.4 ± 8.1 kg (− 9.5 ± 6.5%) and − 3.9 ± 3.0 kg/m2. 46/46 patients treated with OS had a mW of 90.3 ± 12.7 kg and a mBMI of 33.4 ± 4.3 kg/m2. The mW reduction was − 6.7 ± 5.3 kg (− 6.8 ± 5.8%); while the mBMI reduction was − 2.6 ± 2.1 kg/m2.

After 12 months of therapy, 102/129 subjects achieved a mW of 88.5 ± 17.7 kg and mBMI of 31.9 ± 5.5 kg/m2, with a mW and mBMI reduction respectively of − 9.3 ± 7.5 kg (− 9.2 ± 7.7%) and -3.4 ± 2.6 kg/m2. 44/46 patients treated with OS achieved a mW of 89.2 ± 14.0 kg and mBMI of 31.5 ± 4.3 kg/m2 with a mWL of − 10.7 ± 6.5 kg (− 10.4 ± 5.8%); and mBMI reduction of − 3.9 ± 2.4 kg/m2 (Figs. 1 and 2).

Fig. 1
figure 1

Continuing weight loss of patients treated with Injectable Semaglutide. BMI body mass index. Statistical significance from baseline: 6 months p < 0.0001, 12 months p < 0.0001 and months p < 0.0001

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Fig. 2
figure 2

Weight loss of patients treated with Oral Semaglutide. BMI body mass index. Statistical significance from baseline: 6 months p < 0.0001 and 12 months p < 0.0001

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There was no statistical difference in mWL variations and mBMI changes after 6 (weight p = 0.092; BMI p = 0.092) and 12 months (weight p = 0.73; BMI p = 0.74) of therapy between IS and OS therapy.

After 24 months from the beginning of the therapy, only patients of the IS group were assessed. Of these, 92/129 subjects achieved a mW of 83.2 ± 14.0 kg and mBMI of 30.6 ± 4.4 kg/m2, with a mW and mBMI reduction respectively of − 15.9 ± 11.4 kg (− 15.0 ± 8.7%) and − 5.8 ± 3.7 kg/m2 (Fig. 1).

In the IS group there was a statistical significance in mW and mBMI reduction after 6 (W p < 0.0001; BMI p < 0.0001), 12 (W p < 0.0001; BMI p < 0.0001) and 24 (W p < 0.0001; BMI p < 0.0001) months of therapy from baseline using the paired Student's t test.

IS and OS therapy were well tolerated, and no patients in both groups experienced severe adverse events like nausea or vomiting. Furthermore, no patient had optic neuropathy.

Effectiveness on glycemic control

By considering the glycemic control, at the first visit mean HBA1C was of 7.7 ± 1.6% and after 6, 12, and 24 months from the beginning of the treatment was respectively 6.4 ± 0.8%, 6.3 ± 0.6%, and 6.4 ± 1.0%, with a mean percentage reduction of − 1.9 ± 1.4%, − 1.5 ± 1.9%, and − 1.5 ± 1.7% in the IS group (Fig. 3). There was a statistical significance in mean HBA1C reduction after 6 (p < 0.0001), 12 (p < 0.0001) and 24 (p = 0.0024) months of therapy from baseline.

Fig. 3
figure 3

Efficacy of Injectable Semaglutide on glycemic control. HBA1C glycated hemoglobin. Statistical significance from baseline: 6 months p < 0.0001, 12 months p < 0.0001 and 24 months p = 0.0024

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In the OS group at baseline mean HBA1C was 7.6 ± 1.6%. After 6 months of therapy HBA1C was 6.4 ± 0.6%, with a mean reduction of − 1.5 ± 1.6%. After 12 months of OS treatment HBA1C was 6.3 ± 0.7%, with a mean reduction of and − 0.8 ± 0.6% (Fig. 4). There was a statistical significance in mean HBA1C reduction after 6 (p = 0.0010) and 12 (p = 0.01) months from baseline.

Fig. 4
figure 4

Efficacy of Oral Semaglutide on glycemic control. HBA1C glycated hemoglobin. Statistical significance from baseline: 6 months p = 0.0010 and 12 months p = 0.01

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By comparing the mean percentage reduction of HBA1C of IS and OS group, there were no statistical differences at baseline and after 6 and 12 months of therapy (baseline p = 0.088; 6 months p = 0.089; 12 months p = 0.18).

Discussion

The use of semaglutide for the treatment of T2DM subjects was based on the results of the clinical development program called SUSTAIN, which enrolled more than 8000 diabetic subjects. All these studies showed a weight loss markedly superior to the comparison group [2].

A multicenter, phase 2 study on subject with obesity was then performed: 957 people were randomized to the treatment with doses of semaglutide between 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg and 0.4 mg/day or placebo. Liraglutide 3.0 mg/day was included for comparison. Weight loss during the treatment with semaglutide at week 52 was 16.2% compared to baseline at the dose of 0.4 mg/day, versus -2.3% for placebo. To provide a comparison on efficacy, patients on liraglutide 3.0 mg, at week 52, had similar weight loss as those on 0.2 mg of semaglutide [12]. The clinical effectiveness of semaglutide treatment in the management of obesity was then confirmed by the results of Phase 3 Trials: Semaglutide Treatment Effect in People with Obesity (STEP program) [3, 5, 6, 13].

In this study we verified in real-world the efficacy of semaglutide both subcutaneously and orally in T2DM subjects with obesity or overweight. We treated diabetic patients with a personalized nutritional intervention, advice and information material for physical exercise according to the characteristics and possibilities of each patient.

This program has certainly increased the result on weight loss and improvements in glyco-metabolic parameters. One of the reasons that has most disappointed doctors in the management of obesity is the weight regaining after weight loss: this aspect is one of the most controversial in the long-term management of the obese patient.

Our results demonstrated comparable effectiveness both with IS and IS treatment in T2DM adults with obesity and overweight. In our study both therapies provide significant loss of weight allowing patients to reach the glycol-metabolic therapeutic goal in a short time.

In the treatment of overweight T2DM patients, therapy should continue throughout life (at least in patients without disease remission) and long-term studies in this population can help us understand whether maintaining weight after weight loss is an achievable goal.

Recently, in a fundamental study on obese population with pre-existing cardiovascular diseases (Select study) semaglutide determined a weight loss up to approximately the 65th week and this result on weight loss was maintained after 4 years from the beginning of the therapy with semaglutide [14]. For the first time, therefore, weight maintenance is more easily manageable in both overweight and obese T2DM patients. Further studies will be necessary to understand what the dosage will be to maintain weight. In obese patients, further studies should probably be conducted to verify whether the weight maintenance dosage was related to the starting BMI. Other studies will also be necessary to establish whether optimal therapy should be chronic.

Limitations of this study include its retrospective nature as well as the different samples of patients enrolled in the two analyzed subgroups. This difference is also due to the different entry into the market in our country of oral semaglutide compared to the injectable formulation. This allowed us to report data only at 12 months for oral semaglutide from baseline. Furthermore, no patients were excluded from the study according to the retrospective nature of the study, however not all patients treated with IS or OS have reached 6-, 12- or 24-month follow-up considered for the statistical analysis.

In conclusion, in our study, semaglutide treatment confirmed what was reported above. In fact, our results demonstrated the effectiveness and safety over 24 months of semaglutide treatment in T2DM obese subjects on loss of weight and HBA1C improvement. In line with the results of the STEP 4 study, semaglutide therapy induces weight loss and continuing weight loss maintenance after 12 and 24 months of treatment in subjects with obesity or overweight.