Abstract
Background
Obesity is increasingly being recognized as a chronic disease that exacerbates type 2 diabetes and its related complications. Oral semaglutide, a novel glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated efficacy in weight loss and diabetes control in Western populations. However, in real-world clinical practice, its effectiveness in Japanese patients, who typically exhibit a leaner phenotype and unique genetic susceptibilities affecting insulin secretion, remains unclear.
Methods
We retrospectively evaluated the electronic medical records of 313 patients treated with oral semaglutide and 11,239 untreated controls at the Keio University School of Medicine. We performed propensity score matching to adjust for covariates, including age, sex, height, weight, blood pressure, blood test data, medications, and compared the cardiometabolic risk factors, including HbA1c, blood pressure, lipids, and liver function 180 days post-treatment, of both patient groups. We conducted a subgroup analysis for patients who achieved ≥ 3% weight loss.
Results
After propensity score matching, the semaglutide group demonstrated significantly better outcomes for HbA1c reduction and weight loss and improvements in systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C), and liver function than the control group. Subgroup analysis of patients with ≥ 3% weight loss revealed superior HbA1c improvements in the semaglutide group; however, no significant differences in other metabolic parameters, such as SBP, LDL-C, and liver function, were observed.
Conclusion
Oral semaglutide effectively improved metabolic markers in Japanese patients with type 2 diabetes, similar to that in Western populations. Weight loss itself was suggested to significantly contribute to blood pressure, lipid levels, and liver function changes.
Supplementary Information
The online version contains supplementary material available at 10.1007/s13340-024-00744-3.
Keywords: Oral semaglutide, Obesity, Type 2 diabetes, MASH/MASLD, Propensity score matching
Introduction
In recent years, obesity has been increasingly recognized as a chronic and progressive disease that significantly increases the risk of type 2 diabetes and is associated with numerous medical, physical, and psychosocial complications [1]. Although lifestyle interventions have long been the main approach for treating obesity, bariatric surgery and therapeutic drugs have recently become options worldwide. In the treatment of type 2 diabetes, weight loss through lifestyle improvements reportedly improve not only diabetes control but also metabolic parameters such as blood pressure and lipids [2–4]. However, in real-world clinical practice, many cases in which weight loss is not achieved through diet and exercise therapy alone have been recorded. In Western countries, approximately 80% of patients with type 2 diabetes have overweight or obesity [5], and medications that can reduce weight in the treatment of type 2 diabetes are sought. Recently, the use of sodium glucose cotransporter (SGLT)-2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists has been reported to result in weight loss, leading to an increase in their usage [6, 7]. In 2020, orally administered semaglutide was introduced as the first oral GLP-1 receptor agonist. In a randomized controlled trial comparing oral semaglutide against placebo, significant improvements in HbA1c at all doses and a significant weight loss effect with oral semaglutide 14 mg have been demonstrated [8]. Furthermore, comparative trials have demonstrated that oral semaglutide has a stronger weight loss effect than other drugs such as sitagliptin and liraglutide [9, 10]. Nevertheless, these reports were mainly based on Western populations, who have a large proportion of patients with obesity, whereas many Japanese patients with type 2 diabetes are lean, and a decrease in insulin secretion due to genetic factors significantly influences the development of type 2 diabetes [11]. In addition, genome-wide association studies have reported abnormalities in genes related to GLP-1 as susceptibility genes in Japanese patients with type 2 diabetes [12]. Therefore, the effects of oral semaglutide on weight loss, blood glucose, lipid levels, and liver function in Japanese people might differ from those in Western populations. Notably, clinical trials of oral semaglutide conducted in Japan [13, 14] have reported a stronger HbA1c reduction than international clinical trials [8]. However, no reports have used real-world clinical data and propensity score matching to examine groups receiving oral semaglutide and control groups, specifically in Asians, including the Japanese population.
Previous meta-analyses of metabolic parameters other than blood glucose in patients receiving GLP-1 receptor agonists have also reported that blood pressure decreases with weight loss [15–17]. In PIONEER6, the administration of oral semaglutide led to weight loss and a reduction in HbA1c, as well as significant reductions in systolic blood pressure (SBP) and levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs), compared with placebo administration [18]. Furthermore, Yanai et al. have reported in a retrospective study of Japanese patients that SBP significantly decreased 6 months after starting oral semaglutide treatment compared to baseline, although their study was a single-arm trial [19]. The blood pressure-lowering effect of GLP-1 receptor agonists may be primarily associated with weight loss itself; however, this effect is also hypothesized to be related to the wide expression of GLP-1 receptors in endothelial and vascular smooth muscle cells [20]. This includes the inhibition of sodium-hydrogen exchanger 3 (NHE3) located on the brush border of proximal tubular cells by GLP-1 [21], control of SGLT, and enhancement of nitric oxide (NO) release [16]. Moreover, the administration of liraglutide or semaglutide to apolipoprotein E-deficient (ApoE−/−) mice or low-density lipoprotein receptor-deficient (LDLr−/−) mice results in a reduction in vascular plaque expression. This may be attributed to the anti-inflammatory effects of GLP-1 receptor agonists, independent of their weight loss effects [22]. However, in clinical practice, meta-analyses have reported that GLP-1 receptor agonists reduce LDL-C, total cholesterol (TC), and TG levels but do not affect high-density lipoprotein cholesterol (HDL-C) levels [23]. Furthermore, in PIONEER9 [13], which targeted Japanese patients, the oral semaglutide group demonstrated significant reductions in TC and LDL-C levels compared with the placebo group, although no significant changes in HDL-C or TG levels were observed. Nonetheless, the underlying mechanisms remain unclear. Regarding the effects of GLP-1 receptor agonists on liver function, the administration of 1.8 mg of liraglutide in patients with metabolic dysfunction associated steatohepatitis (MASH) significantly improved liver biopsy findings at 48 weeks compared with placebo administration [24], and subcutaneous injections of semaglutide in patients with MASH led to improvements in MASH compared with placebo administration [25]. Additionally, in Japan, studies administering oral semaglutide to patients with metabolic dysfunction associated steatotic liver disease (MASLD) have demonstrated improvements in liver enzymes and liver fibrosis markers, such as the fibrosis-4 index, along with weight loss [26]. Furthermore, the use of oral semaglutide in patients with type 2 diabetes has been reported to significantly reduce alanine aminotransferase (ALT) levels [27].
Overall, previous reports have suggested that the administration of GLP-1 receptor agonists not only leads to weight loss and improved diabetes control but also improves blood pressure, lipid levels, and liver function. However, no clinical studies have examined whether these improvements are caused by the weight loss itself or the effects of GLP-1 receptor agonists. Thus, in this study, we analyzed changes in metabolic parameters using real-world clinical data from Japanese patients who were administered oral semaglutide and examined the extent to which these changes were influenced by weight loss itself.
Methods
Study design
This retrospective observational study was conducted at a single hospital and enrolled all patients with a history of outpatient visits to the Department of Endocrinology, Metabolism and Nephrology, Keio University School of Medicine between February 1 and August 31, 2022. Data were collected from the electronic medical records of 313 patients in the oral semaglutide group and 11,239 patients in the non-administration group. In the oral semaglutide group, data were collected for 1 year before and after the start of oral semaglutide administration. For the non-administration group, data from the past 2 years, starting from the most recent outpatient visit date, were collected. In the oral semaglutide group, the start date of oral semaglutide administration was defined as day 0, whereas in the non-administration group, the most recent outpatient visit date was defined as day 360, setting day 0 accordingly (Fig. 1).
Fig. 1.
Definition of dosing period. In the administration group, the start date of oral semaglutide administration was defined as day 0, whereas in the non-administration group, the most recent outpatient visit date was defined as day 360, setting day 0 accordingly
For the cases included in the analysis, covariates were adjusted using propensity score matching based on the data from day 0. After matching the patient background information, a comparative examination of the clinical data from day 180 was conducted. The propensity score was estimated using logistic regression with the following covariates: age, sex, height, weight, SBP, diastolic blood pressure (DBP), blood test data (creatinine, hemoglobin [Hb], aspartate aminotransferase [AST], ALT, uric acid [UA], glucose, HbA1c, LDL-C, HDL-C, and TG), and whether SGLT-2 inhibitors were used on day 0. A 1:1 nearest-neighbor matching was performed using the propensity score with a caliper value of 0.20. Additionally, to examine the impact of weight loss on clinical data, propensity score matching analysis was conducted specifically for cases that indicated ≥ 3% weight reduction on day 180 (Fig. 2). The reason the rate of weight loss was set at ≥ 3% was because the obesity clinical guidelines of the Japan Society for the Study of Obesity set the weight loss target at 3% [28].
Fig. 2.
Flow diagram of the study. Among the cases analyzed, a total of 118 cases were matched in each group, with 37 cases matched in the group exhibiting a weight loss of 3% or more. GLP-1 glucagon-like peptide-1, SGLT sodium glucose cotransporter
Participants
All patients with a history of outpatient visits to the Department of Endocrinology, Metabolism and Nephrology, Keio University School of Medicine between February 1 and August 31, 2022 were included. The exclusion criteria for the oral semaglutide administration group were as follows: < 3 months of oral semaglutide administration, use of other GLP-1 receptor agonists during the data collection period, and initiation of SGLT-2 inhibitors after day 0. To establish a control group comprising patients who continued treatment for type 2 diabetes with lifestyle interventions and other therapeutic drugs excluding GLP-1 receptor agonists, the following exclusion criteria were set for the non-administration group: use of GLP-1 receptor agonists during the data collection period; initiation of SGLT-2 inhibitors after day 0; and without type 2 diabetes. The type of diabetes was classified based on data registered in the electronic medical records. Patients who started using SGLT-2 inhibitors during the study were excluded in both groups to examine the effect of oral semaglutide on body weight.
Ethics
The Ethics Committee of Keio University School of Medicine approved the study protocol on August 30, 2022 (approval number: 20221071). The study was conducted in accordance with the principles of the Declaration of Helsinki.
Outcomes
The outcome measures of this study included clinical tests and prescription data on days 0 and 180 for both groups. For day 0 data, the data closest to day 0 within the period from day − 44 to day 45 were used. For day 180 data, the closest data to day 180 within the period from day 136 to day 225 were adopted (Fig. 1). The clinical test data included age, sex, height, weight, body mass index (BMI), SBP, DBP, and blood test data (creatinine, estimated glomerular filtration rate [eGFR], Hb, AST, ALT, glucose, HbA1c, UA, LDL-C, HDL-C, and TG) as well as changes in these parameters. The presence and classification of diabetes medications were evaluated from the prescription data. If an actual measurement value for LDL-C was not available, the Friedwald formula was used for the calculation, when possible. The Friedwald formula was not used if the TG level was > 400. BMI was defined as weight in kilograms divided by the square of height in meters. The eGFR was calculated using the following equation: eGFR (mL/min per 1.73 m2) = 194 × serum creatinine−1.094 × age−0.287 (× 0.739 for women).
Statistical analysis
All data are expressed as means (standard deviations) for normally distributed variables and as medians with interquartile ranges for non-normally distributed variables. Patient characteristics were compared using the chi-squared test for categorical variables and Student’s t-test or Wilcoxon rank-sum test for continuous variables. Statistical significance was set at p < 0.05. Analyses were conducted using IBM SPSS Statistics software for Windows version 28.0.0.0 (IBM Corp., Armonk, NY, USA).
Results
Analysis of the total cohort
After excluding cases that met the exclusion criteria from the collected data, 153 cases in the oral semaglutide administration group and 4547 cases in the non-administration group were identified as study participants for analysis. Propensity score matching was performed on the eligible cases, resulting in 118 matched cases in both groups (Fig. 2), and the baseline characteristics were adjusted between the groups (Table 1). In the oral semaglutide administration group, the final doses were 3, 7, and 14 mg in 12, 76, and 30 patients, respectively. The analysis included a group of patients with a BMI of 28.0 ± 5.0 kg/m2 and HbA1c of 7.9 [7.3, 8.6] % in the oral semaglutide administration group and a BMI of 27.6 ± 5.3 kg/m2 and HbA1c of 7.8 [7.0, 8.8] % in the non-administration group. On day 180, the oral semaglutide administration group showed a significantly greater reduction in HbA1c (− 0.6 [− 1.2, − 0.2] vs. 0.0 [− 0.3, 0.3] %, p < 0.001) and amount of weight loss (− 2.6 ± 2.2 vs. − 0.6 ± 2.8 kg, p < 0.001) compared with the non-administration group (Fig. S1). Additionally, the reductions in SBP (− 8 [− 14, 6] vs. 0 [− 10, 11] mmHg, p = 0.012) and LDL-C (− 4 [− 19, 5] vs. 2 [− 7, 16] mg/dL, p < 0.001), AST (− 2 [− 9, 2] vs. 0 [− 3, 3] IU/L, p = 0.018), and ALT levels (− 4 [− 16, 2] vs. 0 [− 5, 5] IU/L, p = 0.002) were also significantly greater in the oral semaglutide administration group than in the non-administration group (Table 2). Furthermore, the oral semaglutide administration group exhibited a significantly greater reduction in Hb (− 0.2 [− 0.5, 0.2] vs. 0.2 [− 0.3, 0.6] g/dL, p = 0.001) and HDL-C levels (− 2 [− 5, 2] vs. 2 [− 2, 6] mg/dL, p < 0.001) than the non-administration group.
Table 1.
Baseline characteristics before and after propensity score matching
| Variables | Before matching | After matching | ||||
|---|---|---|---|---|---|---|
| Oral semaglutide administration group (n = 153) | Non-administration group (n = 4547) | p | Oral semaglutide administration group (n = 118) | Non-administration group (n = 118) | p | |
| Age (years) | 61 (54, 70) | 70 (58, 77) | < 0.001 | 62 (54, 70) | 63 (53, 75) | 0.455 |
| Sex (male) | 107 (70%) | 2665 (59%) | 0.005 | 82 (70%) | 81 (69%) | 0.888 |
| Height (cm) | 165.7 (8.1) | 162.8 (8.8) | < 0.001 | 165.9 (8.2) | 166.2 (8.5) | 0.792 |
| Body weight (kg) | 77.9 (16.5) | 64.1 (14.1) | < 0.001 | 77.5 (16.4) | 76.5 (17.5) | 0.673 |
| BMI (kg/m2) | 28.2 (5.0) | 24.0 (4.4) | < 0.001 | 28.0 (5.0) | 27.6 (5.3) | 0.506 |
| SBP (mmHg) | 137 (127, 148) | 134 (123, 145) | 0.017 | 138 (16) | 137 (18) | 0.459 |
| DBP (mmHg) | 80 (71, 88) | 75 (67, 83) | < 0.001 | 79 (12) | 79 (12) | 0.757 |
| Cr (mg/dL) | 0.80 (0.64, 0.99) | 0.86 (0.71, 1.08) | < 0.001 | 0.80 (0.66, 0.97) | 0.82 (0.66, 1.01) | 0.576 |
| eGFR (mL/min/1.73m2) | 73.5 (59.8, 84.0) | 62.0 (49.0, 73.0) | < 0.001 | 72.0 (60.0, 81.3) | 69.5 (53.8, 84.0) | 0.722 |
| Hb (g/dL) | 15.1 (13.9, 16.3) | 13.8 (12.6, 14.9) | < 0.001 | 15.1 (1.6) | 15.0 (1.6) | 0.446 |
| AST (IU/L) | 24 (18, 33) | 21 (18, 27) | 0.003 | 24 (18, 33) | 23 (17, 31) | 0.332 |
| ALT (IU/L) | 28 (19, 46) | 18 (13, 27) | < 0.001 | 29 (18, 46) | 24 (17, 40) | 0.127 |
| Blood glucose (mg/dL) | 134 (154, 183) | 125 (105, 151) | < 0.001 | 157 (134, 185) | 155 (130, 188) | 0.813 |
| HbA1c (%) | 7.8 (7.3, 8.4) | 6.6 (6.0, 7.2) | < 0.001 | 7.9 (7.3, 8.6) | 7.8 (7.0, 8.8) | 0.644 |
| UA (mg/dL) | 5.3 (4.4, 6.2) | 5.5 (4.5, 6.4) | 0.278 | 5.3 (4.4, 6.1) | 5.4 (4.4, 6.4) | 0.929 |
| LDL-C (mg/dL) | 109 (84, 127) | 106 (86, 126) | 0.968 | 106 (29) | 103 (31) | 0.401 |
| HDL-C (mg/dL) | 51 (43, 59) | 54 (45, 66) | < 0.001 | 52 (43, 58) | 47 (42, 58) | 0.193 |
| TG (mg/dL) | 160 (106, 225) | 118 (82, 176) | < 0.001 | 160 (109, 220) | 149 (96, 244) | 0.534 |
| Diabetes medication classes | ||||||
| SGLT-2 inhibitors | 109 (71%) | 902 (20%) | < 0.001 | 83 (70%) | 83 (70%) | 1.000 |
| Metformin | 114 (75%) | 1016 (22%) | < 0.001 | 65 (55%) | 66 (56%) | 0.896 |
| Sulfonylureas | 24 (16%) | 325 (7%) | < 0.001 | 18 (15%) | 21 (18%) | 0.599 |
| Thiazolidinediones | 13 (9%) | 125 (3%) | < 0.001 | 6 (5%) | 8 (7%) | 0.582 |
| α-GI | 11 (7%) | 383 (8%) | 0.588 | 12 (10%) | 17 (14%) | 0.321 |
| DPP-4 inhibitors | 3 (2%) | 1644 (36%) | < 0.001 | 2 (2%) | 76 (64%) | < 0.001 |
| Glinides | 10 (7%) | 305 (7%) | 0.933 | 5 (4%) | 8 (7%) | 0.392 |
| Insulin | 14 (9%) | 658 (15%) | 0.064 | 19 (16%) | 16 (14%) | 0.583 |
Data are presented as means (SDs), medians (first to third quartiles), or raw numbers (percentages), unless otherwise stated
BMI body mass index, SBP systolic blood pressure, DBP diastolic blood pressure, Cr creatinine, eGFR estimated glomerular filtration rate, AST aspartate aminotransferase, ALT alanine aminotransferase, UA uric acid, LDL-C low density lipoprotein cholesterol, HDL-C high density lipoprotein cholesterol, TG triglyceride, SGLT sodium glucose cotransporter, α-GI α-glucosidase inhibitors, DPP-4 dipeptidyl peptidase 4
Table 2.
Outcome measures in matched cohort on day 180
| Oral semaglutide administration group (n = 118) | Non-administration group (n = 118) | p | |
|---|---|---|---|
| Body weight (kg) | 74.5 (17.5) (n = 86) | 76.2 (17.2) (n = 116) | 0.496 |
| ΔBody weight (kg) | − 2.6 (2.2) (n = 86) | − 0.6 (2.8) (n = 116) | < 0.001 |
| BMI (kg/m2) | 27.0 (5.4) (n = 86) | 27.4 (5.3) (n = 116) | 0.635 |
| ΔBMI (kg/m2) | − 0.9 (0.8) (n = 86) | − 0.2 (1.0) (n = 116) | < 0.001 |
| SBP (mmHg) | 132 (123, 141) (n = 86) | 137 (125, 147) (n = 116) | 0.065 |
| ΔSBP (mmHg) | − 8 (− 14, 6) (n = 86) | 0 (− 10, 11) (n = 116) | 0.012 |
| DBP (mmHg) | 78 (12) (n = 86) | 78 (12) (n = 116) | 0.649 |
| ΔDBP (mmHg) | 0 (− 9, 6) (n = 86) | − 1 (− 10, 6) (n = 116) | 0.711 |
| Cr (mg/dL) | 0.82 (0.66, 0.97) (n = 112) | 0.86 (0.65, 1.05) (n = 114) | 0.846 |
| ΔCr (mg/dL) | 0.00 (− 0.04, 0.06) (n = 112) | 0.00 (− 0.06, 0.05) (n = 114) | 0.551 |
| eGFR (mL/min/1.73m2) | 70.0 (59.0, 81.0) (n = 112) | 70.5 (53.3, 84.0) (n = 114) | 0.960 |
| ΔeGFR (mL/min/1.73m2) | 0.0 (− 5.0, 4.0) (n = 112) | 0.0 (− 4.0, 4.8) (n = 114) | 0.530 |
| Hb (g/dL) | 14.9 (1.5) (n = 111) | 15.1 (1.7) (n = 114) | 0.462 |
| ΔHb (g/dL) | − 0.2 (− 0.5, 0.2) (n = 111) | 0.2 (− 0.3, 0.6) (n = 114) | 0.001 |
| AST (IU/L) | 21 (17, 29) (n = 112) | 22 (17, 31) (n = 114) | 0.418 |
| ΔAST (IU/L) | − 2 (− 9, 2) (n = 112) | 0 (− 3, 3) (n = 114) | 0.018 |
| ALT (IU/L) | 23 (17, 35) (n = 112) | 28 (18, 38) (n = 114) | 0.362 |
| ΔALT (IU/L) | − 4 (− 16, 2) (n = 112) | 0 (− 5, 5) (n = 114) | 0.002 |
| Blood glucose (mg/dL) | 131 (115, 155) (n = 114) | 154 (127, 185) (n = 115) | < 0.001 |
| ΔBlood glucose (mg/dL) | − 17 (− 41, − 1) (n = 114) | − 3 (− 29, 21) (n = 115) | 0.002 |
| HbA1c (%) | 7.0 (6.5, 7.8) (n = 115) | 7.6 (7.0, 9.0) (n = 115) | < 0.001 |
| ΔHbA1c (%) | − 0.6 (− 1.2, − 0.2) (n = 115) | 0.0 (− 0.3, 0.3) (n = 115) | < 0.001 |
| UA (mg/dL) | 5.3 (1.2) (n = 112) | 5.3 (1.5) (n = 115) | 0.798 |
| ΔUA (mg/dL) | − 0.1 (− 0.8, 0.3) (n = 112) | − 0.1 (− 0.6, 0.3) (n = 115) | 0.481 |
| LDL-C (mg/dL) | 100 (27) (n = 112) | 108 (31) (n = 110) | 0.059 |
| ΔLDL-C (mg/dL) | − 4 (− 19, 5) (n = 112) | 2 (− 7, 16) (n = 110) | < 0.001 |
| HDL-C (mg/dL) | 49 (43, 56) (n = 114) | 50 (44, 62) (n = 113) | 0.159 |
| ΔHDL-C (mg/dL) | − 2 (− 5, 2) (n = 114) | 2 (− 2, 6) (n = 113) | < 0.001 |
| TG (mg/dL) | 148 (105, 190) (n = 114) | 134 (95, 200) (n = 113) | 0.609 |
| ΔTG (mg/dL) | − 10 (− 51, 18) (n = 114) | − 12 (− 42, 25) (n = 113) | 0.711 |
Data are presented as means (SDs), medians (first to third quartiles), or raw numbers (percentages), unless otherwise stated. ∆, difference between days 0 and 180
BMI body mass index, SBP systolic blood pressure, DBP diastolic blood pressure, Cr creatinine, eGFR estimated glomerular filtration rate, AST aspartate aminotransferase, ALT alanine aminotransferase, UA uric acid, LDL-C low density lipoprotein cholesterol, HDL-C high density lipoprotein cholesterol, TG triglyceride
Analysis of cases with ≥ 3% weight loss on day 180
Among 153 cases in the oral semaglutide administration group and 4,547 cases in the non-administration group analyzed, only cases that exhibited ≥ 3% weight loss after 180 days were extracted for the subgroup analysis, and background factors were adjusted similarly through propensity score matching. In each group, 37 patients were matched (Fig. 2), and the baseline characteristics between the groups were adjusted (Table 3). In the oral semaglutide administration group, the final doses were 3, 7, and 14 mg in 5, 25, and 7 patients, respectively. The analysis included patients with a BMI of 26.7 ± 4.9 kg/m2 and HbA1c of 7.7 [7.3, 8.2] % in the oral semaglutide administration group and a BMI of 26.3 ± 4.8 kg/m2 and HbA1c of 7.5 [7.0, 8.7] % in the non-administration group. On day 180, no significant difference in the amount of weight loss was observed between the two groups (− 4.3 ± 1.4 vs. − 3.9 ± 2.3 kg, p = 0.383). However, HbA1c was significantly reduced in the oral semaglutide administration group than in the non-administration group (− 0.8 [− 1.4, − 0.4] vs. − 0.2 [− 0.8, 0.1] %, p = 0.002). Meanwhile, no significant differences in the reduction of SBP (− 10 [− 16, 5] vs. − 9 [− 15, 3] mmHg, p = 0.705) and LDL-C (− 3 [− 21, 5] vs. − 3 [− 15, 10] mg/dL, p = 0.854), AST (− 2 [− 9, 0] vs. − 2 [− 9, 1] IU/L, p = 0.897), and ALT levels (− 7 [− 16, − 1] vs. − 3 [− 14, 0] IU/L, p = 0.529) were observed between the groups (Table 4). Additionally, a significantly greater reduction in HDL-C was observed in the oral semaglutide administration group than in the non-administration group (− 1 [− 4, 2] vs. 4 [− 2, 8] mg/dL, p = 0.009).
Table 3.
Baseline characteristics before and after propensity score matching in the group with ≥ 3% weight loss
| Variables | Before matching | After matching | ||||
|---|---|---|---|---|---|---|
| Oral semaglutide administration group (n = 52) | Non-administration group (n = 487) | p | Oral semaglutide administration group (n = 37) | Non-administration group (n = 37) | p | |
| Age (years) | 63 (55, 72) | 70 (57, 78) | 0.016 | 63 (11) | 64 (15) | 0.753 |
| Sex (male) | 36 (69%) | 261 (54%) | 0.031 | 24 (65%) | 25 (68%) | 0.806 |
| Height (cm) | 164.2 (9.1) | 161.5 (8.8) | 0.034 | 165.3 (9.3) | 163.9 (7.7) | 0.481 |
| Body weight (kg) | 72.8 (16.1) | 64.3 (14.5) | < 0.001 | 73.6 (17.7) | 70.9 (14.6) | 0.479 |
| BMI (kg/m2) | 26.8 (4.6) | 24.5 (4.5) | < 0.001 | 26.7 (4.9) | 26.3 (4.8) | 0.712 |
| SBP (mmHg) | 136 (128, 146) | 136 (125, 149) | 0.723 | 136 (15) | 139 (19) | 0.485 |
| DBP (mmHg) | 78 (12) | 75 (14) | 0.078 | 77 (12) | 78 (14) | 0.668 |
| Cr (mg/dL) | 0.81 (0.65, 1.02) | 0.87 (0.69, 1.12) | 0.098 | 0.80 (0.64, 1.01) | 0.89 (0.68, 1.06) | 0.436 |
| eGFR (mL/min/1.73m2) | 73.0 (59.3, 81.8) | 61.0 (46.0, 75.0) | 0.002 | 70.4 (19.3) | 69.9 (26.1) | 0.608 |
| Hb (g/dL) | 14.8 (13.9, 15.9) | 13.7 (12.3, 14.9) | < 0.001 | 14.7 (1.6) | 14.5 (1.5) | 0.579 |
| AST (IU/L) | 24 (18, 30) | 22 (17, 28) | 0.439 | 24 (18, 30) | 24 (19, 30) | 0.758 |
| ALT (IU/L) | 27 (15, 40) | 18 (12, 29) | < 0.001 | 25 (15, 40) | 26 (19, 43) | 0.681 |
| Blood glucose (mg/dL) | 154 (134, 182) | 126 (105, 156) | < 0.001 | 151 (134, 180) | 159 (133, 193) | 0.439 |
| HbA1c (%) | 7.8 (7.4, 8.2) | 6.8 (6.0, 7.3) | < 0.001 | 7.7 (7.3, 8.2) | 7.5 (7.0, 8.7) | 0.523 |
| UA (mg/dL) | 5.0 (4.3, 6.0) | 5.3 (4.4, 6.5) | 0.403 | 4.9 (4.2, 6.1) | 5.2 (4.4, 6.5) | 0.427 |
| LDL-C (mg/dL) | 106 (86, 125) | 104 (82, 129) | 0.938 | 106 (28) | 111 (33) | 0.512 |
| HDL-C (mg/dL) | 52 (43, 58) | 56 (45, 68) | 0.029 | 52 (44, 59) | 52 (39, 63) | 0.808 |
| TG (mg/dL) | 134 (103, 240) | 121 (88, 188) | 0.079 | 134 (106, 231) | 141 (111, 268) | 0.634 |
| Diabetes medication classes | ||||||
| SGLT-2 inhibitors | 40 (77%) | 122 (25%) | < 0.001 | 26 (70%) | 29 (78%) | 0.425 |
| Metformin | 41 (79%) | 115 (24%) | < 0.001 | 25 (68%) | 19 (51%) | 0.155 |
| Sulfonylureas | 11 (21%) | 32 (7%) | < 0.001 | 8 (22%) | 6 (16%) | 0.553 |
| Thiazolidinediones | 2 (4%) | 9 (2%) | 0.333 | 2 (5%) | 2 (5%) | 1.000 |
| α-GI | 4 (8%) | 43 (9%) | 0.782 | 5 (14%) | 7 (19%) | 0.528 |
| DPP-4 inhibitors | 6 (12%) | 198 (41%) | < 0.001 | 2 (5%) | 26 (70%) | < 0.001 |
| Glinides | 5 (10%) | 35 (7%) | 0.525 | 3 (8%) | 5 (14%) | 0.454 |
| Insulin | 5 (10%) | 88 (18%) | 0.125 | 4 (11%) | 2 (5%) | 0.394 |
Data are presented as means (SDs), medians (first to third quartiles), or raw numbers (percentages), unless otherwise stated
BMI body mass index, SBP systolic blood pressure, DBP diastolic blood pressure, Cr creatinine, eGFR estimated glomerular filtration rate, AST aspartate aminotransferase, ALT alanine aminotransferase, UA uric acid, LDL-C low density lipoprotein cholesterol, HDL-C high density lipoprotein cholesterol, TG triglyceride, SGLT sodium glucose cotransporter, α-GI α-glucosidase inhibitors, DPP-4 dipeptidyl peptidase 4
Table 4.
Outcome measures in matched cohort with ≥ 3% weight loss on day 180
| Oral semaglutide administration group (n = 37) | Non-administration group (n = 37) | p | |
|---|---|---|---|
| Body weight (kg) | 69.3 (17.5) (n = 37) | 67.0 (14.2) (n = 37) | 0.538 |
| ΔBody weight (kg) | − 4.3 (1.4) (n = 37) | − 3.9 (2.3) (n = 37) | 0.383 |
| BMI (kg/m2) | 25.1 (4.9) (n = 37) | 24.8 (4.7) (n = 37) | 0.792 |
| ΔBMI (kg/m2) | − 1.6 (0.6) (n = 37) | − 1.5 (0.8) (n = 37) | 0.454 |
| SBP (mmHg) | 128 (121, 136) (n = 37) | 131 (124, 137) (n = 37) | 0.215 |
| ΔSBP (mmHg) | − 10 (− 16, 5) (n = 37) | − 9 (− 15, 3) (n = 37) | 0.705 |
| DBP (mmHg) | 75 (12) (n = 37) | 74 (13) (n = 37) | 0.885 |
| ΔDBP (mmHg) | − 2 (− 9, 6) (n = 37) | − 6 (− 12, 3) (n = 37) | 0.291 |
| Cr (mg/dL) | 0.80 (0.63, 0.92) (n = 35) | 0.85 (0.61, 1.06) (n = 35) | 0.589 |
| ΔCr (mg/dL) | − 0.02 (− 0.07, 0.00) (n = 35) | 0.00 (− 0.08, 0.07) (n = 35) | 0.290 |
| eGFR (mL/min/1.73m2) | 71.8 (20.7) (n = 35) | 69.9 (26.1) (n = 35) | 0.739 |
| ΔeGFR (mL/min/1.73m2) | 3.0 (− 1.0, 7.0) (n = 35) | 0.0 (− 6.0, 11.0) (n = 35) | 0.455 |
| Hb (g/dL) | 14.6 (13.2, 16.0) (n = 35) | 14.6 (13.9, 15.7) (n = 35) | 0.769 |
| ΔHb (g/dL) | − 0.2 (− 0.8, 0.2) (n = 35) | 0.2 (− 0.5, 0.7) (n = 35) | 0.085 |
| AST (IU/L) | 18 (16, 25) (n = 35) | 20 (16, 25) (n = 35) | 0.584 |
| ΔAST (IU/L) | − 2 (− 9, 0) (n = 35) | − 2 (− 9, 1) (n = 35) | 0.897 |
| ALT (IU/L) | 19 (14, 23) (n = 35) | 19 (15, 27) (n = 35) | 0.350 |
| ΔALT (IU/L) | − 7 (− 16, − 1) (n = 35) | − 3 (− 14, 0) (n = 35) | 0.529 |
| Blood glucose (mg/dL) | 119 (112, 140) (n = 37) | 148 (128, 171) (n = 35) | 0.002 |
| ΔBlood glucose (mg/dL) | − 26 (− 52, − 10) (n = 37) | − 9 (− 34, 8) (n = 35) | 0.074 |
| HbA1c (%) | 6.9 (0.9) (n = 37) | 7.5 (1.2) (n = 35) | 0.014 |
| ΔHbA1c (%) | − 0.8 (− 1.4, − 0.4) (n = 37) | − 0.2 (− 0.8, 0.1) (n = 35) | 0.002 |
| UA (mg/dL) | 5.1 (1.5) (n = 35) | 4.9 (1.4) (n = 35) | 0.528 |
| ΔUA (mg/dL) | − 0.2 (− 0.7) (n = 35) | − 0.5 (1.0) (n = 35) | 0.190 |
| LDL-C (mg/dL) | 104 (27) (n = 35) | 109 (33) (n = 36) | 0.441 |
| ΔLDL-C (mg/dL) | − 3 (− 21, 5) (n = 35) | − 3 (− 15, 10) (n = 36) | 0.854 |
| HDL-C (mg/dL) | 51 (13) (n = 36) | 55 (15) (n = 36) | 0.166 |
| ΔHDL-C (mg/dL) | − 1 (− 4, 2) (n = 36) | 4 (− 2, 8) (n = 36) | 0.009 |
| TG (mg/dL) | 138 (93, 165) (n = 36) | 128 (110, 153) (n = 36) | 0.685 |
| ΔTG (mg/dL) | − 18 (− 62, 26) (n = 36) | − 24 (− 87, 10) (n = 36) | 0.600 |
Data are presented as means (SDs), medians (first to third quartiles), or raw numbers (percentages), unless otherwise stated. ∆, difference between days 0 and 180
BMI body mass index, SBP systolic blood pressure, DBP diastolic blood pressure, Cr creatinine, eGFR estimated glomerular filtration rate, AST aspartate aminotransferase, ALT alanine aminotransferase, UA uric acid, LDL-C low density lipoprotein cholesterol, HDL-C high density lipoprotein cholesterol, TG triglyceride
Discussion
In this study, comparison with matched patient groups revealed significant improvements in weight, HbA1c, SBP, and LDL-C, AST, and ALT levels in the oral semaglutide administration group compared with in the non-administration group, which is consistent with previously reported data [18]. Notably, although previous clinical trials have predominantly involved Western populations with an average BMI of approximately 30–35, the average BMI in the present study was approximately 28, indicating that the efficacy of oral semaglutide is also demonstrated in a real-world clinical setting in Japan, where many patients with diabetes had a lower degree of obesity. To the best of our knowledge, this is the first study to use propensity score-matching with real-world clinical data to compare and examine the effects of oral semaglutide in Japanese populations.
Upon comparison with the findings of the PIONEER9 trial targeting Japanese individuals [13], consistent results were observed with regards to significantly decreased LDL-C level in the oral semaglutide group than that in the placebo group. However, in the PIONEER9 trial, no change in blood pressure was observed in the oral semaglutide group compared with the placebo group. One possible reason for this could be that the baseline SBP in the PIONEER9 was approximately 127–129 mmHg, whereas in the participants analyzed in this study the SBP was approximately 137–138 mmHg, which may have made changes in blood pressure more likely to occur. In network meta-analyses with other GLP-1 receptor agonists, the blood pressure-lowering effect of oral semaglutide was similar to that of other drugs [29, 30], suggesting that oral semaglutide does not specifically lower blood pressure more than other agents. However, the fact that the antihypertensive effect has been observed clinically, even from the convenience of not being an injectable formulation, is considered an important advantage of this drug. In the same trial, the oral semaglutide group had a tendency toward higher TG and lower HDL-C levels than the placebo group, although consistent trends have not been observed in lipid profiles in previous reports [8–10]. The reason for the significant decrease in HDL-C levels in the oral semaglutide group in this study is unclear. However, considering that similar trends have been observed in clinical trials involving Japanese participants [13], racial differences in drug responsiveness may have influenced the outcome.
In the analysis of cases with ≥ 3% weight loss on day 180, although the degree of weight loss was comparable between both groups, a significant HbA1c improvement were observed in the oral semaglutide administration group. However, significant differences in the overall analysis for SBP and LDL-C, AST, and ALT levels were not observed in this subgroup analysis (Fig. 3). The smaller number of cases might have influenced this result; however, it is suggested that the effects of weight loss itself were more significant than HbA1c. Yoshino et al. have reported that the impact of weight loss on metabolic functions was equivalent between groups receiving gastric bypass surgery and those receiving diet therapy for patients with obesity and diabetes, mentioning that weight loss itself, regardless of the method, is crucial for improving insulin sensitivity and β-cell function [31]. In their study, the rate of weight loss was approximately 20%, and a post hoc analysis of the LOOK AHEAD trial [32], which examined the effects of lifestyle improvements, has reported that a > 10% weight loss rate over 1 year was associated with reduced cardiovascular risk. Therefore, a greater weight loss may provide greater organ protection. However, there is currently no evidence regarding the optimal level of weight loss with GLP-1 receptor agonists for the prevention of complications.
Fig. 3.
Comparison of changes in HbA1c, SBP, ALT, and LDL-C on day 180. Ad means oral semaglutide administration group. Non-Ad means non-administration group. In the analysis of patients with ≥ 3% weight loss, HbA1c was significantly improved in the oral semaglutide group, while SBP, LDL-C, and ALT did not show the significant differences seen in the overall analysis. The horizontal bars denote the median values, and the lower and upper boundaries of each box indicate the 25th and 75th percentiles, respectively. Whiskers show the most extreme observed values that still fall within 1.5 times of the interquartile ranges. Points represent the more extreme values. SBP systolic blood pressure, ALT alanine aminotransferase, LDL-C low density lipoprotein cholesterol
Furthermore, a significant reduction in AST and ALT levels was observed in the oral semaglutide administration group in this study. MASLD accounts for approximately 20%–30% of patients with chronic liver disease worldwide [33, 34] and is strongly associated with metabolic syndrome, cirrhosis, hepatocellular carcinoma, cardiovascular diseases, and chronic kidney disease [35, 36]. Additionally, type 2 diabetes diagnosis in patients with MASH has been identified as an independent risk factor for the development of cirrhosis and hepatocellular carcinoma [37, 38]. Considering that lifestyle modification is a mainstay of MASLD treatment, many patients are unable to make sufficient improvements to their lifestyle [39]. The potential for weight loss and improvement of fatty liver associated with oral semaglutide administration could also lead to an improvement in life prognosis. Although previous reports have indicated that subcutaneous injections of semaglutide in patients with type 2 diabetes significantly reduced ALT and high-sensitivity C-reactive protein (CRP) levels [40], GLP-1 receptors are reportedly absent in the liver [22]. Therefore, the improvement in liver function and fibrosis in patients with MASH is currently assumed to be primarily attributed to weight loss and consequent improvement in insulin resistance [41]. However, some reports have suggested that semaglutide may reduce inflammation in the liver through mechanisms independent of weight loss [22], indicating that further knowledge is necessary to fully understand this mechanism.
Although the reason for the significantly greater reduction in Hb level in the oral semaglutide administration group in this study was unclear, the effects on the gastrointestinal tract or side effects in some patients could have led to decreased absorption of vitamin B12, folate, or trace elements such as iron and zinc, resulting in a slight decrease in Hb level. Furthermore, the improvement in obstructive sleep apnea syndrome due to weight loss could have led to an improvement in polycythemia. However, similar findings have not been reported in large-scale clinical trials. Although these results might be attributed to a higher inclusion of cases with progressive anemia for other reasons in the oral semaglutide administration group, no such cases were observed among the matched cases. Additionally, while the possibility that the progression of anemia led to lower HbA1c levels in the oral semaglutide group was considered, the difference in Hb change observed in this study was 0.4 mg/dL. Referring to studies that examined the relationship between anemia and changes in HbA1c [42], it was estimated that a 0.4 mg/dL change in Hb results in less than a 0.1% change in HbA1c. Therefore, the impact of anemia on HbA1c levels in this study was presumed minimal.
This study had several limitations. First, owing to the retrospective design, eliminating the influence of confounding factors was difficult in this study. We adjusted background factors using propensity score matching to eliminate the influence of confounding factors as much as possible. However, the presence of unknown confounding factors cannot be ruled out. Second, as this was a single-center study, the number of cases was limited, and further studies with a larger number of cases are warranted. Third, as a retrospective study, the timing of dose escalation for oral semaglutide varied depending on the attending physician, making it inappropriate to conduct a comparative analysis based on oral semaglutide doses. Fourth, at the time of analysis, the number of cases that had reached 360 days after the initiation of oral semaglutide administration was inadequate; thus, the analysis was conducted using data from day 180. Follow-up analyses need to be conducted over extended periods. Additionally, we analyzed cases in which weight loss was observed, setting the weight loss rate at 3%. This was because the obesity clinical guidelines of the Japan Society for the Study of Obesity set the weight loss target at 3% [28], although a target of 5%–10% has been set for individuals with severe obesity. An analysis based on divisions of 5% or 10% was also considered but could not be conducted owing to an insufficient number of cases. Finally, because this study was conducted by extracting information from medical records, collecting information on alcohol consumption was difficult, and caution is needed as liver dysfunction cannot necessarily be attributed to MASLD/MASH.
In conclusion, using real-world clinical data from Japan, we confirmed that oral semaglutide administration led to improvements in weight loss, SBP, and LDL-C, AST, and ALT levels compared with a matched non-administration group. Furthermore, even when compared with non-administered individuals who achieved a similar degree of weight loss, patients receiving oral semaglutide exhibited a greater reduction in HbA1c. However, no significant differences were observed in SBP and LDL-C, AST, and ALT levels between the two groups. Oral semaglutide has been demonstrated to be effective in improving metabolic markers in Japanese individuals, similar to that in Western populations, and weight loss itself has been suggested to significantly contribute to changes in blood pressure, lipid levels, and liver function. Further accumulation of cases and data analyses are required in the future.
Supplementary Information
Below is the link to the electronic supplementary material.
Supplementary file1 Fig. S1 Comparison of changes in body weight and BMI on day 180. Ad means oral semaglutide administration group. Non-Ad means non-administration group. In the overall analysis, the oral semaglutide administration group showed a significant reduction in both weight and BMI on day 180. In the oral semaglutide administration group, the final doses were 3, 7, 14 mg in 10, 52, and 24 patients, respectively. The horizontal bars denote the median values, and the lower and upper boundaries of each box indicate the 25th and 75th percentiles, respectively. Whiskers show the most extreme observed values that still fall within 1.5 times of the interquartile ranges. Points represent the more extreme values. Abbreviations: BMI, body mass index (JPG 68 KB)
Acknowledgements
We would like to thank Honyaku Center Inc. for English language editing.
Author contributions
Kazuki Aoyama: conceptualization; formal analysis, investigation; writing—original draft. Yuya Nakajima: conceptualization; investigation; methodology; writing—review & editing. Shu Meguro: conceptualization; investigation; methodology; project administration, writing—review & editing. Kaori Hayashi: conceptualization; methodology; project administration, supervision; writing, review & editing.
Data availability
The data supporting the findings of this study will be made available by the corresponding author upon reasonable request.
Declarations
Conflict of interest
KA received lecture fees from Novo Nordisk Pharma and MSD. YN received lecture fees from Novo Nordisk Pharma and MSD. SM received lecture fees from Novo Nordisk Pharma and MSD.
Research involving human participants and/or animals
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and the Helsinki Declaration of 1964 and later versions. The Ethics Committee of Keio University School of Medicine approved the study protocol on August 30, 2022 (approval number: 20221071).
Informed consent
Informed consent was not obtained; however, we published an opt-out document so that the participants could withdraw from the study at any time.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, et al. 8. Obesity and weight management for the prevention and treatment of Type 2 diabetes: standards of care in Diabetes-2023. Diabetes Care. 2023;46(1):S128–39. 10.2337/dc23-S008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Wing RR, Look AHEAD Research Group. Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial. Arch Intern Med. 2010;170:1566–75. 10.1001/archinternmed.2010.334. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Aucott L, Gray D, Rothnie H, Thapa M, Waweru C. Effects of lifestyle interventions and long-term weight loss on lipid outcomes—a systematic review. Obes Rev. 2011;12:e412–25. 10.1111/j.1467-789X.2010.00819.x. [DOI] [PubMed] [Google Scholar]
- 4.Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Look AHEAD Research Group, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369:145–54. 10.1056/NEJMoa1212914. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2015;58:429–42. 10.1007/s00125-014-3460-0. [DOI] [PubMed] [Google Scholar]
- 6.Cheong AJY, Teo YN, Teo YH, Syn NL, Ong HT, Ting AZH, et al. SGLT inhibitors on weight and body mass: a meta-analysis of 116 randomized-controlled trials. Obesity (Silver Spring). 2022;30:117–28. 10.1002/oby.23331. [DOI] [PubMed] [Google Scholar]
- 7.Htike ZZ, Zaccardi F, Papamargaritis D, Webb DR, Khunti K, Davies MJ. Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a systematic review and mixed-treatment comparison analysis. Diabetes Obes Metab. 2017;19:524–36. 10.1111/dom.12849. [DOI] [PubMed] [Google Scholar]
- 8.Aroda VR, Rosenstock J, Terauchi Y, Altuntas Y, Lalic NM, Morales Villegas EC, et al. Pioneer 1: randomized clinical trial of the efficacy and safety of oral semaglutide monotherapy in comparison with placebo in patients with Type 2 diabetes. Diabetes Care. 2019;42:1724–32. 10.2337/dc19-0749. [DOI] [PubMed] [Google Scholar]
- 9.Rosenstock J, Allison D, Birkenfeld AL, Blicher TM, Deenadayalan S, Jacobsen JB, et al. Effect of additional oral semaglutide vs sitagliptin on glycated hemoglobin in adults with Type 2 diabetes uncontrolled with metformin alone or with sulfonylurea: the Pioneer 3 randomized clinical trial. JAMA. 2019;321:1466–80. 10.1001/jama.2019.2942. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Pratley R, Amod A, Hoff ST, Kadowaki T, Lingvay I, Nauck M, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (Pioneer 4): a randomised, double-blind, phase 3a trial. Lancet. 2019;394:39–50. 10.1016/S0140-6736(19)31271-1. [DOI] [PubMed] [Google Scholar]
- 11.Kodama K, Tojjar D, Yamada S, Toda K, Patel CJ, Butte AJ. Ethnic differences in the relationship between insulin sensitivity and insulin response: a systematic review and meta-analysis. Diabetes Care. 2013;36:1789–96. 10.2337/dc12-1235. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Suzuki K, Akiyama M, Ishigaki K, Kanai M, Hosoe J, Shojima N, et al. Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population. Nat Genet. 2019;51:379–86. 10.1038/s41588-018-0332-4. [DOI] [PubMed] [Google Scholar]
- 13.Yamada Y, Katagiri H, Hamamoto Y, Deenadayalan S, Navarria A, Nishijima K, et al. Dose-response, efficacy, and safety of oral semaglutide monotherapy in Japanese patients with type 2 diabetes (PIONEER 9): a 52-week, phase 2/3a, randomised, controlled trial. Lancet Diabetes Endocrinol. 2020;8:377–91. 10.1016/S2213-8587(20)30075-9. [DOI] [PubMed] [Google Scholar]
- 14.Yabe D, Nakamura J, Kaneto H, Deenadayalan S, Navarria A, Gislum M, et al. Safety and efficacy of oral semaglutide versus dulaglutide in Japanese patients with type 2 diabetes (Pioneer 10): an open-label, randomised, active-controlled, phase 3a trial. Lancet Diabetes Endocrinol. 2020;8:392–406. 10.1016/S2213-8587(20)30074-7. [DOI] [PubMed] [Google Scholar]
- 15.Katout M, Zhu H, Rutsky J, Shah P, Brook RD, Zhong J, et al. Effect of GLP-1 mimetics on blood pressure and relationship to weight loss and glycemia lowering: results of a systematic meta-analysis and meta-regression. Am J Hypertens. 2014;27:130–9. 10.1093/ajh/hpt196. [DOI] [PubMed] [Google Scholar]
- 16.Sun F, Wu S, Guo S, Yu K, Yang Z, Li L, et al. Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among patients with type 2 diabetes: a systematic review and network meta-analysis. Diabetes Res Clin Pract. 2015;110:26–37. 10.1016/j.diabres.2015.07.015. [DOI] [PubMed] [Google Scholar]
- 17.Tsapas A, Karagiannis T, Kakotrichi P, Avgerinos I, Mantsiou C, Tousinas G, et al. Comparative efficacy of glucose-lowering medications on body weight and blood pressure in patients with type 2 diabetes: a systematic review and network meta-analysis. Diabetes Obes Metab. 2021;23:2116–24. 10.1111/dom.14451. [DOI] [PubMed] [Google Scholar]
- 18.Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, et al. Oral semaglutide and cardiovascular outcomes in patients with Type 2 diabetes. N Engl J Med. 2019;381:841–51. 10.1056/NEJMoa1901118. [DOI] [PubMed] [Google Scholar]
- 19.Yanai H, Hakoshima M, Adachi H, Katsuyama H. A significant effect of oral semaglutide on cardiovascular risk factors in patients with Type 2 diabetes. Cardiol Res. 2022;13:303–8. 10.14740/cr1441. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Ravassa S, Zudaire A, Díez J. GLP-1 and cardioprotection: from bench to bedside. Cardiovasc Res. 2012;94:316–23. 10.1093/cvr/cvs123. [DOI] [PubMed] [Google Scholar]
- 21.Gutzwiller JP, Tschopp S, Bock A, Zehnder CE, Huber AR, Kreyenbuehl M, et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab. 2004;89:3055–61. 10.1210/jc.2003-031403. [DOI] [PubMed] [Google Scholar]
- 22.Rakipovski G, Rolin B, Nøhr J, Klewe I, Frederiksen KS, Augustin R, et al. The GLP-1 analogs liraglutide and semaglutide reduce atherosclerosis in ApoE-/- and LDLr-/- mice by a mechanism that includes inflammatory pathways. JACC Basic Transl Sci. 2018;3:844–57. 10.1016/j.jacbts.2018.09.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Sun F, Wu S, Wang J, Guo S, Chai S, Yang Z, et al. Effect of glucagon-like peptide-1 receptor agonists on lipid profiles among type 2 diabetes: a systematic review and network meta-analysis. Clin Ther. 2015;37:225-241.e8. 10.1016/j.clinthera.2014.11.008. [DOI] [PubMed] [Google Scholar]
- 24.Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387:679–90. 10.1016/S0140-6736(15)00803-X. [DOI] [PubMed] [Google Scholar]
- 25.Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021;384:1113–24. 10.1056/NEJMoa2028395. [DOI] [PubMed] [Google Scholar]
- 26.Arai T, Atsukawa M, Tsubota A, Ono H, Kawano T, Yoshida Y, et al. Efficacy and safety of oral semaglutide in patients with non-alcoholic fatty liver disease complicated by type 2 diabetes mellitus: a pilot study. JGH Open. 2022;6:503–11. 10.1002/jgh3.12780. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Yamada H, Yoshida M, Funazaki S, Morimoto J, Tonezawa S, Takahashi A, et al. Retrospective analysis of the effectiveness of oral semaglutide in type 2 diabetes mellitus and its effect on cardiometabolic parameters in Japanese clinical settings. J Cardiovasc Dev Dis. 2023;10:176. 10.3390/jcdd10040176. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Japan Society for the Study of Obesity. Himanshou shinryou guideline 2022 [Obesity clinical guideline 2022]. Tokyo: Life Science Publishing; 2022. [Google Scholar]
- 29.Chubb B, Gupta P, Gupta J, Nuhoho S, Kallenbach K, Orme M. Once-daily oral semaglutide versus injectable GLP-1 RAs in people with Type 2 diabetes inadequately controlled on basal insulin: systematic review and network meta-analysis. Diabetes Ther. 2021;12:1325–39. 10.1007/s13300-021-01034-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Nuhoho S, Gupta J, Hansen BB, Fletcher-Louis M, Dang-Tan T, Paine A. Orally administered semaglutide versus GLP-1 RAs in patients with Type 2 diabetes previously receiving 1–2 oral antidiabetics: systematic review and network meta-analysis. Diabetes Ther. 2019;10:2183–99. 10.1007/s13300-019-00706-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Yoshino M, Kayser BD, Yoshino J, Stein RI, Reeds D, Eagon JC, et al. Effects of diet versus gastric bypass on metabolic function in diabetes. N Engl J Med. 2020;383:721–32. 10.1056/NEJMoa2003697. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Gregg EW, Jakicic JM, Blackburn G, Bloomquist P, Bray GA, Look AHEAD Research Group, et al. Association of the magnitude of weight loss and changes in physical fitness with long-term cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: a post-hoc analysis of the Look AHEAD randomised clinical trial. Lancet Diabetes Endocrinol. 2016;4:913–21. 10.1016/S2213-8587(16)30162-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15:11–20. 10.1038/nrgastro.2017.109. [DOI] [PubMed] [Google Scholar]
- 34.Le MH, Yeo YH, Li X, Li J, Zou B, Wu Y, et al. 2019 Global NAFLD prevalence: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2022;20:2809-17.e28. 10.1016/j.cgh.2021.12.002. [DOI] [PubMed] [Google Scholar]
- 35.Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67:328–57. 10.1002/hep.29367. [DOI] [PubMed] [Google Scholar]
- 36.Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S. Nonalcoholic steatohepatitis: a review. JAMA. 2020;323:1175–83. 10.1001/jama.2020.2298. [DOI] [PubMed] [Google Scholar]
- 37.Alexander M, Loomis AK, van der Lei J, Duarte-Salles T, Prieto-Alhambra D, Ansell D, et al. Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts. BMC Med. 2019;17:95. 10.1186/s12916-019-1321-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Yang JD, Ahmed F, Mara KC, Addissie BD, Allen AM, Gores GJ, et al. Diabetes is associated with increased risk of hepatocellular carcinoma in patients with cirrhosis from nonalcoholic fatty liver disease. Hepatology. 2020;71:907–16. 10.1002/hep.30858. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology. 2010;52:79–104. 10.1002/hep.23623. [DOI] [PubMed] [Google Scholar]
- 40.Newsome P, Francque S, Harrison S, Ratziu V, Van Gaal L, Calanna S, et al. Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity. Aliment Pharmacol Ther. 2019;50:193–203. 10.1111/apt.15316. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Armstrong MJ. Glucagon-like peptide-1 analogues in nonalcoholic steatohepatitis: from bench to bedside. Clin Liver Dis (Hoboken). 2016;2017(10):32–5. 10.1002/cld.650. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Alzahrani BA, Salamatullah HK, Alsharm FS, Baljoon JM, Abukhodair AO, Ahmed ME, et al. The effect of different types of anemia on HbA1c levels in non-diabetics. BMC Endocr Disord. 2023;23:24. 10.1186/s12902-023-01280-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary file1 Fig. S1 Comparison of changes in body weight and BMI on day 180. Ad means oral semaglutide administration group. Non-Ad means non-administration group. In the overall analysis, the oral semaglutide administration group showed a significant reduction in both weight and BMI on day 180. In the oral semaglutide administration group, the final doses were 3, 7, 14 mg in 10, 52, and 24 patients, respectively. The horizontal bars denote the median values, and the lower and upper boundaries of each box indicate the 25th and 75th percentiles, respectively. Whiskers show the most extreme observed values that still fall within 1.5 times of the interquartile ranges. Points represent the more extreme values. Abbreviations: BMI, body mass index (JPG 68 KB)
Data Availability Statement
The data supporting the findings of this study will be made available by the corresponding author upon reasonable request.