Semaglutide might be a key for breaking the vicious cycle of metabolically associated fatty liver disease spectrum?

Table 1 Completed studies with subcutaneous semaglutide in type 2 diabetes mellitus and their main conclusions

Study	Ref.	Main conclusion
SUSTAIN 1	Sorli et al[38], 2017	Semaglutide significantly improved HbA1c and bodyweight in T2DM patients compared to placebo
SUSTAIN 2	Ahren et al[39], 2017	Semaglutide is superior to sitagliptin at improving glycemia and bodyweight when added to metformin+/-pioglitazon
SUSTAIN 3	Ahmann et al[40], 2018	Semaglutide is superior to exenatide ER in glycemic control and body weight reduction
SUSTAIN 4	Aroda et al[41], 2017	semaglutide is superior to insulin glargine U100 in glycemic control and bodyweight reduction
SUSTAIN 5	Rodbar et al[42], 2018	Semaglutide, added to basal insulin, significantly reduced HbA1c and body weight in patients with uncontrolled T2D vs placebo
SUSTAIN 61	Marso et al[43], 2016	In T2DM patients at high cardiovascular risk, semaglutide was significantly better compared to placebo in reduction of 3 point MACE
SUSTAIN 7	Pratley et al[44], 2018	At low and high doses, semaglutide was superior to dulaglutide in improving glycaemic control and reducing body weight of T2DM patients
SUSTAIN 8	Lingway et al[45], 2019	Once-weekly semaglutide 1.0 mg was superior to daily canagliflozin 300 mg in reducing HbA1c and bodyweight in patients with type 2 diabetes uncontrolled on metformin therapy
SUSTAIN 8 substudy	McCrimmon et al[46], 2019	In individuals with uncontrolled T2DM on stable-dose metformin, the changes in body composition with semaglutide and canagliflozin were not significantly different
SUSTAIN 9	Zinman et al[47], 2019	Adding semaglutide to SGLT-2 inhibitor therapy significantly improves glycaemic control and reduces bodyweight in patients with inadequately controlled T2DM
SUSTAIN 10	Capehorn et al[48], 2020	Semaglutide was superior to liraglutide in reducing HbA1c and body weight
SUSTAIN (Japan)	Kaku et al[49], 2018	Semaglutide treatment significantly reduced HbA1c and body weight vs additional OAD treatment in Japanese people with T2D
SUSTAIN Forte	Frias et al[50], 2021	Semaglutide 2.0 mg was superior to 1.0 mg in reducing HbA1c, with additional body weight loss and a similar safety profile in poorly controlled T2DM
SUSTAIN China MRCT	Ji et al[51], 2020	Once-weekly semaglutide was superior to sitagliptin in improving glycaemic control and reducing body weight in Chinese T2DM patients inadequately controlled on metformin

¹Cardiovascular safety study. CV: Cardiovascular; T2DM: Type 2 diabetes mellitus; HbA1c: Hemoglobin A1c.

Table 2 Completed studies with subcutaneous semaglutide in obesity and their main conclusions

Study	Ref.	Main conclusion
Step 1	Wilding et al[52], 2021	In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight
Step 2	Davies et al[53], 2021	In adults with overweight or obesity, and type 2 diabetes, semaglutide 2.4 mg once a week achieved a superior and clinically meaningful decrease in body weight compared with placebo
Step 3	Wadden et al[54], 2021	Among adults with overweight or obesity, once-weekly subcutaneous semaglutide compared with placebo, used as an adjunct to intensive behavioral therapy and initial low-calorie diet, resulted in significantly greater weight loss during 68 wk
Step 4	Rubino et al[55], 2022	Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, resulted in significantly greater weight loss during 68 wk
Step 6	Kadowaki et al[56], 2022	Adults from east Asia with obesity, with or without type 2 diabetes, given semaglutide 2.4 mg once a week had superior and clinically meaningful reductions in body weight, and greater reductions in abdominal visceral fat area compared with placebo

Step 5: Completed, not published.

Table 3 Completed studies with oral semaglutide and their main conclusions

Study	Ref.	Main conclusion
PIONEER 1	Aroda et al[57], 2019	Oral semaglutide monotherapy demonstrated superior and clinically relevant improvements in HbA1c (all doses) and body weight loss (14 mg dose) versus placebo
PIONEER 2	Rodbard et al[58], 2019	Oral semaglutide was superior to empagliflozin in reducing HbA1c but not body weight at 26 wk in T2DM patients uncontrolled on metformin. At week 52, HbA1c and body weight (trial product estimand) were significantly reduced versus empagliflozin
PIONEER 3	Rosenstock et al[59], 2019	Oral semaglutide, 7 mg/d and 14 mg/d, compared with sitagliptin, resulted in significantly greater reductions in HbA1c over 26 wk
PIONEER 4	Pratley et al[60], 2019	Oral semaglutide was non-inferior to subcutaneous liraglutide and superior to placebo in decreasing HbA1c, and superior in decreasing body weight compared with both liraglutide and placebo at week 26
PIONEER 5	Mosenzon et al[61], 2019	Oral semaglutide was effective in patients with type 2 diabetes and moderate renal impairment
PIONEER 61	Husain et al[62], 2019	The cardiovascular risk profile of oral semaglutide was not inferior to that of placebo in high CV risk T2DM patients
PIONEER 7	Pieber et al[63], 2019	Superior glycemic control and weight loss with once-daily oral semaglutide with flexible dose adjustment versus sitagliptin 100 mg in type 2 diabetes
PIONEER 7 EXTENSION	Buse et al[64], 2020	Switching from sitagliptin to flexibly dosed oral semaglutide maintained HbA1c reductions, helped more patients achieve HbA1c targets with less use of additional glucose-lowering medication, and offers the potential for additional reductions in body weight
PIONEER 8	Zinman et al[65], 2019	Oral semaglutide was superior to placebo in reducing HbA1c and body weight when added to insulin with or without metformin in patients with T2DM
PIONEER 9	Yamada et al[66], 2020	Oral semaglutide provides significant reductions in HbA1c compared with placebo in a dose-dependent manner in Japanese patients with T2DM
PIONEER 10	Yabe et al[67], 2020	Once-daily oral semaglutide reduced HbA1c and bodyweight vs weekly dulaglutide 0.75 µg in Japanese T2DM patients

¹Cardiovascular safety study. CV: Cardiovascular; T2DM: Type 2 diabetes mellitus; HbA1c: Hemoglobin A1c.