The results of the present study showed that switching to semaglutide enabled stricter glycemic control and promoted significant weight loss among obese patients with type 2 diabetes treated with a conventional GLP-1 RA. Also, the improvement in HbA1c with semaglutide was greater in patients with poor glycemic control (higher HbA1c at baseline), regardless of the type of GLP-1 RA used and body weight prior to initiation of semaglutide. The changes in HbA1c and body weight after switching to semaglutide were similar to those in semaglutide-naïve patients. In addition, administration of semaglutide significantly decreased uric acid levels and improved several parameters of lipid metabolism and liver function.
The Guidelines for the Treatment of Diabetes in Japan recommend increasing the dose of administered drugs or combining drugs with different mechanisms of action for targeted glycemic control . However, it is necessary to avoid hypoglycemia when attempting stricter blood glucose control, especially while increasing the dose or administering additional doses . In addition, elderly patients with diabetes must be treated with greater care, because these patients are more likely to be affected by hypoglycemia due to poor patient adherence . In view of these considerations, switching between drugs in the same class may be worthwhile for better glycemic control and avoiding adverse effects, including hypoglycemia, and semaglutide has received considerable attention in this regard in recent years.
A retrospective analysis of clinical practice data indicated that in type 2 diabetes patients receiving the recommended dose of liraglutide or dulaglutide, HbA1c decreased by 0.65% and body weight decreased by 1.69 kg 6 months after switching to semaglutide . Although the decrease in HbA1c after switching to semaglutide was greater than that in the present study, the high HbA1c of 7.9% before switching to semaglutide is considered a factor in that difference. In the present study, the baseline HbA1c of ≥ 6.5% decreased by 0.59%. In the SUSTAIN study series, semaglutide was compared with several GLP-1 RAs. Semaglutide provided more significant improvement in HbA1c than exenatide (once-weekly), dulaglutide, or liraglutide [17–19]. In addition, HbA1c decreased by 0.83% in patients receiving semaglutide for the first time. Taking these data into account, switching to semaglutide is considered a reasonable and relatively safe option for patients under GLP-1 RA treatment. In the present study, the higher the baseline HbA1c level, the greater was the decrease in HbA1c following semaglutide initiation, and no episodes of hypoglycemia were observed.
In the SUSTAIN study, semaglutide was also more cooperative than other GLP-1 RAs in terms of body weight loss assessed concurrently [17–19]. The anorexigenic mechanism of semaglutide differs from that of other GLP-1 RAs  and may be related to its potent weight loss effect. Weight loss associated with semaglutide is considered independent of gastrointestinal adverse reactions such as nausea and vomiting, and gastrointestinal adverse reactions are not directly related to weight loss . In addition to GLP-1 RAs, SGLT2 inhibitors promote a reduction in body weight . In the present study, GLP-1 RAs or SGLT2 inhibitors were administered to all patients; however, switching to semaglutide produced further body weight loss in patients who still required improvement of obesity. This finding suggests that semaglutide may have a stronger body weight–reducing effect than other GLP-1 RAs.
In the present study, lipid metabolism was improved after switching to semaglutide. Improved lipid metabolism with GLP-1 RAs was characterized by reductions in LDL-C, total cholesterol, and triglycerides in a meta-analysis . However, GLP-1 RAs do not necessarily increase HDL-C levels. A combination of changes in lipid metabolism induced by GLP-1 RAs and hypoglycemia resulting from increased insulin secretion may be effective in suppressing cardiovascular events . Liver function parameters also showed significant improvements, and considering the decrease in triglycerides, semaglutide was considered to have a beneficial effect on fatty liver. A meta-analysis of the therapeutic effects of GLP-1 RAs, including semaglutide, on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis indicated that GLP-1 RAs reduce hepatic fibrosis on imaging and decrease ALT and γ-GTP, suggesting the possibility of treating fatty liver with GLP-1 RAs .
The most frequent adverse events associated with GLP-1 RAs are gastrointestinal reactions such as nausea, vomiting, and diarrhea. As these adverse events can lead to dehydration, GLP-1 RAs should be used with caution in elderly patients or those with renal impairment. Although differences in safety between GLP-1 RAs are not clear, gastrointestinal adverse reactions should be carefully considered when semaglutide is used . In the SUSTAIN-6 study, which evaluated the cardiovascular safety of semaglutide, the incidence of retinopathy complications was high . Rapid glycemic improvement with semaglutide may be due in part to the association with worsening diabetic retinopathy ; however, this should also be noted in the clinical use of semaglutide.