Weekly Semaglutide vs. Daily Sitagliptin in T2D Patients  

A study comparing semaglutide to sitagliptin found that one diabetes drug showed superior results for A1C reduction and weight loss.  

Globally, the rate of patients with type 2 diabetes mellitus (T2DM) is increasing every year. It is mainly attributed to sedentary lifestyles, lack of exercise, and increased obesity. Current treatments aim to achieve optimal glycemic controls and prevent the development of DM related complications. Even with the number of currently approved therapies, many patients find it challenging to achieve A1C targets of <7%. Treatment interventions alone may not be sufficient in achieving treatment targets. For example, achieving target BMI may further help in attaining target A1C: it is estimated that a 5% weight reduction is associated with lower A1C readings. Therefore, guidelines recommend individualizing the treatment based on patients’ specific parameters such as weight reduction, hypoglycemia risk, and cardiovascular risk.  

Semaglutide (Ozempic®) is approved as a once-weekly GLP-1 RA for T2DM. It achieved its long-acting effect by adding two amino acids and one fatty acid chain, which leads to increased protein binding, thus increasing its half-life.  Semaglutide has been proven to be effective in multiple studies compared to placebo and other antidiabetic therapies. It was reported to be effective in reducing A1C and BMI compared to the placebo. Additionally, it was reported that it had a significant reduction in the rate of major adverse cardiovascular events (MACE).  

This study aims to compare semaglutide once weekly to sitagliptin once daily in a Chinese population, and to compare its findings to the SUSTAIN trials that included a global community. 

The trial was a randomized, double-blind, active-controlled trial in a multi-center setting over 30 weeks. Investigators were randomized to screen patients for enrolments from different sites. The initial screening was two weeks before the study; the study was then followed by a follow-up for five weeks. 

Study arms included semaglutide 0.5mg + placebo, semaglutide 1mg + placebo, sitagliptin 100mg + placebo, and sitagliptin 100mg + placebo. Patients included had to be 18 years or older with T2DM and an A1C reading of 7-10.5%. They should also be on a stable dose of metformin monotherapy for at least 60 days before the initial screening. The study excluded patients on any other antidiabetic agent within 60 days before screening, as well as any who had a history of acute or chronic pancreatitis, calcitonin ≥50 ng/L, eGFR<60 ml/min/1.73m2, cancer diagnosis within the past five years, or ACS within three months before study screening. 

They defined the primary endpoint as the change in A1C from 30 weeks. Secondary endpoints were described as a change in body weight at the end of the study from baseline. Additional endpoints include the number of patients achieving target A1C (<7% or <6.5%), A1C<7% without severe hypoglycemia, and more than 5-10% weight loss. Additional parameters were also measured, such as HOMA-IR, BMI, FPG, and BP. 

Around 868 patients were randomized to different study groups. The baseline characteristics were similar between the groups. Approximately 70% of the study population were Chinese, whereas 13% were Korean. Out of these, 92.7% completed the study, while 11.4% stopped the treatment early; some of those (6.2%) because of side-effects.   

In terms of the primary outcomes, A1C reduction was the highest in the semaglutide 1mg group (-1.7%), followed by semaglutide 0.5mg (-1.4%), then sitagliptin (-0.9%) from the baseline of 8.1%. In terms of the secondary outcomes, semaglutide 1mg showed the highest weight loss (-4.7kg), followed by semaglutide 0.5mg (-2.9 kilograms) then sitagliptin (-0.4 kilograms) by the end of the trial. Similarly, most patients in the semaglutide groups had better secondary outcomes compared to sitagliptin. Also, other results favored semaglutide; those include FBG readings and insulin resistance. Higher effects were reported in the semaglutide 1mg group.  

In terms of the safety outcomes, most patients experienced mild-moderate side effects between the group. The discontinuation rate was higher with semaglutide groups (5.9% in the 0.5mg and 10.7% in the 1mg group) than sitagliptin (2.1%). The discontinuations were mainly attributed to GI side effects (nausea, vomiting, and diarrhea), which occurred within three months of the treatment. Rates of hypoglycemia were low and similar between the groups. 

The study findings in the Chinese population was similar to the conclusions of the SUSTAIN trial. One of the study limitations was the limited follow-up period. A longer follow-up may be needed to address the effect of long-term use of these agents. 

Practice Pearls: 

• Semaglutide is superior to sitagliptin in reducing A1C in patients with T2DM. 
• Semaglutide had favorable outcomes regarding weight loss and other secondary effects compared to sitagliptin. 
• Semaglutide effect is dose-dependent as higher results were reported with the 1mg dose vs. 0.5mg. 

“Efficacy And Safety Of Once‐Weekly Semaglutide Vs. Once‐Daily Sitagliptin As Add‐On To Metformin In Patients With Type 2 Diabetes ( SUSTAIN China): A 30‐Week Double‐Blind, Phase 3A, Randomised Trial“. Diabetes, Obesity, And Metabolism, 2020. Wiley 

Marso, Steven P. et al. “Semaglutide And Cardiovascular Outcomes In Patients With Type 2 Diabetes“. New England Journal Of Medicine,  

Abdullah Al-Ajmi, PharmD Candidate, Skaggs School of Pharmacy and Pharmaceutical Sciences