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Semaglutide vs Sitagliptin and Exenatide

Jun 25, 2016

In Depth: 76th ADA Scientific Sessions

Is semaglutide a better way to manage type 2 diabetes?

Diabetes is a chronic condition that needs long term therapy. Semaglutide, a once weekly glucagon–like peptide 1 receptor, is therefore a major advancement in diabetes treatment. Though the drug is currently under review, it allows the freedom and flexibility of once weekly injections. It is a structural analogue of liraglutide with a greater albumin binding and could extend the circulating half–life, and also has resistance to cleavage by dipeptidyl peptidase-4 (DPP4).

Semaglutide induces weight loss by reducing appetite and food intake. Semaglutide is also being developed in an oral tablet version for the treatment of type 2 diabetes. Adverse effects of semaglutide include nausea, dyspepsia, vomiting, headache, decreased appetite and no hypoglycemia. Sitagliptin is an oral anti hyperglycemic drug which is a dipeptidyl peptidase 4 (DPP-4) class. It can be used alone or in combination with metformin for the treatment of type 2 diabetes. Exenatide extended release is a glucagon like peptide (GLP-1) receptor agonist that lowers blood sugar by releasing insulin from the pancreas. It also mimics the actions of certain hormones that lower blood sugar level.

Ongoing studies involving the investigational drug semaglutide against a placebo assessed it for its cardiovascular effectiveness and other long term outcomes in type 2 diabetes in SUSTAIN 6.

SUSTAIN 2, which was a double blind, double dummy, randomized multicenter multinational took 56 weeks, so did SUSTAIN 3. The safety and efficacy of semaglutide versus sitagliptin was assessed in 1, 231 subjects with type 2 diabetes. The primary endpoint was a change in HbA1c from baseline after 56 weeks of treatment. SUSTAIN 3 had the same primary and secondary endpoints.

Two trials, SUSTAIN 2 and SUSTAIN 3, involving the glycemic control of semaglutide vs sitagliptin and semaglutide vs exenatide ER respectively, are still ongoing.

In SUSTAIN 2 trial, semaglutide which is given once weekly is compared with sitagliptin using their glycemic reduction, whilst in SUSTAIN 3 the glycemic control of semaglutide was compared to exenatide extended release, both in type 2 diabetes. In SUSTAIN 2 the study arms were semaglutide 0.5mg and 1.0mg and sitagliptin 100 mg, all versus placebo, whilst the intervention drugs were semaglutide, sitagliptin, administered either subcutaneously or orally. Participants had to be more than 18 years, diagnosed with type 2 diabetes and HbA1c 7.0-10.5%.The mean baseline HbA1c of 8.1% with type 2 diabetes treated with 0.5mg and 1.0 mg of semaglutide reached higher HbA1c decrease of 1.3% and 1.6% respectively, vs 0.5% with 100 mg of sitagliptin at 56 weeks with P< 0.0001.

For SUSTAIN 3, the mean baseline HbA1c was 8.3%, a superior HbA1c compared to exenatide ER with a P<0.0001 as add on to other oral antidiabetic. For the weight, an 89.5kg mean baseline had a drastic decrease in body weight when treated with semaglutide compared to sitagliptin in SUSTAIN 2. However, in SUSTAIN 3, a 95.8kg weight reduction with semaglutide was also drastic compared to exenatide ER with a P< 0.0001.The most common adverse effects was gastrointestinal with semaglutide being higher than sitagliptin, whilst in SUSTAIN 3 the adverse effects were also gastrointestinal, with semaglutide still being higher than exenatide ER. Some patients also complained of having injection site reactions with 1.0mg semaglutide (1.2%) vs exenatide ER (22.0%)

In conclusion, semaglutide had a better glycemic control and weight loss as demonstrated in SUSTAIN 2 and SUSTAIN 3. This goes to show that semaglutide is indeed superior to sitagliptin and exenatide ER and it should therefore be used often in the treatment of type 2 diabetes.

Practice Pearls:   

  •       Semaglutide is a new glucagon- like peptide-1 (GLP) analogue that can help people with type 2 diabetes to achieve substantial improvement of blood glucose with low risk of hypoglycemia.
  •       In SUSTAIN 2 trial, it was proven that semaglutide had a better glycemic control and weight reduction as compared to sitagliptin, the superior glucose reductions with the once weekly semaglutide vs sitagliptin are encouraging as new therapy to achieve treatment goals.
  •       In SUSTAIN 3 trial, semaglutide had a better glycemic control and weight reduction as compared to exenatide ER


DeYoung MB, et al. “Encapsulation of exenatide in poly- (D, Lactide-co-glycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes” Diabetes Technol Ther 2011; 13: 1145-54.

Novo Nordisk A/S .Trial to Evaluate Cardiovascular and other long term outcomes with semaglutide in subjects with type 2 diabetes (SUSTAIN 6). In: Clinical Trials.gov [internet} Bethesda (MD): National Library of Medicine (US) – 2000 [June 16 2016] NCT01720446