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04-07-2017 | Semaglutide | At a glance | Article

Updated April 2023

A quick guide to the SUSTAIN trials

There are a confusing number of SUSTAIN phase 3 trials either completed or in process, investigating the once-weekly injectable glucagon-like peptide-1 analog semaglutide in patients with type 2 diabetes. The trials are all sponsored by the drug-maker, Novo Nordisk.

Here is our guide to the 15 trials launched to date, which are complete, and which have so far been published in a peer-reviewed journal.

See also:

SUSTAIN 1: Published

Trial population: type 2 diabetes

Comparator treatment: placebo

The SUSTAIN 1 findings were published in The Lancet Diabetes & Endocrinology in January 2017. They showed that, during 30 weeks of treatment, patients given semaglutide had significantly larger reductions in glycated hemoglobin and in bodyweight than those given placebo.

Related news story: SUSTAIN 1: ‘high degree’ of glycemic control with semaglutide in type 2 diabetes

SUSTAIN 2: Published

Trial population: type 2 diabetes, taking metformin and/or thiazolidinediones

Comparator treatment: sitagliptin

SUSTAIN 2, also published in The Lancet Diabetes & Endocrinology, in April 2017, was a head-to-head study of weekly injectable semaglutide versus daily oral sitagliptin in patients already taking metformin and/or thiazolidinediones.

The findings showed significantly larger reductions in HbA1c with semaglutide, as well as larger reductions in bodyweight.

Related news story: SUSTAIN 2 shows better glycemic control with semaglutide than sitagliptin

SUSTAIN 3: Published

Trial population: type 2 diabetes, taking metformin and/or thiazolidinedione and sulfonylureas

Comparator treatment: extended-release exenatide

The SUSTAIN 3 findings, published in Diabetes Care, show that semaglutide 1.0 mg produced a larger HbA1c reduction than exenatide 2.0 mg, of 1.5% versus 0.9% over 56 weeks. However, the researchers cautioned that this could have been influenced by the "more complex device" used to administer exenatide.

Related news storySemaglutide at least equivalent to exenatide on weekly schedule

SUSTAIN 4: Published

Trial population: type 2 diabetes; insulin-naïve, taking metformin with/without sulfonylurea

Comparator treatment: insulin glargine

SUSTAIN 4, again published in The Lancet Diabetes & Endocrinology, pitted semaglutide against insulin during 30 weeks of treatment. The trial met the noninferiority endpoint and, in fact, patients achieved significantly larger HbA1c reductions with semaglutide than insulin, although the researchers noted that insulin titration may not have been optimal.

Related news story: SUSTAIN 4: weekly semaglutide a good option after metformin failure

SUSTAIN 5: Published

Trial population: type 2 diabetes, taking basal insulin with/without metformin

Comparator treatment: placebo

The SUSTAIN 5 findings are published in The Journal of Clinical Endocrinology & Metabolism. They reveal significant 1.4% (15.8 mmol/mol) and 1.8% (20.2 mmol/mol) reductions in HbA1c during 30 weeks of treatment with 0.5 and 1.0 mg semaglutide, respectively, versus a 0.1% (1.0 mmol/mol) reduction with placebo.

SUSTAIN 6: Published

Trial population: type 2 diabetes at high cardiovascular risk, excluding those using other GLP-1 analogs or dipeptidyl peptidase 4 inhibitors

Comparator treatment: placebo

The results of SUSTAIN 6, published in The New England Journal of Medicine, showed a significant 26% reduction in the composite primary endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. This endpoint occurred in 6.6% of patients taking semaglutide and 8.9% of those taking placebo during a median of 2.1 years of follow-up.

Related news story: Favourable cardiovascular safety profile for semaglutide

SUSTAIN 7: Published

Trial population: type 2 diabetes on stable metformin treatment

Comparator treatment: dulaglutide

The SUSTAIN 7 findings, published in The Lancet Diabetes & Endocrinology, show that semaglutide produced better glycemic control than competitor GLP-1 receptor agonist dulaglutide. The respective average HbA1c reductions were 1.5% versus 1.1% at low doses of 0.5 and 0.75 mg and 1.8% versus 1.4% at high doses of 1.0 and 1.5 mg. Patients taking semaglutide also lost more weight than those taking the equivalent dose of dulaglutide.

Related news storySUSTAIN 7 published: Semaglutide superior to dulaglutide

SUSTAIN 8: Published

Trial population: type 2 diabetes on stable metformin treatment

Comparator treatment: canagliflozin

The SUSTAIN 8 trial – reported in The Lancet Diabetes & Endocrinology – demonstrated a significantly greater reduction in HbA1c levels with semaglutide versus the sodium-glucose cotransporter (SGLT)-2 inhibitor canagliflozin at 1 year, with mean decreases of 1.5% and 1.0%, respectively.

Semaglutide-treated patients also experienced greater weight loss, at an average of 5.3 kg compared with 4.2 kg for those given canagliflozin, but a substudy showed comparable improvements in body composition in both treatment arms.

Related news story: SUSTAIN 8: Semaglutide outperforms canagliflozin as second-line therapy for type 2 diabetes

SUSTAIN 9: Published

Trial population: type 2 diabetes, taking SGLT-2 inhibitor with or without metformin or sulfonylurea

Comparator treatment: placebo

The findings of this trial, published in The Lancet Diabetes & Endocrinology, support the use of semaglutide as an add-on to SGLT-2 inhibitor treatment. During 30 weeks of treatment in 302 patients, those given semaglutide achieved a 1.4% larger HbA1c reduction than those given placebo, and they lost more weight.

Related news story: SUSTAIN 9 supports semaglutide, SGLT2 inhibitor combination

SUSTAIN 10: Published 

Trial population: type 2 diabetes on stable treatment with up to three oral antidiabetics

Comparator treatment: liraglutide

The SUSTAIN 10 findings favor the use of semaglutide over the GLP-1 receptor agonist liraglutide as an add-on therapy to oral antidiabetic drugs. As reported in Diabetes & Metabolism, glycemic control was better with semaglutide, with an average HbA1c reduction of 1.7% versus 1.0% at week 30, and average weight loss was greater, at 5.8 and 1.9 kg, respectively.

Related news story: Semaglutide tops liraglutide in SUSTAIN 10

SUSTAIN 11: Published

Trial population: type 2 diabetes, taking basal insulin plus metformin 

Comparator treatment: insulin aspart

This trial positioned a weekly semaglutide injection as a viable alternative to thrice-daily insulin aspart in people requiring insulin to treat type 2 diabetes.

HbA1c fell by an average of 1.5% and 1.2% in participants taking semaglutide and aspart, respectively, making the former statistically non-inferior to the latter. Additionally, bodyweight decreased with semaglutide but increased with insulin aspart.

SUSTAIN 11 is published in Diabetes, Obesity and Metabolism.

Related news story: Semaglutide offers alternative to prandial insulin in type 2 diabetes


Trial population: type 2 diabetes treated with a daily basal insulin plus metformin with/without an SGLT2 inhibitor

Comparator treatment: titrated insulin glargine U100

All participants in this trial will be given daily basal insulin glargine U100, but those also taking semaglutide will have their insulin glargine dose reduced as the semaglutide dose is escalated, so should require markedly less insulin than those in the control group.

The primary outcome is change in HbA1c during 40 weeks of follow-up and the trial is expected to complete in June 2023.


Trial population: type 2 diabetes, taking metformin with/without a sulfonylurea

Comparator treatment: semaglutide 2.0 mg

In this trial, 961 participants were randomly assigned to receive semaglutide 1.0 or 2.0 mg, the latter given as two injections of 1.0 mg, for 40 weeks.

As reported at the virtual ADA 81st Scientific Sessions, the higher dose achieved a significantly greater HbA1c reduction in trial product estimand analysis, of 2.2 percentage points compared with 1.9 percentage points for the standard dose. The higher dose also resulted in a significantly larger bodyweight reduction, of 6.9 versus 6.0 kg.

The trial is now published in The Lancet.

Related news story: SUSTAIN FORTE supports semaglutide 2.0 mg dose for type 2 diabetes


Trial population: patients with type 2 diabetes, taking metformin

Comparator treatment: sitagliptin

Similar to SUSTAIN 2, this trial tested semaglutide 0.5 and 1.0 mg against sitagliptin, but in a patient population drawn from China, Hong Kong, Brazil, Taiwan, Ukraine, South Korea, and South Africa.

As reported in Diabetes, Obesity and Metabolism, during 30 weeks of treatment semaglutide produced significantly greater reductions in HbA1c than sitagliptin, at estimated treatment differences of –0.51% and –0.85% for the 0.5 and 1.0 mg doses, respectively. Participants taking semaglutide were also more likely to achieve HbA1c targets than those taking sitagliptin, and they lost significantly more weight.

SUSTAIN (Japan): Published

Trial population: Japanese type 2 diabetes patients on stable oral antidiabetic medication

Comparator treatment: oral antidiabetic, selected according to baseline medication

Patients in this trial remained on their baseline treatment and were randomly assigned to receive either semaglutide or investigators’ choice of oral antidiabetic agent. The findings published in Diabetes, Obesity and Metabolism show significantly larger reductions in HbA1c with semaglutide 0.5 and 1.0 mg versus other antidiabetics, at 1.7% and 2.0% versus 0.7%, respectively. Patients on semaglutide also lost weight, compared with a slight increase in the comparator group.

SUSTAIN (Japan, sitagliptin): Published

Trial population: Japanese patients with type 2 diabetes treated with lifestyle management or monotherapy

Comparator treatment: sitagliptin

In this trial, published in Diabetes, Obesity and Metabolism, Japanese patients received weekly semaglutide 0.5 or 1.0 mg or daily oral sitagliptin 100 mg (after washout of pre-existing treatments). Glycated hemoglobin fell by 1.9–2.2% with semaglutide versus 0.7% with sitagliptin, which was a significant difference. There were more adverse effects among patients treated with semaglutide than sitagliptin, most commonly constipation, nausea, and diarrhea.

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