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.

SUSTAIN 1: Published

Trial population: type 2 diabetes	Comparator treatment: placebo
https://clinicaltrials.gov/ct2/show/NCT02054897

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.

SUSTAIN 2: Published

Trial population: type 2 diabetes, taking metformin and/or thiazolidinediones	Comparator treatment: sitagliptin
https://clinicaltrials.gov/ct2/show/NCT01930188

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.

SUSTAIN 3: Published

Trial population: type 2 diabetes, taking metformin and/or thiazolidinedione and sulfonylureas	Comparator treatment: extended-release exenatide
https://clinicaltrials.gov/ct2/show/NCT01885208

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.

SUSTAIN 4: Published

Trial population: type 2 diabetes; insulin-naïve, taking metformin with/without sulfonylurea	Comparator treatment: insulin glargine
https://clinicaltrials.gov/ct2/show/NCT02128932

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.

SUSTAIN 5: Published

Trial population: type 2 diabetes, taking basal insulin with/without metformin	Comparator treatment: placebo
https://clinicaltrials.gov/ct2/show/NCT02305381

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
https://clinicaltrials.gov/ct2/show/NCT01720446

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.

SUSTAIN 7: Published

Trial population: type 2 diabetes on stable metformin treatment	Comparator treatment: dulaglutide
https://www.clinicaltrials.gov/ct2/show/study/NCT02648204

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.

SUSTAIN 8: Published

Trial population: type 2 diabetes on stable metformin treatment	Comparator treatment: canagliflozin
https://www.clinicaltrials.gov/ct2/show/study/NCT03136484

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.

SUSTAIN 9: Published

Trial population: type 2 diabetes, taking SGLT-2 inhibitor with or without metformin or sulfonylurea	Comparator treatment: placebo
https://clinicaltrials.gov/ct2/show/NCT03086330

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.

SUSTAIN 10: Published

Trial population: type 2 diabetes on stable treatment with up to three oral antidiabetics	Comparator treatment: liraglutide
https://www.clinicaltrials.gov/ct2/show/study/NCT03191396

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
https://www.clinicaltrials.gov/ct2/show/NCT03689374

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.

SUSTAIN OPTIMIZE: Recruiting

Trial population: type 2 diabetes treated with a daily basal insulin plus metformin with/without an SGLT2 inhibitor	Comparator treatment: titrated insulin glargine U100
https://clinicaltrials.gov/ct2/show/NCT05514535

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.

SUSTAIN FORTE: Published

Trial population: type 2 diabetes, taking metformin with/without a sulfonylurea	Comparator treatment: semaglutide 2.0 mg
https://clinicaltrials.gov/ct2/show/NCT03989232

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.

SUSTAIN - CHINA MRCT: Published

Trial population: patients with type 2 diabetes, taking metformin	Comparator treatment: sitagliptin
https://clinicaltrials.gov/ct2/show/NCT03061214

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
https://clinicaltrials.gov/ct2/show/NCT02207374

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
https://clinicaltrials.gov/ct2/show/NCT02254291

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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