SUSTAIN trial programme
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| SUSTAIN trial programmePhase 3 programme | |
|---|---|
| Drug | Semaglutide 0.5 and 1.0 mg weekly |
| Indication | Type 2 diabetes |
| Notable member | SUSTAIN 6, cardiovascular outcomes |
| Topic infobox · conventions | |
The SUSTAIN trial programme is the phase 3 series that established weekly semaglutide for type 2 diabetes. Its trials compared semaglutide against placebo and against active comparators including sitagliptin, exenatide extended-release, insulin glargine and dulaglutide.[1]
Across the programme, semaglutide 1.0 mg reduced glycated haemoglobin by roughly 1.5–1.8 percentage points from baseline, with weight reduction of about 4–6 kg — substantially less than the 2.4 mg obesity dose studied in STEP.[1]
SUSTAIN 6 was the cardiovascular safety trial, randomising 3,297 people with type 2 diabetes at high cardiovascular risk. It reported a hazard ratio of 0.74 (95% CI 0.58–0.95) for the primary composite outcome, a result which — being from a trial designed to demonstrate non-inferiority — is generally described as hypothesis-generating for superiority.[2]
Structure of the programme
[edit]| Trial | Comparator | Principal finding |
|---|---|---|
| SUSTAIN 1 | Placebo | HbA1c −1.5% at 1.0 mg |
| SUSTAIN 2 | Sitagliptin | Greater HbA1c and weight reduction |
| SUSTAIN 3 | Exenatide extended-release | Greater HbA1c and weight reduction |
| SUSTAIN 4 | Insulin glargine | Greater HbA1c reduction, weight loss vs gain |
| SUSTAIN 6 | Placebo, CV outcomes | MACE HR 0.74 (0.58–0.95) |
| SUSTAIN 7 | Dulaglutide | Greater HbA1c and weight reduction |
Active-comparator trials are more informative than placebo trials for a class with several members, and SUSTAIN 7 is one of relatively few head-to-head comparisons within the GLP-1 class.[1]
Comparator doses matter in every such trial and are frequently omitted from secondary reporting. A comparison against a comparator's lower approved dose is a different result from one against its highest.[2]
SUSTAIN 6 and its interpretation
[edit]SUSTAIN 6 was powered as a non-inferiority trial for cardiovascular safety, as regulators required for glucose-lowering drugs at the time. The observed hazard ratio of 0.74 excluded 1.0, but the trial's design and event count mean the superiority finding is treated cautiously.[2]
A secondary finding attracted attention: an increase in diabetic retinopathy complications in the semaglutide arm, concentrated in participants with pre-existing retinopathy and rapid glycaemic improvement. Rapid glucose lowering is a recognised precipitant of transient retinopathy worsening by other means, so the finding is generally attributed to the magnitude and speed of improvement rather than to the drug directly — an attribution that is plausible rather than established.[2]
The SELECT trial subsequently addressed cardiovascular outcomes in a different population and with a dedicated superiority design.[3]
Relationship to the obesity programme
[edit]SUSTAIN and STEP study the same molecule at different doses in different populations, and their results are not interchangeable. The diabetes doses are 0.5 and 1.0 mg; the obesity dose is 2.4 mg.[1]
This is the source of a persistent confusion when SUSTAIN 7 or the tirzepatide comparison in SURPASS-2 are cited as though they compared maximal doses. They did not, and the distinction changes what the comparison means. See Tirzepatide.[3]
Weight reduction in SUSTAIN is a secondary outcome in a glycaemic trial, and the populations differ in body-mass index at entry. Comparing a weight figure from a diabetes trial with one from an obesity trial compares two different quantities in two different populations.[4]
See also
References
- ^ a b c d Sorli C, Harashima SI, Tsoukas GM, et al. "Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in type 2 diabetes (SUSTAIN 1)." The Lancet Diabetes & Endocrinology 5(4):251–260 (2017). PMID 28110911.
- ^ a b c d Marso SP, Bain SC, Consoli A, et al. "Semaglutide and cardiovascular outcomes in patients with type 2 diabetes." New England Journal of Medicine 375(19):1834–1844 (2016). DOI:10.1056/NEJMoa1607141. PMID 27633186.
- ^ a b Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. "Semaglutide and cardiovascular outcomes in obesity without diabetes." New England Journal of Medicine 389(24):2221–2232 (2023). PMID 37952131.
- ^ International Council for Harmonisation, E9(R1): Estimands and Sensitivity Analysis in Clinical Trials (2019).