Source of SUSTAIN trial programme

{{Infobox concept | name = SUSTAIN trial programme | subtitle = Phase 3 programme | Drug = [[Semaglutide|Semaglutide]] 0.5 and 1.0 mg weekly | Indication = Type 2 diabetes | Notable member = SUSTAIN 6, cardiovascular outcomes }} The '''SUSTAIN trial programme''' is the phase 3 series that established weekly [[Semaglutide|semaglutide]] for type 2 diabetes. Its trials compared semaglutide against placebo and against active comparators including sitagliptin, exenatide extended-release, insulin glargine and [[Dulaglutide|dulaglutide]].{{r|sorli2017}} 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 trial programme|STEP]].{{r|sorli2017}} 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.{{r|marso2016s}} == Structure of the programme == | 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 receptor agonist|GLP-1 class]].{{r|sorli2017}} 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.{{r|marso2016s}} == SUSTAIN 6 and its interpretation == 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.{{r|marso2016s}} 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.{{r|marso2016s}} The [[SELECT trial|SELECT]] trial subsequently addressed cardiovascular outcomes in a different population and with a dedicated superiority design.{{r|lincoff2023}} == Relationship to the obesity programme == SUSTAIN and [[STEP trial programme|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.{{r|sorli2017}} 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]].{{r|lincoff2023}} 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.{{r|ich_e9}} == References == {{reflist}} <ref name="sorli2017">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.</ref> <ref name="marso2016s">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.</ref> <ref name="lincoff2023">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.</ref> <ref name="ich_e9">International Council for Harmonisation, ''E9(R1): Estimands and Sensitivity Analysis in Clinical Trials'' (2019).</ref> == See also == * [[Semaglutide]] * [[STEP trial programme]] * [[SELECT trial]] * [[Dulaglutide]] {{DEFAULTSORT:SUSTAIN trial programme}} [[Category:Clinical trial programmes]] [[Category:Type 2 diabetes trials]] [[Category:Clinical evidence]]