SUSTAIN-7 Trial: A Plain-English Overview of What It Established

At a glance

Field	Detail
Trial Name	SUSTAIN-7
Design	Open-label, randomized, phase 3b, parallel-group RCT
N	1,201
Intervention	Semaglutide 0.5 mg SC once weekly OR semaglutide 1.0 mg SC once weekly
Comparator	Dulaglutide 0.75 mg SC once weekly OR dulaglutide 1.5 mg SC once weekly
Background Therapy	Metformin (stable dose)
Duration	40 weeks
Primary Endpoints	Change from baseline in A1C and body weight at week 40
Key Results	Semaglutide superior on both endpoints at both dose comparisons
Journal	Lancet Diabetes & Endocrinology, 2018
Primary Source	PubMed 29395633

Why a Head-to-Head Trial Was Needed

By the mid-2010s, GLP-1 receptor agonists had multiplied quickly. Exenatide, liraglutide, dulaglutide, and semaglutide each carried placebo-controlled trial packages, but clinicians trying to choose between them had almost no direct comparative data. Indirect cross-trial comparisons are unreliable because populations, background therapies, and titration schedules differ in ways that inflate or suppress apparent differences. Semaglutide's FDA approval in 2017 was built primarily on the SUSTAIN 1-5 program against placebo, sitagliptin, and insulin, so the question of how it performed against another injectable GLP-1 agonist remained genuinely open before SUSTAIN-7 was published in Lancet Diabetes & Endocrinology in 2018.

Dulaglutide was the natural comparator. It had already demonstrated cardiovascular safety in REWIND (published later, but the compound was widely used), it was once-weekly like semaglutide, and it occupied the same slot in ADA Standards of Care guidance on GLP-1 selection. A direct trial comparing the two at clinically used doses gave prescribers something they could actually apply.

Who Was Enrolled

Investigators recruited adults aged 18 or older with type 2 diabetes who had an A1C between 7.5% and 10.5% and had been on a stable metformin dose (at least 1 to 500 mg/day or maximum tolerated) for 90 days or more before screening. The mean baseline A1C was approximately 8.2%, mean body weight was around 95 kg, and mean duration of diabetes was roughly 8 years. These are fairly typical community patients with moderately uncontrolled diabetes on oral monotherapy, not highly selected academic-center populations.

Exclusion criteria included prior use of any GLP-1 receptor agonist, use of insulin within 90 days, severe renal impairment (eGFR <30 mL/min/1.73 m²), and a history of pancreatitis. The renal cutoff matters clinically because both drugs are used in patients with moderate chronic kidney disease, and excluding the most impaired patients means the results apply cleanly only down to an eGFR around 30.

Participants were randomized 1:1:1:1 across four arms. The two semaglutide arms and two dulaglutide arms were powered to detect superiority within each dose-matched pair separately.

Intervention and Titration Details

Semaglutide was started at 0.25 mg once weekly for four weeks, escalated to 0.5 mg at week 4, and (in the 1.0 mg arm) further escalated to 1.0 mg at week 8. Dulaglutide 0.75 mg was given at the fixed dose throughout. Dulaglutide 1.5 mg was also given at the fixed dose throughout; dulaglutide does not require an escalation scheme in the same way because its gastrointestinal tolerability profile differs from semaglutide's.

This asymmetry in titration is worth noting because critics have pointed out that semaglutide's dose-escalation period means patients in the semaglutide arms spent the first eight weeks at sub-therapeutic doses while dulaglutide patients were at full dose from the start. The 40-week endpoint still favors semaglutide, but the titration imbalance does mean that early tolerability comparisons between arms are not straightforward. The primary SUSTAIN-7 publication acknowledged this design feature explicitly.

The trial was open-label. Both drugs are injected subcutaneously once weekly and have a similar pen-device form, so full blinding would have been logistically possible in principle. The open-label design introduces the risk of differential reporting of subjective outcomes (nausea, adherence) and differential dropout, though the authors used a confirmatory estimand approach to handle missing data.

What Was Measured

The co-primary endpoints were change in A1C from baseline to week 40 and change in body weight from baseline to week 40. Using two co-primary endpoints required a hierarchical testing procedure to control the family-wise error rate. A1C was tested first; if superior, weight was then formally tested. This is conservative and appropriate, and both tests achieved significance in both dose comparisons.

Secondary endpoints included the proportion of patients reaching A1C <7.0%, A1C ≤6.5%, the proportion losing at least 5% of body weight, fasting plasma glucose, seven-point self-measured plasma glucose profiles, blood pressure, lipids, and patient-reported outcomes using the Diabetes Treatment Satisfaction Questionnaire (DTSQ). Safety endpoints covered hypoglycemia (using American Diabetes Association definitions), adverse events, serious adverse events, and discontinuations due to adverse events.

Results in Detail

The results below summarize the outcomes published in Lancet Diabetes & Endocrinology at week 40.

Glycemic Outcomes

ETD = estimated treatment difference. Both semaglutide doses produced statistically and clinically meaningful additional A1C reductions. An ETD of roughly 0.4 percentage points exceeds what most clinicians regard as a minimum clinically important difference for A1C.

Proportions reaching A1C <7.0% were 67% for semaglutide 0.5 mg versus 52% for dulaglutide 0.75 mg, and 79% for semaglutide 1.0 mg versus 67% for dulaglutide 1.5 mg. These responder rates matter at the individual patient level because they translate the mean difference into probability-of-goal language.

Weight Outcomes

The weight difference at the higher-dose comparison is particularly striking. A mean difference of more than 3.5 kg at 40 weeks, on top of baseline weights around 95 kg, represents a clinically meaningful separation. Roughly 49% of semaglutide 1.0 mg patients lost at least 5% of body weight, compared with 26% in the dulaglutide 1.5 mg arm.

Cardiovascular Risk Markers and Blood Pressure

Systolic blood pressure fell more in the semaglutide arms. The difference was approximately 3 mmHg at the higher-dose comparison, consistent with the weight-loss advantage. Both drugs produced broadly similar changes in LDL cholesterol and triglycerides.

Safety and Tolerability

Gastrointestinal adverse events (nausea, diarrhea, vomiting) were more frequent with semaglutide. Nausea occurred in roughly 22-24% of semaglutide patients versus 14-18% of dulaglutide patients. Discontinuation due to adverse events was numerically higher with semaglutide (5-7%) than dulaglutide (3-4%), though these differences did not reach formal significance at standard thresholds.

Hypoglycemia rates were low across all arms, consistent with the metformin background and the mechanism of GLP-1 receptor agonists. No new safety signals emerged. Injection-site reactions, pulse rate, and lipase elevations were reported in line with the established profiles of both agents documented in their respective FDA prescribing information for semaglutide and FDA prescribing information for dulaglutide.

Limitations Worth Knowing

The open-label design is the most commonly cited methodological limitation. Because both patients and investigators knew the treatment assignment, the potential for differential reporting of nausea, injection preferences, and satisfaction scores is real. A double-dummy blinded design was feasible and would have been stronger.

The 40-week duration is relatively short for a chronic disease trial. Weight loss with GLP-1 agonists often continues beyond 40 weeks, and the trajectory may diverge further or narrow at longer follow-up. The REWIND trial for dulaglutide, which ran for a median of 5.4 years, provides important long-term cardiovascular data on dulaglutide but was not a direct glycemic or weight comparison against semaglutide.

The trial enrolled only patients on metformin background, which limits generalizability to those on other oral agents, those with renal impairment, or insulin-naive patients who need a more complex regimen. The cardiovascular outcomes superiority shown in SUSTAIN-6 for semaglutide and in REWIND for dulaglutide were not directly compared here; SUSTAIN-7 was not powered or designed for cardiovascular endpoints.

Sponsor funding (Novo Nordisk manufactures semaglutide) is disclosed and standard for industry-sponsored phase 3b trials. The independent statistical analysis plan and the use of a confirmatory estimand approach strengthen confidence in the analysis, but readers should note that the dose-matching in SUSTAIN-7 is one of several legitimate ways to pair the two drugs and a different dose-matching choice could alter the magnitude of the difference.

What It Means for Clinical Practice

SUSTAIN-7 gave clinicians solid comparative data to inform GLP-1 selection when two goals are present: improving A1C and reducing body weight. The 2024 ADA Standards of Medical Care in Diabetes continue to recommend GLP-1 receptor agonists with proven cardiovascular or renal benefit for patients with established cardiovascular disease or high cardiovascular risk, and semaglutide's profile across SUSTAIN-6 and SUSTAIN-7 supports its positioning in patients where weight reduction is a priority alongside glycemic control.

For patients who prioritize tolerability over maximal weight loss, dulaglutide's lower nausea rates may be a reasonable reason to choose it, and its cardiovascular data from REWIND are independently reassuring. The head-to-head superiority in SUSTAIN-7 does not mean dulaglutide is an inferior drug in absolute terms; it means semaglutide produces larger mean changes on these endpoints in this population at these doses. Individual patient factors, including gastrointestinal history, cost, and cardiovascular risk category, remain important. A 2021 systematic review and network meta-analysis broadly corroborated the SUSTAIN-7 finding that semaglutide produces among the largest A1C and weight reductions of any GLP-1 receptor agonist in the class.

Frequently asked questions

›What was the main question SUSTAIN-7 was designed to answer?

SUSTAIN-7 asked whether once-weekly semaglutide produces greater reductions in A1C and body weight than once-weekly dulaglutide when added to metformin in adults with type 2 diabetes. Each drug was tested at two dose levels, giving two separate head-to-head comparisons within a single trial. The primary publication confirmed superiority for semaglutide on both endpoints at both dose levels.

›How did SUSTAIN-7 choose its dose pairings?

The investigators paired semaglutide 0.5 mg against dulaglutide 0.75 mg and semaglutide 1.0 mg against dulaglutide 1.5 mg. These represent the approved therapeutic doses of each drug at the time of the trial. Critics have noted that a different pairing might produce different magnitude results, but these were the clinically relevant approved doses listed in the respective FDA labeling for semaglutide and FDA labeling for dulaglutide.

›Was the SUSTAIN-7 trial blinded?

No. SUSTAIN-7 was open-label. Both patients and investigators knew which drug was being administered. A double-dummy design was possible but was not used. Open-label trials carry a higher risk of bias for subjective outcomes such as nausea reporting and patient satisfaction scores, which is a limitation the authors acknowledged in the original paper.

›Did semaglutide cause more nausea than dulaglutide in this trial?

Yes. Nausea occurred in approximately 22-24% of patients in the semaglutide arms compared with 14-18% in the dulaglutide arms. Discontinuation due to adverse events was numerically higher with semaglutide as well. This is consistent with pharmacological differences between the two molecules and reflects a real tolerability tradeoff that clinicians and patients should weigh against the greater efficacy.

›How long did SUSTAIN-7 last and does duration matter?

The trial ran for 40 weeks. This is adequate to capture the plateau of A1C lowering with GLP-1 receptor agonists but is short for weight-loss trajectory assessment. GLP-1-mediated weight loss can continue to accrue beyond 40 weeks. It is not known from this trial alone whether the weight gap between semaglutide and dulaglutide would widen, narrow, or stay the same at one to two years. Longer cardiovascular outcome trials like SUSTAIN-6 and REWIND provide durability data for each drug separately but not head-to-head.

›Does SUSTAIN-7 tell us which drug is better for the heart?

No. SUSTAIN-7 was not designed or powered for cardiovascular outcomes. Both semaglutide and dulaglutide have separate cardiovascular outcome trials: SUSTAIN-6 for semaglutide and REWIND for dulaglutide. Both demonstrated cardiovascular benefit in their respective populations. A direct cardiovascular outcome comparison between these two agents does not exist in published trial form, and SUSTAIN-7 cannot fill that gap.

›Who was excluded from SUSTAIN-7?

Key exclusion criteria included prior GLP-1 receptor agonist use, recent insulin use (within 90 days), severe renal impairment (eGFR <30 mL/min/1.73 m²), a history of pancreatitis, and A1C outside the 7.5-10.5% range. Patients with moderate chronic kidney disease (eGFR 30-60) were included, so the trial does cover a common comorbid group, but severe renal impairment was excluded.

›What background medication were participants taking?

All participants were on a stable dose of metformin (at least 1 to 500 mg/day or maximum tolerated) as their only glucose-lowering medication before and during the trial. The results therefore apply most directly to patients who are inadequately controlled on metformin alone. The trial does not establish how semaglutide and dulaglutide compare when added to sulfonylureas, SGLT-2 inhibitors, or as third agents in a multi-drug regimen.

›How have guidelines used the SUSTAIN-7 data?

The 2024 ADA Standards of Medical Care incorporate GLP-1 receptor agonist choice based on cardiovascular and renal evidence alongside efficacy. SUSTAIN-7 is cited in evidence-based comparisons of GLP-1 agents and supports positioning semaglutide when both weight reduction and A1C lowering are priority goals. A 2021 network meta-analysis further contextualizes these findings across the GLP-1 class.

›Are these results still relevant now that higher-dose semaglutide formulations exist?

The SUSTAIN-7 doses (0.5 mg and 1.0 mg weekly) remain the approved doses for Ozempic in type 2 diabetes management. Higher-dose semaglutide (2.4 mg weekly) is approved for chronic weight management under the brand name Wegovy, studied primarily in the STEP program rather than SUSTAIN-7. The SUSTAIN-7 findings remain directly applicable for the type 2 diabetes prescribing context, though the existence of higher doses means the class ceiling for semaglutide-mediated weight loss is above what SUSTAIN-7 tested.

References

1. Pratley R, Aroda VR, Lingvay I, et al. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol. 2018;6(4):275-286. https://pubmed.ncbi.nlm.nih.gov/29397376/

2. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN-6). N Engl J Med. 2016;375(19):1834-1844. https://pubmed.ncbi.nlm.nih.gov/27633186/

3. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND). Lancet. 2019;394(10193):121-130. https://pubmed.ncbi.nlm.nih.gov/31189511/

4. Tsapas A, Avgerinos I, Karagiannis T, et al. Comparative effectiveness of glucose-lowering drugs for type 2 diabetes: a systematic review and network meta-analysis. Ann Intern Med. 2020;173(4):278-286. https://pubmed.ncbi.nlm.nih.gov/33454002/

5. American Diabetes Association Professional Practice Committee. Standards of Medical Care in Diabetes 2024, Section 9: Pharmacologic Approaches to Glycemic Treatment. Diabetes Care. 2024;47(Suppl 1):S158-S178. https://diabetesjournals.org/care/article/47/Supplement_1/S158/153954/9-Pharmacologic-Approaches-to-Glycemic-Treatment

6. Ozempic (semaglutide) injection prescribing information. Novo Nordisk. FDA label, 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf

7. Trulicity (dulaglutide) injection prescribing information. Eli Lilly. FDA label, 2014. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125469lbl.pdf