GLP Watchdog

EXSCEL: The Large Neutral Result

Last verified November 2026 · Phase 3/4 · Finished; published September 2017 · NCT01144338 ↗

By Ruth Calder · Enforcement Editor
Editorially reviewed. Not medical advice · How we verify contentLast reviewed

Size does not guarantee a positive result, and EXSCEL is the clearest demonstration of that here. It enrolled more people than any outcomes trial in this class before it and found no significant reduction. Exenatide is exendin-based rather than a human GLP-1 analog, and its once-weekly formulation produces a different exposure profile from semaglutide or dulaglutide. Those are the usual explanations for why it behaved differently. Poor adherence has also been proposed: the trial had no run-in period, and its authors called the rate at which people stopped the study drug a major limitation.

Enrollment
14,752
Duration
A median 3.2 years, with the trial running until enough events had accumulated rather than to a fixed date
Drug
Exenatide once-weekly (Bydureon)
Population
Adults 18 and over whose type 2 diabetes ran between an HbA1c of 6.5% and 10.0%, with or without heart disease: 73.1% arrived with it, 26.9% without. Average age 62.0, 38.0% women, average HbA1c 8.0%, average BMI 31.8, about 12 years since diagnosis. The background treatment makes this trial unusual. 77% were on metformin, 37% on sulfonylureas and 46% on insulin, and participants were free to add other drugs during the trial. That is a real clinic population rather than a curated one, and it cuts both ways.

Primary endpoint

Cardiac death, a nonfatal heart attack, or a nonfatal stroke — whichever came first

Treatment arm

839 of 7,356 (11.4%); 3.7 events per 100 person-years

Comparator

905 of 7,396 (12.2%); 4.0 events per 100 person-years

Treatment difference: Hazard ratio 0.91 (95% CI 0.83 to 1.00); P<0.001 for non-inferiority, P=0.06 for superiority

A near miss rather than a flat line. The reduction came out at 9%, with the confidence interval touching 1.00 and a p-value of 0.06. It cleared the safety bar the FDA required and failed the conventional test for benefit. Sitting between the neutral lixisenatide trial and the clearly positive liraglutide and semaglutide ones, it is the single result that most complicates any tidy story about this drug class.

Secondary endpoints

EXSCEL secondary endpoints, treatment against comparator. Last verified November 2026.
EndpointTreatmentComparatorDifference
Death from a cardiac cause

Fewer, but it does not count. Because the main test failed, everything below it is descriptive by the trial's own pre-set rules.

340 of 7,356 (4.6%)383 of 7,396 (5.2%)Hazard ratio 0.88 (95% CI 0.76 to 1.02)
Heart attacks, fatal or not

A small numerical difference and nothing more.

483 of 7,356 (6.6%)493 of 7,396 (6.7%)Hazard ratio 0.97 (95% CI 0.85 to 1.10)
Strokes, fatal or not

Slightly fewer, again not formally testable.

187 of 7,356 (2.5%)218 of 7,396 (2.9%)Hazard ratio 0.85 (95% CI 0.70 to 1.03)
Death from any cause at all

This is the most misquoted number in the trial. Deaths were 6.9% against 7.9%, which on its own would look convincing, but the trial's pre-set testing order meant that once the main endpoint failed, this could not be declared significant. Anyone citing this trial as evidence the drug saves lives is reading past the rule the trial set for itself in advance.

507 of 7,356 (6.9%)584 of 7,396 (7.9%)Hazard ratio 0.86 (95% CI 0.77 to 0.97)
Admitted to hospital for heart failure

No effect, matching the pattern across this whole class and standing in contrast to SGLT2 inhibitors, which reduce these admissions substantially.

219 of 7,356 (3.0%)231 of 7,396 (3.1%)Hazard ratio 0.94 (95% CI 0.78 to 1.13)
Admitted with an acute coronary event

Slightly more on the drug, within the range of chance, with nothing to separate the arms.

602 of 7,356 (8.2%)570 of 7,396 (7.7%)Hazard ratio 1.05 (95% CI 0.94 to 1.18)
Three-month average blood sugar

A modest gain that understates the drug, because both arms could freely add other diabetes medication, including drugs from this same class later in the trial.

ReducedReferenceBetween-group difference −0.53 percentage points (95% CI −0.57 to −0.50)
Weight change

Roughly 1 to 2 kg. Nothing here is relevant to the weight drugs sold today, and it is part of why this product could not compete once semaglutide arrived.

ReducedReferenceBetween-group difference −1.27 kg (95% CI −1.40 to −1.13)

Adverse events

EXSCEL adverse events, rate on treatment against rate on comparator. Last verified November 2026.
EventTreatment rateComparator rate
Reactions where the injection went in

A problem specific to this product rather than the class. It used a slow-release microsphere depot, and a meaningful minority of patients developed visible lumps under the skin. The liquid pens do not cause these. The trial's authors pointed to the complicated first-generation injection device and the lack of a run-in period as the likely reasons so many people stopped.

Higher with exenatideLower with placebo
Pancreatitis, confirmed

Similar in both arms and uncommon, consistent with every other large trial in this class.

26 of 7,344 (0.4%)22 of 7,372 (0.3%)
Pancreatic cancer

No imbalance, in a trial large enough for the question to mean something: 14,752 people over three years.

15 of 7,344 (0.2%)16 of 7,372 (0.2%)
Medullary thyroid cancer

Two cases on the drug and one on placebo, and all three people already had raised calcitonin levels when they joined. This is the cancer behind the boxed warning on this class, and that warning comes from rodent studies.

2 of 7,344 (<0.1%)1 of 7,372 (<0.1%)
Severe low blood sugar needing help from someone else

Slightly higher on the drug, and the reason is what people were already taking. Nearly half this trial was on insulin and more than a third on a sulfonylurea, the drugs that cause lows. The GLP-1 does not do it alone.

247 of 7,344 (3.4%)219 of 7,372 (3.0%)
Stopped taking the assigned treatment

43.0% against 45.2%: nearly half of everyone in both arms stopped. That matters for interpretation. A trial where half the participants are no longer taking what they were assigned has a real problem detecting a modest benefit.

43.0%45.2%

Subgroup analyses

  • People who had already had cardiovascular disease — 73.1% of the trial: 10% fewer events, with the confidence interval just clearing 1

    Slightly better than the trial overall. It was a pre-planned subgroup rather than the primary test, so it is a hint about where any benefit lives, not a result.

  • People with no previous cardiovascular disease — 26.9%: No signal at all

    The same split shows up in the liraglutide trial: whatever benefit exists in this class concentrates in people who have already been damaged.

  • People whose kidney function was already reduced: No difference: hazard ratio 1.01 (95% CI 0.86 to 1.19) with filtration under 60

    The reverse of the pattern seen with other drugs in this class, where more kidney damage tended to mean more benefit. People with filtration of 60 or above came out at 0.86, though the test for a difference between the two groups was not significant (P=0.12).

Clinical significance

EXSCEL's value is corrective. It is the trial to remember when a marketing page compresses this literature into 'GLP-1s are cardioprotective', because what was then the largest trial in the class says that is not true of every drug in it. For a weight-management reader, exenatide is not a realistic option in any case; the relevance is entirely to how confidently class-wide claims should be made.

Frequently Asked Questions

On its primary endpoint — Cardiac death, a nonfatal heart attack, or a nonfatal stroke — whichever came first — the treatment arm recorded 839 of 7,356 (11.4%); 3.7 events per 100 person-years against 905 of 7,396 (12.2%); 4.0 events per 100 person-years for the comparator. Hazard ratio 0.91 (95% CI 0.83 to 1.00); P<0.001 for non-inferiority, P=0.06 for superiority. A near miss rather than a flat line. The reduction came out at 9%, with the confidence interval touching 1.00 and a p-value of 0.06. It cleared the safety bar the FDA required and failed the conventional test for benefit. Sitting between the neutral lixisenatide trial and the clearly positive liraglutide and semaglutide ones, it is the single result that most complicates any tidy story about this drug class.
14,752 participants, over A median 3.2 years, with the trial running until enough events had accumulated rather than to a fixed date. It was a Phase 3/4 trial, finished; published September 2017. Registered as NCT01144338, which you can look up yourself rather than taking anyone's summary for it.
Adults 18 and over whose type 2 diabetes ran between an HbA1c of 6.5% and 10.0%, with or without heart disease: 73.1% arrived with it, 26.9% without. Average age 62.0, 38.0% women, average HbA1c 8.0%, average BMI 31.8, about 12 years since diagnosis. The background treatment makes this trial unusual. 77% were on metformin, 37% on sulfonylureas and 46% on insulin, and participants were free to add other drugs during the trial. That is a real clinic population rather than a curated one, and it cuts both ways. ⚠ A trial result describes the population it was measured in. If you differ from it materially — in age, in baseline weight, in whether you have diabetes — the number is context rather than a prediction.
The most commonly reported were reactions where the injection went in (Higher with exenatide against Lower with placebo on comparator), pancreatitis, confirmed (26 of 7,344 (0.4%) against 22 of 7,372 (0.3%) on comparator), pancreatic cancer (15 of 7,344 (0.2%) against 16 of 7,372 (0.2%) on comparator). A problem specific to this product rather than the class. It used a slow-release microsphere depot, and a meaningful minority of patients developed visible lumps under the skin. The liquid pens do not cause these. The trial's authors pointed to the complicated first-generation injection device and the lack of a run-in period as the likely reasons so many people stopped. Rates come from this trial's population under its own dose-escalation schedule; a faster or slower titration changes what people experience.
Secondary endpoints included death from a cardiac cause (340 of 7,356 (4.6%) against 383 of 7,396 (5.2%)); heart attacks, fatal or not (483 of 7,356 (6.6%) against 493 of 7,396 (6.7%)); strokes, fatal or not (187 of 7,356 (2.5%) against 218 of 7,396 (2.9%)). ⚠ Secondary endpoints are weaker evidence than the primary one — a trial is powered for its primary outcome, and the rest are read as supporting rather than as findings in their own right.
Exenatide once-weekly (Bydureon) is what the protocol used. This trial is not complete, so treat the figures as provisional. ⛔ Where a drug is investigational, anything sold under its name online is outside the prescribing system entirely, and this register does not list those sellers.
It cannot tell you that. A trial reports an average across a defined population under a fixed protocol, with monitoring and adherence support most people do not get. It is the best evidence available and it is still a distribution rather than a promise — some participants lost far more than the mean and some lost nothing. What it is genuinely good for is comparing options against each other, which is what the rest of this section is for.

References

  1. 1.Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, Chan JC, Choi J, Gustavson SM, Iqbal N, Maggioni AP, Marso SP, Öhman P, Pagidipati NJ, Poulter N, Ramachandran A, Zinman B, Hernandez AF; EXSCEL Study Group. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2017. PMID: 28910237.
  2. 2.Amylin Pharmaceuticals, LLC; AstraZeneca. Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL): A Trial to Evaluate Cardiovascular Outcomes After Treatment With Exenatide Once Weekly in Patients With Type 2 Diabetes Mellitus. ClinicalTrials.gov, NCT01144338. 2017. https://clinicaltrials.gov/study/NCT01144338
  3. 3.AstraZeneca. Bydureon (exenatide extended-release) product portfolio communication — U.S. market discontinuation, 2024. AstraZeneca corporate disclosure. 2024. https://www.astrazeneca.com/our-therapy-areas/cardiovascular-renal-and-metabolism.html
  4. 4.Mentz RJ, Bethel MA, Gustavson S, et al. Baseline characteristics of patients enrolled in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). Am Heart J. 2017. PMID: 28454792.
  5. 5.Nicholls SJ, Pavo I, Bhatt DL, et al.; SURPASS-CVOT Investigators. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes. N Engl J Med. 2025. PMID: 41406444.
  6. 6.Eli Lilly and Company. MOUNJARO (tirzepatide) injection: Prescribing Information. DailyMed (NIH/NLM). 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d2d7da5d-ad07-4228-955f-cf7e355c8cc0

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