ELIXA: The First One, and It Was Neutral
Last verified November 2026 · Phase 3 · Finished; headline results reported December 2015 · NCT01147250 ↗
The 2008 guidance existed because rosiglitazone had reduced blood glucose while apparently increasing cardiovascular events, and regulators wanted no repeat. ELIXA was designed to answer that narrow question for lixisenatide, in the highest-risk window available, shortly after an acute coronary syndrome, and answered it cleanly. Lixisenatide is a short-acting exendin-based GLP-1, structurally and pharmacokinetically distinct from the long-acting analogs that later produced benefit, which is the most common explanation offered for the difference.
- Enrollment
- 6,068
- Duration
- A median 25 months of follow-up
- Drug
- Lixisenatide 20 mcg (Adlyxin / Lyxumia)
- Population
- Adults 30 and over whose type 2 diabetes had put them in hospital in the previous 180 days with an acute coronary event (a heart attack of either type, or unstable angina with raised cardiac markers). HbA1c had to sit between 5.5% and 11%. The list of what ruled people out ran long: type 1 diabetes, bypass surgery after the qualifying event, a revascularization already scheduled inside 90 days, pancreatitis or pancreas surgery at any point, medullary thyroid cancer in the family or the person, and any other drug in this class. Average age 60, 69% men, average HbA1c 7.7%, average BMI 30.2, about 9 years since diagnosis. For 83%, the qualifying event was a heart attack.
Primary endpoint
Cardiac death, a nonfatal heart attack, a nonfatal stroke, or admission for unstable angina — whichever came first
Treatment arm
406 of 3,034 (13.4%)
Comparator
399 of 3,034 (13.2%)
Treatment difference: Hazard ratio 1.02 (95% CI 0.89 to 1.17); P<0.001 for noninferiority, P=0.81 for superiority
Neutral, and deliberately so. The trial was built to rule out harm and it did, but it found no benefit either. This was the first completed cardiovascular trial in the class, and it established the baseline that these drugs are safe to give shortly after a heart attack.
Secondary endpoints
| Endpoint | Treatment | Comparator | Difference |
|---|---|---|---|
| The same count with heart-failure admissions added No difference. Widening the definition did not surface a hidden benefit. | 456 of 3,034 (15.0%) | 469 of 3,034 (15.5%) | Hazard ratio 0.97 (95% CI 0.85 to 1.10) |
| The widest count, adding stent and bypass procedures as well Still nothing. A neutral result that stays neutral however the endpoint is drawn is far more convincing than one that appears only under a particular definition. | 661 of 3,034 (21.8%) | 659 of 3,034 (21.7%) | Hazard ratio 1.00 (95% CI 0.90 to 1.11) |
| Death from a cardiac cause Identical in both arms. About six months later the liraglutide trial, in the same drug class, reported a 22% reduction. | 156 of 3,034 (5.1%) | 158 of 3,034 (5.2%) | Hazard ratio 0.98 (95% CI 0.78 to 1.22) |
| Heart attacks No effect, and numerically slightly worse on the drug. | Similar to placebo | Reference | Hazard ratio 1.03 (95% CI 0.87 to 1.22) |
| Strokes No effect at all, against the 39% reduction semaglutide produced. This pair is the earliest hard evidence that drugs in this class do not behave alike. | Similar to placebo | Reference | Hazard ratio 1.12 (95% CI 0.79 to 1.58) |
| Admitted with unstable chest pain Too few events either way to contribute much to the overall count. | 1.0% (event rate) | 1.3% (event rate) | Hazard ratio 1.11 (95% CI 0.47 to 2.62) |
| Admitted to hospital for heart failure No effect, which is a real reassurance. A diabetes drug from another class, tested shortly before this, had raised a heart-failure signal. | 4.0% (event rate) | 4.2% (event rate) | Hazard ratio 0.96 (95% CI 0.75 to 1.23) |
| Death from any cause at all No difference across two years. | 211 of 3,034 (7.0%) | 223 of 3,034 (7.4%) | Hazard ratio 0.94 (95% CI 0.78 to 1.13) |
| Three-month average blood sugar Only about 0.27 points better than placebo, and that understates the drug, because both arms could have other diabetes medication added when glucose ran high. | Mean reduction approximately 0.27 percentage points greater than placebo | Reference (background-glycemic-therapy adjusted) | Least-squares mean difference -0.27 percentage points (95% CI -0.31 to -0.22); P<0.001 |
| Weight change Under a kilogram. This is a short-acting drug taken before a meal, in an older post-heart-attack population. Nothing here bears on the weight drugs sold today. | -0.7 kg vs placebo | Reference | Least-squares mean difference -0.7 kg (95% CI -0.9 to -0.5); P<0.001 |
| Protein leaking into the urine, at two years Protein rose in both groups and rose less on the drug, clearly so only in those who already had heavy protein loss. The result in people with moderate protein loss was borderline, and people with normal levels showed no effect. Read the FAQ below before treating this as kidney protection. | +24% from baseline | +34% from baseline | Adjusted treatment difference -1.69% (95% CI -11.69 to 8.30) in the normoalbuminuria subgroup; -21.10% (95% CI -42.25 to 0.04; P=0.05) in the microalbuminuria subgroup; -39.18% (95% CI -68.5 to -9.84; P=0.007) in the macroalbuminuria subgroup |
Adverse events
| Event | Treatment rate | Comparator rate |
|---|---|---|
| Any serious adverse event Slightly lower on the drug than on placebo. | 20.6% | 22.1% |
| Stopped the drug over a side effect 11.4% against 7.2%, mostly stomach and bowel effects, the same pattern as every drug in this class. | 11.4% | 7.2% |
| Nausea Nearly four times the placebo rate, per the trial's ClinicalTrials.gov results, as are the vomiting, diarrhea and low-blood-sugar rows below. Because this drug is taken before a meal and acts briefly, the nausea is tied to eating rather than spread through the week. | 21.7% (659/3,031) | 5.9% (179/3,032) |
| Vomiting About three times the placebo rate. | 8.5% (257/3,031) | 2.7% (82/3,032) |
| Diarrhea Barely different from placebo. | 7.8% (237/3,031) | 7.5% (227/3,032) |
| Low blood sugar reported as a nonserious adverse event Barely different from placebo. This class only pushes insulin out when glucose is already elevated, which is why better control does not come with more lows. | 20.1% (609/3,031) | 18.3% (554/3,032) |
| Severe low blood sugar needing help from someone else The trial reported no excess of severe episodes on the drug. | No higher than on placebo | Reference |
| Pancreatitis, confirmed by independent review No increase, and numerically fewer on the drug. Pancreatitis was written in as a safety endpoint because of the class-wide concern, and the trial found nothing. | 0.2% (5 events) | 0.3% (8 events) |
| Pancreatic tumors Fewer on the drug than on placebo, on very small numbers. | 0.1% (3 events) | 0.3% (9 events) |
| Allergic reactions No excess, despite this being a peptide derived from a lizard protein rather than a copy of the human hormone. | No higher than on placebo | Reference |
Subgroup analyses
- What kind of cardiac event got them into the trial: The same neutral result whichever it was
No group hidden inside the trial did better.
- How soon after the event they started: under 30, 30 to 59, 60 to 89, or 90 or more days: No difference by timing
Starting sooner neither helped nor hurt.
- Kidney function at the start: Consistent across the range
Unlike the liraglutide trial, where the benefit was larger in people with worse kidney function, there was no benefit here to concentrate anywhere.
- Blood sugar control at the start: No difference by starting control
How high the blood sugar was made no difference to the outcome.
- Under 65 against 65 and over: Consistent across ages
No age effect on a result that was neutral to begin with.
- How much protein was in the urine at the start — none, a little, or a lot: Urine protein worsened 39% more slowly among those who arrived with heavy protein loss; borderline with moderate protein loss; unchanged with normal levels
From the Muskiet 2018 renal substudy. A hint rather than a demonstration, pointing the same way as the kidney findings that later trials in this class pursued properly.
Clinical significance
ELIXA is the trial that keeps the class story honest. Cardiovascular benefit is not automatic in this class: two trials, ELIXA and EXSCEL, found none. Anyone told that 'GLP-1s reduce heart attacks' is being given a claim that is true of semaglutide, liraglutide, dulaglutide and albiglutide, and not of lixisenatide or exenatide on the evidence available. The molecule matters, and so does the trial behind the sentence.
Frequently Asked Questions
References
- 1.Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, Lawson FC, Ping L, Wei X, Lewis EF, Maggioni AP, McMurray JJ, Probstfield JL, Riddle MC, Solomon SD, Tardif JC; ELIXA Investigators. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med. 2015. PMID: 26630143.
- 2.Muskiet MHA, Tonneijck L, Huang Y, Liu M, Saremi A, Heerspink HJL, van Raalte DH. Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2018. PMID: 30292589.
- 3.Sanofi. Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010 (Lixisenatide) — ELIXA. ClinicalTrials.gov, NCT01147250. 2015. https://clinicaltrials.gov/study/NCT01147250
- 4.U.S. Food and Drug Administration. Adlyxin (lixisenatide) New Drug Application 208471 — Approval Package. FDA Drugs@FDA, July 2016. 2016. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208471Orig1s000TOC.cfm
- 5.Marso SP, Daniels GH, Brown-Frandsen K, et al.; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016. PMID: 27295427.
- 6.Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019. PMID: 31422062.
- 7.Marso SP, Bain SC, Consoli A, et al.; SUSTAIN-6 Investigators. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016. PMID: 27633186.