LEADER: The Trial That Started the Class Story
Last verified May 2026 · Phase 3b/4 · Finished; headline results reported July 2016 · NCT01179048 ↗
Liraglutide is a daily injection with a 13-hour half-life, and by current standards a modest weight-loss drug. LEADER is the reason it still appears in every discussion of this class. Running for a median 3.8 years with a minimum 42 months of follow-up, it was long enough to detect differences in hard events rather than surrogates, and it found them. The effect size — a hazard ratio of 0.87 — is smaller than what semaglutide later produced, which fits a pattern the field now recognizes: the cardiovascular benefit across this class roughly tracks the potency of the drug.
- Enrollment
- 9,340
- Duration
- A median 3.8 years of follow-up, with a minimum of 42 months of treatment written into the protocol
- Drug
- Liraglutide 1.8 mg (Victoza)
- Population
- Adults whose type 2 diabetes ran at an HbA1c of 7.0% or above, admitted by either of two doors: from age 50 with established disease of the heart, brain, limbs or kidneys, or from age 60 with a single cardiovascular risk factor. ★ That split matters more than it looks — 81.3% arrived having already had cardiovascular disease, and the subgroup analysis below shows the benefit lived almost entirely in that group. Average age 64.3, 64.3% men, average HbA1c 8.7%, nearly 13 years since diagnosis, average BMI 32.5.
Primary endpoint
Cardiac death, a nonfatal heart attack, or a nonfatal stroke — whichever came first
Treatment arm
608 of 4,668 (13.0%)
Comparator
694 of 4,672 (14.9%)
Treatment difference: Hazard ratio 0.87 (95% CI 0.78 to 0.97); P<0.001 for noninferiority, P=0.01 for superiority
★ The first time any drug in this class was shown to prevent cardiovascular events, which is why this trial still gets cited a decade later. ⚠ Keep the size in perspective: a 13% relative reduction works out to about 66 people treated for three years to prevent one event. Later drugs in the class did better.
Secondary endpoints
| Endpoint | Treatment | Comparator | Difference |
|---|---|---|---|
| Death from a cardiac cause ★ A 22% reduction, formally established rather than descriptive, and the strongest single piece of the headline result. This is the component that made the class credible. | 219 of 4,668 (4.7%) | 278 of 4,672 (6.0%) | Hazard ratio 0.78 (95% CI 0.66 to 0.93); P=0.007 |
| Death from any cause at all 15% fewer deaths overall, driven by the cardiac deaths above. | 381 of 4,668 (8.2%) | 447 of 4,672 (9.6%) | Hazard ratio 0.85 (95% CI 0.74 to 0.97); P=0.02 |
| Heart attacks that were not fatal ⚠ Fewer, but the confidence interval crossed 1 — a trend rather than a finding. | 281 of 4,668 (6.0%) | 317 of 4,672 (6.8%) | Hazard ratio 0.88 (95% CI 0.75 to 1.03); P=0.11 |
| Strokes that were not fatal Essentially unchanged. As in the later semaglutide trial, strokes contributed little to the overall benefit. | 159 of 4,668 (3.4%) | 177 of 4,672 (3.8%) | Hazard ratio 0.89 (95% CI 0.72 to 1.11); P=0.30 |
| A wider count adding stent and bypass procedures and admissions for unstable chest pain or heart failure A 12% reduction across the broader definition, consistent with the narrower one. | 948 of 4,668 (20.3%) | 1,062 of 4,672 (22.7%) | Hazard ratio 0.88 (95% CI 0.81 to 0.96); P=0.005 |
| Admitted to hospital for heart failure ⚠ Fewer, but not significantly so. Worth knowing if heart failure is the concern: SGLT2 inhibitors produce a much larger effect on this specific outcome, and that difference still shapes prescribing. | 218 of 4,668 (4.7%) | 248 of 4,672 (5.3%) | Hazard ratio 0.87 (95% CI 0.73 to 1.05); P=0.14 |
| Three-month average blood sugar at three years ⚠ Only 0.4 points better than placebo, which understates the drug. Both arms could have other diabetes drugs added when blood sugar ran high, which deliberately narrows the gap — the trial was measuring hearts, not glucose. | -0.40 percentage points lower than placebo | Reference (background-glycemic-therapy adjusted) | Estimated treatment difference -0.40 percentage points (95% CI -0.45 to -0.34); P<0.001 |
| Weight change at three years ⚠ Just 2.3 kg. Far less than the 5 to 7 kg the same dose produced in obesity trials, because this was an older, sicker population on many other medications. A reminder that trial populations decide trial numbers. | -2.3 kg vs placebo | Reference | Estimated treatment difference -2.3 kg (95% CI -2.5 to -2.0); P<0.001 |
| Kidney decline: new protein in the urine, kidney function halving, kidney failure, or death from kidney causes ★ A 22% reduction, and the first hint that this class does something for kidneys — the observation that eventually justified the dedicated kidney trial. ⚠ Read the driver in the FAQ below before quoting it. | 268 of 4,668 (5.7%) | 337 of 4,672 (7.2%) | Hazard ratio 0.78 (95% CI 0.67 to 0.92); P=0.003 |
Adverse events
| Event | Treatment rate | Comparator rate |
|---|---|---|
| Stopped the drug for good over a side effect 9.5% against 7.3%, mostly stomach and bowel problems — the usual pattern for this class. | 9.5% | 7.3% |
| Nausea About three times the placebo rate, peaking in the first 16 weeks as the dose rose and then settling. | 18.5% | 6.4% |
| Diarrhea Roughly double the placebo rate. | 16.5% | 8.9% |
| Vomiting Around 10%, against under 4% on placebo. | 9.6% | 3.7% |
| Confirmed low blood sugar ★ Slightly LESS common on the drug despite better blood sugar control — because this class only pushes insulin out when glucose is already high. That is the mechanistic advantage over older diabetes drugs, in one row. | 43.7% | 45.6% |
| Severe low blood sugar needing help from someone else About 31% fewer episodes on the drug. For anyone who has had one, this is a meaningful difference. | 2.4% | 3.3% |
| Pancreatitis, confirmed by independent review No increase, and numerically lower than placebo. | 0.4% (18 events) | 0.5% (23 events) |
| Pancreatic cancer ⚠ 13 cases against 5 — an imbalance the authors flagged themselves. Later surveillance and pooled analyses have not confirmed it as a real effect, and the absolute numbers are tiny, but it is the honest reason this question keeps being asked about the class. | 0.3% (13 cases) | 0.1% (5 cases) |
| Gallstones and gallbladder inflammation Modestly more common, in line with rapid weight loss generally and now part of the class labeling. | 3.1% | 1.9% |
| Cancers of any kind No overall difference across nearly four years of exposure. | 6.3% | 6.0% |
| Medullary thyroid cancer ★ Not one case in either arm. This is the cancer behind the boxed warning on the whole class, which originates in rodent studies — and the largest long trial of the drug found none at all. | 0 cases | 0 cases |
Subgroup analyses
- People who had already had cardiovascular disease — 81.3% of the trial: 17% fewer cardiac events, a clear benefit
★ Almost the entire headline result came from this group.
- People 60 and over with risk factors but no previous cardiac event — 18.7% of the trial: No benefit; the estimate pointed the wrong way, with a wide confidence interval
⛔ The most important caveat on this page. In people who had not already had an event, this drug did not demonstrably prevent one. Anyone quoting LEADER as a reason to take a GLP-1 for heart protection without existing heart disease is quoting the wrong subgroup.
- People whose kidney function was already reduced — about 23%: 31% fewer cardiac events, a larger benefit than the trial overall
★ More benefit where there was more damage. The same pattern turns up repeatedly in this class.
- Younger against older participants: Consistent across age bands
No sign that age changed how well the drug worked.
- Men against women: Similar in both
Women made up about a third of the trial, and the benefit held for them.
Clinical significance
LEADER's value today is historical and conceptual rather than commercial. It established that this mechanism does something for cardiovascular risk, which justified the larger and more expensive outcomes trials that followed. For a reader comparing options, its practical relevance is narrow — liraglutide is expensive relative to what it delivers and has largely been displaced. ⚠ Its 1.8 mg dose is the diabetes dose; Saxenda's weight-management dose is 3.0 mg, and LEADER does not speak to that.
Who sells liraglutide, and for how much
This trial tested Liraglutide 1.8 mg (Victoza). Across the 556 sellers on this register, 3 publish a standing monthly cash price for compounded liraglutide, from $160 a month, with a median of $214.
⛔ None of those sellers was in this trial. A compounded preparation is not the product studied here: no agency has reviewed that specific preparation for safety, effectiveness or manufacturing quality, and its concentration is set by whichever pharmacy filled it. The result above is the strongest evidence available for liraglutide and it was generated on something else. Every seller, with its price record.
Frequently Asked Questions
References
- 1.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.
- 2.Mann JFE, Ørsted DD, Brown-Frandsen K, et al.; LEADER Steering Committee and Investigators. Liraglutide and Renal Outcomes in Type 2 Diabetes. N Engl J Med. 2017. PMID: 28854085.
- 3.Novo Nordisk A/S. Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results — A Long Term Evaluation (LEADER). ClinicalTrials.gov, NCT01179048. 2016. https://clinicaltrials.gov/study/NCT01179048
- 4.U.S. Food and Drug Administration. Victoza Prescribing Information Update: Indication to Reduce Risk of Major Adverse Cardiovascular Events in Adults with Type 2 Diabetes and Established Cardiovascular Disease. FDA Label Update, August 2017. 2017. https://www.fda.gov/drugs/drug-safety-and-availability/victoza-liraglutide-injection-drug-safety-communication-fda-approves-changes-prescribing-information