Source of LEADER trial

{{Infobox concept | name = LEADER trial | subtitle = Cardiovascular outcome trial | Drug = [[Liraglutide|Liraglutide]] up to 1.8 mg daily | Population = Type 2 diabetes, high cardiovascular risk | Participants = 9,340 | Primary result = MACE HR 0.87 (95% CI 0.78–0.97) }} '''LEADER''' was a randomised, double-blind, placebo-controlled cardiovascular outcome trial of [[Liraglutide|liraglutide]] in 9,340 adults with type 2 diabetes at high cardiovascular risk, followed for a median 3.8 years.{{r|marso2016}} The primary composite outcome occurred in 13.0% of the liraglutide group and 14.9% of the placebo group, a hazard ratio of 0.87 (95% CI 0.78–0.97). Cardiovascular death was reduced, and all-cause mortality was lower in the liraglutide group.{{r|marso2016}} It was among the first trials to show that an incretin therapy could reduce cardiovascular events rather than merely not increase them, at a time when such trials were being run principally to exclude harm.{{r|marso2016}} == Design and context == Cardiovascular outcome trials for glucose-lowering drugs were mandated by regulators following concerns about an earlier drug class, and were designed as non-inferiority trials to exclude excess risk. LEADER was designed on that basis and tested for superiority in a pre-specified hierarchy after non-inferiority was established.{{r|marso2016}} The population was enriched for events: participants were 50 or older with established cardiovascular, cerebrovascular or renal disease, or 60 or older with risk factors. Enrichment increases the event rate and therefore the power of a trial of a given size, and it also limits generalisation to lower-risk populations.{{r|ich_e9}} Background therapy was standard care, so as in [[SELECT trial|SELECT]] the effect measured is incremental to contemporary treatment. == Results == | Endpoint | Liraglutide | Placebo | |---|---|---| | Primary composite | 13.0% | 14.9% | | Cardiovascular death | 4.7% | 6.0% | | All-cause death | 8.2% | 9.6% | | Nephropathy events | Lower | — | The renal signal in LEADER was a pre-specified secondary outcome and was driven principally by new-onset persistent macroalbuminuria, a marker rather than a hard endpoint. The dedicated renal question was subsequently addressed by [[FLOW trial|FLOW]] with a different agent and a composite of harder outcomes.{{r|perkovic2024}} Glycated haemoglobin was about 0.4 percentage points lower on liraglutide, and weight about 2.3 kg lower. Both differences are modest and are part of why the mechanism of the cardiovascular benefit is not attributed to glycaemic control alone.{{r|marso2016}} == Place in the evidence == LEADER established a cardiovascular benefit for one molecule at one dose in one population. Within the same class, the outcome trials of exenatide and lixisenatide were neutral, so the results do not support a class-wide claim; see [[Exenatide]] and [[GLP-1 receptor agonist]].{{r|marso2016}} Whether the differences between trials reflect molecule, dose, exposure duration, population risk or trial size is unresolved. The trials were not designed to answer that question and no adequately powered head-to-head cardiovascular comparison within the class exists.{{r|ich_e9}} For a reader assessing an individual agent, the useful discipline is to ask which trial supports which claim, in which population, at which dose — rather than to reason from class membership, and to convert relative figures to absolute ones before comparing them.{{r|perkovic2024,nnt_ref}} == References == {{reflist}} <ref name="marso2016">Marso SP, Daniels GH, Brown-Frandsen K, et al. "Liraglutide and cardiovascular outcomes in type 2 diabetes." ''New England Journal of Medicine'' 375(4):311–322 (2016). DOI:10.1056/NEJMoa1603827. PMID 27295427.</ref> <ref name="perkovic2024">Perkovic V, Tuttle KR, Rossing P, et al. "Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes." ''New England Journal of Medicine'' 391(2):109–121 (2024). PMID 38785209.</ref> <ref name="ich_e9">International Council for Harmonisation, ''E9(R1): Estimands and Sensitivity Analysis in Clinical Trials'' (2019).</ref> <ref name="nnt_ref">Laupacis A, Sackett DL, Roberts RS. "An assessment of clinically useful measures of the consequences of treatment." ''New England Journal of Medicine'' 318(26):1728–1733 (1988). PMID 3374545.</ref> == External links == * [https://clinicaltrials.gov/study/NCT01179048 LEADER — NCT01179048] — Registry record. == See also == * [[Liraglutide]] * [[SELECT trial]] * [[FLOW trial]] * [[GLP-1 receptor agonist]] * [[Number needed to treat]] {{DEFAULTSORT:LEADER trial}} [[Category:Cardiovascular outcome trials]] [[Category:Clinical evidence]] [[Category:Type 2 diabetes trials]]