Diabetes Care 1 Michael A. Nauck,1 Thomas Jon Jensen,2 Neoplasms Reported With Carina Rosenkilde,2 Salvatore Calanna,2 and John B. Buse,3 the LEADER Publication Liraglutide or Placebo in People Committee on behalf of the LEADER Trial With Type 2 Diabetes: Results Investigators* From the LEADER Randomized Trial https://doi.org/10.2337/dc17-1825 OBJECTIVE This study explored neoplasm risk with liraglutide versus placebo in the LEADER EMERGING TECHNOLOGIES AND THERAPEUTICS (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) cohort. RESEARCH DESIGN AND METHODS LEADER (NCT01179048) was an international, phase 3b, randomized, double-blind, controlled trial. Participants aged ‡50 years with type 2 diabetes and high car- diovascular risk were assigned 1:1 to receive liraglutide (£1.8 mg daily; n = 4,668) or placebo (n = 4,672) in addition to standard care and monitored for 3.5–5 years (median follow-up 3.8 years). The occurrence of neoplasms was a prespecified, exploratorysecondaryendpoint.Posthocanalysesofthetime tothefirstconfirmed neoplasms were conducted using a Cox regression model. RESULTS 1Diabetes Center Bochum-Hattingen, St. Josef- Neoplasm was confirmed in 10.1% of patients with liraglutide versus 9.0% with Hospital, Ruhr-University Bochum, Bochum, placebo (hazard ratio [HR] 1.12 [95% CI 0.99; 1.28]). The HR (95% CI) for liraglutide Germany 2 versus placebo was 1.06 (0.90; 1.25) for malignant neoplasms and 1.16 (0.93; 1.44) Novo Nordisk A/S, Bagsværd, Denmark 3University of North Carolina School of Medicine, for benign neoplasms. Sensitivity analyses excluding neoplasms occurring <1 year Chapel Hill, NC < or 2 years after randomization and analyses by sex provided similar results. Corresponding author: Michael A. Nauck, michael In our main analyses, the 95% CI for the HR included one for all malignant neo- [email protected]. plasms evaluated (including pancreatic and thyroid neoplasms), except for pro- Received 31 August 2017 and accepted 29 April state neoplasms, which occurred in fewer liraglutide-treated patients. 2018. Clinical trial reg. no. NCT01179048, clinicaltrials CONCLUSIONS .gov. LEADER was not primarily designed to assess neoplasm risk. Firm conclusions cannot This article contains Supplementary Data online be made regarding numeric imbalances observed for individual neoplasm types at http://care.diabetesjournals.org/lookup/suppl/ (e.g., pancreatic cancer) that occurred infrequently. LEADER data do, however, ex- doi:10.2337/dc17-1825/-/DC1. clude a major increase in the risk of total malignant neoplasms with liraglutide *A complete list of the LEADER Committee Mem- bers and Trial Investigators can be found in the versus placebo. Additional studies are needed to assess longer-term exposure. Supplementary Data online. © 2018 by the American Diabetes Association. Diabetes and obesity have been identified as risk factors for cancer and cancer-related Readers may use this article as long as the work mortality (1–5). Glucose-lowering medications may also affect the risk of these events is properly cited, the use is educational and not for profit, and the work is not altered. More infor- (1,3). Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) improve glycemic mation is available at http://www.diabetesjournals control with a low risk of hypoglycemia in people with type 2 diabetes (6). GLP-1 .org/content/license. Diabetes Care Publish Ahead of Print, published online June 13, 2018 2 Neoplasms in LEADER Diabetes Care receptor expression has been reported chemotherapy, surgery, radiotherapy, insufficient evidence (e.g., lack of a pa- in a wide range of rodent and human or palliative therapy in the previous thology report) to confirm an event as a tissues, including the pancreatic islets, 5 years was an exclusion criterion. Also neoplasm. lung, heart, kidney, gastrointestinal tract, excluded were patients with a familial or To confirm the robustness of the anal- pituitary, skin, and several regions of the personal history of multiple endocrine yses based on adjudicated data, a review nervous system (7,8). This widespread neoplasia type 2 or medullary thyroid of investigator-reported adverse events expression of the GLP-1 receptor may cancer (MTC) (11). Patients with intra- of malignant neoplasms was also under- help to explain the range of effects of epithelial squamous cell carcinoma taken by the sponsor, who performed GLP-1RAs (9–15). of the skin (Bowen’sdisease)treated MedDRA term searches after the un- Data from some preclinical (16–19), with topical 5-fluorouracil and patients blinding of data after database lock. In clinical (15), and/or epidemiological da- with basal cell skin cancer were al- addition, case reviews of all investigator- tabase studies (20,21) have suggested lowed to enter the trial (11). Partici- reported adverse events of malignant an increase in the risk of thyroid cancer pants were monitored for 3.5–5 years neoplasms not confirmed by the EAC (16,20,21), pancreatic cancer (17,18,20, (median follow-up, 3.8) (11). The pri- were performed by the sponsor at this 21), intestinal neoplasms (15,19), and mary end point was time to first occur- time. Because the EAC was blinded, breast neoplasms (15) with the use of rence of CV death, nonfatal (including external, and independent, its assess- incretin-based therapy (GLP-1RAs and/or silent) myocardial infarction, or nonfatal ments were prioritized over the spon- dipeptidylpeptidase-4[DPP-4]inhibitors). stroke (11). sor’s assessments; however, the latter In contrast, other clinical and epidemio- are reported for transparency and com- logical database studies have indicated Evaluation of Neoplasms pleteness. that incretin-based therapy does not in- The occurrence of neoplasms was a pre- crease the risk of these events (22–25). specified, exploratory secondary end Evaluation of Cause of Death Results from large, prospective clinical point. The investigators were asked to All deaths were adjudicated by a CV trials may help clarify a potential risk report all types of suspected neoplasms, subcommittee to identify potential CV for neoplasms with GLP-1RAs or other including malignant neoplasm, in situ deaths. The subcommittee classified glucose-lowering medications (26). neoplasm, and neoplasm of uncertain the cause of deaths as “known” or “un- The LEADER (Liraglutide Effect and or unknown behavior. known” and further, for a known cause, Action in Diabetes: Evaluation of Cardio- Potential neoplasms identified via in- as CV or non-CV deaths. This required vascular Outcome Results) trial was de- vestigator reports, Medical Dictionary for formal agreement/adjudication. Based signed to assess the cardiovascular (CV) Regulatory Activities (MedDRA) search, on comments that were not subject to safety of liraglutide but provided the the event adjudication committee (EAC), reconciliation between adjudicators, the opportunity to evaluate other impor- or the contract research organization, sponsor further categorized the non-CV tant safety end points in a population were sent for adjudication (Supplemen- deaths according to plausible cause, which of 9,340 participants monitored for tary Fig. 1). All potential neoplasms were could include neoplastic disease. 3.5–5 years (median follow-up, 3.8) adjudicated in a blinded manner by the (11). The primary analysis showed neoplasms subcommittee of the exter- Statistical Methods liraglutide treatment was associated nal, independent EAC. The clinical eval- Post hoc analyses of the time to the first with a lower rate of major adverse CV uation of neoplasms by the EAC could be EAC-confirmed neoplasm events were events and total mortality (11). The pres- based on diagnostic tests, pathology conducted using a Cox regression model ent report explores intermediate-term reports, specialist consultations, related to compare liraglutide treatment with neoplasm risk with liraglutide versus imaging reports, and/or biomarkers. For placebo. Exploratory statistical testing placebo, based on detailed analyses of thyroid neoplasms, operative reports without correction for multiplicity was data from LEADER. and relevant laboratory findings (e.g., performed if one or more events oc- tumor markers) were also used as di- curred in both treatment groups. The RESEARCH DESIGN AND METHODS agnostic criteria. The EAC used a prespe- main analyses used an intention-to- Trial Design cified definition for adjudication of treat approach, including all first events The design of the LEADER trial (clinicaltrials potential neoplasms, and a pathologic collected from randomization until the .gov, NCT01179048) has been published diagnosis by histology or cytology was end-of-trial follow-up visit. previously (11,27). LEADER was a phase considered of foremost importance for Plots were prepared showing the cu- 3b, randomized, double-blind, controlled confirmation. After database lock, EAC- mulative incidence probability of con- trial, conducted between 2010 and confirmed neoplasm events categorized firmed neoplasm index events with 2015 in 32 countries (11,27). During the as tissue of origin “other” were classified liraglutide or placebo over time. The trial, 9,340 participants aged $50 years according to the organ system affected cumulative incidence was estimated with type 2 diabetes and high CV risk by medically qualified personnel at Novo using the Aalen-Johansen method with were assigned, in a 1:1 ratio, to receive Nordisk. death as a competing risk. Definitions liraglutide (up to 1.8 mg daily) or The EAC was not required to specify its of neoplasm