Neoplasms Reported With Liraglutide or Placebo in People With Type 2 Diabetes: Results From the LEADER Randomized Trial

Nauck, Michael A.; Jensen, Thomas; Rosenkilde, Carina; Calanna, Salvatore; Buse, John B.

doi:10.2337/dc17-1825

Cited by 58 publications

(52 citation statements)

References 36 publications

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“…Regarding acute pancreatitis, pancreatic cancer and any malignant neoplasm as the main outcomes, the numbers of cases reported and the patient-years of observation in each arm were extracted from the main manuscripts reporting cardiovascular outcomes (including online supplementary material) or from specific reports about pancreatitis and/or neoplasms. [18][19][20][21][22] Table S2 (see Supporting Information) presents data on the adjudication process for acute pancreatitis. If the patient-years of observation were not explicitly stated in the manuscripts, the number of patients that could be observed for the main endpoint (major adverse cardiovascular events) was calculated from the mean (or median) duration of the trial times, approximated by subtracting the number of patients that did not provide data for this endpoint.…”

Section: Methodsmentioning

confidence: 99%

Incretin‐based glucose‐lowering medications and the risk of acute pancreatitis and malignancies: a meta‐analysis based on cardiovascular outcomes trials

Aziz

Cahyadi

Meier

et al. 2019

Diabetes Obesity Metabolism

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Some epidemiological data have suggested an elevated risk of acute pancreatitis and pancreatic cancer after exposure to glucagon‐like peptide (GLP)‐1 receptor agonists and dipeptidyl peptidase (DPP)‐4 inhibitors. Recently, such outcomes have been assessed and adjudicated as adverse events of special interest in cardiovascular outcomes studies. We performed a meta‐analysis of cases of acute pancreatitis and pancreatic cancer as well as any malignant neoplasm reported in cardiovascular outcomes trials (CVOTs) with GLP‐1 receptor agonists and DPP‐4 inhibitors. The numbers of cases observed with active drug or placebo (both on a background of standard care) were related to patient‐years of observation. Rate ratios and their confidence intervals were calculated for the individual agents as well as for the classes of GLP‐1 receptor agonists and DPP‐4 inhibitors. Neither data on individual CVOTs of GLP‐1 receptor agonists nor their meta‐analysis [rate ratio: 1.05 (0.78–1.41)] indicated a significantly elevated risk of acute pancreatitis. All individual DPP‐4 inhibitors displayed a non‐significant trend towards an increased risk of acute pancreatitis, which was significant in the meta‐analysis [1.75 (1.14–2.70); P = 0.01]. Neither GLP‐1 receptor agonists nor DPP‐4 inhibitors were associated with a significantly elevated or reduced risk of pancreatic cancer or for the totality of all malignant neoplasms. Based on a large database of randomized, placebo‐controlled, prospective cardiovascular outcomes studies with GLP‐1 receptor agonists and DPP‐4 inhibitors, no signal for pancreatic cancer or any malignant neoplasms were detected. However, a 75% risk increase for the development of an acute pancreatitis was seen in the meta‐analysis of DPP‐4 inhibitor CVOTs.

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Section: Methodsmentioning

confidence: 99%

Incretin‐based glucose‐lowering medications and the risk of acute pancreatitis and malignancies: a meta‐analysis based on cardiovascular outcomes trials

Aziz

Cahyadi

Meier

et al. 2019

Diabetes Obesity Metabolism

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“…Among the numerous cancers associated with DM and metabolic syndromes 25 , the association between prostate cancer and DM is controversial, and some data suggest that patients with type 2 diabetes mellitus have a lower risk of prostate cancer compared with non-diabetic individuals 26 . However, a higher incidence of prostate cancer has been observed in large-scale studies carried out in Western countries 12 , as well as in Japan 9 . Furthermore, a higher body mass index and higher plasma C-peptide concentration increase prostate cancer mortality 27 .…”

Section: Discussionmentioning

confidence: 99%

“…Further reductions in tumor growth and prostate cancer cell proliferation were observed by combination treatment with Ex-4 and metformin 11 , without a relationship to glucose reduction. Following our experimental demonstrations, the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results trial (LEADER), showed that the GLP-1R agonist significantly decreased the prevalence of prostate cancer in patients with type 2 diabetes mellitus, suggesting that GLP-1R agonists attenuate prostate cancer growth in not only experimental animal models, but also patients with type 2 diabetes mellitus 12 . In our previous report, the anti-prostate cancer effect induced by Ex-4 was dependent on GLP-1R expression in cancer cells, and Ex-4 did not attenuate the proliferation of the human prostate cancer cell line ALVA-41 that does not express endogenous GLP-1R 10 .…”

Section: Introductionmentioning

confidence: 94%

Activation of overexpressed glucagon‐like peptide‐1 receptor attenuates prostate cancer growth by inhibiting cell cycle progression

Shigeoka

Nomiyama

Kawanami

et al. 2020

J of Diabetes Invest

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Aims/Introduction Incretin therapy is a common treatment for type 2 diabetes mellitus. We have previously reported an anti‐prostate cancer effect of glucagon‐like peptide‐1 receptor (GLP‐1R) agonist exendin‐4. The attenuation of cell proliferation in the prostate cancer cell line was dependent on GLP‐1R expression. Here, we examined the relationship between human prostate cancer severity and GLP‐1R expression, as well as the effect of forced expression of GLP‐1R using a lentiviral vector. Materials and Methods Prostate cancer tissues were extracted by prostatectomy and biopsy. GLP‐1R was overexpressed in ALVA‐41 cells using a lentiviral vector (ALVA‐41‐GLP‐1R cells). GLP‐1R expression was detected by immunohistochemistry and quantitative polymerase chain reaction. Cell proliferation was examined by growth curves and bromodeoxyuridine incorporation assays. Cell cycle distribution and regulators were examined by flow cytometry and western blotting. In vivo experiments were carried out using a xenografted model. Results GLP‐1R expression levels were significantly inversely associated with the Gleason score of human prostate cancer tissues. Abundant GLP‐1R expression and functions were confirmed in ALVA‐41‐GLP‐1R cells. Exendin‐4 significantly decreased ALVA‐41‐GLP‐1R cell proliferation in a dose‐dependent manner. DNA synthesis and G1‐to‐S phase transition were inhibited in ALVA‐41‐GLP‐1R cells. SKP2 expression was decreased and p27Kip1 protein was subsequently increased in ALVA‐41‐GLP‐1R cells treated with exendin‐4. In vivo experiments carried out by implanting ALVA‐41‐GLP‐1R cells showed that exendin‐4 decreased prostate cancer growth by activation of GLP‐1R overexpressed in ALVA41‐GLP‐1R cells. Conclusions Forced expression of GLP‐1R attenuates prostate cancer cell proliferation by inhibiting cell cycle progression in vitro and in vivo. Therefore, GLP‐1R activation might be a potential therapy for prostate cancer.

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“…The SAVOR‐TIMI 53 trial (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus ‐ Thrombolysis in Myocardial Infarction) followed 16 492 individuals for a median of 2.1 years and reported fewer lung cancer events with saxagliptin vs placebo (54/326 vs 59/362; HR 0.91, 95% CI 0.63–1.32) [12]. Similarly, fewer lung cancer events were reported with liraglutide vs placebo (28/470 vs 33/419; HR 0.85, 95% CI 0.51–1.40) in the LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results), which followed 9340 individuals for a median of 3.8 years [13]. Overall, these trials reported nonsignificant effect estimates, although it was neither powered nor designed to evaluate cancer as a study outcome.…”

Section: Discussionmentioning

confidence: 99%

“…In a recent meta‐analysis of 19 randomized controlled trials (RCTs), there was no association between incretin‐based drugs and lung cancer (relative risk 1.00, 95% CI 0.76–1.33) [9]. In subsequent RCTs, small imbalances were observed, with more lung cancer events with semaglutide than with placebo (8/155 vs 6/139) [11], while there were fewer lung cancer events with liraglutide (28/470 vs 33/419) and saxagliptin (54/326 vs 59/362) than with placebo [12,13]. None of these trials, however, was powered or designed to evaluate lung cancer as a safety outcome.…”

Section: Introductionmentioning

confidence: 99%

Incretin‐based drugs and risk of lung cancer among individuals with type 2 diabetes

Rouette

Yin

et al. 2020

Diabet. Med.

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Aim To assess whether dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists are associated with an increased lung cancer risk among individuals with type 2 diabetes. MethodsWe conducted a population-based cohort study using the UK Clinical Practice Research Datalink. We identified 130 340 individuals newly treated with antidiabetes drugs between January 2007 and March 2017, with follow-up until March 2018. We used a time-varying approach to model use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists compared with use of other second-or third-line antidiabetes drugs. We used Cox proportional hazards models to estimate the adjusted hazard ratios, with 95% CIs, of incident lung cancer associated with use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, separately, by cumulative duration of use, and by time since initiation.Results A total of 790 individuals were newly diagnosed with lung cancer (median follow-up 4.6 years, incidence rate 1.5/1000 person-years, 95% CI 1.4-1.6). Compared with use of second-/third-line drugs, use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists was not associated with an increased lung cancer risk (hazard ratio 1.07, 95% CI 0.87-1.32, and hazard ratio 1.02, 95% CI 0.68-1.54, respectively). There was no evidence of duration-response relationships.

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Neoplasms Reported With Liraglutide or Placebo in People With Type 2 Diabetes: Results From the LEADER Randomized Trial

Cited by 58 publications

References 36 publications

Incretin‐based glucose‐lowering medications and the risk of acute pancreatitis and malignancies: a meta‐analysis based on cardiovascular outcomes trials

Incretin‐based glucose‐lowering medications and the risk of acute pancreatitis and malignancies: a meta‐analysis based on cardiovascular outcomes trials

Activation of overexpressed glucagon‐like peptide‐1 receptor attenuates prostate cancer growth by inhibiting cell cycle progression

Incretin‐based drugs and risk of lung cancer among individuals with type 2 diabetes

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