Incretin based drugs and the risk of pancreatic cancer: international multicentre cohort study

Azoulay, Laurent; Filion, Kristian B.; Platt, Robert W.; Dahl, Matthew; Dormuth, Colin R.; Clemens, Kristin K.; Durand, Madéleine; Juurlink, David N.; Targownik, Laura E.; Turin, Tanvir Chowdhury; Paterson, J. Michael; Ernst, Pierre

doi:10.1136/bmj.i581

Cited by 92 publications

(132 citation statements)

References 35 publications

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“…Early observational studies 15,16 suggested that exenatide could be associated with pancreatic cancer; however, a recent study showed no significant associations. 17 Asymptomatic hyperamylasaemia was reported in one patient in the exenatide group, necessitating drug withdrawal. Exenatide can induce amylase secretion in vitro, and increased amylase concentrations have been reported in patients with type 2 diabetes treated with similar drugs.…”

Section: Discussionmentioning

confidence: 99%

Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial

et al. 2017

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Summary Background Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of Parkinson’s disease. We investigated whether these effects would be apparent in a clinical trial. Methods In this single-centre, randomised, double-blind, placebo-controlled trial, patients with moderate Parkinson’s disease were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placebo once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period. Eligible patients were aged 25–75 years, had idiopathic Parkinson’s disease as measured by Queen Square Brain Bank criteria, were on dopaminergic treatment with wearing-off effects, and were at Hoehn and Yahr stage 2·5 or less when on treatment. Randomisation was by web-based randomisation with a two strata block design according to disease severity. Patients and investigators were masked to treatment allocation. The primary outcome was the adjusted difference in the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor subscale (part 3) in the practically defined off-medication state at 60 weeks. All efficacy analyses were based on a modified intention-to-treat principle, which included all patients who completed any post-randomisation follow-up assessments. The study is registered at ClinicalTrials.gov (NCT01971242) and is completed. Findings Between June 18, 2014, and March 13, 2015, 62 patients were enrolled and randomly assigned, 32 to exenatide and 30 to placebo. Our primary analysis included 31 patients in the exenatide group and 29 patients in the placebo group. At 60 weeks, off-medication scores on part 3 of the MDS-UPDRS had improved by 1·0 points (95% CI −2·6 to 0·7) in the exenatide group and worsened by 2·1 points (−0·6 to 4·8) in the placebo group, an adjusted mean difference of −3·5 points (−6·7 to −0·3; p=0·0318). Injection site reactions and gastrointestinal symptoms were common adverse events in both groups. Six serious adverse events occurred in the exenatide group and two in the placebo group, although none in either group were judged to be related to the study interventions. Interpretation Exenatide had positive effects on practically defined off-medication motor scores in Parkinson’s disease, which were sustained beyond the period of exposure. Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinson’s disease, and effects on everyday symptoms should be examined in longer-term trials. Funding Michael J Fox Foundation for Parkinson’s Research.

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Section: Discussionmentioning

confidence: 99%

Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial

et al. 2017

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“…Similarly, in 2,024,441 person-years of follow-up, examination of health records failed to reveal increased reports of pancreatic cancer in individuals treated with incretin-based therapies (77). Given the long latency required for cancer signals to emerge, coupled with the low incidence rates for malignancies such as MTC, it is not yet possible to completely exclude the possibility that a cancer signal might yet emerge in longer, larger studies or following scrutiny of more extensive drug exposure using electronic health databases.…”

Section: Adverse Events Associated With Glp-1r Agonistsmentioning

confidence: 99%

The Ascending GLP-1 Road From Clinical Safety to Reduction of Cardiovascular Complications

Drucker

2018

Diabetes

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Glucagon-like peptide 1 (GLP-1) was originally identified as a gut-derived incretin hormone that lowered glycemia through potentiation of glucose-dependent insulin secretion. Subsequent studies expanded the actions of GLP-1 to include inhibition of glucagon secretion, gastric emptying, and appetite, collectively useful attributes for a glucose-lowering agent. The introduction of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes was associated with questions surrounding their safety, principally with regard to medullary thyroid cancer, pancreatitis, and pancreatic cancer, yet cardiovascular outcome trials subsequently revealed reductions in rates of stroke, myocardial infarction, and cardiovascular death with a paucity of major safety signals. We discuss the controversies, unanswered questions, and established use of GLP-1R agonists from a mechanistic and clinical perspective. We highlight methods for detection and cellular sites of GLP-1R expression, key uncertainties, recent insights, and experimental caveats surrounding the use of GLP-1R agonists for the treatment of diabetes and the reduction of diabetes-related complications.

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“…Long-term exposure to oxidative stress will lead to intestinal damage, but part of lactic acid bacteria in the intestine can play an antioxidant role, remove free radicals and ease UC [8]. Intestinal mucosa permeability will change as the intestinal tract gradually becomes inflammatory, and the mucous membrane permeability will be greatly improved when inflammation is increased [9,10]. Study has shown that some lactic acid bacteria can alleviate DSS-induced colitis by improving the permeability of intestinal mucosa [11].…”

Section: Biomedical Research 2018; 29 (4): 768-774mentioning

confidence: 99%

Colitis reducing effects of Lactobacillus plantarum YS-4 in dextran sulfate sodium-induced C57BL/6J mice

Li¹,

Long²,

Pan³

et al. 2018

biomedicalresearch

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Incretin based drugs and the risk of pancreatic cancer: international multicentre cohort study

Cited by 92 publications

References 35 publications

Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial

Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial

The Ascending GLP-1 Road From Clinical Safety to Reduction of Cardiovascular Complications

Colitis reducing effects of Lactobacillus plantarum YS-4 in dextran sulfate sodium-induced C57BL/6J mice

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