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Reanalysis of study of pancreatic effects of incretin therapy: methodological deficiencies.

ABSTRACT: A recently published study by Butler et al. concluded that incretin treatment had adverse effects on the human type 2 diabetic pancreas including 'a marked expansion of the exocrine and endocrine pancreatic compartments, the former being accompanied by increased proliferation and dysplasia and the latter by ?-cell hyperplasia with the potential for evolution into neuroendocrine tumours'. Incretin therapy has become widely used for type 2 diabetes, so these conclusions have instigated major concerns with regard to patient safety. We reassessed both the clinical case information and virtual microscopy images of the same 34 cases that were used in the Butler study as well as Network for Pancreatic Organ Donation (nPOD) cases that were not included. Whereas we would like to stress that it is important to investigate in depth any indication that incretin treatment may lead to inflammation or dysplasia in the pancreas, we find that the data presented in the Butler paper have serious methodological deficiencies that preclude any meaningful conclusions.

SUBMITTER: Bonner-Weir S

PROVIDER: S-EPMC5678976 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Reanalysis of study of pancreatic effects of incretin therapy: methodological deficiencies.

Bonner-Weir S S In't Veld P A PA Weir G C GC

Diabetes, obesity & metabolism 20140129 7

A recently published study by Butler et al. concluded that incretin treatment had adverse effects on the human type 2 diabetic pancreas including 'a marked expansion of the exocrine and endocrine pancreatic compartments, the former being accompanied by increased proliferation and dysplasia and the latter by α-cell hyperplasia with the potential for evolution into neuroendocrine tumours'. Incretin therapy has become widely used for type 2 diabetes, so these conclusions have instigated major conce ...[more]

PMID: 24400596

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Project description:ObjectiveTo determine whether the use of incretin based drugs compared with sulfonylureas is associated with an increased risk of incident pancreatic cancer in people with type 2 diabetes.DesignPopulation based cohort.SettingLarge, international, multicentre study combining the health records from six participating sites in Canada, the United States, and the United Kingdom.ParticipantsA cohort of 972,384 patients initiating antidiabetic drugs between 1 January 2007 and 30 June 2013, with follow-up until 30 June 2014.Main outcome measuresWithin each cohort we conducted nested case-control analyses, where incident cases of pancreatic cancer were matched with up to 20 controls on sex, age, cohort entry date, duration of treated diabetes, and duration of follow-up. Hazard ratios and 95% confidence intervals for incident pancreatic cancer were estimated, comparing use of incretin based drugs with use of sulfonylureas, with drug use lagged by one year for latency purposes. Secondary analyses assessed whether the risk varied by class (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists) or by duration of use (cumulative duration of use and time since treatment initiation). Site specific hazard ratios were pooled using random effects models.ResultsDuring 2,024,441 person years of follow-up (median follow-up ranging from 1.3 to 2.8 years; maximum 8 years), 1221 patients were newly diagnosed as having pancreatic cancer (incidence rate 0.60 per 1000 person years). Compared with sulfonylureas, incretin based drugs were not associated with an increased risk of pancreatic cancer (pooled adjusted hazard ratio 1.02, 95% confidence interval 0.84 to 1.23). Similarly, the risk did not vary by class and evidence of a duration-response relation was lacking.ConclusionsIn this large, population based study the use of incretin based drugs was not associated with an increased risk of pancreatic cancer compared with sulfonylureas. Although this potential adverse drug reaction will need to be monitored long term owing to the latency of the cancer, these findings provide some reassurance on the safety of incretin based drugs.

Project description:IntroductionThe present study aims to evaluate the risk of pancreatic cancer with incretin-based therapy among patients with type 2 diabetes mellitus (T2DM).MethodsWe searched EMBASE, MEDLINE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov for eligible studies published up to March 06 2016. This meta-analysis includes all studies reporting adverse events of pancreatic cancer with use of incretin-based therapies compared with placebo or non-incretin anti-diabetic drugs in patients with T2DM. We used fixed-effect model to compare pooled relative risk (RR) with related 95% confidence intervals (CI).ResultsA total of 159 randomized trials were identified. Out of these, 135 studies were excluded as pancreatic cancer occurrence had not been included as an end point. The remaining 24 trials enrolling 47,904 participants were further assessed. Overall, no increased risk of pancreatic cancer were detected in association with incretin-based treatment (RR = 0.7, 95% CI 0.37-1.05). The incidence of pancreatic neoplasm was even lower among incretin-based groups than controls (RR = 0.50, 95% CI 0.29-0.87) in trials with duration more than 104 weeks. There was even decreased risk of pancreatic cancer within groups paralleled by incretin-matched placebos (RR = 0.55, 95% CI 0.32-0.93) than by non-incretin anti-diabetic drugs. Neither monotherapy (RR = 0.62, 95% CI 0.38-1.01) nor combination regimen (RR = 0.92, 95% CI 0.45-1.90) of incretin mimetics increased the risk of pancreatic cancer.ConclusionThis meta-analysis shows that incretin-based therapies are not associated with increase in the risk of pancreatic cancer. Interestingly, subgroup analyses suggested lower risk of pancreatic cancer in incretin groups than placebo in long-term studies (>104 weeks). Considering the inconsistent results among randomized trials and previous epidemiological investigations, more such studies should be conducted to clarify the existence or non-existence of this association.FundingThis work was supported by grants from the National Natural Science Foundation of China (Nos. 81270476 and 81470830).

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Reanalysis of study of pancreatic effects of incretin therapy: methodological deficiencies.

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Reanalysis of study of pancreatic effects of incretin therapy: methodological deficiencies.

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