Incretin‐based therapies and risk of pancreatic cancer in patients with type 2 diabetes: <scp>A</scp> meta‐analysis of randomized controlled trials

Wang, Haining; Liu, Ye; Tian, Qing; Yang, Jin; Lu, Ran; Zhan, Siyan; Haukka, Jari; Hong, Tianpei

doi:10.1111/dom.13177

Cited by 26 publications

(45 citation statements)

References 73 publications

(138 reference statements)

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“…PC cases were identified using an algorithm, possibly introducing misclassification; however, severity of PC, rapid time course once diagnosed, and use of an algorithm developed in the source database contribute to the accuracy of case identification. The number of cases was similar to that of those in studies included in pooled RCT analyses of GLP‐1 drugs and in several other observational studies focused on PC …”

Section: Discussionsupporting

confidence: 76%

“…The follow‐up period ranged between 1.3 and 2.8 years across sites, not including the one discounted year. A recent summary of RCTs of GLP‐1 RAs revealed no elevation in PC risk (Peto OR, 0.77 [95% CI, 0.42‐1.42]) comparing GLP‐1 RAs with either placebo or control . In addition, recent meta‐analyses have provided additional evidence that PC is not a major concern in populations treated with incretin‐based therapies …”

Section: Discussionmentioning

confidence: 99%

“…42 Overall, however, there appears to be increasing support for the absence of association between GLP-1 RA therapies and AP. 15 In PC analyses, the majority of ITT RRs were below 1.0; the only statistically significant finding was a lower risk with liraglutide use, rel- 46 In addition, recent metaanalyses have provided additional evidence that PC is not a major concern in populations treated with incretin-based therapies. 19 The strengths of this study include the use of a large administrative claims database, supplemented with a medical record review.…”

Section: Discussionmentioning

confidence: 99%

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Liraglutide use and evaluation of pancreatic outcomes in a US commercially insured population

Funch

Mortimer

Ziyadeh

et al. 2019

Diabetes Obesity Metabolism

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Aims Both acute pancreatitis (AP) and pancreatic cancer (PC) have been areas of focus for studies of incretin drugs. This 5‐year prospective cohort study aimed to quantify possible associations between liraglutide and risk of AP and PC as compared to other antidiabetic drugs (ADs). Materials and methods Patients initiating liraglutide or other ADs who were enrolled in a US health plan (2010‐2014) were included. Comparisons of AP and PC incidence rates were made between matched cohorts of liraglutide initiators and initiators of other ADs. Adjudicated AP cases and algorithm‐based PC cases were identified. Propensity score‐matched intention‐to‐treat (ITT) and time‐on‐drug (TOD) analyses were completed using Poisson regression. A latency analysis was performed for PC. Results Median follow‐up was 405 days for AP cohorts (9995 liraglutide, 1:1 matched to all comparators) and 503 days for PC cohorts (35 163 liraglutide, 1:1 matched to all comparators). In the primary AP analysis, “current” use of liraglutide was not significantly associated with elevated risk across comparators (all comparators relative risk [RR] = 1.2; 95% confidence interval [CI], 0.6‐2.3). ITT results were similar where, in the primary analysis, no RRs were significantly associated with PC (all comparators RR = 0.7; 95% CI, 0.3‐1.4); latency and TOD analyses did not alter findings. There was no evidence of a dose‐response effect. Conclusions Liraglutide was not associated with an increased risk of AP or PC, although risk estimates were more variable for AP, and numbers of cases for both outcomes were limited because of the rarity of outcomes.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Liraglutide use and evaluation of pancreatic outcomes in a US commercially insured population

Funch

Mortimer

Ziyadeh

et al. 2019

Diabetes Obesity Metabolism

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“…In 2014, a joint study was published in the New England Journal of Medicine , stating that the agencies had not yet reached a final conclusion regarding a possible relationship . Since then, several literature reviews have been conducted regarding incretin‐based drugs and pancreatic cancer …”

Section: Introductionmentioning

confidence: 99%

“…4 Since then, several literature reviews have been conducted regarding incretin-based drugs and pancreatic cancer. [5][6][7][8][9] However, as DPP-4 inhibitors are involved in many physiological processes, the influence of DPP-4 inhibitors might be more far reaching than the influence on the glucose homeostasis. There is evidence in animal models that DPP-4 inhibition is related to pancreatic cancer, ovarian cancer, neuroblastoma, prostate cancer, melanoma, and lung cancer.…”

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confidence: 99%

Risk of dipeptidyl peptidase‐4 (DPP‐4) inhibitors on site‐specific cancer: A systematic review and meta‐analysis

Overbeek

Bakker

Heijden³

et al. 2018

Diabetes Metabolism Res

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The long-term impact of dipeptidyl peptidase-4 (DPP-4) inhibition is unknown, and there are concerns about the influence of DPP-4 inhibition on carcinogenesis of the pancreas and thyroid. As DPP-4 is a rather unselective enzyme present in many tissues, we focused on all specific cancer types. PubMed and EMBASE were searched between January 2005 and April 2017 to identify studies comparing DPP-4 inhibitors with either placebo or active drugs on cancer risk. Studies were included if they reported on at least one specific cancer outcome and had a follow-up of at least 1 year after start of drug use. Methodological quality of the studies was assessed by the Cochrane Collaboration's tool and the Newcastle-Ottawa Scale. Twenty-five studies met the inclusion criteria (12 randomized controlled trials and 13 observational studies). Sample sizes of the DPP-4 inhibitor groups ranged from 29 to 8212 patients for randomized controlled trials and from 2422 to 71 137 patients for observational studies. Mean age ranged from 51 to 76 years, and mean follow-up was 1.5 years. None of the pooled (sensitivity) analyses, except the observational studies studying breast cancer (hazard ratio [95% CI]: 0.76 [0.60-0.96]), showed evidence for an association between DPP-4 inhibitors and site-specific cancer. Also for pancreatic and thyroid cancer, no statistically significant risk was found. Based on the current literature, it is not possible to conclude whether DPP-4 inhibitors were associated with an increased risk of site-specific cancer. Future studies should address the methodological limitations and follow patients for a longer period to determine the long-term cancer risk of DPP-4 inhibitors.

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A systematic review and meta‐analysis of observational studies of the association between the use of incretin‐based therapies and the risk of pancreatic cancer

Hidayat

Zhou

et al. 2022

Pharmacoepidemiology and Drug

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Background: Some early reports in the medical literature have raised concern about a possible increased risk of pancreatic cancer associated with the use of two broad classes of incretin-based therapies, dipeptidyl peptidase-4 inhibitors, and glucagon-like peptide-1 receptor agonists. This possibility has been somewhat mitigated by the null findings meta-analyses of randomized controlled trials, but the usefulness of their findings was hampered by serious shortcomings of lack of power and representativeness.These shortcomings can typically be addressed by observational studies, but observational studies on the topic have yielded conflicting findings. A systematic review and meta-analysis of observational studies was performed to qualitatively and quantitatively appraise the totality of evidence on the association between the use of incretin-based therapies and the risk of pancreatic cancer in routine clinical practice. Methods:The PubMed, Web of Science, Embase, and Google Scholar databases were searched. The study quality was appraised using the ROBINS-I tool and based on the presence of pharmacoepidemiology biases. A random-effects model was used to estimate the summary relative risks with corresponding CIs.Results: A total of 14 studies were included. The qualitative assessment revealed that all studies had inadequate follow-up (≤5 years), 12 studies were suspected to suffer from time-lag bias (due to inappropriate choice of comparator group) to varying extent, five studies included prevalent users, five studies did not implement exposure lag period, five studies had a serious risk of bias due to confounding, and one study had a time-window bias. The quantitative assessment showed no indication of an increased risk when all studies were pooled together (RR 1.04, 95% CI 0.87, 1.24) and when the analysis was restricted to the studies with the least bias (RR 0.77, 95% CI 0.51, 1.17). However, the pooled RRs were more frequently higher in the studies with less rigorous design and analysis. Specifically, a tendency toward an increased risk was observed in the studies with (RR 1.34, 95% CI 1.04, 1.72) or possibly with (RR 1.10, 95% CI 0.89, 1.36) time-lag bias, in the studies that did not apply (RR 1.23, 95% CI 0.93, 1.63) or with potentially inadequate exposure lag period of 6 months (RR 1.13, 95% CI 0.66, 1.94), in the studies that inappropriate comparator group of a combination of unspecified (RR 1.49, 95% CI Khemayanto Hidayat and Ying-Yi Zhou contributed equally to this study.

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Incretin‐based therapies and risk of pancreatic cancer in patients with type 2 diabetes: A meta‐analysis of randomized controlled trials

Abstract: Treatment with incretin drugs was not associated with an increased risk of pancreatic cancer in people with T2DM. Instead, it might protect against pancreatic malignancy in patients treated for ≥104 weeks.

Cited by 26 publications

References 73 publications

Liraglutide use and evaluation of pancreatic outcomes in a US commercially insured population

Liraglutide use and evaluation of pancreatic outcomes in a US commercially insured population

Risk of dipeptidyl peptidase‐4 (DPP‐4) inhibitors on site‐specific cancer: A systematic review and meta‐analysis

A systematic review and meta‐analysis of observational studies of the association between the use of incretin‐based therapies and the risk of pancreatic cancer

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