Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study

Ruiter, Rikje; Visser, Loes E.; Herk‐Sukel, Myrthe P. P. van; Coebergh, Jan Willem; Haak, Harm R.; Geelhoed-Duijvestijn, Petronella; Straus, Sabine M. J. M.; Herings, Ron M. C.; Stricker, Bruno H.

doi:10.1007/s00125-011-2312-4

Cited by 101 publications

(112 citation statements)

References 39 publications

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“…1). Following our inclusion criteria, 16 cohort and 3 case-control studies were included in this systematic review (5)(6)(7)(8)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). All studies evaluated insulin glargine, with four studies also investigating insulin detemir (15,17,25,28).…”

Section: Study Selectionmentioning

confidence: 99%

“…One study examined duration of time since starting long-acting insulin analogs, and one examined mean daily dose (22,28). Four studies used time-dependent exposure definitions (15,17,20,24). All included studies evaluated cancer incidence as a primary outcome.…”

Section: Study Characteristics and Effect Estimatesmentioning

confidence: 99%

“…2) (5,8,(14)(15)(16)(17)(19)(20)(21)23,25,26,28). Four of 13 studies reported an association of insulin glargine and breast cancer (8,19,21,24).…”

Section: Study Characteristics and Effect Estimatesmentioning

confidence: 99%

“…However, residual confounding may have resulted due to the presence of unmeasured confounders. HbA 1c and diabetes duration were not accounted for in 15 of the 19 studies, resulting in likely residual confounding (7,8,(14)(15)(16)(17)(18)(20)(21)(22)(23)(24)(25)(26)28). In addition, residual confounding may have occurred in all 19 studies because none of these studies adjusted for time-dependent covariates, such as the addition of short-acting insulins or other antidiabetic medication (e.g., metformin), at all or appropriately (e.g., used a marginal structural model and inverse probability weighting to adjust for time-dependent confounders in the causal pathway).…”

Section: Residual Confoundingmentioning

confidence: 99%

“…These studies raised important concerns but were also criticized for important methodological shortcomings (9)(10)(11)(12)(13). Since then, several observational studies assessing the association between longacting insulin analogs and cancer have been published but yielded inconsistent findings (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Such discrepancies may be due to methodological limitations, including inadequate durations of followup between insulin initiation and cancer incidence, protopathic bias, detection bias, the inclusion of prevalent users, and time-related biases such as immortal time bias, time-window bias, and time-lag bias (29).…”

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confidence: 99%

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Effect of Long-Acting Insulin Analogs on the Risk of Cancer: A Systematic Review of Observational Studies

Filion

Azoulay

et al. 2016

Diabetes Care

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OBJECTIVEObservational studies examining the association between long-acting insulin analogs and cancer incidence have produced inconsistent results. We conducted a systematic review of these studies, focusing on their methodological strengths and weaknesses. RESEARCH DESIGN AND METHODSWe systematically searched MEDLINE and EMBASE from 2000 to 2014 to identify all observational studies evaluating the relationship between the long-acting insulin analogs and the risk of any and site-specific cancers (breast, colorectal, prostate). We included cohort and case-control studies published in English on insulin glargine and detemir and any cancer incidence among patients with type 1 or 2 diabetes. The methodological assessment involved the inclusion of prevalent users, inclusion of lag periods, time-related biases, and duration of follow-up between insulin initiation and cancer incidence. RESULTSA total of 16 cohort and 3 case-control studies met our inclusion criteria. All studies evaluated insulin glargine, and four studies also examined insulin detemir. Follow-up ranged from 0.9 to 7.0 years. Thirteen of 15 studies reported no association between insulin glargine and detemir and any cancer. Four of 13 studies reported an increased risk of breast cancer with insulin glargine. In the quality assessment, 7 studies included prevalent users, 11 did not consider a lag period, 6 had time-related biases, and 16 had short (<5 years) follow-up. CONCLUSIONSThe observational studies examining the risk of cancer associated with long-acting insulin analogs have important methodological shortcomings that limit the conclusions that can be drawn. Thus, uncertainty remains, particularly for breast cancer risk.NPH insulin has been the mainstay treatment for type 1 diabetes and advanced type 2 diabetes since the 1950s. However, this insulin is associated with an increased risk of nocturnal hypoglycemia, and its relatively short half-life requires frequent administration (1,2). Consequently, structurally modified insulins, known as longacting insulin analogs (glargine and detemir), were developed in the 1990s to circumvent these limitations. However, there are concerns that long-acting insulin

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Section: Study Selectionmentioning

confidence: 99%

Section: Study Characteristics and Effect Estimatesmentioning

confidence: 99%

“…2) (5,8,(14)(15)(16)(17)(19)(20)(21)23,25,26,28). Four of 13 studies reported an association of insulin glargine and breast cancer (8,19,21,24).…”

Section: Study Characteristics and Effect Estimatesmentioning

confidence: 99%

Section: Residual Confoundingmentioning

confidence: 99%

mentioning

confidence: 99%

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Effect of Long-Acting Insulin Analogs on the Risk of Cancer: A Systematic Review of Observational Studies

Filion

Azoulay

et al. 2016

Diabetes Care

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(Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus

Hemmingsen

Richter

Metzendorf

2019

Cochrane Database of Systematic Reviews

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Diabetes and cancer: the mechanistic implications of epidemiological analyses from the Hong Kong Diabetes Registry

Yang

et al. 2012

Diabetes Metabolism Res

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Diabetes is a disorder of energy metabolism associated with increased cancer risk, but the underlying mechanism is poorly understood. In a prospective cohort of patients enrolled in the Hong Kong Diabetes Registry, we explored risk factors for cancer including drug usage in type 2 diabetes. In a series of published papers, we reported a linear risk association of cancer with glycated haemoglobin with a threshold at 6.0%-6.5% and non-linear risk associations of body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride and white blood cell (WBC) count in V-shaped or A-shaped manners. Detailed pharmacoepidemiological analysis revealed markedly attenuated cancer risk in patients treated with insulin and oral anti-diabetic drugs compared with non-users of these drugs. We further observed significant drug-subphenotype interactions with attenuated cancer risk in metformin users with low high-density lipoprotein cholesterol, renin-angiotensin system (RAS) inhibitor users with high WBC count and statin users with co-presence of low low-density lipoprotein cholesterol plus albuminuria or low triglyceride. These novel observations corroborate with experimental findings of possible consequences of hyperglycaemia on dysregulation of cholesterol metabolism, renin-angiotensin system and adenosine 5'-monophosphate-activated protein kinase pathways, all of which may be implicated in carcinogenesis. On the basis of these epidemiological and experimental findings, we argue for the strong need to strengthen the health care system to ensure that type 2 diabetes subjects receive appropriate drugs to optimize internal milieu to reduce all events including cancer. Apart from mechanistic studies, large-scale, randomized clinical trials using medications such as statin, renin-angiotensin system inhibitors and metformin in patients with risk-conferring subphenotypes are needed to confirm their anti-cancer effects.

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Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study

Cited by 101 publications

References 39 publications

Effect of Long-Acting Insulin Analogs on the Risk of Cancer: A Systematic Review of Observational Studies

Effect of Long-Acting Insulin Analogs on the Risk of Cancer: A Systematic Review of Observational Studies

(Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus

Diabetes and cancer: the mechanistic implications of epidemiological analyses from the Hong Kong Diabetes Registry

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