Similar risk of malignancy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: findings from a 5 year randomised, open-label study
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- Rosenstock, J., Fonseca, V., McGill, J.B. et al. Diabetologia (2009) 52: 1971. doi:10.1007/s00125-009-1452-2
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KeywordsCancerInsulin analoguesInsulin glargineInsulin therapyMalignancyNPH insulinType 2 diabetes
Medical Dictionary for Regulatory Activities
Neutral protamine Hagedorn
To the Editor: We have reported a randomised, long-term safety study comparing the effects of using the insulin analogue glargine (A21Gly,B31Arg,B32Arg human insulin) versus human neutral protamine Hagedorn (NPH) insulin for 5 years in the management of type 2 diabetes . The study, in which 1017 patients were randomised and treated, was designed to assess ocular complications of diabetes: there was no excess of such effects with insulin glargine compared with NPH insulin treatment and there was a similar slow progression of diabetic retinopathy with both types of insulin. Because of recent concerns about postulated neoplastic effects of insulins [2–5], we report here additional information from our study that bears on this question.
Summary of extent of exposure (safety population)
Insulin glargine (n = 514)
NPH insulin (n = 503)
Cumulative exposure (patient-years)
Extent of exposure (days)
1523.55 ± 571.77
1521.82 ± 562.14
The baseline demographics and diabetes status were similar between the two treatment groups (insulin glargine vs NPH insulin): diabetes duration (10.7 vs 10.8 years), BMI (34.5 vs 34.1 kg/m2), oral hypoglycaemic agent duration (9.0 vs 8.9 years), prior insulin use (67% vs 70%), HbA1c (8.4% vs 8.3%) and fasting plasma glucose (10.5 vs 10.0 mmol/l).
Patients with neoplasms reported as treatment-emergent adverse events
Insulin glargine (n = 514)
NPH insulin (n = 503)
Breast neoplasms, malignant
Cutaneous neoplasms, benign
Endocrine neoplasms, malignant
Gastrointestinal neoplasms, malignant
Hepatobiliary neoplasms, malignant
Lymphomas, non-Hodgkin's B cell
Metastases, unspecified neoplasm
Miscellaneous and site unspecified neoplasms, malignant
Nervous system neoplasms, benign
Ocular neoplasms, benign or malignant
Plasma cell neoplasms, benign or malignant
Renal and urinary tract neoplasms, malignant
Reproductive neoplasms female, benign
Reproductive neoplasms female, malignant
Reproductive neoplasms male, malignant
Respiratory and mediastinal neoplasms, malignant
Skin neoplasms, malignant
Soft tissue neoplasms, benign
Soft tissue sarcomas, benign or malignant
The overall number of patients with neoplasms (using the standard MedDRA coding dictionary) occurring during the trial was similar in the two treatment groups: 57 patients (11.1%) in the insulin glargine group vs 62 patients (12.3%) in the NPH insulin group, with an RR for insulin glargine of 0.90 (95% CI 0.64–1.26). In addition, when only the number of patients with malignant neoplasms reported as serious treatment-emergent events was captured, the rate was also similar in both treatment groups: 20 patients (3.9%) with 23 events in the insulin glargine group vs 31 patients (6.2%) with 32 events in the NPH insulin group, with an RR for insulin glargine of 0.63 (95% CI 0.36–1.09).
The number of patients with malignant breast tumours reported was also similar between the two treatment groups: three patients in the insulin glargine group (all reported as serious) compared with five patients (four reported as serious) in the NPH insulin group.
The RR estimate of all malignant breast tumour cases, including non-serious cases (three in the insulin glargine group vs five in the NPH insulin group) numerically favours insulin glargine (RR 0.59, 95% CI 0.14–2.44). Although the 95% CI includes 2, it must be noted that due to the small numbers of patients and the small number of cases, there was only a 22% power to reject a doubling in the risk (RR 2.0) of developing this tumour, should the true risks be equal.
Considering all neoplasms (RR 0.9) and all malignant neoplasms (RR 0.63), the results numerically favour insulin glargine with 95% upper CI limits of 1.26 and 1.09, respectively, indicating at most a 26% and 9% increase in risk.
In summary, this study is the longest controlled treatment comparison of insulin glargine versus NPH insulin in patients with type 2 diabetes mellitus. No new safety issues emerged for either insulin studied based on the data from this 5 year trial. Additional data reported here also confirm that there was no evidence of any difference in the rate of benign or malignant tumour development with insulin glargine compared with NPH insulin.
Duality of interest
J. Rosenstock has received grants for research from and/or has been a consultant to Amylin, Boehringer-Ingelheim, Bristol-Myers Squibb, Centocor, Eli Lilly, Emisphere, GlaxoSmithKline, Johnson & Johnson, MannKind, Merck, Novartis, Novo Nordisk, Pfizer, Roche, Sankyo, sanofi-aventis and Takeda. V. Fonseca has received research support (to Tulane University) with grants from GlaxoSmithKline, Novartis, Novo Nordisk, Takeda, Astra-Zeneca, Pfizer, sanofi-aventis, Eli Lilly, Daiichi-Sankyo, Novartis, the National Institutes of Health (NIH) and the American Diabetes Association (ADA), and honoraria for consulting and lectures from GlaxoSmithKline, Novartis, Takeda, Pfizer, sanofi-aventis and Eli Lilly. J. McGill has received grant support (to Washington University) from sanofi-aventis, Pfizer, Eli Lilly, Novo Nordisk, Novartis, GlaxoSmithKline, Elixir, Tolerx, Biodel, MannKind, Takeda; served on advisory boards and speakers' bureaus for sanofi-aventis and Novo Nordisk, and on speakers' bureaus for Eli Lilly, Merck, Novartis, Daiichi-Sankyo, Forest and GlaxoSmithKline; and has been a consultant/advisor for Merck, Novo Nordisk, Elixir, MannKind and Amgen. I. Hramiak has received research grant support from Pfizer, sanofi-aventis, Novo Nordisk and Eli Lilly, and has served on advisory boards for GlaxoSmithKline, Novo Nordisk, sanofi-aventis and Merck. J.-P. Hallé has received grants for research from and/or has been a consultant and/or on the speaker bureau of Bristol-Myers Squibb, ConjuChem, Bellus Health, Eli Lilly, GlaxoSmithKline, Merck Frosst, Novartis, Novo Nordisk, Pfizer, Roche, sanofi-aventis and Takeda. M. Riddle has received grants for research and/or honoraria for consulting or lectures from Amylin, Lilly, the Amylin-Lilly Alliance, Novo Nordisk, Pfizer, sanofi-aventis and Valeritas. P. Johnston is an employee of, and holds stock options from sanofi-aventis. M. Davis has received research support from sanofi-aventis.
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