NPC Archive Item: Are higher doses of insulin glargine associated with cancer?

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13 July 2010

New data show that insulin glargine is not associated with an increase in cancer (07/08/12)
Since these materials were published, ORIGIN (2012), a 6-year randomised controlled trial, has been completed. This found that insulin glargine was not associated with a significant increase in the incidence of any cancer, death from cancer, or cancer at specific sites, as had been suggested by some earlier epidemiological data.

An observational study has found that higher mean daily doses of insulin glargine, but not other types of insulin, were associated with a five times higher relative risk of cancer after adjusting for confounders.

Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.

Following an evaluation of the available evidence suggesting a possible association between insulin and cancer, in July 2009, the EMEA advised that no change in practice is required at present, and patients being treated with insulin glargine can continue their treatment as normal (in accordance with NICE guidance on type 1 and type 2 diabetes). However, this paper adds to the evidence providing a further signal about the long-term safety of high doses of insulin glargine for regulators to consider.

The effect of NICE guidance ought to be that long-acting insulin analogues are not used routinely. However, the prescribing data for England shows that the uptake of insulin glargine and insulin detemir is extensive. Based on the figures for the quarter to March 2010, there are about 1,200,000 items of insulin glargine prescribed each year, and 500,000 items of insulin detemir. This equates to over 40% of all intermediate or long-acting insulin items.

What is the background to this?
As we reported in a previous blog, several studies have signalled a possible association between the long-acting human insulin analogue, insulin glargine (Lantus®) and an increased risk of developing cancer. The concerns raised by these papers were investigated in a CHMP review. The EMEA reported the conclusion of the review in a press release on 23rd July 2009. (See also September 2009 edition of Drug Safety Update). The CHMP concluded that the available data did not provide a cause for concern and that changes to the prescribing advice were therefore not necessary. Due to methodological limitations the studies were found to be inconclusive and did not allow a relationship between insulin glargine and cancer to be confirmed or excluded. In addition, the CHMP noted that the results of the studies were not consistent. The CHMP asked the manufacturer of insulin glargine to develop a strategy for generation of further research in this area.

This study was designed to overcome, to some extent, the limitations of previous studies (e.g. limited information on comorbidities, short duration of observation, the inclusion of probably pre-existing cases of cancer diagnosed shortly after initiation of insulin, and the failure to discriminate between basal and prandial human insulin used as a comparator). It aimed to assess the longer term association between incidence of cancer and use of different insulin analogues, considering different insulin doses and a larger number of confounders than those included in previous studies, in a cohort of 1,340 diabetic outpatients starting insulin.

What does this study claim?
Over a median follow-up of 75.9 months, there were 112 cases of incident cancer, which were compared with 370 controls, matched from the same cohort with respect to follow-up time, five-year age class, sex and body mass index (BMI) class.

A significantly higher mean daily dose of glargine was observed in cases, compared with controls (0.24 vs 0.16 IU/day/kg, P=0.036). A dose of glargine greater than >0.3 IU/day/kg was associated with a five times higher relative risk of incident cancer, compared with controls, even after adjusting for comorbidity score, other types of insulin administration, and metformin exposure (OR 5.43, 95%CI 2.18 to 13.53, P<0.001). No association was found between incident cancer and insulin doses for human insulin or other analogues. However, this finding could be due to insufficient sample size.

So what?
As the authors point out, in observational studies, different agents are prescribed to patients with different characteristics and those diversities cannot be entirely eliminated by statistical adjustments. Although this study took many confounding variables into account it is likely that some remain, and the study does not confirm that high doses of insulin glargine cause cancer. Nevertheless, it does suggest that dosages should be considered when the possible association between cancer and insulin and its analogues is assessed.

What does NICE say?

Type 1 diabetes

In CG15 (2004), NICE advises that: Long-acting insulin analogues (insulin glargine) should be used when:

  • nocturnal hypoglycaemia is a problem on isophane (NPH) insulin
  • morning hyperglycaemia on isophane (NPH) insulin results in difficult daytime blood glucose control
  • rapid-acting insulin analogues are used for meal-time blood glucose control.

Type 2 diabetes

In CG87, NICE advises: Initiate insulin therapy from a choice of a number of insulin types and regimens.

  • Begin with human NPH insulin injected at bed-time or twice daily according to need.
  • Consider, as an alternative, using a long-acting insulin analogue (insulin detemir, insulin glargine) if:

− the person needs assistance from a carer or healthcare professional to inject insulin, and use of a long-acting insulin analogue (insulin detemir, insulin glargine) would reduce the frequency of injections from twice to once daily, or
− the person’s lifestyle is restricted by recurrent symptomatic hypoglycaemic episodes, or
− the person would otherwise need twice-daily NPH insulin injections in combination with oral glucose-lowering drugs, or
− the person cannot use the device to inject NPH insulin. Consider switching to a long-acting insulin analogue (insulin detemir, insulin glargine) from NPH insulin in people:

  • who do not reach their target HbA1c because of significant hypoglycaemia, or
  • who experience significant hypoglycaemia on NPH insulin irrespective of the level of HbA1c reached, or
  • who cannot use the device needed to inject NPH insulin but who could administer their own insulin safely and accurately if a switch to a long-acting insulin analogue were made, or
  • who need help from a carer or healthcare professional to administer insulin injections and for whom switching to a long-acting insulin analogue would reduce the number of daily injections.

Study details:
Mannucci E, et al. Doses of insulin and its analogues and cancer occurrence in insulin-treated type 2 diabetic patients. Published online before print June 14, 2010, doi: 10.2337/dc10-0476

Design: Nested case-control study

Patients: Out of a consecutive series of 1,533 diabetic outpatients referred to the diabetes clinic at the University of Florence, Italy, and starting insulin therapy between January 1st 1998 and December 31st 2007, those free of previous malignancies were enrolled in the study. Case finding was performed on 1,340 patients (746 women and 594 men), mean age 63.1 years, median duration of diabetes 7.5 years, mean HbA1c 8.7% and mean BMI 27.9kg/m2.

Comparison: From within the cohort, those with cancer during follow-up were identified as cases and compared for treatments received with matched controls from the same cohort. For each case, up to five controls were chosen randomly from those members of the same cohort who were at risk for the same follow-up time as the case. Five-year age-classes, sex and BMI-classes (<18.5, 18.5 to 24.9, 25 to 29.9, >30 kg/m2) were considered as additional matching variables.

Outcomes and results: During a median follow-up of 75.9 months, 112 cases of incident cancer (incidence 1.9/100 persons/year) were compared with 370 matched controls. A significantly higher mean daily dose of glargine was observed in cases than in controls (0.24 vs. 0.16 IU/day/kg, P=0.036). Incident cancer was associated with a dose of glargine ≥0.3 IU/kg/day even after adjusting for Charlson comorbidity score, other types of insulin administration, and metformin exposure (OR 5.43, 95%CI 2.18 to 13.53, P<0.001). No association between incident cancer and insulin doses was found for human insulin or other analogues.

Sponsorship: Six of the authors have received consultancy fees and/or speaking fees and/or research grants from drug companies who manufacture insulin.

More information on diabetes can be found on the type 1 diabetes and type 2 diabetes sections of NPC.

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