 |
 |
9th July 2009
| 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. |
Following an initial observational study signaling a possible association between the long-acting human insulin analogue, insulin glargine (Lantus®) and an increased risk of developing cancer, a series of papers has now been published. The results of the retrospective observational studies are inconsistent and can neither confirm nor exclude a relationship between insulin glargine and cancer. A post-hoc analysis of data from a RCT is more reassuring. However, the concerns raised are to be investigated fully in a CHMP review.
Action
The EMEA has advised 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, these papers could constitute an important signal about the long-term safety of insulin glargine, and until the CHMP review is complete some patients and prescribers may wish to review their use of it in the light of their own particular circumstances.
The effect of NICE guidance ought to be that the insulin analogues are not used routinely. However, the prescribing data for England shows that the uptake of insulin glargine and insulin detemir is now extensive. Based on the figures for the quarter to December 2008, there are about 1,200,000 items of insulin glargine prescribed each year, and 400,000 items of insulin detemir. This equates to approximately 40% of all intermediate / long acting insulin items.
Whether or not a link between an increased risk of cancer and insulin glargine is established, given that the costs per QALY are so large for these analogue insulins, it may be prudent for prescribers and prescribing managers to now review the use of these drugs to see if their current use is indeed in line with NICE guidance.
Update 28th July 2009: The EMEA reported the conclusion of the CHMP review in a press release on 23rd July 2009. The CHMP concluded that the available data do not provide a cause for concern and that changes to the prescribing advice are 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 has asked the manufacturer of insulin glargine to develop a strategy for generation of further research in this area.
What is the background to this?
Both type 1 and type 2 diabetes are associated with an excess risk of cancer and, in type 2 diabetes, this excess risk is also associated with obesity. Therapies that increase levels of circulating insulin might also contribute to this risk, possibly accelerating the progression of pre-existing malignant foci. There is a view that insulin analogues in particular, which have different receptor binding, metabolic and mitogenic potencies from human insulin, require further study to assess their long-term safety with regard to cancer risk.
The European Association for the Study of Diabetes (EASD) has recently published a series of papers investigating whether the long-acting human insulin analogue, insulin glargine (Lantus®) influences the risk of cancer. Four retrospective follow-up studies from patient registries in Germany, Sweden, the UK and Scotland have been published alongside a related editorial and data from a post-hoc analysis of a randomised controlled trial (RCT).
What do these studies claim?
The results of the four observational studies are inconsistent and a major limitation of all of them is the short duration of exposure and / or observation (a few years).
The German study was the largest and its results triggered the other three studies. In an analysis of more than 127,000 patients over a median of 1.4 years (maximum 4.4 years), a dose-dependent association between use of insulin glargine and cancer was found. A higher risk of cancer was associated with higher doses of all types of insulin, but unit for unit the risk appeared greater with insulin glargine than with human insulin. In the final modeling, taking account of dose and other confounding factors, the hazard ratio (HR) was 1.09 (95% confidence interval [CI] 1.00 to 1.19) for a daily dose of 10 IU, 1.19 (95% CI 1.10 to 1.30) for a daily dose of 30 IU and 1.31 (95% CI 1.20 to 1.42) for a daily dose of 50 IU. In this study, only patients who used only one type of insulin were included (i.e. patients were excluded if they used both insulin glargine and another type of insulin). No information is available on the types of cancer found.
The Scottish study examined a database covering all patients in Scotland with diabetes. The authors performed several analyses with different modeling approaches. In summary, there was an increased risk of cancer overall and breast cancer specifically, in the small number (447) of patients who used insulin glargine as monotherapy compared with those who used other insulins. However, in patients using insulin glargine in combination with other types of insulin, no such increased risk was seen. Overall, the incidence of all cancers and breast cancer specifically was not significantly different in the total population using insulin glargine from the incidence in those not receiving insulin glargine. In this study dose-dependency was not evaluated.
The Swedish study also found an association with an increased risk of breast cancer in patients taking insulin glargine as monotherapy, but not in patients using insulin glargine with other types of insulin. Again, for other cancers, no association was found and this study also did not evaluate dose-dependency.
In the UK study, there was no difference in the risk of cancer for patients on human insulin alone compared with insulin glargine alone.
The RCT was an open-label, five-year study comparing insulin glargine with human NPH insulin on the progression of diabetic retinopathy. Results of a post-hoc analysis of tumour development (captured as adverse events in the course of routine safety monitoring) have been published in a letter. The overall number of patients with all neoplasms (benign, malignant or unspecified pathology) 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 (relative risk [RR] for insulin glargine 0.90; 95% CI 0.64 to 1.26). The rate of malignant neoplasms was also similar in both treatment groups: 20 patients (3.9%) in the insulin glargine group vs. 31 patients (6.2%) in the NPH insulin group (RR for insulin glargine 0.63; 95% CI 0.36–1.09). Malignant breast tumours were reported in three patients in the insulin glargine group compared with five patients in the NPH insulin group.
This longer-term post-hoc analysis of data from a RCT, rather than observational data as above, is at first sight reassuring about the safety of insulin glargine. However, the number of patients included was relatively low (514 treated with insulin glargine vs. 503 treated with NPH insulin, mean cumulative exposure just over 4 years), and the average age of patients recruited was a relatively young 55 years – a group which would be expected to have a relatively low incidence of cancer compared to patients in their 60s and 70s. In the observational studies the German and Swedish studies which report increased rates of cancer have a mean age some ten years older than the people in this longer term RCT. However, the UK study which does not report a possible safety signal also had a mean age some ten years old than those in the RCT. The Scottish study adjusts for age in its analyses.
So what?
The EMEA has stated that on the basis of the currently available data, a relationship between insulin glargine and cancer cannot be confirmed or excluded. However, the concerns raised by the four observational studies require further in-depth evaluation and a review of insulin glargine by the Committee for Medicinal Products for Human Use (CHMP) is planned. The manufacturers of insulin glargine, Sanofi-aventis, have stated that they will continue to vigorously monitor the safety of this drug in close collaboration with the regulatory agencies.
The safety concerns come from retrospective analyses of data from patient registries. This type of analysis of observational data has inherent limitations, particularly around confounding, and data from a longer-term RCT is possibly more reassuring. However, the observational data could constitute an important signal about the long-term safety of insulin glargine, and until the CHMP review is complete some patients and prescribers may wish to review their use of it in the light of their own particular circumstances. The current research did not investigate the other long-acting insulin analogue, insulin detemir, but the authors of the editorial suggest further investigation of this product would also be prudent.
How clinically and cost effective are long-acting insulin analogues when compared with other insulin regimens?
The long-acting insulin analogues have a role in some patients, but their benefits over standard insulin preparations are not as convincing as may be perceived. A Health Technology Assessment systematic review of insulin glargine concluded that for type 1 diabetes patients, insulin glargine appears to be more effective than NPH insulin in reducing fasting blood glucose (FBG) but not in reducing HbA1c. For type 2 diabetes patients for whom oral antidiabetic agents provide inadequate glycaemic control, there is no evidence that insulin glargine is more effective than NPH insulin in reducing either FBG or HbA1c and some evidence that both types of insulin are as effective as each other in both FBG and HbA1c control. There is no conclusive evidence that insulin glargine is superior to NPH in controlling symptomatic hypoglycaemia and severe hypoglycaemia.
A recent Canadian meta-analysis from February 2009 has also concluded that long-acting insulin analogues offer little benefit relative to conventional insulins in terms of glycaemic control or reduced hypoglycemia. Differences in HbA1c between long-acting insulin analogues and NPH insulin were marginal, at best, and of debatable clinical significance. In type 1 diabetes the weighted mean difference (WMD) in HbA1c for insulin glargine compared to NPH insulin was a reduction of 0.11% points (95% CI –0.21% to –0.02%) and for insulin detemir it was a reduction of –0.06% points (95% CI –0.13% to 0.02%). In type 2 diabetes the WMD compared to NPH insulin was not statistically significantly different in patients using insulin glargine who were also using oral antidiabetic agents, and in those not taking oral agents it was marginally greater: 0.28% points (95% CI 0.07% to 0.49%). The WMD for insulin detemir in patients also taking oral agents was also slightly increased: 0.13% (95% CI 0.03% to 0.22%). Benefits in terms of reduced hypoglycemia were inconsistent. The authors emphasized that long-term, high-quality studies are still needed to determine whether insulin analogues reduce the risk of long-term complications of diabetes.
In an accompanying health economic analysis, it was concluded that use of long-acting analogues, particularly in type 2 diabetes, was unlikely to represent an efficient use of finite health care resources. In type 1 diabetes, the incremental cost per quality-adjusted life-year (QALY) compared with NPH insulin was 87,932 Canadian dollars for insulin glargine and 387,729 Canadian dollars for insulin detemir. In type 2 diabetes, insulin glargine was associated with an incremental cost of 642,994 Canadian dollars per QALY and insulin detemir was less effective and more costly. At present, 1 Canadian dollar is approximately £0.53.
What does NICE say?
Type 1 diabetes
In CG15 (2004), NICE advises that:
1.9.3.8 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
Recently, NICE updated its clinical guideline on management of type 2 diabetes (CG87, May 2009). The Assessment Group also undertook a de novo cost-effectiveness analysis of the various regimens, including insulin glargine and insulin detemir, and identified costs per QALY of a similar or greater magnitude to those in the Canadian analysis above. Men and women were modelled separately.
The base-case results of the comparison of insulin glargine and insulin detemir against NPH insulin found the insulin analogues to be more effective but more costly (p 62 of the document). In the case of a male population with starting BMI 30kg/m2, the incremental cost effectiveness ratio (ICER) for insulin glargine was £281,349 per QALY (no complications at baseline) and £320,029 per QALY (with complications). For insulin detemir, the ICERs were £187,726 per QALY with no complications at baseline and £417,625 per QALY with complications. Importantly, this analysis incorporates the anticipated health-related quality of life gain associated with the reduced fear of severe hypoglycaemic episodes.
In the case of a female population with a starting BMI of 30kg/m2, the ICERs are lower, but still outside conventional limits of cost effectiveness: for insulin glargine they were £177,940 per QALY with no complications at baseline and £179,074 per QALY with complications, and for insulin detemir they were £102,007 per QALY with no complications at baseline and £113,988 per QALY with complications.
With a starting BMI of 35kg/m2, the cost effectiveness improves in men, but the ICERs remained well outside conventional limits of cost effectiveness (more than £189,000 per QALY for insulin glargine and more than £146,000 for insulin detemir). In women, the ICERs worsen.
In reviewing the evidence, the guideline development group (GDG) noted that insulin glargine and insulin detemir did not appear to be cost-effective options when compared with NPH insulin in the analysis undertaken by the Assessment Group. However, the GDG accepted that episodes of hypoglycaemia have the potential to be highly detrimental to a person’s health-related quality of life. This is partly because of a person’s fear of symptomatic hypoglycaemic episodes. Taking these considerations into account, it was the GDG’s view that when starting basal insulin therapy NPH insulin should be preferred on the basis of its cost effectiveness and well-known safety profile. The GDG concluded that it would be more cost effective to target the use of the long-acting insulin analogues to those people with type 2 diabetes who would be most likely to benefit, particularly people whose lifestyle is significantly restricted by symptomatic hypoglycaemic episodes. In addition, the GDG accepted that, on the balance of probabilities, the healthcare resources spent on helping people who need assistance with their insulin injections would be reduced significantly (mainly in terms of the time spent by healthcare professionals in giving the injections) to the extent that the use of insulin analogues in this group is likely to be cost effective. The relevant guidance issued was as follows:
1.1.20 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.
1.1.21 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
- 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.
This guidance is broadly similar to that issued by NICE in 2002 in their technology appraisal of insulin glargine (TA 53). This stated that:
1.2 Insulin glargine is not recommended for routine use for people with type 2 diabetes who require insulin therapy. Insulin glargine treatment should be considered only for those people with type 2 diabetes who require insulin therapy and who fall into one of the following categories.
- Those who require assistance from a carer or healthcare professional to administer their insulin injections.
- Those whose lifestyle is significantly restricted by recurrent symptomatic hypoglycaemic episodes.
- Those who would otherwise need twice-daily basal insulin injections in combination with oral antidiabetic drugs.
So what?
In type 2 diabetes, we have consistently pointed out in other blogs the evidence that interventions (both lifestyle and medicines) aimed at reducing cardiovascular risk confer greater benefit than tight control of blood glucose.
The effect of NICE guidance ought to be that the insulin analogues are not used routinely. However, the prescribing data for England (below) shows that the uptake of insulin glargine and insulin detemir is now extensive. Based on the figures for the quarter to December 2008, there are about 1,200,000 items of insulin glargine prescribed each year, and 400,000 items of insulin detemir. This equates to approximately 40% of all intermediate / long acting insulin items.
Whether or not a link between an increased risk of cancer and insulin glargine is established, given that the costs per QALY are so large for these analogue insulins, it may be prudent for prescribers and prescribing managers to now review the use of these drugs to see if their current use is indeed in line with NICE guidance.
Trends in prescribing of intermediate and long-acting insulin in General Practice in England
Click image to enlarge
Trends in spending on intermediate and long-acting insulin in General Practice in England
Click image to enlarge
More information on diabetes can be found on the type 1 diabetes and type 2 diabetes floors of NPC
Details of papers
Editorial
Smith U, Gale EAM. Does diabetes therapy influence the risk of cancer? Diabetologia DOI 10.1007/s00125-009-1441-5
Feedback
Please comment on this blog in the NPC discussion rooms, or using our feedback form.
Make sure you are signed up to NPC Email updates — the free email alerting system that keeps you up to date with the NPC news and outputs relevant to you.