Debate: the long-term safety of insulin in type 2 diabetes

(This article was originally published in the March 2014 issue of Diabetes Voice)

More and more frequently insulin is being recommended as an ‘add-on’ to oral hypoglycaemic therapy for the achievement of blood glucose targets in people with established type 2 diabetes. Indeed, there are now trials of insulin therapy in type 2 diabetes from diagnosis. Concerns have been raised in medical literature that long-term insulin therapy in type 2 diabetes increases the risk of cardiovascular disease and some cancers. We asked specialists in the fields of clinical diabetes and pharmacoepidemiology to comment on the question:

Insulin therapy in people with type 2 diabetes: is it safe in terms of the risk of cardiovascular disease, cancer and all-cause mortality?

No

Sarah Holden and Craig Currie

Insulin has an unlimited potential to lower blood glucose and is a well-established treatment for type 2 diabetes. IDF recommends that it should be used as an optional third line when a combination of metformin, where indicated, and one other glucose-lowering medication has failed to adequately control blood glucose. ADA and EASD guidelines recommend a patient-centred approach with the aim of achieving adequate glucose control while minimising side effects.

Two common side effects associated with insulin injections are weight gain and hypoglycaemia. Weight gain is associated with an increased risk of cardiovascular disease and should be minimised in type 2 diabetes. Both insulin and hypoglycaemia may have vascular effects which are thought to be greatest in people with pre-existing cardiovascular disease and diabetes.(1,2) In addition, as a growth factor, insulin may affect cancer progression.(3) However, this is a complex area where high glucose levels have also been linked to increased cancer risk.(4) Some epidemiological studies have shown that the use of insulin is associated with an increased risk of cardiovascular events, cancer and all-cause mortality in comparison with other glucose-lowering therapies.(5,6,7)

In one of these studies (a retrospective cohort study using data from the UK General Practice Research Database)⁶ mortality and other diabetes-related outcomes for just under 85,000 individuals were examined in relation to five diabetes therapies – monotherapy with either metformin, sulfonylurea or insulin, metformin plus sulfonylurea or insulin plus metformin. Treatment with insulin alone conferred a statistically significantly increased risk of a first major cardiac event or a first diagnosis of cancer ranging from 1.8 to 2.6 times the risk seen in those treated with metformin alone (the comparison group). This excess risk was lower in the group treated with insulin plus metformin than in the insulin monotherapy group, though was still significant at 1.3 times the risk of the comparison group. However, even though these results are consistent and despite the use of statistical adjustment, observational data such as these should be interpreted with caution due to the risk of a form of analytical bias that is termed confounding by indication. This form of confounding is a common feature of studies of outcomes in relation to drug and other therapies simply because the reasons patients have been prescribed the therapies may themselves be related to the perceived risks of any particular outcome occurring. In other words, people may be prescribed insulin partly because they are perceived of being at risk to adverse outcomes, including risk of cardiovascular disease.

In contrast, large randomised controlled trials such as Action to Control Cardiovascular Risk in Diabetes (ACCORD) found no adverse safety signals associated with the use of insulin.(8) However, these studies were designed to assess the benefits of intensive glucose control rather than the safety of insulin, and subjects could receive multiple glucose-lowering therapies making individual comparisons difficult. Also, the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial demonstrated that insulin glargine had a neutral impact on cardiovascular outcomes and cancers compared with standard treatment.(9) However, it should be noted that people included in ORIGIN were newly diagnosed with type 2 or impaired glucose tolerance, impaired fasting glucose or only using one glucose-lowering therapy. In addition, by the end of the study, 65% of the insulin glargine group were also using other glucose-lowering agents, including 47% using metformin.

When used in combination, metformin may attenuate any risks associated with insulin. Metformin is thought to protect against cancer and have cardio-protective effects that cannot be fully explained by its ability to lower blood glucose.(10) When used in conjunction with insulin, metformin has been associated with similar glucose control, but lower insulin doses and less weight gain.(11) In addition, relative to the use of insulin alone, the use of metformin in combination with insulin has been associated with a reduced risk of cardiovascular events, cancer and death from any cause.⁶ Current ADA/EASD and IDF guidelines advocate that, when starting insulin, it should be added to existing metformin therapy and not replace it.

Any potential risks associated with insulin therapy need to be seen in the context of its clear benefits for achieving good glucose control. However, the shortage of randomised controlled trials examining the risks and benefits of using insulin on long term clinical outcomes such as cardiovascular events, cancer and death from all causes needs to be addressed in order to provide more evidence on the safety of insulin in people with type 2 diabetes.

In the UK, the Medical and Healthcare Products Regulatory agency will soon report on the safety of insulin in people with type 2 diabetes. Regardless, there are question marks about the safety of insulin in type 2 diabetes. There is, therefore, a need to show caution while our lack of understanding of this potential problem is addressed, and we can recommend injection of insulin in people with type 2 diabetes with confidence.

Yes

Steve Bain

Insulin is a established glucose-lowering therapy for both type 1 and type 2 diabetes. However, insulin is a growth factor. It is administered in an un-physiological manner and it is present in the circulation at levels that are far higher than in the people without diabetes. For these reasons, concerns regarding insulin safety have been long-standing and this has led to them being extensively investigated and, to my mind, repudiated.

First the concerns regarding cancer: these emerged following suggestions that the long-acting insulin analogue, glargine, increased the risk of cancer (12) and were supported by papers suggesting that insulin or insulin secretagogues were associated with a higher cancer risk.(7) However, slowly the picture became less certain. Scrutiny of the original report showed that the patients receiving glargine were on tiny doses of insulin, the cancer risk disappeared completely if they were on any other glucose lowering medications (including other insulins) and the increased risk was only seen after an ‘adjustment’ by the authors.(12) Attempts to replicate the original findings floundered, despite analyses of huge data sets. Finally a prospective randomised clinical trial (RCT) was published which demonstrated that exogenous insulin therapy (with glargine) over more than 6 years’ follow-up was associated with no evidence of increased risk of cancer.(9) So, concerns raised by pharmacoepidemiology, which can only identify possible safety signals and generate hypotheses, were laid to rest by an RCT.

The case of cardiovascular disease has been longer and more convoluted. Once again, insulin had been implicated because of its potential to act as a growth factor and thereby promoting and/or enhancing the development of atheroma in the circulation. This hypothesis seemed to be supported by observations from epidemiological studies suggesting an association between hyperinsulinaemia and cardiovascular mortality.(13) Subsequently, a meta-analysis of data from eleven different studies in non-diabetic men and women concluded that hyperinsulinaemia was significantly associated with cardiovascular mortality.(14) However, this does not imply causality since the fasting insulinaemia seen in these studies may have been a consequence of insulin resistance, and hence an innocent surrogate.

An RCT was clearly needed – the United Kingdom Prospective Diabetes Study (UKPDS). In the seminal publication of 1998, the introduction clearly stated that ‘there is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation’. UKPDS conclusively demonstrated no such increase and, almost, showed a benefit from tight control using insulin and the sulphonylureas.(15) Now the hypothesis had changed leading to attempts to demonstrate a beneficial impact of tight glycaemic control on cardiovascular outcomes; ultimately this led to the controversy surrounding the ACCORD study.(8)

ACCORD enrolled middle-aged and elderly people with type 2 diabetes and a very high risk of cardiovascular disease. To the researchers’ surprise, near-normal glucose control, achieved with the use of multiple drugs, was associated with increased all-cause mortality and cardiovascular mortality. At five years of follow-up, nonfatal myocardial infarction was reduced, but five-year mortality was increased in patients who received intensive glucose-lowering therapy. Of note, over 75% of the intensive group were using insulin at study end.

Meta-analyses were subsequently performed to include all major studies examining the impact of tight glycaemic control on cardiovascular outcomes and drew the opposite conclusion from that reported in ACCORD.(16) These trials did not compare insulin with non-insulin regimens, however, all had higher proportions of insulin users in the intensive therapy arms. Given the large numbers involved in the studies, one might have expected that any intrinsic harmful effect of insulin would show up as a consistently increased hazard ratio in the intensive arms of the trials but it did not.

Cue the pharmaco-epidemiologists: Currie et al. conducted a retrospective database study of 84,622 primary care patients, defined a primary endpoint of all-cause mortality, incident cancer, or major cardiac adverse events, and reported hazard ratios (relative to metformin monotherapy) of 1.808 for insulin monotherapy and 1.309 for insulin plus metformin.(6) Several other observational studies, based on databases, supported the association between increasing insulin use and serious events.(17) Fortunately, an RCT was already in progress which, for most people, would settle the argument.

The ORIGIN trial (9) randomised 12,537 people with cardiovascular risk factors as well as impaired fasting glucose, impaired glucose tolerance or type 2 diabetes, to receive standard care or insulin glargine. The aim was to identify any intrinsic benefit on cardiovascular outcomes from early use of insulin and the population of ORIGIN included patients who were very well controlled (indeed, approximately 10% did not have diabetes), with HbA_1c values of 6.3% or less in the insulin glargine group and 6.5% or less in the standard care group. Early use of titrated basal insulin had no impact on cardiovascular outcomes compared with standard guideline-suggested glycaemic control. The ORIGIN investigators pointed out that a large between-group difference in insulin use was achieved, and only a small difference in HbA_1c; the results were therefore relevant to the effect of insulin therapy rather than the effect of glucose lowering on cardiovascular outcomes. Once again, an RCT had come to the rescue.

The final question is whether the controversies about cancer and cardiovascular disease affect clinical practice. For people with type 1 diabetes, insulin is currently the only therapy option. For people with type 2 diabetes, the progressive nature of the condition means that, given current therapies, everyone will eventually need insulin for symptomatic relief of hyperglycaemia (assuming they survive the complications of the condition). In the UK at least, the average starting HbA_1c for insulin of over ~9.5%, suggests that neither patients nor clinicians feel that insulin is an easy or early treatment option. In this setting, the debates around safety can be seen as rather academic.

References:

1. Rensing KL, Reuwer AQ, Arsenault BJ, et al. Reducing cardiovascular disease risk in patients with type 2 diabetes and concomitant macrovascular disease: can insulin be too much of a good thing? Diabetes Obes Metab 2011; 13: 1073-87.
2. Nordin C. The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence. Diabetologia 2010; 53: 1552-61.
3. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 2008; 8: 915-28.
4. Jee SH, Ohrr H, Sull JW, et al. Fasting serum glucose level and cancer risk in Korean men and women. JAMA 2005; 293: 194-202.
5. Currie CJ, Peters JR, Tynan A, et al. Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study. Lancet 2010; 375: 481-9.
6. Currie CJ, Poole CD, Evans M, et al. Mortality and other important diabetes-related outcomes with insulin vs other antihyperglycemic therapies in type 2 diabetes. J Clin Endocrinol Metab 2013; 98: 668-77.
7. Currie CJ, Poole CD, Gale EAM. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009; 52: 1766-77.
8. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545-59.
9. ORIGIN Trial Investigators, Gerstein HC, Bosch J, Dagenais GR, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012; 367: 319-28.
10. Zakikhani M, Dowling R, Fantus IG, et al. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 2006; 66: 10269-73.
11. Goudswaard AN, Furlong NJ, Rutten GE, et al. Insulin monotherapy versus combinations of insulin with oral hypoglycaemic agents in patients with type 2 diabetes mellitus. Cochrane Database Syst Rev 2004: CD003418.
12. Hemkens LG, Grouven U, Bender R, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 2009; 52:1732-44.
13. Despres JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996; 334: 952-7.
14. DECODE Insulin Study Group. Plasma insulin and cardiovascular mortality in non-diabetic European men and women: a meta-analysis of data from eleven prospective studies. Diabetologia 2004; 47: 1245-56.
15. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837-53.
16. Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009; 373: 1765-72.
17. Östgren CJ, Sundström J, Svennblad B, et al. Associations of HbA1c and educational level with risk of cardiovascular events in 32,871 drug-treated patients with type 2 diabetes: a cohort study in primary care. Diabet Med 2013; 30: e170-7.