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Does insulin increase the risk of type 2 diabetes-related complications?

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Insulin treatment of patients with type 2 diabetes could expose such patients to complications including myocardial infarction, stroke, cancer, renal complications, and eye complications, according to data from a retrospective cohort study by researchers in the United Kingdom.

The data “are consistent with a variety of previous evidence observing worse outcomes in people with type 2 diabetes mellitus treated with insulin,” write the investigators.

As published in the February Journal of Clinical Endocrinology and Metabolism, investigators from Cardiff University’s School of Medicine examined the UK Clinical Practice Research Datalink to assess the risk of death for patients treated with insulin compared with other glucose-lowering therapies in people with type 2 diabetes.1

Use of exogenous insulin to treat type 2 diabetes has grown markedly in recent years, probably as a result of findings from the UK Prospective Diabetes Study, said the study’s lead author Craig Currie, Professor of Applied Pharmacoepidemiology at Cardiff University School of Medicine, UK.

Initial concerns over the use of insulin in type 2 diabetes first emerged from a population-based study in Canada, which reported a 3-fold increase in mortality in the group of patients with the greatest exposure to insulin.2

A similar epidemiological study of people in UK primary care with type 2 diabetes  also reported a 50% increased mortality among those treated with insulin compared with those whose disease was managed with a combination of metformin plus a sulfonylurea.3

The database used in this study is derived from 600 primary care practices in the UK, containing records for more than 10 million people. The researchers identified 84,622 individuals exposed to glucose-lowering regimens, with a total of nearly 300,000 person-years of follow-up. Outcomes for 5 glucose-lowering regimens were compared:

  • Metformin monotherapy (the reference group)
  • Sulfonylurea monotherapy
  • Metformin plus a sulfonylurea
  • Insulin monotherapy
  • Insulin plus metformin

At baseline, patients treated with insulin had higher mean HbA1c values. They also had a tendency for higher utilization of aspirin and other antiplatelet drugs, lipid-lowering therapy, and antihypertensive drugs.

By reviewing data from the database between 2000 and 2010 “we’ve confirmed there are increased health risks for patients with type 2 diabetes who take insulin to manage their condition,” said Dr. Currie.

In a multivariate analysis, insulin monotherapy, sulfonylurea monotherapy, and insulin plus metformin each significantly increased the risk of mortality compared with metformin alone. The adjusted hazard ratio (aHR) ranged from 1.344 for insulin plus metformin to 2.197 with insulin monotherapy.

For major adverse cardiac events, the aHRs were greater with all of the therapies compared with metformin alone, ranging from a non-significant aHR of 1.095 for metformin plus sulfonylurea to 1.736 (P <.0001) for insulin monotherapy.

For cancer, there were significantly increased aHRs for sulfonylurea (1.097; P =.0410), insulin monotherapy (1.437; P <.0001), and insulin plus metformin (1.394; P =.0001).

For the primary endpoint—the risk of a first major adverse cardiac event, first cancer, or mortality—sulfonylurea monotherapy increased the risk by 43%, insulin monotherapy by 81%, and insulin plus metformin by 31%.

All therapies significantly increased the risk of neuropathy and renal complications compared with metformin, and all but sulfonylurea monotherapy significantly increased the risk of eye complications.

“In my view, insulin should be a treatment of last resort, a salvage treatment,” said Dr. Currie in an e-mail correspondence. “There is too much non-randomized evidence from across the scientific spectrum to suggest otherwise. The possibility of increased risk needs eliminating as a possibility in order to justify the use of insulin widely in these patients. The vast majority of people who take insulin will experience no adverse effects and it remains a reliable and common form of treatment worldwide, but this study shows that we need to investigate this matter urgently and the drug regulatory authorities should take interest in this issue.”


  1. Currie CJ, Poole CD, Evans M, Peters JR, Morgan CLI. Mortality and other important diabetes-related outcomes with insulin vs other antihyperglycemic therapies in type 2 diabetes. J Clin Endocrinol Metab. 2013;98:668-677.
  2. Gamble JM, Simpson SH, Eurich DT, Majumdar SR, Johnson JA. Insulin use and increased risk of mortality in type 2 diabetes: a cohort study. Diabetes Obes Metab. 2010;12:47-53.
  3. 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;375:481-489.
Last modified: August 30, 2021