Mortality and other important diabetes-related outcomes with insulin vs other antihyperglycemic therapies in type 2 diabetes

J Clin Endocrinol Metab. 2013 Feb;98(2):668-77. doi: 10.1210/jc.2012-3042. Epub 2013 Jan 31.


Context: The safety of insulin in the treatment of type 2 diabetes mellitus (T2DM) has recently undergone scrutiny.

Objective: The objective of the study was to characterize the risk of adverse events associated with glucose-lowering therapies in people with T2DM.

Design and setting: This was a retrospective cohort study using data from the UK General Practice Research Database, 2000-2010.

Patients: Patients comprised 84 622 primary care patients with T2DM treated with one of five glucose-lowering regimens: metformin monotherapy, sulfonylurea monotherapy, insulin monotherapy, metformin plus sulfonylurea combination therapy, and insulin plus metformin combination therapy. There were 105 123 exposure periods.

Main outcome measures: The risk of the first major adverse cardiac event, first cancer, or mortality was measured. Secondary outcomes included these individual constituents and microvascular complications.

Results: In the same model, and using metformin monotherapy as the referent, the adjusted hazard ratio (aHR) for the primary end point was significantly increased for sulfonylurea monotherapy (1.436, 95% confidence interval [CI] 1.354-1.523), insulin monotherapy (1.808, 95% CI 1.630-2.005), and insulin plus metformin (1.309, 95% CI 1.150-1.491). In glycosylated hemoglobin/morbidity subgroups, patients treated with insulin monotherapy had aHRs for the primary outcome ranging from 1.469 (95% CI 0.978-2.206) to 2.644 (95% CI 1.896-3.687). For all secondary outcomes, insulin monotherapy had increased aHRs: myocardial infarction (1.954, 95% CI 1.479-2.583), major adverse cardiac events (1.736, 95% CI 1.441-2.092), stroke (1.432, 95% CI 1.159-1.771), renal complications (3.504, 95% CI 2.718-4.518), neuropathy (2.146, 95% CI 1.832-2.514), eye complications (1.171, 95% CI 1.057-1.298), cancer (1.437, 95% CI 1.234-1.674), or all-cause mortality (2.197, 95% CI 1.983-2.434). When compared directly, aHRs were higher for insulin monotherapy vs all other regimens for the primary end point and all-cause mortality.

Conclusions: In people with T2DM, exogenous insulin therapy was associated with an increased risk of diabetes-related complications, cancer, and all-cause mortality. Differences in baseline characteristics between treatment groups should be considered when interpreting these results.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / mortality*
  • Drug Therapy, Combination
  • Female
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Insulin / therapeutic use*
  • Male
  • Metformin / therapeutic use*
  • Middle Aged
  • Prognosis
  • Retrospective Studies
  • Risk
  • Sulfonylurea Compounds / therapeutic use*
  • Treatment Outcome


  • Hypoglycemic Agents
  • Insulin
  • Sulfonylurea Compounds
  • Metformin