Mortality in Individuals Treated With Glucose-Lowering Agents: A Large, Controlled Cohort Study

J Clin Endocrinol Metab. 2016 Feb;101(2):461-9. doi: 10.1210/jc.2015-3184. Epub 2015 Dec 17.


Context: Several observational studies and meta-analyses have reported increased mortality of patients taking sulfonylurea and insulin. The impact of patient profiles and concomitant therapies often remains unclear.

Objective: The objective of the study was to quantify survival of patients after starting glucose-lowering agents (GLAs) and compare it with control subjects, matched for risk profiles and concomitant therapies.

Design: This was a retrospective, controlled, cohort study.

Setting: The study is based on health expenditure records of the largest Belgian health mutual insurer, covering more than 4.4 million people.

Patients: A total of 115 896 patients starting metformin, sulfonylurea, or insulin (alone or in combination) between January 2003 and December 2007 participated in the study. Control subjects without GLA therapy were matched for age, gender, history of cardiovascular events, and therapy with antihypertensives, statins and blood platelet aggregation inhibitors.

Intervention(s): There were no interventions.

Main outcome measure: Five-year survival after the start of GLA was measured.

Results: Profiles of patients using different GLAs varied, with patients on sulfonylurea being oldest and patients on insulin having more frequently a history of cardiovascular disease. Excess mortality differed across GLA therapies compared with matched controls without GLAs, even after adjusting for observable characteristics. Only metformin monotherapy was not associated with an increased 5-year mortality compared with matched controls, whereas individuals on a combination of sulfonylurea and insulin had the highest mortality risks. Age and concomitant use of statins strongly affect survival.

Conclusions: Differences exist in 5-year survival of patients on GLA, at least partly driven by the risk profile of the individuals themselves. Metformin use was associated with lowest 5-year mortality risk and statins dramatically lowered 5-year mortality throughout all cohorts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Belgium / epidemiology
  • Cardiovascular Diseases / complications
  • Cardiovascular Diseases / mortality
  • Cohort Studies
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / mortality*
  • Drug Therapy, Combination
  • Female
  • Follow-Up Studies
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Hypoglycemic Agents / adverse effects*
  • Hypoglycemic Agents / therapeutic use*
  • Insulin / adverse effects
  • Insulin / therapeutic use
  • Male
  • Metformin / adverse effects
  • Metformin / therapeutic use
  • Middle Aged
  • Mortality
  • Retrospective Studies
  • Risk Assessment
  • Sulfonylurea Compounds / adverse effects
  • Sulfonylurea Compounds / therapeutic use
  • Survival Analysis


  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Hypoglycemic Agents
  • Insulin
  • Sulfonylurea Compounds
  • Metformin