Combination Therapy With Sulfonylureas and Metformin and the Prevention of Death in Type 2 Diabetes: A Nested Case-Control Study

Pharmacoepidemiol Drug Saf. 2010 Apr;19(4):335-42. doi: 10.1002/pds.1834.


Purpose: To determine whether combination of sulfonylureas and metformin increases the risk of death from any cause in patients with type 2 diabetes.

Methods: A nested case-control study was conducted within a population-based cohort from the UK General Practice Research Database (GPRD). The cohort included patients over the age of 40 who were prescribed a first oral hypoglycaemic agent between 1 January 1988 and 30 June 2008. Cases included all patients who deceased during follow-up. Up to 10 controls were matched to each case on year of birth, date of cohort entry (+/-1 year) and duration of follow-up. Conditional logistic regression was used to estimate rate ratios (RRs) of death from any cause associated with the use of combination of sulfonylureas and metformin, relative to sulfonylurea monotherapy.

Results: The cohort comprised 84 231 users of oral hypoglycaemic agents, of whom 14 996 died from any cause during a mean of 4.3 years of follow-up (mortality rate 4.1 per 100 per year). Patients currently exposed to a combination of sulfonylureas and metformin were at a decreased risk of death from any cause compared to patients exposed to sulfonylurea monotherapy (adjusted RR: 0.77, 95%CI: 0.70, 0.85). Similar results were obtained for patients currently exposed to metformin monotherapy (adjusted RR: 0.70, 95%CI: 0.64, 0.75) when compared to sulfonylurea monotherapy. Patients had to be exposed to the combination therapy for at least 4 months prior to index date to experience a lower risk of mortality compared to sulfonylurea monotherapy.

Conclusions: The combination of sulfonylureas and metformin does not increase the risk of death. In contrast, it may moderately reduce this risk compared to sulfonylurea monotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Cohort Studies
  • Databases, Factual
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / mortality*
  • Drug Therapy, Combination
  • Female
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / therapeutic use*
  • Logistic Models
  • Male
  • Metformin / administration & dosage
  • Metformin / adverse effects
  • Metformin / therapeutic use*
  • Middle Aged
  • Mortality / trends
  • Risk
  • Sulfonylurea Compounds / administration & dosage
  • Sulfonylurea Compounds / adverse effects
  • Sulfonylurea Compounds / therapeutic use*
  • Treatment Outcome
  • United Kingdom / epidemiology


  • Hypoglycemic Agents
  • Sulfonylurea Compounds
  • Metformin