Antidiabetic therapy and the risk of heart failure in type 2 diabetic patients: an independent effect or confounding by indication

Pharmacoepidemiol Drug Saf. 2005 Oct;14(10):697-703. doi: 10.1002/pds.1069.


Purpose: This study assesses the effect of the type of antidiabetic treatment on the risk of developing congestive heart failure (CHF) in type 2 diabetes.

Methods: The study was derived from the U.K.-based General Practice Research Database (GPRD) comprised of 3.5 million subjects followed between 1987 and 2001. A total of 21 888 type 2 diabetic patients were identified. A 6:1 matched nested case-control design was employed. Conditional logistic regression was used to derive adjusted odds ratios (ORs) for the association of drug treatment with CHF controlling for diabetes duration and for diseases known to affect the risk of CHF. Antidiabetic drug exposure was defined as the receipt of at least one prescription for an antidiabetic medication within the 3 months prior to the date of CHF diagnosis.

Results: There were 1301 incident cases of CHF in the cohort, matched to 7788 controls. After risk factor adjustment, there was a 1.2-fold increase in the risk of CHF for sulphonylureas (SUs) (OR = 1.17; 95%CI = 1.00-1.37) and metformin monotherapies (OR = 1.22; 95%CI = 0.97-1.52), a 1.6-fold increase with combinations of metformin and SUs (OR = 1.62; 95%CI = 1.30-2.02), a 2.2-fold increase with oral tricombinations (OR = 2.16; 95%CI = 0.96-4.86) and a 1.5-fold increase for insulin compared to no exposure (OR = 1.52; 95%CI = 1.06-2.17). Compared to SUs, bicombinations of metformin and SUs showed a statistically significant 1.4-fold increase in the odds of CHF (OR = 1.38; 95%CI = 1.13-1.69).

Conclusions: All antidiabetic medications were associated with an increased likelihood of CHF compared to no antidiabetic exposure. The risk of CHF increased with the complexity of the antidiabetic regimen suggesting that it is the diabetes severity, which imparts risk and not necessarily the antidiabetic regimen itself.

MeSH terms

  • Adult
  • Aged
  • Cohort Studies
  • Confounding Factors, Epidemiologic
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / pathology
  • Drug Therapy, Combination
  • Female
  • Heart Failure / chemically induced
  • Heart Failure / epidemiology
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / therapeutic use*
  • Incidence
  • Insulin / adverse effects
  • Insulin / therapeutic use
  • Male
  • Metformin / adverse effects
  • Metformin / therapeutic use
  • Middle Aged
  • Risk Factors
  • Sulfonylurea Compounds / adverse effects
  • Sulfonylurea Compounds / therapeutic use
  • Time Factors
  • United Kingdom / epidemiology


  • Hypoglycemic Agents
  • Insulin
  • Sulfonylurea Compounds
  • Metformin