Antihypertensive drug therapy and the risk of lower extremity amputations in pharmacologically treated type 2 diabetes patients

Pharmacoepidemiol Drug Saf. 2004 Mar;13(3):139-46. doi: 10.1002/pds.932.


Purpose: The objective of this study was to determine the association between different antihypertensive drug therapies and lower extremity amputations (LEAs) in type 2 diabetes patients.

Methods: Data were obtained from the PHARMO Record Linkage System comprising pharmacy records and data on hospitalisations for all 450,000 residents of eight Dutch cities. In a nested case-control study among 12,140 type 2 diabetes patients who used antihypertensive drugs, 26 cases with a first LEA and 94 controls without a LEA matched on age, sex and calendar time were identified. Logistic regression was used to estimate the relative risk of LEA and to adjust for potential confounding factors.

Results: Among type 2 diabetes patients who used antihypertensive drugs, subjects who used thiazide diuretics, alone or in combination, had a higher risk of LEA compared to subjects who used Angiotensin Converting Enzyme (ACE) inhibitor monotherapy (crude odds ratio (OR): 6.11 [95% confidence interval (CI): 1.32-28.27]). The use of thiazide diuretics was also associated with an increased risk of LEA when compared to the use of any non-thiazide antihypertensive drug (adjusted OR: 7.04 [1.10-45.30]). The increased risk of LEA associated with the use of thiazides compared to the use of non-thiazides depended on the duration of use (adjusted OR(< or = 365 days), 4.82 [0.61-38.34] and adjusted OR(>365 days), 26.16 [1.02-674.02], p-trend = 0.01).

Conclusions: Treatment with thiazide diuretics compared to treatment with other antihypertensive drugs was associated with excess amputations in type 2 diabetes patients. Due to several limitations of this study, our findings do not preclude the use of thiazides in type 2 diabetes mellitus patients as yet.

Publication types

  • Comparative Study

MeSH terms

  • Aged
  • Amputation / statistics & numerical data*
  • Antihypertensive Agents / classification
  • Antihypertensive Agents / therapeutic use*
  • Benzothiadiazines
  • Case-Control Studies
  • Cohort Studies
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diuretics
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Female
  • Humans
  • Logistic Models
  • Lower Extremity / pathology
  • Lower Extremity / surgery*
  • Male
  • Peptidyl-Dipeptidase A / therapeutic use
  • Risk
  • Sodium Chloride Symporter Inhibitors / adverse effects
  • Sodium Chloride Symporter Inhibitors / therapeutic use
  • Time Factors


  • Antihypertensive Agents
  • Benzothiadiazines
  • Diuretics
  • Sodium Chloride Symporter Inhibitors
  • Peptidyl-Dipeptidase A