Comparative effectiveness of canagliflozin, SGLT2 inhibitors and non-SGLT2 inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus: A real-world meta-analysis of 4 observational databases (OBSERVE-4D)

Diabetes Obes Metab. 2018 Nov;20(11):2585-2597. doi: 10.1111/dom.13424. Epub 2018 Jun 25.


Aims: Sodium glucose co-transporter 2 inhibitors (SGLT2i) are indicated for treatment of type 2 diabetes mellitus (T2DM); some SGLT2i have reported cardiovascular benefit, and some have reported risk of below-knee lower extremity (BKLE) amputation. This study examined the real-world comparative effectiveness within the SGLT2i class and compared with non-SGLT2i antihyperglycaemic agents.

Materials and methods: Data from 4 large US administrative claims databases were used to characterize risk and provide population-level estimates of canagliflozin's effects on hospitalization for heart failure (HHF) and BKLE amputation vs other SGLT2i and non-SGLT2i in T2DM patients. Comparative analyses using a propensity score-adjusted new-user cohort design examined relative hazards of outcomes across all new users and a subpopulation with established cardiovascular disease.

Results: Across the 4 databases (142 800 new users of canagliflozin, 110 897 new users of other SGLT2i, 460 885 new users of non-SGLT2i), the meta-analytic hazard ratio estimate for HHF with canagliflozin vs non-SGLT2i was 0.39 (95% CI, 0.26-0.60) in the on-treatment analysis. The estimate for BKLE amputation with canagliflozin vs non-SGLT2i was 0.75 (95% CI, 0.40-1.41) in the on-treatment analysis and 1.01 (95% CI, 0.93-1.10) in the intent-to-treat analysis. Effects in the subpopulation with established cardiovascular disease were similar for both outcomes. No consistent differences were observed between canagliflozin and other SGLT2i.

Conclusions: In this large comprehensive analysis, canagliflozin and other SGLT2i demonstrated HHF benefits consistent with clinical trial data, but showed no increased risk of BKLE amputation vs non-SGLT2i. HHF and BKLE amputation results were similar in the subpopulation with established cardiovascular disease. This study helps further characterize the potential benefits and harms of SGLT2i in routine clinical practice to complement evidence from clinical trials and prior observational studies.

Keywords: SGLT2 inhibitor; type 2 diabetes.

Publication types

  • Comparative Study
  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Amputation / statistics & numerical data*
  • Canagliflozin / therapeutic use*
  • Databases as Topic / statistics & numerical data
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diabetes Mellitus, Type 2* / epidemiology
  • Diabetic Angiopathies / epidemiology
  • Diabetic Angiopathies / prevention & control
  • Diabetic Angiopathies / therapy
  • Diabetic Foot / epidemiology
  • Diabetic Foot / etiology
  • Diabetic Foot / prevention & control
  • Diabetic Foot / surgery
  • Female
  • Heart Failure* / epidemiology
  • Heart Failure* / etiology
  • Heart Failure* / prevention & control
  • Hospitalization / statistics & numerical data*
  • Humans
  • Male
  • Middle Aged
  • Observational Studies as Topic / statistics & numerical data
  • Retrospective Studies
  • Risk Factors
  • Sodium-Glucose Transporter 2 Inhibitors / therapeutic use*
  • Treatment Outcome
  • Young Adult


  • Sodium-Glucose Transporter 2 Inhibitors
  • Canagliflozin