Comparison of Canagliflozin vs. Alternative Antihyperglycemic Treatments on Risk of Below Knee Lower Extremity Amputation for Patients with Type 2 Diabetes Mellitus and the Subpopulation with Established Cardiovascular Disease

Study type

• Study topic:
  Human medicinal product

  Disease /health condition
• Study type:
  Non-interventional study
• Scope of the study:
  Assessment of risk minimisation measure implementation or effectiveness

  Disease epidemiology

  Safety study (incl. comparative)
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Name of medicine:
  INVOKANA
• Study drug International non-proprietary name (INN) or common name:
  CANAGLIFLOZIN
• Anatomical Therapeutic Chemical (ATC) code:
  (A10BK02) canagliflozin

  canagliflozin
• Medical condition to be studied:
  Amputation

Population studied

• Short description of the study population:
  Patients who are new users of anti-hyperglycemic agent (AHA) of interest with at least 365 days of prior observation and a diagnosis of T2DM, but no diagnosis of type 1 DM (T1DM) or “secondary diabetes”, prior to the pre-specified AHA exposure.
• Age groups:
  Adults (18 to < 46 years)

  Adults (46 to < 65 years)

  Adults (65 to < 75 years)

  Adults (75 to < 85 years)

  Adults (85 years and over)
• Special population of interest:
  Other
• Special population of interest, other:
  Type 2 diabetes mellitus patients
• Estimated number of subjects:
  714582

Study design details

• Main study objective:
  The main objective of this study is to assess in healthcare databases whether Canagliflozin and other sodium-glucose co-transporter 2 inhibitors (SGLT2i) are associated with the risk of below-knee lower extremity (BKLE) amputation compared to non-SGLT2i antihyperglycemic agents (AHAs) and whether the risk of BKLE amputation is different between patients treated with Canagliflozin and other SGLT2i.
• Outcomes:
  below-knee lower extremity (BKLE) amputation, lower extremity osteomyelitis, lower extremity ulcer, gangrene, peripheral occlusive disease
• Data analysis plan:
  Crude incidence rates of BKLE amputation in each exposure cohort and pre-defined subgroups will be estimated. Baseline patient characteristics including risk factors for amputation will be summarized for those treated with target drugs versus comparator drugs. Cox proportional hazards model will be used to estimate Hazard Ratio (HR) for new user patients treated with target drugs versus comparator drugs. Exposure propensity-score (PS) will be estimated through large-scale regularized regression using all available data and used to control for confounding by imbalanced baseline covariates. Both PS matching and PS stratification will be used for adjustment. P-values in comparative analyses will be calibrated using negative control outcomes to address residual bias. Data source-specific HRs, 95% CIs, pre- and post- calibration p values will be generated for each comparison in each database. Meta-analytic estimates across 4 databases will be generated when there is sufficient homogeneity.