Generalizability of Cardiovascular Safety Trials on SGLT2 Inhibitors to the Real World: Implications for Clinical Practice

Adv Ther. 2019 Oct;36(10):2895-2909. doi: 10.1007/s12325-019-01043-z. Epub 2019 Aug 13.


Introduction: Following the US Food and Drug Administration (FDA) guidance on the evaluation of novel agents for the treatment of type 2 diabetes mellitus (T2DM), a number of cardiovascular outcomes safety trials (CVOTs) on sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been conducted. These trials show similarities in study design and definition of primary endpoints, but differ in their eligibility criteria. The aim of the present study was to investigate the generalizability of CVOTs on SGLT2i to Italian adults with T2DM; we estimated the proportions of this patient population who would be eligible for enrollment in EMPA-REG OUTCOME (empagliflozin), CANVAS (canagliflozin), DECLARE-TIMI 58 (dapagliflozin), and VERTIS-CV (ertugliflozin) studies.

Methods: This observational, cross-sectional study was conducted in 222 Italian diabetes clinics. Data on 455,662 adult patients with T2DM seen during 2016 were analyzed against the published patient eligibility criteria for the four CVOTs. The current use of SGLT2i in potentially eligible patients was assessed.

Results: Among the population identified, the proportion of patients meeting major eligibility criteria was 11.7% for EMPA-REG OUTCOME, 29.4% for CANVAS, 55.9% for DECLARE-TIMI 58, and 12.8% for VERTIS-CV. Of the patients eligible for these CVOTs, only a minority (range 4.4-6.8%) was actually prescribed an SGLT2i. Compared with patients in the CVOTs, eligible patients in the real world showed older age and longer diabetes duration, lower BMI and HbA1c levels, lower prevalence of established cardiovascular and cerebrovascular disease, and higher rates of microvascular complications and peripheral arterial disease.

Conclusion: The percentage of patients potentially eligible for treatment with SGLT2i varies as a reflection of different eligibility criteria applied in the trials. A large number of patients that could benefit from SGLT2i in terms of not only cardiovascular protection but also renal protection do not receive the treatment.

Funding: AstraZeneca.

Trial registration: NCT02993614.

Keywords: Cardiovascular outcomes safety trials; Electronic medical records; Eligibility criteria; Endocrinology; Quality of care; Real-world data; Sodium-glucose cotransporter-2 inhibitors; Type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Benzhydryl Compounds / adverse effects
  • Benzhydryl Compounds / therapeutic use
  • Canagliflozin / adverse effects
  • Canagliflozin / therapeutic use
  • Cardiovascular Diseases / chemically induced*
  • Cardiovascular Diseases / prevention & control*
  • Cross-Sectional Studies
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Female
  • Glucosides / adverse effects
  • Glucosides / therapeutic use
  • Humans
  • Hypoglycemic Agents / adverse effects*
  • Hypoglycemic Agents / therapeutic use*
  • Male
  • Middle Aged
  • Sodium-Glucose Transporter 2 / drug effects
  • Sodium-Glucose Transporter 2 Inhibitors / adverse effects*
  • Sodium-Glucose Transporter 2 Inhibitors / therapeutic use*
  • United States


  • Benzhydryl Compounds
  • Glucosides
  • Hypoglycemic Agents
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors
  • Canagliflozin
  • dapagliflozin
  • empagliflozin

Associated data

  • figshare/10.6084/m9.figshare.8982734