Modeling effects of SGLT-2 inhibitor dapagliflozin treatment versus standard diabetes therapy on cardiovascular and microvascular outcomes

Diabetes Obes Metab. 2014 Jul;16(7):628-35. doi: 10.1111/dom.12261. Epub 2014 Feb 19.

Abstract

Aims: Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, has been shown to lower glycated hemoglobin (HbA1c), weight, blood pressure and serum uric acid in clinical trials. Plasma lipids were also evaluated as exploratory variables. The goal of this study was to estimate the long-term cardiovascular (CV) and microvascular outcomes of dapagliflozin added to the standard of care (SOC) versus SOC using simulation methodology.

Methods: The Archimedes Model, a validated model of human physiology, diseases and healthcare systems, was used to model a type 2 diabetes mellitus (T2DM) population derived from National Health and Nutrition Examination Survey (NHANES) with HbA1c 7-10%, taking a single oral antidiabetic agent [metformin, sulfonylureas SU or thiazolidinedione (TZD)] at the beginning of the trial. A 20-year trial was simulated comparing dapagliflozin 10 mg, given in addition to SOC, with SOC alone. SOC was based on American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) 2012 guidelines and included diet, metformin, SU, TZD, dipeptidyl peptidase-4 (DPP-4), glucagon-like peptide-1 (GLP-1), and insulin therapies, with usage levels reflective of those in NHANES. Dapagliflozin effects were derived from phase 3 clinical trial results. End points included CV and microvascular outcomes.

Results: Over a 20-year period, patients on dapagliflozin were projected to experience relative reductions in the incidence of myocardial infarction (MI), stroke, CV death, and all-cause death of 13.8, 9.1, 9.6 and 5.0%, respectively, and relative reductions in the incidence of end-stage renal disease (ESRD), foot amputation, and diabetic retinopathy of 18.7, 13.0 and 9.8%, respectively, when compared with SOC.

Conclusions: On the basis of simulation results, adding dapagliflozin to currently available treatment options is projected to further decrease the CV and microvascular complications associated with T2DM.

Keywords: SGLT2 inhibitor; antidiabetic drug; diabetes mellitus; renal glucose handling; type 2 diabetes; weight loss therapy.

Publication types

  • Comparative Study

MeSH terms

  • Amputation
  • Benzhydryl Compounds / therapeutic use*
  • Blood Glucose / drug effects
  • Blood Pressure / drug effects
  • Body Weight / drug effects
  • Cardiovascular Diseases / etiology
  • Cardiovascular Diseases / physiopathology
  • Cardiovascular Diseases / prevention & control*
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / physiopathology
  • Diabetic Angiopathies / etiology
  • Diabetic Angiopathies / physiopathology
  • Diabetic Angiopathies / prevention & control*
  • Diabetic Retinopathy / prevention & control
  • Disease Progression
  • Glucosides / therapeutic use*
  • Glycated Hemoglobin A / drug effects
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Incidence
  • Kidney Failure, Chronic / prevention & control
  • Metformin / administration & dosage
  • Microcirculation / drug effects
  • Middle Aged
  • Myocardial Infarction / prevention & control
  • Nutrition Surveys
  • Sodium-Glucose Transporter 2 Inhibitors*
  • Stroke / prevention & control
  • Sulfonylurea Compounds / administration & dosage
  • Thiazolidinediones / administration & dosage
  • Treatment Outcome
  • Uric Acid / metabolism

Substances

  • Benzhydryl Compounds
  • Blood Glucose
  • Glucosides
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Sodium-Glucose Transporter 2 Inhibitors
  • Sulfonylurea Compounds
  • Thiazolidinediones
  • hemoglobin A1c protein, human
  • dapagliflozin
  • Uric Acid
  • Metformin
  • 2,4-thiazolidinedione