Elsevier

American Heart Journal

Volume 156, Issue 4, October 2008, Pages 623-632
American Heart Journal

Trial Design
Prevention of diabetes and cardiovascular disease in patients with impaired glucose tolerance: Rationale and design of the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial

https://doi.org/10.1016/j.ahj.2008.05.017Get rights and content

Patients with impaired glucose tolerance (IGT) have increased risk for developing type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Lifestyle modification and medication can prevent or delay progression to diabetes (PD), but whether such interventions also reduce the risk of CVD has not been rigorously tested. The Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial is a multinational, randomized, double-blind, 2 × 2 factorial trial in subjects with IGT (on a screening oral glucose tolerance test [OGTT]) aged ≥50 years with known CVD or aged ≥55 years with ≥1 CVD risk factor. Enrollment began in January 2002 and was completed January 2004, with 9,518 patients randomized to receive 1 of 4 possible treatment combinations as follows: nateglinide with valsartan, nateglinide with valsartan-placebo, nateglinide-placebo with valsartan, or nateglinide-placebo with valsartan-placebo. All subjects are participating in a clinic-based and telephone-based lifestyle intervention aimed at reducing weight and dietary fat and increasing physical activity. The 3 coprimary end points are new onset of T2DM, a “core” composite of major cardiovascular events (death, myocardial infarction, stroke, or hospitalization for heart failure), and an “extended” composite including the components of the core composite plus coronary revascularization and hospitalization for unstable angina. The study was designed to evaluate whether reducing postprandial hyperglycemia, blockade of the renin-angiotensin-aldosterone system, or both interventions reduce the risk of T2DM or cardiovascular events in patients with IGT.

Section snippets

Overview of the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial

The NAVIGATOR trial is a multinational, randomized, double-blind, placebo-controlled, 2 × 2 factorial trial investigating whether treatment with nateglinide or valsartan will reduce progression to diabetes (PD) and new CV events in subjects with impaired glucose tolerance (IGT) who have established CVD or are at high risk for CVD. A total of 9,306 of the 9,518 patients enrolled (Table I) and randomized were included in the final analysis. Patients were allocated randomly in a 1:1:1:1 ratio to

Key issues in trial design

Numerous recent studies in CVD and diabetes underscore the complexity and risk of using biochemical measures to predict which therapies are preferable for treating long-term diseases.35, 36, 37 Rather than simply attempting to determine whether nateglinide and valsartan reduce diabetes incidence or delay PD, NAVIGATOR directly addresses the effect of interventions on the CV mortality and morbidity that dominate clinical decision-making, thus markedly increasing the sample size required to

Conclusion

The enormous burden of diabetes worldwide is leading to an increase in prevalence of CVD.3 The resulting excess morbidity, mortality, and costs will overburden many health care delivery systems unless action is taken. The NAVIGATOR trial is unique in addressing both the relationship between the metabolic abnormalities in IGT and diabetes and the later development of CVD by testing 2 distinct but unified hypotheses. The nateglinide treatment arm tests whether reducing postprandial hyperglycemia

References (49)

  • D.M. Nathan et al.

    Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes

    N Engl J Med

    (2005)
  • J.L. Chiasson et al.

    Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial

    JAMA

    (2003)
  • J. Tuomilehto et al.

    Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance

    N Engl J Med

    (2001)
  • Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin

    N Engl J Med

    (2002)
  • Expert Committee on the Diagnosis and Classification of Diabetes Mellitus

    Report of the expert committee on the diagnosis and classification of diabetes mellitus

    Diabetes Care

    (1999)
  • K.G.M.M. Alberti et al.

    Definition, diagnosis, and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus

    (1999)
  • C. Weyer et al.

    The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus

    J Clin Invest

    (1999)
  • S. Efendic et al.

    Aspects of the pathogenesis of type 2 diabetes

    Endocrine Rev

    (1984)
  • Novartis Pharmaceutical Corp

    Nateglinide prescribing information

  • F.M. Gribble et al.

    Randomized dose ranging study of the reduction of fasting and postprandial glucose in type 2 diabetes by nateglinide (A-4166)

    Diabetes Care

    (2001)
  • E. Vermes et al.

    Enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the studies of left ventricular dysfunction (SOLVD)

    Circulation

    (2003)
  • The Heart Outcomes Prevention Evaluation Study Investigators

    Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients

    N Engl J Med

    (2002)
  • The ALLHAT Investigators

    Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic

    JAMA

    (2002)
  • E. Vermes et al.

    Enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the Studies Of Left Ventricular Dysfunction (SOLVD)

    Circulation

    (2003)
  • Cited by (86)

    • Updated risk factors should be used to predict development of diabetes

      2017, Journal of Diabetes and its Complications
      Citation Excerpt :

      Comparatively little is known about the impact of change in common risk factors over time on risk prediction.8 Using data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study (ClinicalTrials.gov NCT00097786), we investigated the incremental benefit to diabetes risk prediction of updating risk factors after 1 year of follow up.9–11 The NAVIGATOR study design and results have been previously published.9–11

    View all citing articles on Scopus

    This study is funded by Novartis Pharma AG, Basel, Switzerland.

    *

    See Appendix A for executive committee members. As chair of the trial, Dr Califf takes responsibility for the content of this article.

    View full text