International Variation in Outcomes Among People with Cardiovascular Disease or Cardiovascular Risk Factors and Impaired Glucose Tolerance: Insights from the NAVIGATOR Trial

Marilia Harumi Higuchi Dos Santos, Abhinav Sharma, Jie-Lena Sun, Karen Pieper, John J V McMurray, Rury R Holman, Renato D Lopes, Marilia Harumi Higuchi Dos Santos, Abhinav Sharma, Jie-Lena Sun, Karen Pieper, John J V McMurray, Rury R Holman, Renato D Lopes

Abstract

Background: Regional differences in risk of diabetes mellitus and cardiovascular outcomes in people with impaired glucose tolerance are poorly characterized. Our objective was to evaluate regional variation in risk of new-onset diabetes mellitus, cardiovascular outcomes, and treatment effects in participants from the NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) trial.

Methods and results: NAVIGATOR randomized people with impaired glucose tolerance and cardiovascular risk factors or with established cardiovascular disease to valsartan (or placebo) and to nateglinide (or placebo) with a median 5-year follow-up. Data from the 9306 participants were categorized by 5 regions: Asia (n=552); Europe (n=4909); Latin America (n=1406); North America (n=2146); and Australia, New Zealand, and South Africa (n=293). Analyzed outcomes included new-onset diabetes mellitus; cardiovascular death; a composite cardiovascular outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke; and treatment effects of valsartan and nateglinide. Respective unadjusted 5-year risks for new-onset diabetes mellitus, cardiovascular death, and the composite cardiovascular outcome were 33%, 0.4%, and 4% for Asia; 34%, 2%, and 6% for Europe; 37%, 4%, and 8% for Latin America; 38%, 2%, and 6% for North America; and 32%, 4%, and 8% for Australia, New Zealand, and South Africa. After adjustment, compared with North America, European participants had a lower risk of new-onset diabetes mellitus (hazard ratio 0.86, 95% CI 0.78-0.94; P=0.001), whereas Latin American participants had a higher risk of cardiovascular death (hazard ratio 2.68, 95% CI 1.82-3.96; P<0.0001) and the composite cardiovascular outcome (hazard ratio 1.48, 95% CI 1.15-1.92; P=0.003). No differential interactions between treatment and geographic location were identified.

Conclusions: Major regional differences regarding the risk of new-onset diabetes mellitus and cardiovascular outcomes in NAVIGATOR participants were identified. These differences should be taken into account when planning global trials.

Clinical trial registration: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00097786.

Keywords: cardiovascular disease; diabetes mellitus; risk factor.

© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1
Figure 1
Adjusted event curves for incidence of diabetes mellitus by region. Other indicates Australia, New Zealand, and South Africa.
Figure 2
Figure 2
Adjusted event curves for cardiovascular death by region. Other indicates Australia, New Zealand, and South Africa.
Figure 3
Figure 3
Adjusted event curve for cardiovascular death, myocardial infarction (MI), and stroke by region. Other indicates Australia, New Zealand, and South Africa.

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