Nateglinide And Valsartan In Impaired Glucose Tolerance Outcomes Research Research Articles

Benchmarking the Cost-Effectiveness of Interventions Delaying Diabetes: A Simulation Study Based on NAVIGATOR Data.

OBJECTIVETo estimate using the UK Prospective Diabetes Study Outcomes Model Version 2 (UKPDS-OM2) the impact of delaying type 2 diabetes onset on costs and quality-adjusted life expectancy using trial participants who developed diabetes in the NAVIGATOR (Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research) study.RESEARCH DESIGN AND METHODSWe simulated the impact of delaying diabetes onset by 1–9 years, utilizing data from the 3,058 of 9,306 NAVIGATOR trial participants who developed type 2 diabetes. Costs and utility weights associated with diabetes and diabetes-related complications were obtained for the U.S. and U.K. settings, with costs expressed in 2017 values. We estimated discounted lifetime costs and quality-adjusted life years (QALYs) with 95% CIs.RESULTSGains in QALYs increased from 0.02 (U.S. setting, 95% CI 0.01, 0.03) to 0.15 (U.S. setting, 95% CI 0.10, 0.21) as the imposed time to diabetes onset was increased from 1 to 9 years, respectively. Savings in complication costs increased from $1,388 (95% CI $1,092, $1,669) for a 1-year delay to $8,437 (95% CI $6,611, $10,197) for a delay of 9 years. Interventions costing up to $567–$2,680 and £201–£947 per year would be cost-effective at $100,000 per QALY and £20,000 per QALY thresholds in the U.S. and U.K., respectively, as the modeled delay in diabetes onset was increased from 1 to 9 years.CONCLUSIONSSimulating a hypothetical diabetes-delaying intervention provides guidance concerning the maximum cost and minimum delay in diabetes onset needed to be cost-effective. These results can inform the ongoing debate about diabetes prevention strategies and the design of future intervention studies.

An outcome model approach to transporting a randomized controlled trial results to a target population.

Participants enrolled into randomized controlled trials (RCTs) often do not reflect real-world populations. Previous research in how best to transport RCT results to target populations has focused on weighting RCT data to look like the target data. Simulation work, however, has suggested that an outcome model approach may be preferable. Here, we describe such an approach using source data from the 2 × 2 factorial NAVIGATOR (Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research) trial, which evaluated the impact of valsartan and nateglinide on cardiovascular outcomes and new-onset diabetes in a prediabetic population. Our target data consisted of people with prediabetes serviced at the Duke University Health System. We used random survival forests to develop separate outcome models for each of the 4 treatments, estimating the 5-year risk difference for progression to diabetes, and estimated the treatment effect in our local patient populations, as well as subpopulations, and compared the results with the traditional weighting approach. Our models suggested that the treatment effect for valsartan in our patient population was the same as in the trial, whereas for nateglinide treatment effect was stronger than observed in the original trial. Our effect estimates were more efficient than the weighting approach and we effectively estimated subgroup differences. The described method represents a straightforward approach to efficiently transporting an RCT result to any target population.

Possible Ways to Improve Postprandial Glucose Control in Type 1 Diabetes.

Possible Ways to Improve Postprandial Glucose Control in Type 1 Diabetes.

Updated risk factors should be used to predict development of diabetes

AimsPredicting incident diabetes could inform treatment strategies for diabetes prevention, but the incremental benefit of recalculating risk using updated risk factors is unknown. We used baseline and 1-year data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial to compare diabetes risk prediction using historical or updated clinical information. MethodsAmong non-diabetic participants reaching 1year of follow-up in NAVIGATOR, we compared the performance of the published baseline diabetes risk model with a “landmark” model incorporating risk factors updated at the 1-year time point. The C-statistic was used to compare model discrimination and reclassification analyses to demonstrate the relative accuracy of diabetes prediction. ResultsA total of 7527 participants remained non-diabetic at 1year, and 2375 developed diabetes during a median of 4years of follow-up. The C-statistic for the landmark model was higher (0.73 [95% CI 0.72–0.74]) than for the baseline model (0.67 [95% CI 0.66–0.68]). The landmark model improved classification to modest (<20%), moderate (20%–40%), and high (>40%) 4-year risk, with a net reclassification index of 0.14 (95% CI 0.10–0.16) and an integrated discrimination index of 0.01 (95% CI 0.003–0.013). ConclusionsUsing historical clinical values to calculate diabetes risk reduces the accuracy of prediction. Diabetes risk calculations should be routinely updated to inform discussions about diabetes prevention at both the patient and population health levels.

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

BackgroundRegional 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.ConclusionsMajor 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 RegistrationURL: http://www.ClinicalTrials.gov. Unique identifier: NCT00097786.

Noncardiovascular deaths are more common than cardiovascular deaths in patients with cardiovascular disease or cardiovascular risk factors and impaired glucose tolerance: Insights from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial

Patients with impaired glucose tolerance have an elevated risk of cardiovascular (CV) death; however, the causes and risk factors associated with non-CV deaths are poorly understood. The NAVIGATOR trial enrolled 9,306 participants with impaired glucose tolerance and CV disease or at high CV risk, with a median follow-up of 6.4years. Using this population, we identified (1) the proportion of deaths attributed to CV, non-CV, and unknown causes, and (2) the risk factors associated with non-CV death. During the NAVIGATOR trial follow-up, 622 patients died. Investigators reported 244 (39.2%) CV deaths, 313 (50.3%) non-CV deaths, and 65 (10.5%) deaths of unknown cause. Myocardial infarction was the leading cause of investigator-reported death (57/622 [9.2%]). Among non-CV deaths, the most commonly identified cause related to malignancy (177/313 [56.5%]). Using adjudicated causes of death, Cox proportional hazard models identified 3 independent prognostic markers that increased the risk of non-CV death: history of non-melanoma skin cancer (hazard ratio 2.67 [95% CI 1.65-4.33]; P<.0001), white blood cell count (1 unit >5000/mm3; 1.10 [1.02-1.18]; P=.011), and serum potassium levels (per 1mmol/L above any value; 1.67 [1.302.15]; P<.0001). Despite the high baseline CV risk among patients in the NAVIGATOR trial, the most common cause of death was non-CV. The high burden of non-CV death in this population has potential implications for future CV event-driven trials.

Prospective relationships between body weight and physical activity: an observational analysis from the NAVIGATOR study

ObjectivesWhile bidirectional relationships exist between body weight and physical activity, direction of causality remains uncertain and previous studies have been limited by self-reported activity or weight and small sample size....

Venous Thromboembolism and Cardiovascular Risk: Results from the NAVIGATOR Trial

BackgroundContemporary studies suggest an association between venous thromboembolism and a higher incidence of major cardiovascular events, mostly attributed to arterial atherothrombosis. Using data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, we assessed the association of venous thromboembolism with major cardiovascular events. MethodsIn NAVIGATOR, patients with impaired glucose tolerance were randomly allocated to receive valsartan or placebo and nateglinide or placebo in addition to lifestyle modification. Baseline characteristics and prior history of venous thromboembolism were assessed. After adjusting for important baseline covariates, Cox proportional hazards regression models were used to assess the association between venous thromboembolism and major cardiovascular outcomes. ResultsOf the 9306 patients enrolled, 129 (1.4%) had a history of venous thromboembolism. Patients with venous thromboembolism were older, more frequently white and female, and had a higher body mass index. Patients with venous thromboembolism had higher 5-year event rates for the composite of death, myocardial infarction, and stroke, as compared with patients without venous thromboembolism (10.7% vs 5.9%; P < .001; adjusted hazard ratio 2.12; 95% confidence interval, 1.36-3.31; P = .001). ConclusionIn patients with impaired glucose tolerance at high risk for cardiovascular events, the prevalence of venous thromboembolism was rare but associated with worse long-term cardiovascular outcomes, including arterial events. Venous thromboembolism is a marker of risk, and attention should be paid to this high-risk group of patients.

Change in levels of physical activity after diagnosis of type 2 diabetes: an observational analysis from the NAVIGATOR study

Increased physical activity is known to be beneficial in people with type 2 diabetes mellitus (T2DM), but it is not known whether individuals change their activity levels after T2DM diagnosis. The present Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, conducted in participants with impaired glucose tolerance at high cardiovascular risk, assessed ambulatory activity annually using research-grade pedometers. Oral glucose tolerance tests were performed annually and repeated to confirm T2DM diagnosis. This observational analysis used general linear models to compare step counts before and after T2DM diagnosis in the 2816 participants with the requisite data. Participants were relatively inactive at baseline, taking a median (interquartile range) of 5488 (3258-8361) steps/day, which decreased after T2DM diagnosis by a mean (s.e.) of 258 (64) steps/day (p < 0.0001); however, after adjusting for background trend for activity, step count after T2DM diagnosis was unchanged [mean (s.e.) of 103 (87) fewer steps/day; p = 0.23]. Awareness of T2DM diagnosis had no impact on the trajectory of activity established before the diagnosis.

Role of diuretics, β blockers, and statins in increasing the risk of diabetes in patients with impaired glucose tolerance: reanalysis of data from the NAVIGATOR study

Objective To examine the degree to which use of β blockers, statins, and diuretics in patients with impaired glucose tolerance and other cardiovascular risk factors is associated with new onset...

Predictors of Stroke in Patients With Impaired Glucose Tolerance

Risk factors for stroke are well-established in general populations but sparsely studied in individuals with impaired glucose tolerance. We identified predictors of stroke among participants with impaired glucose tolerance in the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. Cox proportional-hazard regression models were constructed using baseline variables, including the 2 medications studied, valsartan and nateglinide. Among 9306 participants, 237 experienced a stroke over 6.4 years. Predictors of stroke included classical risk factors such as existing cerebrovascular and coronary heart disease, higher pulse pressure, higher low-density lipoprotein cholesterol, older age, and atrial fibrillation. Other factors, including previous venous thromboembolism, higher waist circumference, lower estimated glomerular filtration rate, lower heart rate, and lower body mass index, provided additional important predictive information, yielding a C-index of 0.72. Glycemic measures were not predictive of stroke. Variables associated with stroke were similar in participants with no prior history of cerebrovascular disease at baseline. The most powerful predictors of stroke in patients with impaired glucose tolerance included a combination of established risk factors and novel variables, such as previous venous thromboembolism and elevated waist circumference, allowing moderately effective identification of high-risk individuals.

Predictors of Incident Heart Failure Hospitalizations Among Patients With Impaired Glucose Tolerance

Background— Impaired glucose tolerance and metabolic syndrome are associated with increased risk of heart failure (HF). However, predictors associated with the increased risk of incident HF have not been well characterized. We aimed to identify independent predictors of incident HF hospitalization among patients with impaired glucose tolerance. Methods and Results— In Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR), 9306 research participants with impaired glucose tolerance and ≥1 cardiovascular risk factors were randomized to valsartan versus placebo and nateglinide versus placebo in a 2×2 factorial manner, with a median follow-up of 6.5 years. Using a multivariable Cox proportional hazards model, we analyzed the relationships among baseline clinical factors and the outcome of incident HF hospitalization in patients without history of HF. Significant predictors were identified by forward selection. Increasing age, history of coronary heart disease, and atrial fibrillation or flutter were among several known independent predictors of incident HF hospitalization. Increased waist circumference (hazard ratio per 10 cm, 1.37; 95% confidence interval, 1.21–1.55; P &lt;0.001) and increased urinary albumin–creatinine ratio ( P &lt;0.001) were identified as novel predictors. The predictive model for incident HF hospitalization showed good discrimination, with an optimism-corrected C-index of 0.79. Conclusions— Among research participants with impaired glucose tolerance, there are several easily identifiable predictors of incident HF hospitalization, including traditional risk factors and novel indices of central adiposity and increased urinary albumin–creatinine ratio, which enable further risk stratification and help distinguish patients who could benefit from more aggressive risk factor management.

Effects of Changes in Potassium With Valsartan Use on Diabetes Risk: Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial

Low and low-normal serum potassium is associated with an increased risk of diabetes. We hypothesized that the protective effect of valsartan on diabetes risk could be mediated by its effect of raising serum potassium. We analyzed data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, which randomized participants at risk for diabetes to either valsartan (up to 160mg daily) or no valsartan. Using Cox models, we evaluated the effect of valsartan on diabetes risk over a median of 4 years of follow-up and calculated the mediation effect of serum potassium as the difference in treatment hazard ratios from models excluding and including 1-year change in serum potassium. The 95% confidence interval (CI) for the difference in log hazard ratios was computed by bootstrapping. The hazard ratio for developing diabetes among those on valsartan vs. no valsartan was 0.866 (95% CI = 0.795-0.943) vs. 0.868 (95% CI = 0.797-0.945), after controlling for 1-year change in potassium. The bootstrap 95% CI for a difference in these log hazard ratios was not statistically significant (-0.003 to 0.009). Serum potassium does not appear to significantly mediate the protective effect of valsartan on diabetes risk.

Predictors of cardiovascular events in a contemporary population with impaired glucose tolerance: an observational analysis of the Nateglinide and Valsartan in impaired glucose tolerance outcomes research (NAVIGATOR) trial

ObjectivesRisk factors for cardiovascular events are well established in general populations and those with diabetes but have been sparsely studied in impaired glucose tolerance (IGT). We sought to identify predictors...

Metabolic syndrome and alanine aminotransferase: a global perspective from the NAVIGATOR screening population

Non-alcoholic fatty liver disease (NAFLD) is associated with features of the metabolic syndrome (MetS) and may be an expression of the syndrome within the liver. Using screening data from the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study (n = 42 149), we examined whether alanine aminotransferase (ALT), a biomarker for NAFLD, clustered with features of MetS and whether the clusters differed across global geographic regions. Exploratory factor analysis using principle components analysis was applied to data drawn from the NAVIGATOR screening population (n = 41 111). Demographic data, anthropomorphic measurements and blood pressure (BP) collected during the screening visit, as well as blood samples analysed for ALT, total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, and fasting and 2-h glucose measures after an oral glucose tolerance test were used for our analysis. Two factors, interpreted as lipid (Factor 1), and BP/obesity (Factor 2) were identified, explaining approximately 50% of the variance in the overall population. Similar patterns of aggregation were reproducible across all geographic regions except Asia, where fasting glucose loaded more consistently on Factor 1. ALT loaded with mean arterial pressure, fasting glucose and waist circumference except in Asia, where it loaded only with mean arterial pressure and waist circumference. ALT aggregated with components of MetS, and the pattern of aggregation of ALT with other features of MetS was similar across regions except Asia, possibly indicating a different pathophysiology for NAFLD in Asia. Predictive models of NAFLD may need to be adjusted for regional and ethnic differences.

Are Renin-Angiotensin-Aldosterone System Blockers Distinguishable Based on Cardiovascular and Renal Outcomes in Nephropathy?

Drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) are the cornerstone of therapy for cardiovascular and renal disease because they protect against worsening outcomes in the respective target organs. Recent results from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) have confirmed that angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) confer similar cardioprotection and renoprotection, showing little to no benefit from the combination in cardiovascular disease. It is not yet clear whether one class is superior to another for renoprotection. Whether dual RAAS blockade is more advantageous than single blockade, and in which patients, is also yet to be clearly determined. The Long-Term Impact of RAS Inhibition on Cardiorenal Outcomes (LIRICO) study will compare the cardiorenoprotective effects of ACE inhibitors and ARBs in patients with albuminuria, and clarify the role of dual blockade. Preliminary evidence that RAAS inhibitors reduce incident diabetes is intriguing. Whether ARBs can reduce incident diabetes and related cardiovascular outcomes is awaited with the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial.

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

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 x 2 factorial trial in subjects with IGT (on a screening oral glucose tolerance test [OGTT]) aged > or = 50 years with known CVD or aged > or = 55 years with > or = 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.

Angiotensin Receptor Blockers: Cardiovascular Protection in the Metabolic Syndrome

It is well recognised that the metabolic syndrome, a constellation of risk factors including obesity, hypertension, insulin resistance and dyslipidaemia, is associated with an increased risk of cardiovascular complications and the development of Type 2 diabetes. Consequently, timely identification and management of all components of the metabolic syndrome is warranted. In particular, guidelines have emphasised the importance of targeting elevated blood pressure (BP) and dyslipidaemia as a method of reducing global cardiovascular risk. Findings from the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial show that the angiotensin receptor blocker, valsartan, reduces cardiovascular events and the development of Type 2 diabetes in high-risk individuals. This profile is being further explored in the ongoing Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. Given the potential advantages to patients and physicians of tackling more than one of the components of the metabolic syndrome, antihypertensive agents such as valsartan would appear to be and important addition to the management of vulnerable patients at high risk of cardiovascular events.

Preventing type II diabetes mellitus.

Burgeoning obesity is increasing the prevalence of type II diabetes mellitus. As a consequence, there will be an even greater burden of cardiovascular disease, end-stage renal disease, blindness, and lower extremity amputations. If diagnosed, impaired glucose tolerance presents an opportunity for intervention that potentially could delay or prevent the development of diabetes. Recent prospective studies document the effectiveness of exercise and weight reduction in preventing diabetes. Metformin is less effective than intense lifestyle interventions. Acarbose, losartan, orlistat, pravastatin, ramipril, and hormone replacement therapy are associated with lower rates of the development of diabetes. The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial and the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial were designed to assess not only the prevention of diabetes but also the impact on cardiovascular morbidity and mortality.

Prevention of Type 2 Diabetes Mellitus Through Inhibition of the Renin-Angiotensin System

Type 2 diabetes mellitus is becoming a major health problem associated with excess morbidity and mortality. As the prevalence of type 2 diabetes is rapidly increasing, prevention of the disease should be considered as a key objective in the near future. Besides lifestyle changes, various pharmacological treatments have proven their efficacy in placebo-controlled clinical trials, including antidiabetic drugs such as metformin, acarbose and troglitazone, or antiobesity agents such as orlistat. Arterial hypertension, a clinical entity in which insulin resistance is common, is strongly associated with type 2 diabetes and may precede the disease by several years. While antihypertensive agents such as diuretics or beta-adrenoceptor antagonists may worsen insulin resistance and impair glucose tolerance, newer antihypertensive agents exert neutral or even slightly positive metabolic effects. Numerous clinical trials have investigated the effects of ACE inhibitors or angiotensin II receptor antagonists (ARAs) on insulin sensitivity in hypertensive patients, with or without diabetes, with no consistent results. Almost half of the studies with ACE inhibitors in hypertensive nondiabetic individuals demonstrated a slight but significant increase in insulin sensitivity as assessed by insulin-stimulated glucose disposal during a euglycaemic hyperinsulinaemic clamp, while the other half failed to reveal any significant change. The effects of ARAs on insulin sensitivity are neutral in most studies. Mechanisms of improvement of glucose tolerance and insulin sensitivity through the inhibition of the renin-angiotensin system (RAS) are complex. They may include improvement of blood flow and microcirculation in skeletal muscles and, thereby, enhancement of insulin and glucose delivery to the insulin-sensitive tissues, facilitating insulin signalling at the cellular level and improvement of insulin secretion by the beta cells. Six recent large-scale clinical studies reported a remarkably consistent reduction in the incidence of type 2 diabetes in hypertensive patients treated with either ACE inhibitors or ARAs for 3-6 years, compared with a thiazide diuretic, beta-adrenoceptor antagonist, the calcium channel antagonist amlodipine or even placebo. The relative risk reduction averaged 14% (p = 0.034) in the CAPPP (Captopril Prevention Project) with captopril compared with a thiazide or beta1-adrenoceptor antagonist, 34% (p < 0.001) in the HOPE (Heart Outcomes Prevention Evaluation) study with ramipril compared with placebo, 30% (p < 0.001) in the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) with lisinopril compared with chlortalidone, 25% (p < 0.001) in the LIFE (Losartan Intervention For Endpoint reduction in hypertension study) with losartan compared with atenolol, and 25% (p = 0.09) in the SCOPE (Study on Cognition and Prognosis in the Elderly) with candesartan cilexetil compared with placebo, and 23% (p < 0.0001) in the VALUE (Valsartan Antihypertensive Long-term Use Evaluation) trial with valsartan compared with amlodipine. All these studies considered the development of diabetes as a secondary endpoint, except the HOPE trial where it was a post hoc analysis. These encouraging observations led to the initiation of two large, prospective, placebo-controlled randomised clinical trials whose primary outcome is the prevention of type 2 diabetes: the DREAM (Diabetes REduction Approaches with ramipril and rosiglitazone Medications) trial with the ACE inhibitor ramipril and the NAVIGATOR (Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research) trial with the ARA valsartan. Finally, ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) will also investigate as a secondary endpoint whether it is possible to prevent the development of type 2 diabetes by blocking the RAS with either an ACE inhibitor or an ARA or a combination of both. Thus, the recent consistent observations of a 14-34% reduction of the development of diabetes in hypertensive patients receiving ACE inhibitors or ARAs are exciting. From a theoretical point of view, they emphasise that there are many aspects of the pathogenesis, prevention and treatment of type 2 diabetes that still need to be uncovered. From a practical point of view, they may offer a new strategy to reduce the ongoing epidemic and burden of type 2 diabetes.