The CASE-J trial was a prospective, multicenter, randomized, open-label, active-controlled, two-arm parallel-group comparison with response-dependent dose titration and blinded assessment of end points conducted in high-risk Japanese hypertensive patients. The trial protocol was approved by the Ethics Committee of Kyoto University Graduate School of Medicine in accordance with the principles of the Declaration of Helsinki. Details of the study and the main results have been reported previously (¹⁴,¹⁵). In brief, 4,728 high-risk Japanese hypertensive patients aged 20–84 years were randomly assigned to either candesartan- or amlodipine-based regimens. Blood pressure was measured at a clinic with the patient in the sitting position. The average of two consecutive measurements of blood pressure on separate visits was used. High-risk was defined as the presence of any one or more of the following: 1) severe hypertension (SBP/DBP ≥180/110 mmHg); 2) type 2 diabetes (fasting blood glucose ≥126 mg/dl, casual blood glucose ≥200 mg/dl, A1C ≥6.5%, 2-h blood glucose on a 75-g oral glucose tolerance test ≥200 mg/dl, or current treatment with a hypoglycemic agent at baseline); 3) a history of stroke or transient ischemic attack > 6 months before screening; 4) left ventricular hypertrophy (LVH), angina pectoris, or a history of myocardial infarction >6 months before screening; 5) proteinuria or renal dysfunction (serum creatinine ≥1.3 mg/dl); or 6) arteriosclerotic peripheral artery obstruction. Exclusion criteria have been reported elsewhere (¹⁴,¹⁵).

Enrolled patients were randomly assigned to receive candesartan by oral administration at 4–12 mg/day or amlodipine by oral administration at 2.5–10 mg/day. Patients already under treatment with diuretics, α-blockers, and β-blockers at enrollment were allowed to continue taking these drugs, but the new addition of other ARBs and CCBs or any ACE inhibitors was prohibited.

In this study, we demonstrated that pulse pressure was a predictor of new-onset diabetes in high-risk hypertensive patients, independent of the effects of antihypertensive treatment and other possible risk factors for new-onset diabetes. Further, a higher pulse pressure arising mainly due to a lower DBP, indicating that the increased pulse pressure resulted largely from increased arterial stiffness, was associated with a higher risk of new-onset diabetes. This finding suggests that increased arterial stiffness, reflected in an increased pulse pressure, may be related to the process of new-onset diabetes in high-risk hypertensive patients, albeit that the mechanism of this association remains to be elucidated.

Two potential interpretations may explain these results. First, increased pulse pressure may be a surrogate marker for the risk of new-onset diabetes. Supporting this suggestion, a higher pulse pressure, reflecting increased arterial stiffness, was observed in hypertensive patients with metabolic syndrome than in those without (¹⁷). Further, accumulating evidence supports the concept of increased arterial stiffness in patients with a metabolic disturbance, which is considered a potential mechanism linking metabolic disturbance to increased CVD risk (^{11, B12}–¹³). Arterial properties are affected both functionally and structurally by many factors, including aging, blood pressure, sympathetic nervous system function, endothelial function, inflammation, bioactive peptides, and other cardiovascular risk factors. Impaired glucose metabolism, including metabolic syndrome and insulin resistance, usually precedes the development of overt type 2 diabetes (¹⁸). Prolonged exposure to hyperglycemic conditions can lead to increased arterial stiffness via collagen cross-linking due to nonenzymatic glycation, endothelial dysfunction, inflammation, and local activation of the renin-angiotensin-aldosterone system in pre-diabetic as well as diabetic individuals (¹⁸). Indeed, PP_f, represented as a parameter of the pulsatile component of blood pressure, was superior to pulse pressure in terms of the risk stratification of new-onset diabetes.

Second, increased pulse pressure may directly affect glucose metabolism. Recent findings have clarified that microvascular dysfunction may be a cause rather than a consequence of hypertension (¹⁹). Microvascular dysfunction may also contribute to impaired insulin-mediated changes in muscle perfusion and glucose metabolism, providing a novel pathophysiological framework for understanding the association among hypertension, obesity, and impaired insulin-mediated glucose disposal (¹⁹,²⁰). Microvascular dysfunction is thus a potential mechanism explaining the clustering of hypertension and type 2 diabetes. Interestingly, relations between microvascular function and both aortic stiffness and pressure pulsatility have been reported (²¹). Abnormalities in peripheral vascular resistance may have deleterious consequences for aortic stiffness, and microvascular dysfunction may in turn be further aggravated by increased transmission of the forward wave into the microcirculation. Accordingly, increased pulse pressure, reflecting increased arterial stiffness, may be both a cause and a consequence of microvascular dysfunction, leading to a “vicious cycle” in impaired glucose metabolism as well as arteriosclerosis (⁹,¹⁹,²⁰).

The present study also revealed that electrocardiographic or echocardiographic LVH at baseline was an independent predictor of new-onset diabetes. In their recent subanalysis of the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, Oki et al. (²²) reported that in-treatment resolution or continued absence of electrocardiographic LVH was associated with a lower incidence of diabetes. Because pulse pressure was positively related to LVH (²³), our study might validate their findings from a different perspective. Interestingly, in another subanalysis of the LIFE study, Olsen et al. (²⁴) found that treatment with the ARB losartan was associated with less peripheral vascular hypertrophy/rarefaction and higher insulin sensitivity than that with atenolol, supporting the hypothesis that microvascular dysfunction in hypertension may induce insulin resistance. In the present study, the suppressive effect of the ARB candesartan against new-onset diabetes tended to strengthen as PP_f increased. These results suggest that ARBs decrease the risk of new-onset diabetes partly via the improvement of microcirculation.

Although the prevalence of diabetes increases with age (²⁵), it remains unclear whether age is a risk factor for new-onset diabetes (^{6, B7}–⁸). In the present study, age at baseline was not an independent predictor of new-onset diabetes. We assumed that high-risk elderly hypertensive patients who did not have diabetes at baseline were survivors who had avoided the development of diabetes and that their underlying risk of new-onset diabetes and ability to metabolize glucose may thus have differed from those of younger subjects. We also observed a strong association between pulse pressure and new-onset diabetes in patients aged <65 years, possibly owing to the same mechanism.

Several limitations of this study warrant mention. First, it was conducted as a post hoc analysis. Second, although we found an interesting association between pulse pressure and the risk of new-onset diabetes, the CASE-J trial was not designed to prospectively evaluate this association, and we were consequently unable to elucidate causality, because we did not directly measure parameters of arterial stiffness or collect the data to clarify the underlying mechanism. Third, we were unable to include baseline data regarding glucose metabolism into the multiple Cox regression analysis or information about a family history of diabetes, physical activity, or diet, which are well-known and important risk factors for new-onset diabetes. Fourth, new-onset diabetes was prespecified as the end point just before the completion of the CASE-J trial. Accordingly, there was a possibility of nonreporting bias, because the definition of new-onset diabetes was not in the original protocol and determination of whether new-onset diabetes had occurred depended on the participating investigators' reports. Thus, we may have underestimated the overall incidence of new-onset diabetes. Nevertheless, the present study is the first to examine the association of pulse pressure with new-onset diabetes in hypertensive patients and may provide useful information in understanding the underlying mechanism between hypertension and new-onset diabetes. Finally, because the study population consisted of Japanese patients with high-risk hypertension, the generalizability of our findings to other ethnic groups or general populations may be limited.

In summary, we found that pulse pressure is an independent predictor of new-onset diabetes in high-risk Japanese hypertensive patients. The development of type 2 diabetes may involve increased arterial stiffness, suggesting the importance of the “microvascular dysfunction” theory in the underlying pathophysiological mechanism between hypertension and new-onset diabetes. To our knowledge, this study is the first to report the relation between pulse pressure and new-onset diabetes in hypertensive patients. Further studies are required to elucidate the significance of pulse pressure in new-onset diabetes in hypertensive patients.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The CASE-J trial was funded by the EBM Research Center, Kyoto University Graduate School of Medicine, with an unrestricted grant from Takeda Pharmaceutical Co., and supported by the Japanese Society of Hypertension.

No potential conflicts of interest relevant to this article were reported.

We thank all collaborating investigators in the CASE-J trial and colleagues at the EBM Research Center of Kyoto University for their contributions to the present study.