The renin-angiotensin system (RAS) is activated in all insulin resistant states, including type II diabetes mellitus and metabolic syndrome.1 RAS is also activated in arterial hypertension or congestive heart failure (CHF), which are associated with insulin resistant states. Angiotensin II has been shown to increase hepatic glucose production, decrease insulin sensitivity, and contribute to insulin resistance.2 Nevertheless, other components, such as aldosterone and renin, are also involved in insulin resistance.3 Meta-analysis of 10 randomized controlled trials in 75950 patients with hypertension or CHF showed a 22% risk reduction of new onset diabetes mellitus (NODM) with angiotensin converting enzyme inhibitor (ACEI)/angiotensin II receptor blockers (ARB) therapy after a mean follow up of 4.5 years.2 The mechanisms underlying this protective effect appear to be complex and may involve improvements in both insulin sensitivity and insulin secretion.2 However, there were limited data to compare the protective effect of ACEI versus ARB on development of NODM, particularly in an Asians populations. Therefore, the aim of this study was to compare the protective effect of ACEIs versus ARBs on NODM in an Asian population.

In this study, all of the patients were prescribed ARB or ACEI due to hypertension. Among the patients, 59.9% patients (1688/2817) had a history of hypertension and 40.1% patients (1129/2817) were prescribed ARB or ACEI for the first time. Mean follow-up duration was 1839±1019 days in all groups before baseline adjustment and 1864±1034 days in PSM group. After PSM, a total of 1024 patients (ARB group=512 and control group=512) were enrolled for this analysis. Before baseline adjustment, clinical characteristics showed that male gender, history of cardiovascular disease, including MI and prior PTCA, cerebrovascular disease (CVD), history of smoking, and current smoking were higher in the ACEI group, compared with the ARB group. However, age, BMI, previous medical history of hypertension, hyperlipidemia, congestive heart failure, atrial fibrillation, and mean duration of RAS inhibitors were similar between the two groups (Table 1). Before baseline adjustment, baseline laboratory findings showed that the levels of fasting glucose, HbA1c, lipid levels, creatinine levels, and high sensitive C-reactive protein (hs CRP) were higher in the ARB group than the ACEI group. Before baseline adjustment, previous medical treatment showed that the previous use of BB, nitrate, and statins were higher in the ACEI groups, compared with the ARB groups. However, after PSM, baseline clinical characteristics, laboratory findings, previous medical treatment were well balanced between the two groups. Before baseline adjustment, the cumulative incidence of NODM for up to the three years was higher in the ARB group than the ACEI group (Table 2). Further, clinical events up to the three years, including total death, myocardial infarction, and MACCE, were higher in the ACEI group than the ARB groups (Table 2). After PSM, the cumulative incidence of NODM was also higher in the ARB group than the ACEI group. However, clinical events up to the three years were similar between the two groups (Table 2). Multivariate analysis was adjusted for gender (male), age, body mass index (≥30 kg/m²), hypertension, cardiovascular disease, coronary spasm, hyperlipidemia, current smoking, ARBs, ACEIs, calcium channel blockers, beta blockers, diuretics, nitrate, and statins. In multivariate analysis, previous history of coronary artery spams, and the use of ARB vs. ACEI were independent predictors of the incidence of NODM (Table 3).

Kaplan-Meier curves for the cumulative probabilities of NODM are presented in Fig. 1. Before PSM, the cumulative incidence of NODM was significantly higher in the ARB group than the ACEI group (p=0.019). After PSM, the cumulative incidence of NODM remained significantly higher in the ARB group than the ACEI group (p=0.012). Kaplan-Meier curves for cumulative incidence for MACCE are presented in Fig. 2. Before PSM, the cumulative incidence for MACCE was significantly higher in the ACEI group than the ARB group (p=0.014). However, after PSM, the cumulative incidences for MACCE were similar between the two groups (p=0.682). Cox proportional hazards regression models showed that after PSM, the use of ACEI had a 46% risk reduction of NODM, compared with the use of ARB (hazard ratio 0.54, 95% confidence interval 0.29-0.99, p-value 0.049), and the use of ACEI had a 63% risk elevation for MACCE, compared with the use of ARB, although there was no statistically significant difference between the two groups (hazard ratio 1.63, 95% confidence interval 0.83-3.21, p-value 0.154).

Recent studies from Western populations suggest a possible reduction in NODM with using RAS inhibitors. However, whether these findings could be extended to Asian patients remains unclear. Furthermore, data are needed to ascertain whether there are effect differences between different types of RAS inhibitors. The present study addressed this interesting issue using data from a large-scale single center registry. The authors constructed two similar groups of patients using propensity score matching methods, which made possible comparisons of patients with ACEI versus with ARB.

Insulin resistance is a well-known risk factor for type 2 diabetes, cardiovascular disease, and metabolic syndrome. RAS contributes to the underlying pathophysiology of insulin resistance. Previous studies showed that blockade of RAS prevents insulin resistance and type 2 diabetes mellitus.56 RAS blockade is known to improve blood circulation and cellular ionic balance, including potassium and magnesium, of skeletal muscle and pancreatic cells. As a result, RAS blockade improves peripheral insulin action, insulin secretion of pancreatic cell and prevent diabetes by promoting the recruitment and differentiation of adipocytes via A1 receptors.7 However, there are different mechanisms for preventing insulin resistance between ACEIs and ARBs. ACEI works not only by inhibiting the conversion of angiotensin I to angiotensin II, but also by inhibiting the degradation of bradykinin. Therefore, ACEI allow the beneficial effects of nitric oxide and prostacycline, such as lowering blood pressure, and improving endothelial function. On the other hand, ARBs offer complete angiotensin II inhibition by interacting selectively with the receptor site, and thus, may result in accumulation of angiotensin II, which is the predominant renin angiotensin aldosteron system component contributing to insulin resistance.6 Thus, ARB migh exert more stimuli for the incidence of NODM than ACEI, although the mechanisms should be investigated from different studies. Actually, the incidence of MACE was similar between the two groups after baseline adjustment, suggesting the possibility for two different mechanisms for ACEI and ARB did not result in clinical differences. In this study, the use of ACE reduced the incidence of NODM, but did not reduce the incidence of MACCE, compared to ARB. Therefore, the different mechanisms for preventing insulin resistance may be associated with different results of NODM. However, to get final results, a large scale multicenter study si needed.

In this study, clinical outcomes, including death, MI, and cerebro-cardiovascular events, up to 3 years were similar between teh two groups, suggesting similar protective effects for both drugs in preventing major cardiovascular hard endpoints. However, the cumulative incidence of NODM up to 3 years was higher in the ARB group than the ACEI group, and in Kaplan-Meyer curves, the incidence of NODM was higher in the ARB group than the ACEI group. Therefore, we suspect that ACEI may be more effective in preventing NODM than ARB, with a similar protective effect for cardiovascular events with ARB.

In this study, subgroup analysis of the ACEI group showed that the incidence of NODM seems to be numerically lower in the perindopril group, compared with the ramipril group and other ACEI groups (Table 2). Perindopril is a long acting, once-daily lipophilic ACEI with high tissue ACE affinity, which is associated with lowering angiotensin II and potentiating bradykinin, and may protect more efficiently against NODM than other usual ACEIs.7

A previous study in Sweden reported that the risk of NODM was lower in the candesartan group, compared with the enalapril group (hazard ratio 0.81, 95% confidence interval 0.69-0.96, p-value 0.01).5 Our study results showed that the incidence of NODM was lower in the ACEI group than ARB group. When we consider our subgroup analysis results, the incidence of NODM by candesartan was relatively lower (4.6%) than other ARBs, and enalapril is an older ACEI than perindopril. Thus it may be difficult to see the differences between candesartan and enalapril with regard to the incidence of NODM.

In our study, subgroup analysis of ARB group showed that the incidence of NODM seems to be lower with telmisartan (2.8%), losartan (3.7%), and candesartan (4.6%), compared with valsartan (7.2%), irbesartan (7.4%), and eprosartan (8.4%) after adjustment (Table 2). Potent ARBs, such as telmisartan and candesartan, offer long lasting inhibition of angiotensin 1 receptor, which is associated with sustained blood pressure reduction and more efficient protection against NODM than other usual ARBs.8

In the JUPITER study, pre-diabetic disease was the most important risk factor for NODM in patients receiving longterm statin treatment.9 Therefore, in this study, pre-diabetic disease, such as IGT and IFG, was not co-analyzed with the other risk factors in multivariable analysis regarding the independent predictors of NODM, because pre-diabetic disease is strong bias of results. In this study, hyperlipidemia, as well as the use of statins and beta-blockers, were not independent risk factors for NODM, because the patients in this study had less cardiovascular risk factors, metabolic syndrome components, and less diabetogenic as compared with previous studies to get more clear messages from the analysis.

In this study, there were several limitations. First, we analyzed patients taking ACEI or ARB for more than three months continuously. However, there were no data about the treatment gaps/stops and the compliance during the 3-years follow up in the present study. However, we could easily identify drug intolerance, such as dry cough due to ACEI after the 3 months prescription, and in general, once a patient is comfortable with either ACEI or ARB, most physicians should have maintained their use for more a prolonged time period. We excluded crossover cases within short time period due to drug intolerance to exclude bias. Second, we could not include more detailed risk factors of atherosclerosis, such as family history, abdominal circumference, and socio-economic status. Although this can be a limitation, the rest of other factors will indirectly reflect on the possible missing variables.

In conclusion, RAS inhibitors are known to be effective in preventing NODM. However, there may be different mechanisms of RAS inhibition between ACEI and ARB. In this study, after the PSM analysis, the cumulative incidence of NODM up to 3 years was lower in the ACEI group than the AEB group. Similarly, in Kaplan-Meyer curves, the incidence of NODM was lower in the ACEI group than the ARB group. Therefore, we assumed that ACEI might be more effective in preventing NODM than ARB, with similar protective effects for major cardiovascular events. Nevertheless, larger clinical trial would be needed to identify the difference between ACEI and ARB in preventing NODM and clinical events.