To the Editor: Several large-scale clinical studies have demonstrated the efficacy of angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs), and calcium-channel blockers (CCBs) in reducing the incidence of new-onset diabetes mellitus in patients with hypertension.1–4 A recent meta-analysis reported greater reduction in risk of experiencing new-onset diabetes mellitus with these three classes of antihypertensive drugs in the order of ARB>ACEI>CCB.5

The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial was a large-scale clinical study comparing the preventive effects of candesartan (an ARB) and amlodipine (a CCB) against cardiovascular (CV) events in 4,728 high Japanese patients with hypertension at high risk of experiencing a CV event.6 The number of CV events was similarly lower with candesartan and amlodipine in patients under strict blood pressure control (<140/80 mmHg), but candesartan was significantly more effective in preventing new-onset diabetes mellitus (36% risk reduction, P=.03). In the subgroup of patients with a body mass index (BMI) of 25 kg/m2 and higher, the incidence of new-onset diabetes mellitus was 47% lower in the candesartan than the amlodipine treatment group (P=.03).7,8

A subanalysis of the CASE-J trial was performed to determine possible differences between candesartan and amlodipine in the incidence of new-onset diabetes mellitus when groups were stratified according to age. The present subanalysis involved 2,685 patients who were free from diabetes mellitus at the time of enrollment (1,471 men, mean age 63.7, mean BMI 24.8 kg/m2). In principle, diabetes mellitus is diagnosed on the basis of fasting plasma glucose levels and an oral glucose tolerance test. Because blood glucose data in the present series represented fasting and postprandial values, new-onset diabetes mellitus was defined as the initiation of antidiabetic pharmacotherapy.

During the mean follow-up period of 3.3 years, 97 patients (3.6%) were found to have new-onset diabetes mellitus. The incidence of new-onset diabetes mellitus in the subgroup younger than 65 was significantly lower in the candesartan arm than in the amlodipine arm (55% risk reduction; P=.02). In the subgroup aged 65 and older, the incidence was also lower with candesartan, but the difference was not statistically significant compared with amlodipine (20% risk reduction; P=.39). The incidence of new-onset diabetes mellitus was further stratified according to age in decades (<50, 50–59, 60–69, ≥70). The incidence was found to be lower with candesartan than amlodipine across all age categories and reached statistical significance in patients younger than 50 (P=.04, Figure 1).

Figure 1.

 Incidence of new-onset diabetes mellitus (DM) stratified according to age.

The results of the present subanalysis indicated that candesartan was significantly more effective than amlodipine in preventing new-onset diabetes mellitus in young and middle-aged patients with hypertension than it was in older patients. This finding can be explained as follows. The renin-angiotensin system (RAS) is thought to play a significant role in insulin resistance and in reducing insulin secretion; ARBs and ACEIs are considered to suppress new-onset diabetes mellitus by blocking the RAS. Elderly patients with hypertension generally present with low plasma renin levels, suggesting suppression of RAS activity.9 It has also been reported that RAS enzymes in adipose tissues are involved in glucose metabolism,10 and obesity is recognized as a significant predictor of new-onset diabetes mellitus. In the current analysis, older patients had significantly lower BMI values than young and middle-aged patients (mean BMI 24.7 kg/m2 <65 vs 23.7 kg/m2≥65) and included fewer obese patients. Thus, candesartan did not show significant differences from amlodipine with respect to a lower incidence of new-onset diabetes mellitus in elderly patients, who generally have lower RAS activity.

Although the morbidity of diabetes mellitus increases with aging, the contribution of aging to new-onset diabetes mellitus remains controversial. Differences in study design and in the statistical analysis set may influence the incidence of new-onset diabetes mellitus related to aging. Elderly patients with hypertension in our series who did not have diabetes mellitus at the time of enrollment in the CASE-J trial were considered to represent a population surviving the onset of diabetes mellitus. Therefore, older patients with hypertension but without diabetes mellitus may represent individuals with less susceptibility to new-onset diabetes mellitus and may differ from younger patients with hypertension with new-onset diabetes mellitus in terms of the presence of risk factors for new-onset diabetes mellitus and in glucose metabolism function. This may also be a reason why the older subgroup of patients was less sensitive to the preventive effects of candesartan against new-onset diabetes mellitus.

In conclusion, the ARB candesartan prevented new-onset diabetes mellitus significantly more effectively than the CCB amlodipine in the CASE-J trial in high-risk patients with hypertension, although there was a significant difference between ARB and CCB in the incidence of new-onset diabetes mellitus stratified according to age only for the younger subgroup (<65) and not for the older subgroup (≥65).


Conflict of Interest: TO, TS, and KN have received honoraria for lectures from Takeda Pharmaceutical Co Ltd. and Pfizer Japan Inc. AF has no conflict of interest.

Author Contributions: TO and AF: study concept and design, analysis and data interpretation, preparation of the manuscript. TS and KN: study concept and design, analysis.

Sponsor's Role: No sponsor.