Safety and tolerability of diazoxide in Japanese patients with hyperinsulinemic hypoglycemia

Diazoxide is a non-diuretic benzothiadiazine derivative, one of a group of substances introduced into clinical practice in the 1950s for the treatment of hypertension. Fajans reported the use of diazoxide for the treatment of insulinoma in 1979. Although patients with hyperinsulinemic hypoglycemia worldwide have been treated with diazoxide for more than 30 years, there are no recent reports about the adverse effects of this drug in Asian patients, including Japanese patients. Herein, we report the results of our retrospective clinical record review of 6 Japanese patients (3 females and 3 males, ranging in age from 58 to 91 years) with hyperinsulinemic hypoglycemia and inoperable insulinoma treated with diazoxide. Diazoxide improved control of hypoglycemic symptoms and maintained normoglycemia in 5 of the 6 patients, and was ineffective in one patient. Surprisingly, although all 6 patients received diazoxide according to the treatment strategy recommended in Western patients, 5 of the 6 patients developed edema and two developed congestive heart failure. Thus, when starting treatment with diazoxide in Japanese patients, the symptoms and signs of fluid retention should be evaluated carefully. Also, appropriate protocols for treatment with diazoxide should be evaluated by means of clinical trials in Japanese patients with hyperinsulinemic hypoglycemia

Safety and tolerability of diazoxide in Japanese patients with hyperinsulinemic hypoglycemia

Diazoxide is a non-diuretic benzothiadiazine derivative, one of a group of substances introduced into clinical practice in the 1950s for the treatment of hypertension. Fajans reported the use of diazoxide for the treatment of insulinoma in 1979. Although patients with hyperinsulinemic hypoglycemia worldwide have been treated with diazoxide for more than 30 years, there are no recent reports about the adverse effects of this drug in Asian patients, including Japanese patients. Herein, we report the results of our retrospective clinical record review of 6 Japanese patients (3 females and 3 males, ranging in age from 58 to 91 years) with hyperinsulinemic hypoglycemia and inoperable insulinoma treated with diazoxide. Diazoxide improved control of hypoglycemic symptoms and maintained normoglycemia in 5 of the 6 patients, and was ineffective in one patient. Surprisingly, although all 6 patients received diazoxide according to the treatment strategy recommended in Western patients, 5 of the 6 patients developed edema and two developed congestive heart failure. Thus, when starting treatment with diazoxide in Japanese patients, the symptoms and signs of fluid retention should be evaluated carefully. Also, appropriate protocols for treatment with diazoxide should be evaluated by means of clinical trials in Japanese patients with hyperinsulinemic hypoglycemia

Comparison of Azelnidipine and Trichlormethiazide in Japanese Type 2 Diabetic Patients with Hypertension: The COAT Randomized Controlled Trial

<div><p>Objective</p><p>This study compared the efficacy and safety of azelnidipine with that of trichlormethiazide in Japanese type 2 diabetic patients with hypertension.</p><p>Methods</p><p>In a multicenter, open-label trial, 240 patients with adequately controlled diabetes (HbA1c ≤ 7.0%) under lifestyle modification and/or administration of hypoglycemic agents and inadequately controlled hypertension (systolic blood pressure [sBP] ≥ 130 mmHg or diastolic blood pressure [dBP] ≥ 80 mmHg) who were being treated with olmesartan were enrolled. Participants were randomly assigned to an azelnidipine group or a trichlormethiazide group and were followed up for 48 weeks. Main outcome measure was the difference in the change in HbA1c levels from the baseline values at 48 weeks between these two groups.</p><p>Results</p><p>Of the 240 subjects that were enrolled, 209 subjects (azelnidipine group: 103 patients, trichlormethiazide group: 106 patients) completed this trial. At 48 weeks, the following changes were observed in the azelnidipine and trichlormethiazide groups, respectively: HbA1c levels, 0.19 ± 0.52% and 0.19 ± 0.54%; sBP/dBP, -10.7 ± 9.6/-6.6 ± 6.6 mmHg and -7.1 ± 7.7/-3.3 ± 6.1 mmHg (P < 0.001 for both sBP and dBP). In both groups, dizziness (12 patients [11.7%] and 16 patients [15.1%]) and edema (16 patients [15.5%] and 7 patients [6.6%], P = 0.047) were observed during the 48-week follow-up period.</p><p>Conclusions</p><p>Azelnidipine was more effective for controlling blood pressure than trichlormethiazide in Japanese type 2 diabetes patients, whereas trichlormethiazide was more effective for reducing albuminuria than azelnidipine. Both of these agents, however, similarly exacerbated glycemic control in type 2 diabetic patients with hypertension.</p><p>Trial Registration</p><p>UMIN <a href="https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&recptno=R000007197&type=summary&language=E" target="_blank">000006081</a>.</p></div

Flow chart of study participants throughout the trial.

<p>Of the 250 patients who were enrolled, 209 patients (azelnidipine group: 103 patients, trichlormethiazide group: 106 patients) completed the trial. Seventeen patients in the azelnidipine group and fourteen patients in the trichlormethiazide group were excluded because they were lost-to-follow-up or because of missing data.</p

Changes in clinical parameters at 48 weeks relative to baseline values.

<p>The changes in the parameters between 0 and 48 weeks were described as the mean (95% confidence interval) and were analyzed using an unpaired <i>t</i>-test* or Mann-Whitney test†.</p><p>Changes in clinical parameters at 48 weeks relative to baseline values.</p

Baseline characteristics of the subjects.

<p>The parameters were described as the mean ± SD at baseline in each group.</p><p>Baseline characteristics of the subjects.</p

Time courses for clinical parameters in the azelnidipine group and the trichlormethiazide group.

<p>The parameters are described as “mean ± SD” at 0, 24, and 48 weeks. The differences in parameters at 24 and 48 weeks relative to the baseline values (0 weeks) were analyzed using a paired <i>t</i>-test (*<i>P</i> < 0.05, **<i>P</i> < 0.01) or a Wilcoxon signed rank test (†<i>P</i> < 0.05, ††<i>P</i> < 0.01).</p><p>Time courses for clinical parameters in the azelnidipine group and the trichlormethiazide group.</p

Changes in clinical parameters at 48 weeks relative to baseline values in per-protocol analyses.

<p>The changes in the parameters between 0 and 48 weeks were described as the mean (95% confidence interval) and were analyzed using an unpaired <i>t</i>-test* or Mann-Whitney test†.</p><p>Changes in clinical parameters at 48 weeks relative to baseline values in per-protocol analyses.</p