Lampeter E F, Klinghammer A, Scherbaum W A, Heinze E, Haastert B, Giani G, Kolb H
Diabetes Research Institute at the University of Düsseldorf, Germany.
Diabetes. 1998 Jun;47(6):980-4. doi: 10.2337/diabetes.47.6.980.
On the basis of the positive outcome of animal experiments, several large placebo-controlled trials are underway and aiming for the first time at the prevention of an immune-mediated disease, type 1 diabetes. The first of these trials, The Deutsche Nicotinamide Intervention Study (DENIS), evaluated the clinical efficacy of high doses of nicotinamide in children at high risk for IDDM. Nicotinamide has been shown to protect beta-cells from inflammatory insults and to improve residual beta-cell function in patients after onset of IDDM. Individuals at high risk for developing IDDM within 3 years were identified by screening the siblings (age 3-12 years) of patients with IDDM for the presence of high titer (> or =20 Juvenile Diabetes Foundation [JDF] U) islet cell antibodies. Probands (n = 55) were randomized into placebo and nicotinamide (slow release, 1.2 g x m(-2) x day(-1)) receiving groups and followed prospectively in a controlled clinical trial using a sequential design. Rates of diabetes onset were similar in both groups throughout the observation period (maximum 3.8 years, median 2.1 years). This sequential design provides a 10% probability of a type II error against a reduction of the cumulative diabetes incidence at 3 years from 30 to 6% by nicotinamide. The trial was terminated when the second sequential interim analysis after the eleventh case of diabetes showed that the trial had failed to detect a reduction of the cumulative diabetes incidence at 3 years from 30 to 6% (P = 0.97). The group receiving nicotinamide exhibited decreased first-phase insulin secretion in response to intravenous glucose (P = 0.03). No other side effects were observed. We conclude that in this subgroup of diabetes-prone individuals at very high risk and with an assumed rapid disease progression, nicotinamide treatment did not cause a major decrease or delay of diabetes development. However, the data do not exclude the possibility of a less strong, but potentially meaningful, risk reduction in this cohort, or a major clinical effect of nicotinamide in individuals with less risk of progression to IDDM than studied here.
基于动物实验的阳性结果，目前正在进行几项大型安慰剂对照试验，首次旨在预防一种免疫介导的疾病——1型糖尿病。这些试验中的第一个，即德国烟酰胺干预研究（DENIS），评估了高剂量烟酰胺对患IDDM高风险儿童的临床疗效。烟酰胺已被证明可保护β细胞免受炎症损伤，并改善IDDM发病后患者的残余β细胞功能。通过筛查IDDM患者的兄弟姐妹（3至12岁）是否存在高滴度（≥20青少年糖尿病基金会[JDF]单位）胰岛细胞抗体，确定3年内患IDDM高风险的个体。先证者（n = 55）被随机分为接受安慰剂和烟酰胺（缓释，1.2 g×m⁻²×天⁻¹）的组，并在一项采用序贯设计的对照临床试验中进行前瞻性随访。在整个观察期（最长3.8年，中位数2.1年）内，两组的糖尿病发病几率相似。这种序贯设计针对烟酰胺使3年累积糖尿病发病率从30%降至6%的情况，存在10%的II类错误概率。在第11例糖尿病病例后的第二次序贯中期分析表明，该试验未能检测到3年累积糖尿病发病率从30%降至6%（P = 0.97）时，试验终止。接受烟酰胺的组对静脉注射葡萄糖的第一相胰岛素分泌减少（P = 0.03）。未观察到其他副作用。我们得出结论，在这个极易患糖尿病且疾病进展迅速的亚组中，烟酰胺治疗并未导致糖尿病发展的显著降低或延迟。然而，这些数据并不排除在该队列中存在强度较小但可能有意义的风险降低的可能性，或者烟酰胺对进展为IDDM风险低于本研究对象的个体有重大临床效果的可能性。
