添加双水杨酸可改善控制不良的2型糖尿病

《内科学年鉴》7月1日在线发表的一份研究报告称，对于控制不良的2型糖尿病患者，水杨酸盐前体药物双水杨酸(salsalate)可能是一种有效的添加治疗。

美国哈佛医学院的Allison B. Goldfine博士及其同事是在概念验证研究之后开展这项临床试验的。概念验证研究表明，双水杨酸能降低血糖、甘油三酯、游离脂肪酸以及C反应蛋白的浓度；提高葡萄糖利用率；增加循环胰岛素和脂联素水平。开展临床试验是为了评估双水杨酸降糖效果的强度和持久性以及药物的耐受性。

这项1年随机对照试验总共纳入了286例已经开始使用1~3种抗糖尿病药物的患者。受试者来自全美21个试验基地，均为年龄≤75岁的成年人，HbA_1c水平介于7.0%~9.5%，并且已经开始接受生活方式调整、二甲双胍、胰岛素、胰岛素促分泌剂和/或二肽基肽酶-4抑制剂单药或联合治疗。受试者被随机分组，在其现有治疗方案上加用双水杨酸每日3次(前2周每日3 g，之后每日3.5 g)或与之相匹配的安慰剂，总共治疗48周。

试验期间，如有必要患者可继续使用稳定剂量的降脂药和降压药。频繁随访患者以评估安全因素、治疗依从性和治疗应答情况。

主要疗效终点是第48周时HbA_1c水平的变化。结果显示，双水杨酸组的平均水平比对照组低0.37%，差异有统计学意义。而且，在每次随访评估时，包括仅治疗4周后的初始评估，两个治疗组在HbA_1c水平上的差异都具有统计学意义。

此外，试验结束时双水杨酸组的平均HbA_1c水平比基线时下降了0.33%，差异有统计学意义。相比之下，对照组的平均HbA_1c水平基本上没有发生变化，第48周时较之基线平均增加了0.04个百分点，差异无统计学意义。

研究者报告称，在基线HbA_1c水平最高的患者中，治疗效应最为显著。基线HbA_1c每增加1%，HbA_1c平均下降0.43%。

试验结束时，双水杨酸组达到HbA_1c水平下降≥0.5%的患者比例(41%)高于安慰剂对照组(23%)。与HbA_1c的变化相符，也只有双水杨酸组患者的空腹血糖水平获得了显著改善。

此外，双水杨酸组其他抗糖尿病药物减量或停药的发生率(62%)也显著高于安慰剂组(13%)。Goldfine博士及其同事报告称：“相反，安慰剂组伴随抗糖尿病药物加量或开始接受新治疗的患者比例(87%)高于双水杨酸组(38%)。”

双水杨酸的抗炎效应包括循环白细胞、中性粒细胞和淋巴细胞减少。在双水杨酸组中，来源于脂肪细胞的心脏保护蛋白脂联素的水平较之安慰剂组上升了27%；与心脏代谢疾病和肾功能不全加重相关的尿酸水平较之安慰剂组下降了18%。

双水杨酸还降低了甘油三酯水平。不过，该药同时也增加了总胆固醇和LDL胆固醇水平，HDL胆固醇水平无变化。双水杨酸还增加了尿白蛋白/肌酐比以及血清肌酐水平。此外，双水杨酸组患者的体重增加了1.3 kg。研究者称，这些轻微的不良反应“尚需进一步评估”。

双水杨酸没有导致任何严重不良事件。不过，当在磺脲类药物的基础上加用双水杨酸时，发生轻度低血糖的相对风险比安慰剂高6倍。此外，双水杨酸组报告轻度耳鸣的患者比例(11%) 高于安慰剂组(5%)，但所有患者的耳鸣最终都消失了。两组的消化道不良反应无明显差异，均无消化道出血的证据。两组患者的生活质量也相似。

研究者总结称，作为添加治疗，每日口服双水杨酸不仅降低了HbA_1c和空腹血糖水平，而且还改善了其他心脏代谢危险因素。其治疗效应的强度与目前采用的其他糖尿病添加治疗的报告结果相似。而且，双水杨酸耐受良好，没有发生严重不良事件，也没有消化道不良反应的证据。不过，研究者也指出：“在推荐双水杨酸广泛应用于2型糖尿病患者之前，还需要针对肾功能和胆固醇水平的变化开展进一步研究。”

该试验由美国国家糖尿病、消化病与肾病研究所资助。Caraco Pharmaceutical Laboratories提供了双水杨酸和安慰剂，但并没有参与试验。

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By: MARY ANN MOON, Cardiology News Digital Network

The salicylate prodrug salsalate may be an effective add-on therapy for poorly controlled type 2 diabetes, according to a report published online July 1 in Annals of Internal Medicine.

In a 1-year randomized, controlled trial involving 286 patients already taking one to three medications for diabetes, adding daily oral salsalate consistently reduced hemoglobin A1c and fasting glucose levels, as well as improving other cardiometabolic risk factors, said Dr. Allison B. Goldfine of Harvard Medical School, Boston, and her associates.

The magnitude of the treatment effect was similar to that reported for other add-on diabetes therapies currently in use.

The treatment was well tolerated, no serious adverse events occurred, and there was no evidence of gastrointestinal adverse effects. However, some changes in renal function and cholesterol levels "require continued evaluation before salsalate can be recommended for widespread use in type 2 diabetes," the investigators noted.

Dr. Goldfine and her colleagues performed the clinical trial after proof-of-principle studies showed that salsalate reduced blood glucose, triglycerides, free fatty acids, and C-reactive protein concentrations; improved glucose utilization; and increased circulating insulin and adiponectin levels. Their trial was intended to assess the magnitude and durability of the drug’s glycemic efficacy, as well as its tolerability, when taken for 1 year.

The study patients treated at 21 U.S. sites were adults who were aged 75 years or younger and who had HbA1c levels of 7.0%-9.5% and were already being managed with lifestyle modification, metformin, insulin, secretagogues, and/or dipeptidyl peptidase-4 inhibitors, alone or in combination. They were randomly assigned to add three daily doses of either salsalate (3 g daily for 2 weeks, then 3.5 g daily) or matching placebo to their drug regimen for 48 weeks.

Patients maintained stable doses of lipid-lowering and hypertension medications whenever possible for the course of the study. They were followed frequently to assess safety factors, treatment adherence, and treatment response.

The primary efficacy outcome was change in HbA1c level at 48 weeks. The salsalate group’s mean level was 0.37 percentage points lower than the control group’s, a significant difference. Moreover, the difference between the two study groups in HbA1c levels was significant at all of the frequent assessments, including the initial assessment after just 4 weeks of treatment.

In addition, the mean HbA1c level was 0.33 percentage points lower in the salsalate group at the end of the study than it had been at baseline, a significant difference. In contrast, the mean HbA1c level was essentially unchanged over time in the control group, with a mean, nonsignificant increase of 0.04 percentage points at week 48.

The magnitude of the treatment benefit was greatest among patients who had the highest HbA1c levels at baseline. For every 1% increase in baseline HbA1c, the mean reduction in HbA1c was 0.43 percentage points, the investigators said.

At the conclusion of the study, more patients receiving salsalate (41%) had achieved 0.5 percentage points or greater decreases in HbA1c levels than those receiving placebo (23%).

Consistent with these changes in HbA1c, fasting glucose levels also showed significant improvement only in the patients receiving salsalate.

Reductions in and discontinuation of other diabetes medications also were significantly more frequent with salsalate (62%) than with placebo (13%). "Conversely, concomitant diabetes medications were increased and new therapies instituted more frequently for patients receiving placebo (87%) than those receiving salsalate (38%)," Dr. Goldfine and her associates said.

Among the active drug’s anti-inflammatory effects were decreases in circulating leukocytes, neutrophils, and lymphocytes.

Levels of adiponectin, a cardioprotective protein derived from adipocytes, rose by 27% in the salsalate group, compared with the placebo group. Levels of uric acid, which is associated with cardiometabolic disorders and the progression of renal insufficiency, dropped by 18% in the salsalate group, compared with the placebo group.

Salsalate also reduced triglyceride levels. However, the drug increased total and LDL cholesterol levels without altering HDL cholesterol levels. It also increased the urinary albumin-creatinine ratio and increased serum creatinine levels. And it was associated with a 1.3-kg increase in weight.

These modest adverse effects "warrant further assessment," the investigators said.

No serious adverse events were attributed to salsalate. However, the relative risk for mild hypoglycemia was six times greater when salsalate was added to sulfonylureas than when placebo was.

Mild tinnitus was reported by more patients receiving salsalate (11%) than placebo (5%), but it resolved in all patients.

Gastrointestinal adverse effects did not differ between the two study groups, and there was no evidence of GI bleeding. Quality of life also was similar between patients taking salsalate and those taking placebo.

The National Institute of Diabetes and Digestive and Kidney Diseases funded the study. Caraco Pharmaceutical Laboratories provided the salsalate and placebo, but it had no other role in the study.