心血管事件阻碍巴多索隆用于糖尿病肾病治疗

在美国肾病学会(ASN)主办的肾病周年会上报告的一项Ⅲ期临床试验显示，甲基巴多索隆(bardoxolone methyl)可降低2型糖尿病伴4期慢性肾病患者终末期肾病(ESRD)风险，但也同时增加心血管疾病死亡、心衰事件、非致命性心梗以及非致命性卒中发生率，因此导致这项研究被提前终止。

该试验结果同时在线发表在11月9日的《新英格兰医学杂志》上(doi:10.1056/NEJMoa1306033)。

甲基巴多索隆被认为是一种最有效的抗氧化基因转录因子活化剂。早期研究显示，它可提高糖尿病相关肾病患者估算的肾小球滤过率(eGFR)，但同时也增加蛋白尿发生率和导致意外体重下降。

为评估甲基巴多索隆长期治疗能否将eGFR获益转化为减缓ESRD进展，荷兰格罗宁根大学Dick de Zeeuw医生及其同事开展了这项双盲BEACON试验(甲基巴多索隆用于2型糖尿病伴慢性肾病患者评价：肾脏事件发生率)。该试验纳入了来自美国、欧洲、澳大利亚、加拿大、以色列和墨西哥的患者，因而包括了不同年龄、种族/民族和居住地的患者。心血管疾病以及糖尿病视网膜病变和神经病变是常见共病。

2,185例受试者为2型糖尿病伴中至重度慢性肾病患者，基线eGFR为15~30 mL/min/1.73 m2 体表面积。他们被随机分组，分别接受每日1次甲基巴多索隆20mg(1,088例)或相应的安慰剂(1,097例)治疗，并根据医嘱接受传统基础治疗，包括肾素-血管紧张素-醛固酮系统抑制剂、胰岛素或其他降糖药物以及适当的心血管药物。甲基巴多索隆中位暴露时间为7个月，安慰剂为8个月，中位随访时间均为9个月。

结果显示，与安慰剂相比，甲基巴多索隆可显著改善eGFR，且治疗组患者较少发展为ESRD。但因治疗组患者较多发生CV事件，BEACON试验被提前终止。试验时间“缩短”限制了该试验判定甲基巴多索隆真实作用的统计功效，仅为预计的40%。

主要复合终点指标为进展为ESRD或心血管死亡，两组均为6%。但治疗组CV死亡病例(27例)显著高于安慰剂组(19例)，风险比(HR)为1.44。特别是治疗组中有96例出现心衰(HF)事件，而安慰剂组仅为55例。此外，治疗组因心衰事件需要住院治疗或导致死亡的严重患者比例也显著高于安慰剂组。

同样，治疗组非致命性心梗、非致命性卒中、HF住院治疗或CV死亡复合结局患者也显著高于安慰剂组。虽未达到统计学显著水平，但治疗组全因死亡病例(44例)也高于安慰剂组(31例) (HR，1.47；P =0.10)。

与安慰剂相比，甲基巴多索隆还使患者血压和心率升高， B型钠尿肽水平提高，蛋白尿发生率增加，并导致较多意外体重下降。研究者未能确定身体脂肪、细胞 (骨骼肌) 内液或细胞(间质)外液是否减少。血清白蛋白和血红蛋白水平同时下降，表明体液潴留导致了血液稀释。

研究者推测，血压和心率升高可能构成了导致风险人群出现HF的强大复合因素，而B型钠尿肽水平提高与左心室壁应力增加相一致。研究者试图确定与甲基巴多索隆导致HF相关的患者特征，但未能如愿。

BEACON试验由Reata制药公司资助。de Zeeuw医生报告与AbbVie、安斯泰来、Chemocentryx、强生和Reata存在利益关系，其同事报告与多家业内公司存在利益关系。

随刊述评：当心糖尿病肾病患者蛋白尿

华盛顿大学肾病研究所和肾病科的Jonathan Himmelfarb 医生和Katherine R.Tuttle医生称，BEACON研究显示，与甲基巴多索隆相关的不良事件包括过多的HF和心血管事件，以及高血压、高心率、蛋白尿、GI症状和肌肉相关症状发生率增加。

他们指出，作者推测体液潴留、后负荷增加和高心率促使心衰，但心衰也可能是甲基巴多索隆对心脏的直接毒性作用所致。

他们强调，无论如何，对于任何增加蛋白尿而非减少蛋白尿的糖尿病肾病治疗药物都应特别小心(N. Engl. J. Med. 2013 Nov. 9 [doi:10.1056/NEJMe1313104])。

Himmelfarb医生报告与雅培实验室存在利益关系；Tuttle医生还就职于斯波坎儿童医院和普罗维登斯圣心医学中心，她报告与礼来公司存在关系。

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By: MARY ANN MOON, Cardiology News Digital Network

Bardoxolone methyl may have reduced the risk of end-stage renal disease in patients with type 2 diabetes and stage 4 chronic kidney disease in a phase III clinical trial, but researchers stopped the study early after patients taking the drug had an increased rate of cardiovascular deaths, heart failure events, nonfatal myocardial infarction, and nonfatal stroke.

The BEACON trial had only an estimated 40% statistical power to determine bardoxolone methyl’s true effects, given its termination because of safety concerns, according to data reported at the annual Kidney Week meeting sponsored by the American Society of Nephrology.

The findings were simultaneously reported online Nov. 9 in the New England Journal of Medicine (doi:10.1056/NEJMoa1306033).

Bardoxolone methyl, the most potent known activator of a transcription factor that regulates antioxidant genes, was previously shown to raise the estimated glomerular filtration rate (eGFR) in patients with diabetes-related kidney disease. However, it also increased the incidence of albuminuria and induced unintended weight loss.

To determine whether longer-term treatment with bardoxolone methyl might translate that eGFR benefit into a slower progression to end-stage renal disease (ESRD), Dr. Dick de Zeeuw of the University of Groningen (the Netherlands) and his associates performed the double-blind BEACON trial (Bardoxolone Methyl Evaluation in Patients With Chronic Kidney Disease and Type 2 Diabetes Mellitus: The Occurrence of Renal Events).

BEACON was sponsored by Reata Pharmaceuticals and included patients from the United States, Europe, Australia, Canada, Israel, and Mexico, resulting in a diverse patient population with regard to age, race/ethnicity, and area of residence. Both diabetic retinopathy and neuropathy were common comorbidities, as was cardiovascular disease.

The 2,185 study participants had type 2 diabetes and moderate to severe chronic kidney diseases, with a baseline eGFR of 15 to less than 30 mL/min per 1.73 m2 of body surface area. They were randomly assigned to receive either once-daily bardoxolone methyl 20 mg (1,088 patients) or a matching placebo (1,097 patients), along with conventional background therapies given at the discretion of their treating physicians. Those included inhibitors of the renin-angiotensin-aldosterone system, insulin or other hypoglycemic agents, and appropriate cardiovascular medications.

The median duration of exposure was 7 months for bardoxolone methyl and 8 months for placebo, and the median follow-up for both was 9 months.

Bardoxolone significantly improved eGFR, compared with placebo, and fewer patients who took the drug progressed to ESRD. But BEACON was terminated early because of an excess of CV events among patients receiving bardoxolone methyl. That "truncated" study duration limited the trial’s statistical power.

The primary endpoint was a composite of progression to ESRD or cardiovascular death, and it occurred in 6% of both study groups. However, deaths from CV causes were significantly more frequent in the active treatment group (27 patients) than in the placebo group (19 patients), with a hazard ratio of 1.44, Dr. de Zeeuw reported.

In particular, 96 patients in the bardoxolone group had heart failure (HF) events, compared with only 55 patients in the placebo group. Moreover, significantly more of the HF events in the active treatment group were severe enough to require hospitalization or cause death.

Similarly, significantly more patients taking bardoxolone methyl had a composite outcome of nonfatal myocardial infarction, nonfatal stroke, HF hospitalization, or CV death. And the number of deaths from any cause was greater – though not significantly – with bardoxolone methyl (44 deaths) than with placebo (31 deaths) (HR, 1.47; P = .10).

Compared with placebo, bardoxolone methyl also raised blood pressure and heart rate, increased levels of B-type natriuretic peptide, raised the rate of albuminuria, and caused substantial unintended weight loss. The investigators were unable to determine whether there was a loss of body fat, intracellular (that is, skeletal muscle) water, or extracellular (interstitial) water. There was a concomitant fall in serum albumin and hemoglobin levels, which may reflect hemodilution caused by fluid retention, the investigators found.

The increases in blood pressure and heart rate "constitute a potentially potent combination of factors that are likely to precipitate HF in an at-risk population." and the increase in B-type natriuretic peptide "is consistent with an increase in left ventricular wall stress," Dr. de Zeeuw said.

The investigators attempted to identify patient characteristics that might be associated with the development of HF in the bardoxolone methyl recipients, but were unable to do so.

Reata Pharmaceuticals funded the BEACON trial. Dr. de Zeeuw reported ties to AbbVie, Astellas, Chemocentryx, Johnson & Johnson, and Reata, and his associates reported ties to numerous industry sources.

*This article was updated November 11, 2013.

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Beware albuminuria in diabetic kidney disease

The adverse events linked to bardoxolone methyl in this study included excess HF and cardiovascular events, as well as increased rates of high blood pressure, high heart rate, albuminuria, GI symptoms, and muscle-related symptoms, said Dr. Jonathan Himmelfarb and Dr. Katherine R. Tuttle.

"The authors speculate that fluid retention, increased afterload, and higher heart rate contributed to heart failure," but it also is possible that bardoxolone methyl may exert direct toxic effects on the heart, Dr. Himmelfarb and Dr. Tuttle said.

In any case, "caution should be exercised whenever any drug for diabetic kidney disease increases, rather than decreases, albuminuria," they noted.

Dr. Himmelfarb and Dr. Tuttle are at the Kidney Research Institute and the division of nephrology at the University of Washington, Seattle. Dr. Tuttle also is at Providence Sacred Heart Medical Center and Children’s Hospital, Spokane. Dr. Himmelfarb reported ties to Abbott Laboratories, and Dr. Tuttle reported ties to Eli Lilly. These remarks were taken from their editorial accompanying Dr. de Zeeuw’s report (N. Engl. J. Med. 2013 Nov. 9 [doi:10.1056/NEJMe1313104]).