心血管事件阻礙巴多索隆用于糖尿病腎病治療

    CV events scuttle bardoxolone for diabetic kidney disease

    在美國(guó)腎病學(xué)會(huì)（ASN）主辦的腎病周年會(huì)上報(bào)告的一項(xiàng)Ⅲ期臨床試驗(yàn)顯示，甲基巴多索?。╞ardoxolone methyl）可降低2型糖尿病伴4期慢性腎病患者終末期腎?。‥SRD）風(fēng)險(xiǎn)，但也同時(shí)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發(fā)生率，因此導(dǎo)致這項(xiàng)研究被提前終止。

    該試驗(yàn)結(jié)果同時(shí)在線發(fā)表在11月9日的《新英格蘭醫(yī)學(xué)雜志》上（doi:10.1056/NEJMoa1306033）。

    甲基巴多索隆被認(rèn)為是一種最有效的抗氧化基因轉(zhuǎn)錄因子活化劑。早期研究顯示，它可提高糖尿病相關(guān)腎病患者估算的腎小球?yàn)V過(guò)率（eGFR），但同時(shí)也增加蛋白尿發(fā)生率和導(dǎo)致意外體重下降。

    為評(píng)估甲基巴多索隆長(zhǎng)期治療能否將eGFR獲益轉(zhuǎn)化為減緩ESRD進(jìn)展，荷蘭格羅寧根大學(xué)Dick de Zeeuw醫(yī)生及其同事開(kāi)展了這項(xiàng)雙盲BEACON試驗(yàn)（甲基巴多索隆用于2型糖尿病伴慢性腎病患者評(píng)價(jià)：腎臟事件發(fā)生率）。該試驗(yàn)納入了來(lái)自美國(guó)、歐洲、澳大利亞、加拿大、以色列和墨西哥的患者，因而包括了不同年齡、種族/民族和居住地的患者。心血管疾病以及糖尿病視網(wǎng)膜病變和神經(jīng)病變是常見(jiàn)共病。

    2,185例受試者為2型糖尿病伴中至重度慢性腎病患者，基線eGFR為15——30 mL/min/1.73 m2 體表面積。他們被隨機(jī)分組，分別接受每日1次甲基巴多索隆20mg（1,088例）或相應(yīng)的安慰劑（1,097例）治療，并根據(jù)醫(yī)囑接受傳統(tǒng)基礎(chǔ)治療，包括腎素-血管緊張素-醛固酮系統(tǒng)抑制劑、胰島素或其他降糖藥物以及適當(dāng)?shù)男难芩幬?。甲基巴多索隆中位暴露時(shí)間為7個(gè)月，安慰劑為8個(gè)月，中位隨訪時(shí)間均為9個(gè)月。

    結(jié)果顯示，與安慰劑相比，甲基巴多索隆可顯著改善eGFR,且治療組患者較少發(fā)展為ESRD.但因治療組患者較多發(fā)生CV事件，BEACON試驗(yàn)被提前終止。試驗(yàn)時(shí)間“縮短”限制了該試驗(yàn)判定甲基巴多索隆真實(shí)作用的統(tǒng)計(jì)功效，僅為預(yù)計(jì)的40%.

    主要復(fù)合終點(diǎn)指標(biāo)為進(jìn)展為ESRD或心血管死亡，兩組均為6%.但治療組CV死亡病例（27例）顯著高于安慰劑組（19例），風(fēng)險(xiǎn)比（HR）為1.44.特別是治療組中有96例出現(xiàn)心衰（HF）事件，而安慰劑組僅為55例。此外，治療組因心衰事件需要住院治療或?qū)е滤劳龅膰?yán)重患者比例也顯著高于安慰劑組。

    同樣，治療組非致命性心梗、非致命性卒中、HF住院治療或CV死亡復(fù)合結(jié)局患者也顯著高于安慰劑組。雖未達(dá)到統(tǒng)計(jì)學(xué)顯著水平，但治療組全因死亡病例（44例）也高于安慰劑組（31例） （HR,1.47;P =0.10）。

    與安慰劑相比，甲基巴多索隆還使患者血壓和心律升高， B型鈉尿肽水平提高，蛋白尿發(fā)生率增加，并導(dǎo)致較多意外體重下降。研究者未能確定身體脂肪、細(xì)胞 （骨骼?。?內(nèi)液或細(xì)胞（間質(zhì)）外液是否減少。血清白蛋白和血紅蛋白水平同時(shí)下降，表明體液潴留導(dǎo)致了血液稀釋。

    研究者推測(cè)，血壓和心律升高可能構(gòu)成了導(dǎo)致風(fēng)險(xiǎn)人群出現(xiàn)HF的強(qiáng)大復(fù)合因素，而B(niǎo)型鈉尿肽水平提高與左心室壁應(yīng)力增加相一致。研究者試圖確定與甲基巴多索隆導(dǎo)致HF相關(guān)的患者特征，但未能如愿。

    BEACON試驗(yàn)由Reata制藥公司資助。de Zeeuw醫(yī)生報(bào)告與AbbVie、安斯泰來(lái)、Chemocentryx、強(qiáng)生和Reata存在利益關(guān)系，其同事報(bào)告與多家業(yè)內(nèi)公司存在利益關(guān)系。

    隨刊述評(píng)：當(dāng)心糖尿病腎病患者蛋白尿

    華盛頓大學(xué)腎病研究所和腎病科的Jonathan Himmelfarb 醫(yī)生和Katherine R.Tuttle醫(yī)生稱，BEACON研究顯示，與甲基巴多索隆相關(guān)的不良事件包括過(guò)多的HF和心血管事件，以及高血壓、高心律、蛋白尿、GI癥狀和肌肉相關(guān)癥狀發(fā)生率增加。

    他們指出，作者推測(cè)體液潴留、后負(fù)荷增加和高心律促使心衰，但心衰也可能是甲基巴多索隆對(duì)心臟的直接毒性作用所致。

    他們強(qiáng)調(diào)，無(wú)論如何，對(duì)于任何增加蛋白尿而非減少蛋白尿的糖尿病腎病治療藥物都應(yīng)特別小心（N. Engl. J. Med. 2013 Nov. 9 [doi:10.1056/NEJMe1313104]）。

    Himmelfarb醫(yī)生報(bào)告與雅培實(shí)驗(yàn)室存在利益關(guān)系；Tuttle醫(yī)生還就職于斯波坎兒童醫(yī)院和普羅維登斯圣心醫(yī)學(xué)中心，她報(bào)告與禮來(lái)公司存在關(guān)系。

    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 transc**tion 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.

    View on the News

    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]）。