CKD病患使用Bardoxolone Methyl治療同時可減重


  【24drs.com】根據發表於第49屆歐洲腎臟協會歐洲透析與移植協會研討會的研究,使用Bardoxolone methyl控制發炎與保留腎功能的慢性腎臟病(CKD)及第2型糖尿病患,體重也顯著減輕,但是僅限身體指量指數(BMI)高者。
  
  體型較瘦、體重減輕較少或者無變化者,接受同樣的治療。
  
  Bardoxolone methyl是一種活化Nrf2的抗氧化發炎調節劑,Nrf2是細胞抗氧化劑與去毒性酵素的主要調節物,此成分被研發為抗發炎劑,保留CKD病患的腎臟功能。
  
  Nrf藉由抗氧化發炎調節的作用也和脂肪酸合成減少有關,獲得改善脂質調節與減少脂肪累積。
  
  根據西南大學醫院、內科、腎臟科、重症照護學科的Robert Toto醫師指出,在52週的第2b期BEAM臨床試驗中,bardoxolone methyl在第3b/4期CKD和第2型糖尿病患顯示出安全性和效果。使用bardoxolone methyl治療和eGFR [估計腎絲球過濾速率]增加顯著有關,也與體重安全地顯著降低有關。
  
  Toto醫師發表了BEAM試驗中,bardoxolone methyl在體重減輕方面的結果,該試驗包括了eGFR值20-45 mL/min/1.73m2的227名病患,這些病患隨機分成4組:bardoxolone methyl每日劑量25 mg (n= 57人)、75 mg (n= 57人)、150 mg (n= 56人)或安慰劑(n= 57人)。
  
  開始時,bardoxolone methyl組的平均BMI為35.6 ± 7.4 kg/m2、平均體重為101.4 ± 23.4kg;安慰劑組中,平均BMI為34.4 ± 8.0 kg/m2,而平均體重為95.2 ± 22.8 kg。
  
  治療52週之後,治療意向族群安全性分析顯示,接受bardoxolone methyl的病患體重減輕程度多於安慰劑組,25 mg組平均體重減輕7.7 kg,75 mg組平均體重減輕9.2 kg,150 mg組平均體重減輕10.1 kg,安慰劑組平均體重減輕2.4 kg。
  
  藉由bardoxolone methyl治療,體重最重的病患減輕最多體重,如果病患開始時的BMI較高,則體重明顯減輕較多。
  
  開始時BMI正常者(18.5-24.9 kg/m2),bardoxolone methyl組和安慰劑組的體重減輕程度相同。
  
  如果根據副作用類型分析治療52週時的體重平均變化時,體重減輕較多的bardoxolone methyl組比安慰劑組出現較多的噁心和腹瀉,但差異不顯著。Bardoxolone methyl組病患體重減輕時比較顯著出現的副作用是味覺改變(P< .01)。
  
  與安慰劑組相比,bardoxolone methyl組的病患體重減輕較多,但是厭食發生率沒有比較高(2% vs 0%)。
  
  根據Toto醫師表示,52週時的體重減輕和血清白蛋白變化無關(Pearson氏關聯係數;r= 0.13;P= .12)。
  
  Toto醫師發表的其中一張投影片,比較了體重隨時間變化時的eGFR改變情況;顯示eGFR在第12週時增加,之後維持穩定,體重持續減輕到第52週,因此使研究結論指出,eGFR增加和體重漸漸減輕無關。
  
  評估eGFR改變和體重改變的關聯時顯示,不論體重減輕大於或小於開始時體重之5%,eGFR同樣增加,支持eGFR改善是因為bardoxolone治療而非體重減輕之結論。
  
  Antwerp大學醫學名譽教授、Marc de Broe博士向Toto醫師提出評論:體重減輕10 kg也意味著體表面積改變,而我們是根據體表面積測量GFR,考量這點後,公式中的分母減少意味著GFR效應甚至大於投影片中所顯示的效果。
  
  至於體重減輕是否代表脂肪或蛋白質減少,Toto醫師表示,沒有看到蛋白質被異化的跡象,但並未進行正式的身體組成評估,不過,這項評估已經納入進行中的bardoxolone methyl第3期BEACON試驗。
  
  資料來源:http://www.24drs.com/professional/list/content.asp?x_idno=6837&x_classno=0&x_chkdelpoint=Y
  

Weight Loss Accompanies Bardoxolone Methyl Treatment of CKD Patients

By Jenny Powers
Medscape Medical News

May 29, 2012 (Paris, France) — Bardoxolone methyl used to control inflammation and preserve kidney function in patients with chronic kidney disease (CKD) and type 2 diabetes also stimulates significant weight loss, but only in patients with a high body mass index (BMI), according to research presented here at the 49th European Renal Association-European Dialysis and Transplant Association Congress.

Little or no weight loss was seen in leaner patients receiving the same treatment.

Bardoxolone methyl is an antioxidant inflammation modulator that activates Nrf2, the primary regulator of cellular antioxidant and detoxification enzymes. It was developed as an antiinflammatory agent to preserve kidney function in patients with CKD.

The induction of Nrf by an antioxidant inflammation modulator has also been associated with a decrease in fatty acid synthesis, leading to improved lipid regulation and a subsequent decrease in fat accumulation.

According to Robert Toto, MD, who practices internal medicine, nephrology, and critical care medicine at Southwestern University Hospital–St. Paul in Dallas, Texas, "the safety and efficacy of bardoxolone methyl in patients with stage 3b/4 CKD and type 2 diabetes were demonstrated in the 52-week phase 2b BEAM clinical trial. Treatment with bardoxolone methyl was significantly associated with an increase in eGFR [estimated glomerular filtration rate], but was also associated with a safety finding of significant weight loss."

Dr. Toto presented findings specific to the weight loss effects of bardoxolone methyl from the BEAM trial, which involved 227 patients with an eGFR of 20 to 45 mL/min per 1.73 m2. Patients were randomized into 1 of 4 groups: daily doses of bardoxolone methyl at 25 mg (n = 57), 75 mg (n = 57), or 150 mg (n = 56), or placebo (n = 57).

In the bardoxolone methyl groups at baseline, mean BMI was 35.6 ± 7.4 kg/m2 and mean weight was 101.4 ± 23.4 kg; in the placebo group, mean BMI was 34.4 ± 8.0 kg/m2 and mean weight was 95.2 ± 22.8 kg.

After 52 weeks of treatment, the safety analysis of the intent-to-treat population showed that patients receiving bardoxolone methyl lost more weight than those receiving placebo. Mean weight loss was 7.7 kg with 25 mg, 9.2 kg with 75 mg, and 10.1 kg with 150 mg, and 2.4 kg with placebo.

With bardoxolone methyl treatment, patients with the most weight to lose lost the most weight. Patients had more significant weight loss on the study drug if they had a higher baseline BMI.

Patients with a normal BMI at baseline (18.5 to 24.9 kg/m2) had the same degree of weight loss with bardoxolone methyl and with placebo.

When the mean change in weight at week 52 was analyzed by type of adverse event, a nonsignificant trend toward more weight loss in the bardoxolone methyl groups than in the placebo group was seen in patients reporting nausea and diarrhea. A significant change in weight was seen in patients in the bardoxolone methyl groups who reported altered taste (P < .01).

Patients with greater weight loss in the bardoxolone methyl groups, compared with the placebo group, did not have a higher incidence of anorexia (2% vs 0%).

According to Dr. Toto, weight loss at 52 weeks did not correlate with changes in serum albumin (Pearson's correlation coefficient, r = 0.13; P = .12).

Dr. Toto presented a slide comparing the change in eGFR with weight loss over time; it showed that eGFR had increased by week 12 and remain fairly stable thereafter, whereas weight loss continued steadily up to week 52, leading the researchers to conclude that the increase in eGFR was not dependent on a progressive loss of body weight.

An evaluation of the relation between change in eGFR and change in weight showed that the same increase in eGFR was achieved regardless of whether weight loss was more or less than 5% of baseline body weight, supporting the conclusion that eGFR improvement was due to bardoxolone treatment, not to weight loss.

Marc de Broe, MD, PhD, an emeritus professor of medicine at the University of Antwerp in Belgium, made the following comment to Dr. Toto: "A 10 kg weight loss also means the body surface area of these patients changed, and you normalized the GFR measurement by body surface area. Taking this into account, the decrease of the denominator in your equation means the GFR effect is even greater than the effect you showed in your slide."

Addressing whether the weight loss represents fat or protein loss, Dr. Toto said that they saw no signs that protein was being catabolized, but formal body composition assessments had not been done. However, this assessment is a component of the large phase 3 BEACON trial of bardoxolone methyl that is underway.

The study sponsors were Reata Pharmaceuticals and Abbott. Dr. Toto is a consultant for Reata Pharmaceutical. Dr. de Broe has disclosed no relevant financial relationships.

49th European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Congress: Abstract FO064. Presented May 25, 2012.

    
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