根据DAPA-HF试验的结果，对于射血分数降低的心力衰竭（HFrEF）患者，无论是否伴有糖尿病，在标准治疗中加入SGLT2抑制剂达格列净可降低心力衰竭恶化、心血管死亡和全因死亡的风险。
在欧洲心脏病学会上公布的数据表明，达格列净（安达唐，阿斯利康）获益超出了其作为糖尿病药物的作用。
“最重要的发现是对无糖尿病患者的益处。苏格兰格拉斯哥大学心血管与医学科学研究所心脏病学教授John J.V. McMurray博士说：“这确实是一种治疗心力衰竭的方法，而不仅仅是治疗糖尿病的药物。”
DAPA-HF在20个国家招募了4744名患有HFrEF（左心室射血分数<40%）的成年人。基线资料中45%有2型糖尿病，55%没有2型糖尿病。入选者的N-末端B型利钠肽前体也有中度升高，估计肾小球滤过率≥30ml/min/1.73m2。除了标准治疗外，所有患者随机接受每日一次10mg达格列净或安慰剂治疗。达格列净目前已被FDA批准用于治疗2型糖尿病患者。
McMurray说，目标是纳入一个典型的HFrEF人群。
他在记者招待会上说：“我们认为达格列净是一种治疗心衰的药物，而不单单是糖尿病药物，我们想在所有人群中进行试验。”
无论有无糖尿病，患者均有改善
在18.2个月的中位随访中，与安慰剂组相比，达格列净组的心血管死亡或心衰恶化的主要结局减少了26%（16.3%对21.2%；HR=0.74；需要治疗的人数=21）。心衰恶化被定义为计划外心衰住院或需要静脉用药治疗的急症心衰。
当研究人员分别分析主要复合终点的组分时，达格列净也分别与每个组分显着改善相关，包括心衰恶化减少30%（HR=0.70；95%CI，P=0.00003），心血管死亡率减少18%（HR=0.82；95%CI，p=0.029）。
达格列净组的全因死亡发生率为11.6%，安慰剂组为13.9%，达格列净治疗组的全因死亡发生率降低了17%（HR=0.83；95%CI：0.71-0.97）。
研究人员在14个预先设定的亚组中发现了一致的益处。McMurray说，这个“非常重要”的亚组是根据是否有糖尿病进行比较的。基线有糖尿病的患者主要复合结局（HR=0.75；95%CI，0.63-0.9）和基线无糖尿病的患者主要复合结局（HR=0.73；95%CI，0.6-0.88）分别降低了25%和27%。
McMurray在记者招待会上说：“与伴糖尿病的患者相比，我们在不伴糖尿病的患者身上看到了相同的治疗效果。
另一个重要的亚组是接受或不接受血管紧张素脑啡呔受体抑制剂沙库巴曲/缬沙坦（entreso，诺华）治疗的患者。在基线时，只有11%的DAPA-HF患者接受了沙库巴曲/缬沙坦治疗。McMurray说，当DAPA-HF开始入组患者时，这种疗法刚刚开始应用。再次发现，在不同背景治疗的基础上，整体治疗效果是一致的。McMurray说，在基线接受沙库巴曲/缬沙坦治疗的患者中，达格列净的主要结局降低了25%（HR=0.75；95%CI，0.5-1.13），而未接受沙库巴曲/缬沙坦治疗的患者中，主要疗效降低了26%（HR=0.74；95%CI，0.65-0.86）。
达格列净的安全性与之前的药物试验一致。两组的不良事件包括容量衰竭、严重低血糖、下肢截肢、骨折和/或肾功能不全的发生率总体较低，且无显着差异。达格列净组严重不良事件（包括死亡）发生率较低（38例vs. 42例；p<0.01）。此外，导致停药的不良事件在两组中相似（达格列净组为4.7%，安慰剂组为4.9%，p=0.79）。
在其他结果中，达格列净治疗可显着改善患者症状。从基线到8个月，根据堪萨斯城心肌病问卷，与安慰剂组相比，更多接受达格列净治疗的患者出现心衰症状的临床显着改善（58% vs. 51%；OR=1.15；95%ci，1.03-1.23）。
McMurray说：“总的来说，我们发现达格列净具有我们期望心衰治疗的所有效果：减少心衰恶化事件、特别是心衰住院；减少心血管死亡；改善症状。”“绝对风险降低（使用达格列净）是相当大的，并且在各亚组之间一致。”
“心衰治疗的新时代”
DAPA-HF是一项对广泛的HF患者进行的平行、随机、双盲研究。麦克默里说，需要注意的是，除了随机治疗外，还进行了标准治疗，包括大量使用ACEI、ARB、沙库巴曲/缬沙坦、β受体阻滞剂和盐皮质激素受体拮抗剂。
“这是此类疾病患者的一个重要突破。我们认为这些发现为心衰患者的治疗提供了一种全新的治疗方法。“这是来第一个没有通过神经体液机制起作用的有益的心衰治疗。当添加到优秀的现有治疗，包括沙库巴曲/缬沙坦，达格列净是有益的。”
意大利布雷西亚大学（Universityof Brescia，Italy）心脏病学教授、医学博士Marco Metra在ESC大会上讨论结果时，将DAPA-HF的发现结合起来。
Metra说：“如果我们将DAPA-HF的主要和次要结果与过去十年的成功试验结果进行比较，我们可以看到所有的危险比都是可比的，即使不大于主要临床试验中的危险比。”
Metra说，关于达格列净的作用机制，以及这种作用是否可以转化为不同的心衰表型，如射血分数保留的心衰，还有待进一步研究。然而，这些答案将会到来，因为有将近20个正在进行的SGLT2抑制剂的试验，包括达格列净、恩格列净、卡格列净和Sotagliflozin。
“我们正面临一个新的心力衰竭治疗时代，”Metra说。
SGLT2抑制剂，包括达格列净，已被证明能降低2型糖尿病患者发生心衰的风险。DAPA-HF的独特之处在于，它是首个使用SGLT2抑制剂的心衰结局试验，研究达格列净是否也有助于治疗已有的心衰，甚至对没有糖尿病的患者。
自从达格列净在首次被FDA批准用于治疗成人2型糖尿病以来，一些研究已经证明SGLT2抑制剂在预防和治疗心衰方面的潜力。如前所述，DECLARE-TIMI58心血管预后试验的总体结果显示，在2型糖尿病患者中，达格列净10mg降低了4年内心血管死亡和心衰住院的复合终点，主要是由于心衰住院减少所驱动。在3月份美国心脏病学会科学会议上公布的一项预设的亚组分析中，研究人员报告说，用达格列净治疗可以在广泛的左室射血分数范围内减少心衰的住院率，并且可以在降低患者的心血管死亡和死亡率的情况下提供更大的益处。
达格列净目前没有被FDA批准用以降低心衰或心血管死亡的风险。
专家评论：
我认为这是一个真正的游戏改变者。首先，在糖尿病和HFrEF患者中，这项研究证实了我们在其他试验的先前亚组分析中看到的情况。例如，DECLARE-TIMI 58中有这方面的信号。真正的新发现是，HFrEF的非糖尿病患者似乎也有显着的益处。这真的推动了这个领域的发展。如果你仔细想想，前，说我们要用一种糖尿病药物在非糖尿病患者身上进行试验是一个奇怪的概念。大多数人都会说它不起作用，不安全或者很疯狂。但是，事实上，现在我们看到这类药物，或者特别是达格列净，可以显着降低心衰的转归。对于糖尿病患者，这也应该与SGLT2类中的其他药物一起验证。我认为这项研究显示了一个惊人的发现，它改变了我们看待心衰和糖尿病药物的方式。SGLT2抑制剂看起来是一类非常好的药物；似乎每周都有一份新的文献问世，表明这些药物正在做一些我们不知道的新事情，这很好。我预计这将继续下去。根据我们从糖尿病患者的DAPA-HF中看到的情况，我可能很乐意将其推广到其他SGLT2类药物。在非糖尿病患者中，我可能会坚持使用达格列净，直到其他SGLT2抑制剂证明自己。
Deepak L.Bhatt，医学博士，MPH
哈佛医学院
DAPA-HF: Dapagliflozin offers new approach to treatment of HFrEF,even without diabetes
Treatment withthe SGLT2 inhibitor dapagliflozin reduced risk for worsening HF and CV deathwhen added to standard therapy in patients with HF with reduced ejectionfraction, regardless of diabetes status, according to results of the DAPA-HFtrial.
PARIS — In patients with HF, with and without diabetes, treatment withthe SGLT2 inhibitor dapagliflozin reduced risk for worsening HF and CV deathwhen added to standard therapy, according to anticipated results of the DAPA-HFtrial.
Data presentedtoday at the European Society of Cardiology Congress suggest that the benefitsof dapagliflozin (Farxiga, AstraZeneca) extend beyond its effects as a diabetesdrug.
“The most important finding of all is the benefit in patients withoutdiabetes. This is truly a treatment for heart failure, and not just a drug fordiabetes,”John J.V. McMurray, MD,professor of cardiology atthe Institute of Cardiovascular and Medical Sciences at University of Glasgowin Scotland, said.
DAPA-HF enrolled4,744 adults in 20 countries who had HFrEF (left ventricular EF 40%). Atbaseline, 45% had type 2 diabetes and 55% did not. Those enrolled also hadmoderately elevated N-terminal pro-B-type natriuretic peptide and an estimatedglomerular filtration rate of 30 mL/min/1.732or higher. All patientsunderwent random assignment to receive once-daily dapagliflozin 10 mg ormatching placebo, in addition to standard care. Dapagliflozin is currentlyapproved by the FDA to treat patients with type 2 diabetes.
McMurray said the goal was to enroll a typical HFrEF population.
“We thought ofdapagliflozin as a HF drug, not a diabetes drug, and we wanted to test it in anall-comers population,” he said during a press conference.
Improvement with,without diabetes
During a medianfollow-up of 18.2 months, the primary outcome of CV death or worsening HF wasreduced by 26% in the group assigned dapagliflozin compared with those assignedplacebo (16.3% vs. 21.2%; HR = 0.74; 95% CI, 0.65-0.85; number needed to treat= 21).Worsening HF was defined asunplanned HF hospitalization or an urgent HF visit requiring IV therapy.
Dapagliflozin was also associated with significantimprovement when the researchers analyzed components of the primary compositeendpoint separately, including a 30% reduction in worsening HF (HR = 0.7; 95%CI, 0.59-0.83;P= .00003) and an 18% reduction in CVmortality (HR = 0.82; 95% CI, 0.69-0.98;P =.029).
All-cause death,which occurred in 11.6% of the dapagliflozin group vs. 13.9% of the placebogroup, was reduced by 17% with dapagliflozin treatment (HR = 0.83; 95% CI,0.71-0.97).
The researchersfound a consistent benefit across 14 prespecified subgroups. The “criticallyimportant” subgroup, McMurray said, was comparison based on the presence orabsence of diabetes. The primary composite outcome was reduced by 25% withdapagliflozin in the patients with diabetes at baseline (HR = 0.75; 95% CI,0.63-0.9) and by 27% in those without diabetes (HR = 0.73; 95% CI, 0.6-0.88).
“We saw anidentical treatment effect in patients without diabetes, compared to those withdiabetes,” McMurray said at the press conference.
Another importantsubgroup was patients treated or not treated with the angiotensin receptorneprilysin inhibitor sacubitril/valsartan (Entreso, Novartis). At baseline,only 11% of patients enrolled in DAPA-HF were receiving sacubitril/valsartan.McMurray said this therapy was just being introduced into practice when DAPA-HFstarted enrollment. Again, the overall treatment effect was consistent based onbackground treatment. The primary outcome was reduced by 25% with dapagliflozinin the patients receiving sacubitril/valsartan at baseline (HR = 0.75; 95% CI,0.5-1.13) and by 26% in those not receiving sacubitril/valsartan (HR = 0.74;95% CI, 0.65-0.86), according to McMurray.
The safetyprofile of dapagliflozin was consistent with previous trials of the drug.Adverse events including volume depletion, major hypoglycemia, lower limbamputation, fracture and/or renal dysfunction were low overall and notsignificantly different between the two groups. The rate of serious adverseevents, including death, was lower in the dapagliflozin group (38 vs. 42events;P< .01). Moreover, adverse events leading todiscontinuation were similar in both groups (4.7% with dapagliflozin vs. 4.9%with placebo;P= .79).
In other results, patient symptoms were significantly improved withdapagliflozin treatment. From baseline to 8 months, more patients assigneddapagliflozin reported a clinically significant improvement in symptoms of HFbased on the Kansas City Cardiomyopathy Questionnaire, compared with thoseassigned placebo (58% vs. 51%; OR = 1.15; 95% CI, 1.03-1.23).
“Overall, wefound that dapagliflozin does what we would like any HF treatment to do: inother words, reduce worsening HF events, particularly hospital admissions; toreduce CV death; and to improve symptoms,” McMurray said here. “The absoluterisk reduction [with dapagliflozin] is quite substantial and was consistentacross subgroups.”
‘A new era in HF treatment’
DAPA-HFwas aparallel-group, randomized, double-blind study performed in a broad spectrum ofpatients with HF. McMurray said it is important to note that the randomizedtherapies were administered in addition to standard care, including high use ofACE inhibitors, angiotensin receptor blockers, sacubitril/valsartan, beta-blockersand mineralocorticoid receptor antagonists.
“This is animportant breakthrough for patients with a terrible disease. We think these[findings] show a completely new therapeutic approach to the management ofpatients with HF,” McMurray said. “This is the first beneficial heart failuretreatment in 10 years not acting through neurohumoral mechanisms. [It was]beneficial when added to excellent existing therapy, includingsacubitril/valsartan.”
Marco Metra, MD,FESC, FHFA,professor of cardiology at the University of Brescia, Italy, put theDAPA-HF findings into context during a discussion of the results at ESCCongress.
“If we comparethe results on the primary and secondary outcomes in DAPA-HF with the resultsof successful trials of the last decade, we can see that all the hazard ratiosare comparable, if not larger, than those in the major clinical trials in HF,”Metra said.
Questions remainregarding the mechanisms of action of dapagliflozin and also whether theeffects can be translated to different HF phenotypes, such as HF with preservedEF, Metra said. However, these answers will come, as there are almost 20ongoing trials underway with the SGLT2 inhibitors, including dapagliflozin andalso empagliflozin (Jardiance, Boehringer Ingelheim), ertugliflozin (Steglatro,Merck) and sotagliflozin (Zynquista, Sanofi and Lexicon), he said.
“We are facing anew era in heart failure treatment,” Metra said.
SGLT2 inhibitorsincluding dapagliflozin have been shown to reduce risk for developing HF inpatients with type 2 diabetes. DAPA-HF was unique in that it is the first HFoutcomes trial with an SGLT2 inhibitor investigating whether dapagliflozin wasalso useful in treating established HF, even in patients without diabetes.
Sincedapagliflozin was first approved by the FDA in for the treatment of type 2diabetes in adults, several studies have demonstrated the potential for SGLT2 inhibitorsas a class in the prevention and treatment of HF.As previously reported,overall findings from the DECLARE-TIMI 58 CV outcome trial showed thatdapagliflozin 10 mg reduced the composite endpoint of CV death and HFhospitalization over 4 years, mainly driven by a reduction in HF hospitalization,in a broad population of patients with type 2 diabetes. In aprespecified subanalysispresented in Marchat the American College of CardiologyScientific Session, researchers reported that treatment with dapagliflozinreduced HF hospitalization in a broad range of LVEF and may provide evengreater benefit with lower CV death and mortality in patients with HFrEF.
Dapagliflozindoes not currently have an FDA indication to reduce the risk for HF or CVdeath. –by Katie Kalvaitis
Reference:
McMurray J, etal. Hot Line Session 1. Presented at: European Society of Cardiology Congress;Aug. 31-Sept. 4, ; Paris.
I think this is a real game-changer. First, in the patients withdiabetes and HFrEF, this study confirms what we saw in previous subgroupanalyses of other trials. For example, there were signals of this inDECLARE-TIMI 58. What is really paradigm-shifting is that there appears to be asignificant benefit in the nondiabetic patients with HFrEF too. That reallymoves the field forward. If you think about it, 10 years ago, it would havebeen an outlandish concept to say we were going to do a trial in nondiabeticswith a diabetes drug. Most people would have said it wouldn"t work, it"s unsafeor it"s crazy. But, in fact, now we see with this particular class of drugs, orperhaps specifically dapagliflozin, a significant reduction in HF outcomes.This should also be validated with other drugs in the SGLT2 class in patientswith diabetes. I think this study shows an amazing finding that changes the waywe are going to think about HF and diabetes drugs. The SGLT2 inhibitors look tobe a really good class of drugs; it seems like every week there is a newpublication coming out showing that these drugs are doing something new wedidn"t know about, and that"s good. I anticipate this will continue. Based onwhat we saw from DAPA-HF in patients with diabetes, I"d likely be comfortablegeneralizing this to the SGLT2 class. In the nondiabetic patients, I likelywould stick with dapagliflozin until the other SGLT2 inhibitors provethemselves.
·Deepak L. Bhatt, MD, MPH
·Cardiology Today EditorialBoard MemberBrigham and Womens HospitalHarvard Medical School
本文转自：海医附院内分泌
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