TW202400213A - 杜拉魯肽(dulaglutide)之治療用途 - Google Patents
杜拉魯肽(dulaglutide)之治療用途 Download PDFInfo
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Abstract
本發明係關於降低2型糖尿病(T2DM)患者中主要不良心血管事件風險之方法,該患者具有多種心血管風險因子但無經確立心血管疾病或罹患經確立心血管疾病,該方法包含投與升糖素樣肽-1 (GLP-1)受體激動劑杜拉魯肽(dulaglutide)。
Description
本發明係關於醫學領域。更具體而言,本發明係關於用於降低具有多種心血管風險因子或經確定心血管疾病之2型糖尿病(T2DM)患者之主要不良心血管事件風險的方法,該方法包括投與升糖素樣肽-1 (GLP-1)受體激動劑杜拉魯肽(dulaglutide)。
患有T2DM之患者經常遭受多種合併症,其中之一係心血管疾病(CVD)。CVD在T2DM患者中之發病率為非糖尿病個體者約兩倍,且改變CVD危險因子(包括飲食及運動)係T2DM治療計劃之標準組成部分,但CVD相關之死亡仍係T2DM患者最常見的死亡原因。
已研究葡萄糖降低及非葡萄糖降低療法二者對心血管事件發生率之效應。研究已顯示非葡萄糖降低療法(包括他汀類(statins),例如阿托伐他汀(atorvastatin);腎素血管收縮肽系統調節劑,例如雷米普利(ramipril)及替米沙坦(telmisartan);及培哚普利(perindopril)(血管收縮肽轉化酶(ACE)抑制劑)與吲達帕胺(indapamide)(噻嗪利尿劑(TZD))之組合)能降低T2DM患者中心血管之發病率。
關於葡萄糖降低療法對心血管事件發生率之效應的研究產生不同結果。舉例而言,吡格列酮(pioglitazone)對心血管結果具有混合效應,基礎胰島素及二肽基肽酶-4 (DPP-4)抑制劑對心血管結果具有中性效應,且恩格列淨(empagliflozin)(鈉-葡萄糖共轉運蛋白-2 (SGLT2)抑制劑)降低心血管死亡率及因心臟衰竭之住院治療。
類似地,關於GLP-1受體激動劑類別中不同藥劑對心血管事件發生率之效應的研究亦產生不同的結果。一方面,已發現利西拉肽(lixisenatide)不會顯著改變罹患經確立CVD之患者的主要不良心血管事件或其他嚴重不良事件的發生率(Pfeffer MA等人,
Lixisenatide in patients with type 2 diabetes and acute coronary syndrome, 373 N. ENGL. J MED. 2247-2257 (2015) (「ELIXA」)),且發現與安慰劑相比,每週一次艾塞那肽(exenatide)不會在患者群體(包括罹患及未罹患經確立CVD之患者)中產生主要不良心血管事件發生率之顯著差異(Holman RR等人,
Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes, 377 N. ENGL. J. MED. 1228-1239 (2017) (「EXCSEL」))。另一方面,發現阿必魯肽(albiglutide)、利拉魯肽(liraglutide)及索馬魯肽(semaglutide)降低患者群體(包含完全(阿必魯肽)或主要(利拉魯肽及索馬魯肽)之罹患經確立CVD之患者)之主要不良心血管事件的風險。(Hernandez AF等人,
Albiglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Cardiovascular Disease (Harmony Outcomes): a Double-blind, Randomized Placebo-controlled Trial, 392 LANCET 1519-1529 (2018) (「Harmony
Outcomes」);Marso SP等人,
Liraglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes, 375 N. ENGL. J. MED. 311-322 (2016) (「LEADER」));Marso SP等人,
Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes375 N. ENGL. J. MED. 1834-1844 (2016) (「SUSTAIN-6」))。
儘管存在上述療法,但仍需要能夠降低T2DM患者中主要不良心血管事件風險之新治療選項。具體而言,仍需要能夠降低尚未罹患經確立心血管疾病之T2DM患者中主要不良心血管事件風險之治療選項。
本發明方法試圖滿足彼等需要。實際上,最近發現杜拉魯肽在統計學上能夠顯著地降低群體(包括罹患及未罹患經確立心血管疾病患者)中主要不良心血管事件的風險。此外,罹患及未罹患經確立心血管疾病患者兩者均可促使整體風險降低且整體風險的降低係相似的。
因此,本發明提供降低患有2型糖尿病之患者中主要不良心血管事件風險之方法,該方法包含每週一次向該患者投與治療有效量之杜拉魯肽,其中該患者具有2型糖尿病及以下中之任一者:多種心血管風險因子但無經確立心血管疾病;或經確立心血管疾病。
在另一態樣中,本發明提供降低患有2型糖尿病之患者中主要不良心血管事件風險之方法,該方法包含:鑑別具有2型糖尿病及多種心血管風險因子但無經確立心血管疾病或經確立心血管疾病之患者;及每週一次向該患者投與治療有效量之杜拉魯肽。
在另一態樣中,本發明提供延遲患有2型糖尿病之患者中主要不良心血管事件發生之方法,該方法包含每週一次向該患者投與治療有效量之杜拉魯肽,其中該患者具有2型糖尿病及以下中之任一者:多種心血管風險因子但無經確立心血管疾病;或經確立心血管疾病。
在另一態樣中,本發明提供在患有2型糖尿病之患者中改善血糖控制及降低首次發生主要不良心血管事件之風險的方法,該方法包含每週一次向該患者投與治療有效量之杜拉魯肽,其中該患者具有2型糖尿病及以下中之任一者:多種心血管風險因子但無經確立心血管疾病;或經確立心血管疾病。
在另一態樣中,本發明提供杜拉魯肽,其用於降低具有2型糖尿病及以下中任一者之患者之主要不良心血管事件之風險:多種心血管風險因子但無經確立心血管疾病;或經確立心血管疾病。
在另一態樣中,本發明提供杜拉魯肽用於製備藥劑之用途,該藥劑用於降低具有2型糖尿病及以下中任一者之患者之主要不良心血管事件風險:多種心血管風險因子但無經確立心血管疾病;或經確立心血管疾病。
此申請案根據35 U.S.C. §119(e)主張於2019年4月5日提交之美國臨時申請案序列號第62/829,717號之權益;其公開內容以引用的方式併入本文。
杜拉魯肽係人類GLP-1受體激動劑,其包含在GLP-l類似物之C-末端經由肽連接體融合至免疫球蛋白Fc部分之類似物的N-末端的二聚體,且由提供以下化學名稱之CAS登記號923950-08-7鑑別:7-37-類升糖素肽I [8-甘胺酸,22-麩胺酸,36-甘胺酸](合成人類)融合蛋白與肽(合成16-胺基酸連接體)融合蛋白與免疫球蛋白G4 (合成人類Fc片段)二聚體。杜拉魯肽之每一單體具有SEQ ID NO:1中所陳述之胺基酸序列:
HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGGGGGGSGGGGSGGGGSAESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO:1)。
兩個單體藉由SEQ ID NO:1之位置55及58處的半胱胺酸殘基之間的二硫鍵連接以形成二聚體。杜拉魯肽之結構、功能、產生及在治療T2DM中之用途更詳細的闡述於U.S. 7,452,966及美國專利申請公開案第US20100196405號中。在本文中使用時,術語「杜拉魯肽」係指具有SEQ ID NO:1之胺基酸序列之兩個單體的任何GLP-1 受體激動劑蛋白質二聚體,其包括作為正尋求批准GLP-1受體激動劑產品之監管提交主題之任何蛋白質,其全部或部分依賴於由禮來公司(Eli Lilly and Company)提交給監管機構之有關杜拉魯肽的數據,無論正尋求批准該蛋白質的一方實際上將蛋白質鑑別為杜拉魯肽還是使用其他一些術語。杜拉魯肽激動GLP-1受體,從而刺激胰島素合成及分泌,且已顯示在T2DM患者中提供經改善之血糖控制。
已發現,杜拉魯肽能降低患有T2DM且具有經確立心血管疾病或不具有經確立心血管疾病但具有多種心血管風險因子之患者中主要不良心血管事件之風險。
如上所述,先前已研究幾種其他GLP-1受體激動劑對心血管結果之效應(稱為心血管結果試驗或「CVOT」),且彼等研究之結果喜憂參半,其中一些證明對患有T2DM之患者有益且一些並未證明此一益處。將來自彼等研究所得之招募及複合MACE 3結果匯總提供於下表1。
表1. GLP-1受體激動劑CVOT招募及MACE3結果。
a83.0% 經確立心血管疾病(包括CKD 3+),且58.8%具有經確立心血管疾病但無CKD;
b心血管疾病、腦血管疾病、PVD、CRF、CHF;
c在篩選前180天內發生急性冠心病事件;
d73%至少一次先前心血管事件(70% CAD、24% PAD、22%腦血管疾病);
e冠狀動脈疾病、腦血管疾病或周圍動脈疾病。
索馬魯肽 (SUSTAIN-6) | 利拉魯肽(LEADER) | 利西拉肽(ELIXA) | 艾塞那肽QW (EXSCEL) | 阿必魯肽QW (Harmony Outcomes) | |
患者數 | 3297 | 9340 | 6068 | 14752 | 9463 |
年齡 | 65 (平均值) | 64 (平均值) | 60 (平均值) | 62 (中值) | 64 (平均值) |
先前CVD | 83% a | 81% b | 100% c | 73% d | 100% e |
他汀使用 | 73% | 72% | 93% | 74% | 84% |
BMI | 33 (平均值) | 33 (平均值) | 30 (平均值) | 32 (中值) | 32 (平均值) |
HbA1c | 8.7% (平均值) | 8.7% (平均值) | 7.7% (平均值) | 8.0% (中值) | 8.7% (平均值) |
事件數量 | 254 | 1302 | 805 | 1744 | 766 |
中值隨訪 | 2.1年 | 3.8年 | 2.1年 | 3.2年 | 1.6年 |
MACE 3 危險比(CI) | 0.74 (0.58-0.95) | 0.87 (0.78-0.97) | 1.02 (0.89-1.17) | 0.91 (0.83- 1.00) | 0.78 (0.68- 0.90) |
如在表1中可看出,三項研究結果表明所測試藥劑具有正面作用,而兩項研究結果與安慰劑在統計學上並未有顯著性差異。
此外,甚至在彼等證明益處之研究中,罹患經確立心血管疾病患者可促使正面的結果。如表1中亦看出,該等研究中之兩者僅包括罹患先前CVD之患者。關於包括無經確立CVD之患者的研究,在其餘研究中罹患經確立CVD之患者與無經確立CVD (但具有多種風險因子)之患者的結果比較提供於下表2中。
表2. 「無先前CVD」係指無經確立CVD (但具有多種風險因子)之患者。「先前CVD」係指罹患經確立CVD之患者。
藥劑 | 利拉魯肽 | 索馬魯肽 | 艾塞那肽QW | |||
群體 | 無先前CVD (N=1742;18.7%) | 先前 CVD (N=7598;81.3%) | 無先前 CVD (N=562;17.0%) | 先前 CVD (N=2735;83.0%) | 無先前 CVD (N=3970;26.9%) | 先前 CVD (N=10782;73.1%) |
MACE 3 危險比 (CI) | 1.20 (0.86 - 1.67) | 0.83 (0.74 – 0.93) | 1.00 (0.41 - 2.46) | 0.72 (0.55 - 0.93) | 0.99 (0.77 - 1.28) | 0.90 (0.82 – 1.00) |
相互作用P=0.04 | 相互作用P=0.49 | 相互作用P=0.50 |
如上文在表2所看到,在所招募無經確立CVD之患者的研究中,沒有一個研究能促使患者群體改善主要不良心血管事件。與此相反地,如下文在實例中更詳細描述,發現利用杜拉魯肽治療在統計學上能夠顯著地降低群體(包括罹患及未罹患經確立心血管疾病之患者)中主要不良心血管事件風險,且可見該兩組病患群組均可促使風險之降低且降低的風險是相似的。
當用於描述患者時,術語「經確立CVD」或「經確立心血管疾病」係指患者具有以下中之一或多者:先前心肌梗塞(MI);先前缺血性中風;先前不穩定性心絞痛;先前血管重建術(冠狀動脈、頸動脈或周圍動脈);針對缺血相關事件之先前住院(成像中發現之不穩定性心絞痛或心肌缺血或需要經皮冠狀動脈介入術);及先前有記錄之心肌缺血。
當在本文中使用時,術語「主要不良心血管事件」係指心血管死亡、非致命性心肌梗塞及非致命性中風。該等事件有時亦稱為MACE或MACE 3事件。該等事件中任何首先發生者係經常用於CVOT中之複合終點。
當在本文中關於主要不良心血管事件使用時,術語「風險因子」係指被理解為增加T2DM患者之主要不良心血管事件風險的特徵。該等風險因子包括尤其包括以下中之任一者:目前使用菸草(菸草之任何形式);使用至少1種經批准之脂質改質療法(例如他汀類,例如阿托伐他汀、瑞舒伐他汀(rosuvastatin)、斯伐他汀(simvastatin)、普伐他汀(pravastatin)、洛伐他汀(lovastatin)、氟伐他汀(fluvastatin)或匹伐他汀(pitavastatin);PCSK9抑制劑,例如依伏庫單抗(evolocumab)或阿利庫單抗(alirocumab);及依折麥布(ezetimibe))以治療高膽固醇血症或在過去6個月內有記錄但未治療之低密度脂蛋白膽固醇(LDL-C) ≥3.4 mmol/L (130 mg/dL);在過去6個月內有記錄且經治療或未治療之高密度脂蛋白膽固醇(HDL-C) <1.0 mmol/L (40 mg/dL) (對於男性)及<1.3 mmol/L (50 mg/dL) (對於女性)或三酸甘油酯 ≥2.3 mmol/L (200 mg/dL);使用至少1種降血壓藥以治療高血壓(例如血管收縮肽轉化酶(ACE)抑制劑、血管收縮肽受體阻斷劑(ARB)、噻嗪樣利尿劑及二氫吡啶鈣通道阻斷劑)或未治療之收縮壓(SBP) ≥140 mm Hg或舒張壓(DBP) ≥95 mmHg;經量測對於男性腰臀比率 >1.0且對於女性>0.8。
當在本文中使用時,術語「多種」意指一種以上。
當在本文中使用時,術語「治療(treatment, treat, treating)」及諸如此類意欲包括減緩或減弱疾病或病症之進展。該等術語亦包括緩和、改善、減弱、消除或減輕病症或病況之一或多種症狀,即使並未實際上消除該病症或病況及即使該病症或病況之進展自身並未減緩或逆轉。
當在本文中結合主要不良心血管事件之風險使用時,術語「減輕(reduce, reduced, reduces, reducing)」及諸如此類係指減少主要不良心血管事件發生之機率。當在本文中使用時,術語主要不良心血管事件之「延遲發生」意指增加在發生主要不良心血管事件之前之時期。
當在本文中結合多個結果使用時,術語「複合」係指結果中任何首先出現者。
當在本文中使用時,術語「危險比」係指與對照組相比進展至終點之相對率的量度。在基於結果之臨床試驗(例如本文所述之CVOT),與對照相比,測試臂之危險比降低指示測試臂中所用之療法降低終點(在本文所述研究之情形中,主要不良心血管事件)之風險。
本文所述之方法及用途可與用於降低主要不良心血管事件風險之標準護理同時或依序提供,該標準護理包括投與最大耐受劑量之ACE抑制劑及ARB、及按當地指南適當治療血壓、血脂及HbA1c。在某些實施例中,本文所述之方法進一步包含向患者投與最大耐受劑量之ACE抑制劑。在某些實施例中,本文所述之方法進一步包含向患者投與最大耐受劑量之ARB。可投與之其他藥劑包括β阻斷劑、鈣通道阻斷劑、利尿劑、抗血栓劑、阿斯匹林(aspirin)及他汀類。
「治療有效量」意指用於本發明方法及用途之杜拉魯肽或包含用於本發明方法及用途之杜拉魯肽的醫藥組合物的量,該量將引起研究人員、醫師或其他臨床醫師所尋求的對患者的生物學或醫學反應或所期望的治療效應。杜拉魯肽之有效量可根據諸如以下等因素而變化:疾病狀態、個體之年齡、性別及體重以及杜拉魯肽在該個體內引發期望反應之能力。有效量亦為治療有益效應勝過任何毒性或有害效應之量。在某些實施例中,用於本文所述方法之杜拉魯肽的治療有效量選自由1.5、3.0及4.5 mg組成之群。在某些實施例中,杜拉魯肽之治療有效量係3.0 mg。在某些實施例中,杜拉魯肽之治療有效量係4.5 mg。在較佳實施例中,杜拉魯肽之治療有效量係1.5 mg。
下文闡述本發明之額外實施例:
一種降低患有2型糖尿病之患者中主要不良心血管事件風險之方法,其包含每週一次向該患者投與治療有效量之杜拉魯肽,其中該患者具有2型糖尿病及以下中之任一者:多種心血管風險因子但無經確立心血管疾病;或經確立心血管疾病。
一種降低患有2型糖尿病之患者中主要不良心血管事件風險之方法,其包含:鑑別具有2型糖尿病及多種心血管風險因子但無經確立心血管疾病或經確立心血管疾病之患者;及每週一次向該患者投與治療有效量之杜拉魯肽。
一種延遲患有2型糖尿病之患者中主要不良心血管事件發生之方法,其包含每週一次向該患者投與治療有效量之杜拉魯肽,其中該患者具有2型糖尿病及以下中之任一者:多種心血管風險因子但無經確立心血管疾病;或經確立心血管疾病。
一種在患有2型糖尿病之患者中改善血糖控制及降低首次發生主要不良心血管事件之風險的方法,其包含每週一次向該患者投與治療有效量之杜拉魯肽,其中該患者具有2型糖尿病及以下中之任一者:多種心血管風險因子但無經確立心血管疾病;或經確立心血管疾病。
一種在患有2型糖尿病之患者中改善血糖控制之方法,其包含每週一次向該患者投與治療有效量之杜拉魯肽,其中該患者具有2型糖尿病及以下中之任一者:多種心血管風險因子但無經確立心血管疾病;或經確立心血管疾病;且其中該患者中主要不良心血管事件之風險降低。
在實施例中,主要不良心血管事件之風險降低至少約10%。
在實施例中,主要不良心血管事件之風險降低至少約11%。
在實施例中,主要不良心血管事件之風險降低約12%。
在實施例中,心血管死亡之風險降低。
在實施例中,非致命性中風之風險降低。
在實施例中,非致命性心肌梗塞之風險降低。
在實施例中,降低以下結果複合發生之風險:需要雷射、抗VEGF療法或玻璃體切除術之糖尿病視網膜病變;臨床蛋白尿;eGFR下降30%;或慢性腎臟替代療法。
在實施例中,患者具有多種心血管風險因子但無經確立心血管疾病。
在實施例中,心血管疾病之風險因子係選自由以下組成之群:目前使用菸草(菸草之任何形式);使用至少1種經批准之脂質改質療法以治療高膽固醇血症或在過去6個月內有記錄但未治療之低密度脂蛋白膽固醇(LDL-C) ≥3.4 mmol/L (130 mg/dL);在過去6個月內有記錄且經治療或未治療之高密度脂蛋白膽固醇(HDL-C) <1.0 mmol/L (40 mg/dL)(對於男性)及<1.3 mmol/L (50 mg/dL) (對於女性)或三酸甘油酯 ≥2.3 mmol/L (200 mg/dL);使用至少1種降血壓藥以治療高血壓或未治療之收縮壓(SBP) ≥140 mm Hg或舒張壓(DBP) ≥95 mmHg;經量測對於男性腰臀比率 >1.0且對於女性>0.8。
在實施例中,杜拉魯肽之量係選自由以下組成之群:約1.5 mg、約3.0 mg及約4.5 mg。
在實施例中,杜拉魯肽之量係約1.5 mg。
在實施例中,杜拉魯肽之量係約3.0 mg。
在實施例中,杜拉魯肽之量係約4.5 mg。
在實施例中,每週一次投與杜拉魯肽持續大約5年。
在實施例中,患者亦投與標準照護以降低主要不良心血管事件之風險。
在實施例中,患者亦投與最大耐受劑量之ACE抑制劑。
在實施例中,患者亦投與最大耐受劑量之ARB。
在實施例中,患者亦投與β阻斷劑。
在實施例中,患者亦投與鈣通道阻斷劑。
在實施例中,患者亦投與利尿劑。
在實施例中,患者亦投與抗血栓劑。
在實施例中,患者亦投與阿斯匹林。
在實施例中,患者亦投與他汀。
一種用於以上實施例中任一者之杜拉魯肽。
一種杜拉魯肽在製備用於以上實施例中任一者之藥劑的用途。
實例設計一項名為研究糖尿病中每週一次腸促胰島素之心血管事件(Researching Cardiovascular Events with a Weekly INcretin in Diabetes, REWIND)之3期臨床研究以評價與安慰劑相比,每週一次投與杜拉魯肽在添加至處於高CV事件之風險的2型糖尿病患者現有抗高血糖方案時對主要不良CV事件之效應。下表3中列出之招募準則係經設計以包括與典型糖尿病實務中所見患者相似之參與者,該等參與者具有不同的心血管風險因子或經確立心血管疾病:
表 3.招募準則.
關鍵納入準則 |
T2DM,其中HbA1c ≤9.5% |
穩定劑量之0、1或2種口服降血糖藥物 +基礎胰島素達≥3個月 |
BMI ≥ 23 kg/m 2 |
若年齡≥50歲,則以下中之至少1者:先前MI;先前缺血性中風;2年前或更早實施過冠狀動脈血管重建術;2個月前或更早實施過頸動脈或周圍動脈血管重建術;不穩定性心絞痛住院;影像證實心肌缺血;或經皮冠狀動脈介入術 |
若年齡≥55歲,則以上中之任一者或以下中之至少1者:有記錄之心肌缺血,藉由壓力測試或成像;>50% 冠狀動脈、頸動脈或下肢動脈狹窄;踝肱指數 <0.9; eGFR持續地 <60 mL/min/1.73 m2;高血壓伴左心室肥大;或持續蛋白尿 |
若年齡≥ 60歲,則以上中之任一者或以下中之至少2者:使用任何菸草;在過去6個月內使用脂質改質療法或有記錄之未治療LDL膽固醇 ≥3.4 mmol/L (130 mg/dL);在過去6個月內,HDL膽固醇 <1.0 mmol/L (40 mg/dL)(對於男性)且 <1.3 mmol/L (50 mg/dL) (對於女性)或三酸甘油酯≥2.3 mmol/L (200 mg/dL);使用≥1種血壓藥物或未治療之收縮壓 ≥ 140 mm Hg或舒張壓 ≥ 95 mm Hg;或腰臀比率 >1.0 (男性)及>0.8 (女性) |
對研究藥物之準備期依從性 = 100% |
簽署知情同意書 |
研究經設計包括篩選訪視、隨後單盲3週安慰劑準備期。之後,患者係以隨機化方式分配至杜拉魯肽1.5 mg或安慰劑,並以大約6個月的間隔進行隨訪。對患者進行隨訪,直至大約1200名患者經歷主要終點事件(如此裁定)為止。
主要效能量度係首次出現(隨機化之後)因CV原因死亡、非致命性心肌梗塞(MI)或非致命性中風之複合終點的時間。次要結果包括主要複合心血管結果之每一組成部分、包含視網膜或腎病之複合臨床微血管結果、因不穩定型心絞痛住院治療、需要住院治療之心臟衰竭或緊急心臟衰竭就診以及全因死亡率。該等結果見表4。所有死亡及心血管、胰臟及甲狀腺事件(即效能及安全性結果二者)均由對治療分配盲目的外部裁定委員裁定。
表 4.次要及安全性結果. 縮寫:VEGF,血管內皮生長因子;eGFR,估計之腎小球濾過率.
次要結果 | 安全性結果 |
複合微血管結果:糖尿病 需要雷射、抗VEGF療法或玻璃體切除術之視網膜病變;或臨床蛋白尿;或eGFR下降30%;或慢性腎臟替代療法 | 急性胰臟炎 |
不穩定性心絞痛住院 | 嚴重胃腸事件 |
心臟衰竭住院或緊急就診 | 癌症:胰臟、髓樣甲狀腺、其他甲狀腺、其他(不包括非黑色素瘤皮膚癌) |
非致命性MI | 嚴重低血糖 |
非致命性中風 | 免疫反應 |
心血管死亡 | 嚴重肝事件 |
死亡 | 嚴重腎事件 |
室上性心律不整及心血管傳導障礙 | |
藥物停用 |
樣本大小計算係基於3年招募期、對照組中每年2%之預期主要結果事件率、0.15%之每年中途退出率及5%之雙側型一錯誤。該等假設指示,招募9600名患者將導致總共1200名參與者在8年之最長隨訪期內發生至少1次主要心血管結果,並將提供90%檢定力以檢測危險比為0.82之心血管事件。藉由裁定確認1200名參與者之主要心血管結果後,隨訪結束。
所有效能及安全性分析均設計為使用意向治療方法進行,該方法包括所有隨機化參與者,無論其依從性如何。基線連續變量概括為平均值或中值以及其標準偏差或四分位距範圍,且類別變量意欲概括為數量及百分比。對主要結果首次出現之時間的干預效應設計為使用Cox比例危險模型進行分析,其中唯一的自變量係分配給杜拉魯肽對安慰劑。比例危害假設應以圖表方式進行評價。應生成卡本-麥爾(Kaplan-Meier)曲線以及對數秩P值。將針對所有關鍵結果計算每一治療組之每100人年的發生率。所有次要結果將以圖表方法所定義之預定順序進行分析,以控制總體I型錯誤。若無效應之虛無假設被主要結果拒絕,則圖表測試方法將精簡地為每一次要結果分配α。欲檢查之探索性子組包括先前CVD之患者對無已知CVD之彼等。對於子組分析,認為相互作用P值<0.1暗示相互作用。不需要對多重性進行調整。
篩選12,137個個體,並將位於24個國家之370個地點的9901個個體隨機分配至杜拉魯肽或安慰劑。未能隨機化的主要原因包括不符合合格準則(68%)或個人決定(25%)。第一名參與者於2011年8月經隨機化且招募於2013年8月結束。如表5及6中所示,參與者之平均年齡為66歲,平均BMI為32 kg/m
2,且31%的參與者具有CVD病史(定義為MI病史、缺血性中風、血管重建術、不穩定性心絞痛住院伴新的一致性缺血性ECG改變或正壓力測試伴一致性成像)。此另外,93%的參與者具有高血壓病史,9%具有先前心臟衰竭病史,且平均血壓為137/78 mmHg。糖尿病之平均報告持續時間為10年,24%的參與者服用胰島素,81%服用二甲雙胍,57%服用磺脲類,且平均基線HbA1c為7.3%。81%的參與者使用血管收縮肽-轉化酶(ACE)抑制劑或血管收縮肽受體阻斷劑(ARB),45%服用β-阻斷劑,66%在基線時服用他汀,51%服用乙醯基柳酸,8%服用抗血小板劑,且平均基線LDL膽固醇為2.56 nmol/L。
表 5.9901個經隨機化參與者之基線臨床特徵. 縮寫:IQR, 四分位距;s.d.,標準偏差;
a 冠狀動脈、頸動脈或周圍動脈;
b 成像中發現之不穩定性心絞痛或心肌缺血,或需要經皮冠狀動脈介入術;
c 白蛋白/肌酸酐 ≥3.39 mg/mmol.
表 6.經隨機化參與者中基線使用之藥物類別。值代表所有經隨機化之計數及百分比。
特徵 | 所有參與者 |
年齡,歲:平均值(s.d.) | 66.2 (6.5) |
女性, n (%) | 4589 (46.3) |
地理位置, n (%) 美國(USA)及加拿大(Canada) 墨西哥(Mexico)及南美洲(South America) 歐洲(Europe)、俄羅斯(Russia)及南非(South Africa) 亞洲(Asia):臺灣(Taiwan)及韓國(Korea) 太平洋(Pacific):澳大利亞(Australia)及新西蘭(New Zealand) | 2071 (20.9) 3021 (30.5) 4339 (43.8) 148 (1.5) 322 (3.3) |
先前心血管疾病(以下6者中之≥1), n (%) 先前MI 先前缺血性中風 先前不穩定性心絞痛 先前血管重建術 a 因缺血相關事件之先前住院治療 b 先前有記錄之心肌缺血 | 3111 (31.4) 1600 (16.2) 526 (5.3) 587 (5.9) 1787 (18.1) 1193 (12.1) 922 (9.3) |
先前高血壓, n (%) | 9223 (93.2) |
先前心臟衰竭, n (%) | 852 (8.6) |
先前糖尿病視網膜病變, n (%) | 891 (9.0) |
先前骨折, n (%) | 1510 (15.3) |
先前膽囊切除術, n (%) | 1465 (14.8) |
目前使用菸草, n (%) | 1407 (14.2) |
糖尿病持續時間, 年:平均值(s.d.) | 10.0 (7.2) |
重量, kg:平均值(s.d.) | 88.7 (18.5) |
BMI, kg/m 2:平均值(s.d.) | 32.3 (5.7) |
血壓, mm Hg:平均值(s.d.) | 137.2 (16.8)/78.5 (9.8) |
脈搏, 跳動次數/min:平均值(s.d.) | 71.5 (10.9) |
男性腰臀比率:平均值(s.d.) | 110.6 (13.1)/108.4 (11.2) |
女性腰臀比率:平均值(s.d.) | 106.7 (13.1)/113.3 (13.7) |
HbA1c, %:平均值(s.d.) | 7.3 (1.1) |
膽固醇, mmol/L:平均值(s.d.) | 4.52 (1.16) |
LDL膽固醇, mmol/L:平均值(s.d.) | 2.56 (0.98) |
HDL膽固醇, mmol/L:平均值(s.d.) | 1.18 (0.34) |
三酸甘油酯, mmol/L: 中值(IQR) | 1.60 (1.17, 2.22) |
eGFR, mL/min/1.73 m2:平均值(s.d.) | 77.6 (24.1) |
eGFR <60 mL/min/1.73 m 2, n (%) | 2199 (22.2) |
白蛋白/肌酸酐, mg/mmol: 中值(IQR) | 1.94 (0.75, 8.02) |
大量或微量蛋白尿 c , n (%) | 3491 (35.3) |
糖尿病特異性藥物類別 | 其他藥物類別 | ||
無 | 600 (6.1) | ACE抑制劑 | 4909 (49.6) |
僅1種口服藥劑 | 4926 (49.8) | ARB | 3366 (34.0) |
僅2種口服藥劑 | 3894 (39.3) | ACE抑制劑或ARB | 8054 (81.4) |
任何胰島素 | 2398 (24.2) | 醛固酮拮抗劑 | 464 (4.7) |
二甲雙胍 | 8016 (81.0) | 所有利尿劑 | 4592 (46.4) |
格列本脲/格列苯脲(Glibenclamide/glyburide) | 1271 (12.8) | 噻嗪 | 652 (6,6) |
其他磺醯脲 | 4373 (44.2) | β阻斷劑 | 4502 (45.5) |
DPP-4抑制劑 | 88 (0.9) | Ca通道阻斷劑 | 3385 (34.2) |
SGLT2抑制劑 | 12 (0.1) | 乙醯基柳酸 | 5001 (50.5) |
美格替耐(Meglitinide) | 64 (0.7) | 其他抗血小板劑 | 820 (8.3) |
α-葡萄糖苷酶抑制劑 | 118 (1.2) | 他汀 | 6537 (66.0) |
噻唑啶二酮 | 168 (1.7) | 纖維酸 | 892 (9.0) |
多巴胺激動劑 | 47 (0.5) | 其他脂質藥物 | 112 (1.1) |
其他 | 84 (0.9) | 質子幫浦抑制劑 | 1673 (16.9) |
隨訪患者直至2018年8月。在中位隨訪5.4年(四分位距5.1、5.9)期間(包括51,820人年),得知9610名患者之最終複合結果狀態。在隨訪期間,分配給杜拉魯肽之1731名參與者及分配給安慰劑之1761名參與者具有至少1例研究藥物停用,而分配給杜拉魯肽之4277名及分配給安慰劑之4196在最後一次訪視時服用研究藥物。自隨機化直至經歷主要結果或進行末次隨訪,分配給杜拉魯肽或安慰劑之參與者分別服用研究藥物達85.8%及87.1%之隨訪時間。
結果提供於下表7及8中。
表 7.杜拉魯肽對主要及次要結果之效應.
結果 | 杜拉魯肽(N=4949) N (%) | 安慰劑(N=4952) N (%) | HR (95% CI) |
MACE | 594 (12.0) | 663 (13.4) | 0.88 (0.79, 0.98) |
MI | 223 (4.5) | 231 (4.7) | 0.96 (0.80, 1.15) |
中風 | 158 (3.2) | 205 (4.1) | 0.76 (0.62, 0.94) |
CV死亡 | 317 (6.4) | 346 (7.0) | 0.91 (0.78, 1.06) |
複合微血管 | 1072 (21.7) | 1221 (24.7) | 0.85 (0.78, 0.92) |
不穩定性心絞痛 | 88 (1.8) | 77 (1.6) | 1.14 (0.84, 1.55) |
心臟衰竭 | 213 (4.3) | 226 (4.6) | 0.93 (0.77, 1.12) |
所有死亡率 | 536 (10.8) | 592 (12.0) | 0.90 (0.80, 1.01) |
如表7所示,與安慰劑相比,每週一次注射杜拉魯肽顯著且安全地將CV結果之危險降低12%。此外,益處在複合主要結果之所有3個組成部分中係一致的,其中注意到最大估計效應值係非致命性中風。與安慰劑相比,複合微血管結果之發生率在分配給杜拉魯肽之參與者中亦較低。
表 8.子組分析.
子組 | 杜拉魯肽 事件/總計(%) | 安慰劑 事件/總計(%) | HR (95% CI) | 相互作用之P值 |
先前CVD | 280 / 1560 (17.9) | 315 / 1554 (20.3) | 0.87 (0.74-1.02) | 0.80 |
無已知先前CVD | 314 / 3389 (9.3) | 3487 / 3398 (10.2) | 0.89 (0.76-1.04) |
如表8中所示,在具有或沒有先前CV事件之參與者中,杜拉魯肽對主要結果之積極作用係類似的。
<![CDATA[<110> 美商美國禮來大藥廠(Eli Lilly and Company)]]> <![CDATA[<120> 杜拉魯肽(DULAGLUTIDE)之治療用途]]> <![CDATA[<130> TW108139459]]> <![CDATA[<150> US 62/829,717]]> <![CDATA[<151> 2019-04-05]]> <![CDATA[<160> 1 ]]> <![CDATA[<170> PatentIn version 3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 275]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成構建體]]> <![CDATA[<400> 1]]> His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly 20 25 30 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu 35 40 45 Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala 50 55 60 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 65 70 75 80 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 85 90 95 Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu 100 105 110 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr 115 120 125 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 130 135 140 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 145 150 155 160 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 165 170 175 Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val 180 185 190 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 195 200 205 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 210 215 220 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr 225 230 235 240 Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val 245 250 255 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 260 265 270 Ser Leu Gly 275
Claims (9)
- 一種杜拉魯肽(dulaglutide)在製造藥劑中之用途,該藥劑係用於在罹患經確立心血管疾病之2型糖尿病患者中降低主要不良心血管事件之風險,其中該藥劑係用於每週一次向該患者投與治療有效量之杜拉魯肽,其中該患者具有多種選自由(a)、(b)、(c)、(d)及(e)組成之群之心血管風險因子: (a) 使用菸草; (b) 以下中之至少一者: i) 使用至少1種經批准之脂質改質療法以治療高膽固醇血症;或 ii) 在過去6個月內有紀錄但未治療之低密度脂蛋白膽固醇(LDL-C) ≥3.4 mmol/L (130 mg/dL); (c) 以下中之至少一者: i) 在過去6個月內,高密度脂蛋白膽固醇(HDL-C)量測值:對於男性<1.0 mmol/L (40 mg/dL);且對於女性<1.3 mmol/L (50 mg/dL);或 ii) 在過去6個月內,三酸甘油酯≥2.3 mmol/L (200 mg/dL); (d) 以下中之至少一者: i) 使用至少1種降血壓藥以治療高血壓;或 ii) 未治療之收縮壓(SBP) ≥140 mm Hg或舒張壓(DBP) ≥95 mmHg;及 (e) 經量測腰臀比率:男性>1.0,及女性>0.8。
- 一種杜拉魯肽在製造藥劑中之用途,該藥劑係用於在罹患經確立心血管疾病之2型糖尿病患者中改善血糖控制及降低發生主要不良心血管事件之風險,其中該藥劑係用於每週一次向該患者投與治療有效量之杜拉魯肽,其中該患者具有多種選自由(a)、(b)、(c)、(d)及(e)組成之群之心血管風險因子: (a) 使用菸草; (b) 以下中之至少一者: i) 使用至少1種經批准之脂質改質療法以治療高膽固醇血症;或 ii) 在過去6個月內有紀錄但未治療之低密度脂蛋白膽固醇(LDL-C) ≥3.4 mmol/L (130 mg/dL); (c) 以下中之至少一者: i) 在過去6個月內,高密度脂蛋白膽固醇(HDL-C)量測值:對於男性<1.0 mmol/L (40 mg/dL);且對於女性<1.3 mmol/L (50 mg/dL);或 ii) 在過去6個月內,三酸甘油酯≥2.3 mmol/L (200 mg/dL); (d) 以下中之至少一者: i) 使用至少1種降血壓藥以治療高血壓;或 ii) 未治療之收縮壓(SBP) ≥140 mm Hg或舒張壓(DBP) ≥95 mmHg;及 (e) 經量測腰臀比率:男性>1.0,及女性>0.8。
- 如請求項1或2之用途,其中該主要不良心血管事件係非致命性中風。
- 如請求項1或2之用途,其中該患者之該主要不良心血管事件風險係降低至少約10%。
- 如請求項1或2之用途,其中杜拉魯肽之治療有效量係選自由1.5 mg、3.0 mg及4.5 mg組成之群。
- 如請求項1或2之用途,其中杜拉魯肽之治療有效量係1.5 mg。
- 如請求項1或2之用途,其中該藥劑每週一次投與持續大約5年。
- 如請求項1或2之用途,其中該藥劑進一步包含以下中之一或多者或與其組合投與:血管收縮肽轉化酶(ACE)抑制劑、血管收縮肽受體阻斷劑(ARB)、β阻斷劑、鈣通道阻斷劑、利尿劑、抗血栓劑或他汀(statin)。
- 如請求項8之用途,其中該抗血栓劑為阿斯匹林(aspirin)。
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