To examine whether the empagliflozin-induced stimulation of EGP, lipolysis, and ketone production in T2D individuals can be blocked by pioglitazone (which has direct hepatic and adipose tissue effects).

开始日期2026-02-01

申办/合作机构

University of Texas Health Science Center At San Antonio

[+1]

TCTR20241215007

/ Not yet recruiting临床1期IIT

A Bioequivalence study of a randomized, single dose, two-way crossover design with two-period, two-treatment and two-sequence of EMPAGLINAZ 25 (Empagliflozin Tablets 25 mg) relative to JARDIANCE film-coated tablets 25 mg in healthy Thai adult volunteers under fasting condition

开始日期2025-10-07

申办/合作机构

Bio-innova Co., Ltd

NCT06643442

/ Not yet recruiting临床2期IIT

Repurposing Empagliflozin for Duchenne Muscular Dystrophy - Associated Cardiomyopathy: a Pharmacokinetics, Safety and Proof-of-concept Study Among Children 6-18 Years of Age

This study aims at exploring the use of empagliflozin in children and adolescents 6-18 years old with Duchenne muscular distrophy (DMD) - associated cardiomyopathy. This molecule is effective in reducing hospitalizations and mortality in adults with heart failure and is used in adolescents with type 2 diabetes mellitus, but little is known on children and adolescents with heart failure. Particularly, the best dose to use in this population is currently unknown. This trial aims to:
1. define a dose rationale for this indication and age group (pharmacokinetic study),
2. assess and monitor safety,
3. assess ease-of-swallow,
4. explore middle-term (3-6 months) efficacy and efficacy markers.
Participants will be asked to attend 5 study visits over 6 months, and one end-study visit 2-12 weeks thereafter. Visit 1 will entail an 8h day-hospital stay, while Visits 2, 3, 4 and 5, as well as the end-study visit, will be outpatient clinics (approximately 2h). Participants will be asked to take the studied drug once daily during the 6 months of the study period.
No comparison group is foreseen for this study.

开始日期2025-10-01

申办/合作机构

Centre Hospitalier Universitaire Vaudois

[+2]

100 项与恩格列净相关的临床结果

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100 项与恩格列净相关的转化医学

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100 项与恩格列净相关的专利（医药）

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4,651

项与恩格列净相关的文献（医药）

2025-12-31·JOURNAL OF MEDICAL ECONOMICS

Cost-utility analysis of empagliflozin for heart failure in the Philippines

Article

作者: Llanes, Elmer Jasper ; Salvador, Dante ; Añonuevo, John ; Montilla, Precious Juzenda ; Ong-Garcia, Helen ; Encarnacion, Patrick James ; Taneo, Mary Joy ; Orolfo, Diana Dalisay ; Aquino, Camilo Oliver ; Permejo, Chito ; Villanueva, Anthony Russell ; Cunanan, Elaine

AIMS:

Empagliflozin confers cardioprotective benefits among patients with heart failure, across the range of ejection fraction (EF), regardless of type 2 diabetes status. The long-term cost-effectiveness of empagliflozin for the treatment of heart failure (HF) in the Philippines remains unclear. This study aims to determine the economic benefit of adding empagliflozin to the standard of care (SoC) vs the SoC alone for HF in the Philippines.

METHODS:

Using a Markov model, we predicted lifetime costs and clinical outcomes associated with treating HF in the Philippine setting. We used estimates of treatment efficacy, event probabilities, and derivations of utilities from the EMPEROR trials. Costs were derived from hospital tariffs and expert consensus. Separate analyses were performed for patients with left ventricular EF > 40%, categorized under mid-range ejection fraction or preserved ejection fraction (HFmrEF/HFpEF), and patients with left EF ≤ 40%, categorized under HF with reduced ejection fraction (HFrEF).

RESULTS:

Our model predicted an average of 0.09 quality-adjusted life year (QALY) gains among HFmrEF/HFpEF patients and HFrEF patients when empagliflozin was compared to SoC. The addition of empagliflozin in the treatment results in a discounted incremental lifetime cost of PHP 62,692 (USD 1,129.99) and PHP 17,215 (USD 308.67) for HFmrEF/HFpEF and HFrEF, respectively. The incremental cost-effectiveness ratio (ICER) of empagliflozin is PHP 198,270 (USD 3,570.72)/QALY and PHP 742,604 (USD 13,385.08)/QALY for HFrEF and HFmrEF/HFpEF, respectively.

LIMITATIONS:

This study employed parameters derived from short-term clinical trial data, alongside metrics representative of Asian populations, which are not specific to the Philippine cohort.

CONCLUSIONS:

Adding empagliflozin to the SoC in comparison to the SoC is associated with improved clinical outcomes and quality-of-life, at additional costs for both HFrEF and HFmrEF/HFpEF.

2025-12-31·JOURNAL OF MEDICAL ECONOMICS

Cost-utility analysis of empagliflozin on chronic kidney disease progression in Thailand

Article

作者: Satirapoj, Bancha ; Susantitaphong, Paweena ; Singhan, Wanchana ; Ophascharoensuk, Vuddhidej ; Dilokthornsakul, Piyameth

OBJECTIVE:

The prevalence of chronic kidney disease (CKD) in Thailand is high and kidney disease progression remains a problem. Empagliflozin has been known to be used to slow CKD progression, but its accessibility remains limited. This study aimed to assess the cost-utility of empagliflozin for CKD progression in Thailand.

METHODS:

A state-transition model was developed consisting of eight health states: five eGFR health states (G2, G3a, G3b, G4, and G5), dialysis, kidney transplantation, and death. Empagliflozin 10 mg was assessed as an add-on treatment to standard of care (SoC). The efficacy of empagliflozin was derived from the EMPA-KIDNEY trial, while other inputs were obtained from a comprehensive literature review. The incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) was calculated. A probabilistic sensitivity analysis (PSA) was performed to explore uncertainties.

RESULTS:

Empagliflozin could improve QALYs by 0.62 and 0.71 for patients with CKD without and with diabetes mellitus (DM) compared with SoC, respectively. However, it required higher total lifetime costs of 77,966 Thai baht (THB) and 59,454 THB for patients with CKD without and with DM, respectively. The ICER for CKD without DM was 126,201 THB/QALY, while the ICER for CKD with DM was 83,473 THB/QALY. The PSA indicated that empagliflozin had a 64.00% probability of being cost-effective for CKD without DM and an 89.18% probability for CKD with DM.

LIMITATIONS:

An important limitation was that the treatment effects of empagliflozin were derived from the EMPA-KIDNEY, which was conducted in DM patients and assumed to be the same for non-DM patients because of the limited evidence in non-DM patients.

CONCLUSION:

At the current willingness-to-pay threshold of 160,000 THB/QALY, empagliflozin was cost-effective for treating patients with CKD without or with DM.

2025-12-01·Current Neurology and Neuroscience Reports

The Role of Diabetes and SGLT2 Inhibitors in Cerebrovascular Diseases

Review

作者: Moustafa, Bayan ; Trifan, Gabriela

PURPOSE OF REVIEW:

Diabetes is a well-established risk factor for stroke. Understanding the pathophysiology of this connection is crucial to implementing appropriate prevention strategies. Lately, there has been a paradigm shift in the care of individuals with diabetes toward the use of glucose-lowering medications with potential cardiovascular, cerebrovascular or cardiorenal benefits. The aim of this article is to provide a critical analysis of the role of diabetes in cerebrovascular disease and current evidence and recommendations for the use of glucose-lowering medication with particular focus on the sodium glucose cotransporter-2 inhibitor (SGLT2i) class.

RECENT FINDINGS:

Intensive glycemic control in individuals with diabetes reduces the risk of microvascular complications, but there is less clear evidence for decreasing risk of macrovascular events (e.g., stroke). A multifaceted management of diabetes addressing healthy lifestyle practices, glycemic control, and optimization of other cardiovascular risk factors is highly recommended. SGLT2i are the latest class of antihyperglycemic agents available for diabetes management. Canagliflozin and empagliflozin are associated with reduction in major adverse cardiovascular events (MACE). Dapagliflozin did not reduce the rate of MACE but is associated with reduction in heart-failure related death and hospitalization and has the potential to decrease dementia risk. Ertugliflozin decreases rates of hospitalization related to heart failure however it was non-inferior to placebo in reducing MACE. There is increasing evidence that the use of SGLT2i may reduce the risk of stroke, particularly hemorrhagic stroke, in individuals with type 2 diabetes and a high risk of cardiovascular events, and that SGLT2i may also be beneficial for brain health by decreasing risk of cognitive decline and dementia. Antihyperglycemic therapy should be tailored to patients' circumstances. SGLT2i treatment should be considered in patients with type 2 diabetes and established or high-risk cardiovascular disease, heart failure, or chronic kidney disease, to reduce the overall cerebro-cardiovascular and renal risks.

865

项与恩格列净相关的新闻（医药）

2025-07-15

·医学新视点

华山医院包丽雯：高血压合并糖尿病，优选这5类药物！

重点凝练高血压合并糖尿病并不是一道“加法题”，而是一道“乘法题”。高血压合并糖尿病患者的治疗，选择具有心血管以及肾脏保护作用的降压药物十分重要，如血管紧张素转换酶抑制剂及血管紧张素受体阻滞剂、盐皮质激素受体拮抗剂等。高血压及糖尿病是发生心血管疾病（CVD）的2个重要独立危险因素。当患者同时存在糖尿病合并高血压，他们发生CVD的风险及全因死亡风险比仅有糖尿病或仅有高血压的患者成倍增加，需要引起我们更多的重视及积极的干预。糖尿病患者容易出现高血压流行病学调查研究表明，患有胰岛素抵抗与糖尿病的患者不仅会出现以肥胖为代表的代谢异常，也更易出现高血压、动脉硬化。在2型糖尿病的队列研究及随机对照研究中，我们不难发现，其中约70%左右患者合并存在高血压；然而，在高血压的临床研究中，合并存在2型糖尿病的比例约为30%~50%。在李勇教授牵头的中国多中心横断面研究UPPDATE的数据分析中，在高血压患者中，合并糖尿病的比例大约为20.38%。由此，我们推测在2型糖尿病中，以胰岛素抵抗为代表的一系列病理生理变化会对高血压发生、发展产生深远影响，也有专家提出糖尿病性高血压这一定义。因此，本论述将主要从糖尿病性高血压的可能机制及糖尿病合并高血压的推荐治疗手段这两个方面入手，对高血压与糖尿病的cross-talk进行阐述。我们主要关注2型糖尿病。糖尿病性高血压的可能机制Framingham Offspring研究曾在1933例基线无高血压的患者中，观察胰岛素抵抗与高血压发生、发展的关系，在4年随访期间，即使调整了体重指数（BMI）增加这一混杂效应，胰岛素抵抗与高血压发生、发展也呈显著正相关。4701例参与者的队列研究发现，糖耐量受损和2型糖尿病人群发生动脉硬化的风险远高于血糖正常者，而胰岛素抵抗通过增加动脉僵硬度，进一步导致高血压及CVD发生。由此可见，以胰岛素抵抗为核心的病理生理改变是糖尿病性高血压的主要发生机制。▲胰岛素抵抗或为糖尿病性高血压的主要病理生理机制① RAAS过度激活体内和体外的观察研究发现，胰岛素抵抗会诱导RAAS过度激活，使得血管阻力及动脉压力增加；RAAS过度激活也可以通过损伤胰岛素信号通路影响血压。血管紧张素Ⅱ及醛固酮水平的上调会增加丝氨酸磷酸化水平，使得P13K通路活性下降，导致内皮细胞一氧化氮合成与激活能力降低，抑制一氧化氮介导的血管舒张作用。此外，激活的RAAS通过上调SGK-1通路，增加血管内皮钠离子通道（EnNaC）的活性，促进动脉硬化与高血压发生、发展。在临床研究中，我们发现在糖尿病人群中使用AT-1受体阻滞剂和盐皮质激素受体拮抗剂可以降低糖尿病患者高血压的发病率。▲RAAS激活可通过多途径影响动脉硬化及血压② 线粒体功能异常与过度的氧化应激线粒体生物合成障碍、自噬能力降低、线粒体产能下降等线粒体功能异常是2型糖尿病的主要病理生理改变之一，其所导致的内皮细胞功能异常是高血压发生、发展的主要原因。此外，NADPH氧化酶激活也是过量氧化应激产物（ROS）产生的重要来源，胰岛素抵抗可诱导血管内NADPH氧化酶激活，后者导致过量ROS生成，促使内皮衍生-舒张因子和内皮衍生-收缩因子失衡，使得血管张力增加，过量的ROS也会通过减少NO产生，促进动脉硬化和高血压发生、发展。因此，线粒体功能障碍和氧化应激是胰岛素抵抗和糖尿病状态下高血压发生、发展的重要机制之一。糖尿病合并高血压的推荐治疗手段如前所述，高血压与糖尿病是CVD的重要病因，选择具有心血管以及肾脏保护作用的降压药物十分重要。目前，各临床指南一致推荐，应当使用血管紧张素转换酶抑制剂及血管紧张素受体阻滞剂作为糖尿病患者合并高血压的一线用药。对于糖尿病合并存在难治性高血压患者，建议加用盐皮质激素受体拮抗剂（螺内酯、非奈利酮、依普利酮），此类药物被证实可以显著降低合并存在肾功能不全的2型糖尿病患者的心衰风险及肾功能进一步恶化风险。GLP-1受体激动剂（GLP1-RA）及钠-葡萄糖共转运蛋白2抑制剂（SGLT2i）可以显著降低2型糖尿病患者的心肾事件风险及全因死亡风险。临床研究也发现，这两类药物具有降低2型糖尿病患者血压的作用。GLP-1RA的降压作用猜测与其减重作用相关，SGLT2i的降压作用可能与排钠、排糖、生酮等作用相关，作为口服药物，SGLT2i在降压领域的研究比较全面。关于SGLT2i的荟萃分析一项荟萃分析发现，在2型糖尿病合并高血压和高血压前期的患者中，SGLT2i具有显著的降压疗效。这项荟萃分析纳入了2450例患者，与使用安慰剂相比，使用SGLT2i者其收缩压及舒张压（诊室血压）降幅分别为5.04 mmHg（95%CI：-3.79~-6.30，P＜0.01）和1.67 mmHg（95%CI：-2.45~-0.89，P＜0.01），其中恩格列净的降压幅度最大，并且其降压效果随着药物剂量的增加而增加。此项荟萃分析还对SGLT2i对血压变异度的影响做了相关研究。研究人员分析发现，SGLT2i降低平均日间收缩压的幅度（-4.57 mmHg，95%CI：-3.71~-5.43，P＜0.01）大于降低平均夜间收缩压的幅度（-2.8 mmHg，95%CI：-1.84~-3.76，P＜0.01）。此外，在亚组分析中，发现达格列净5 mg qd治疗14天，可以将血压从非杓型转变为杓型血压，但由于样本缺失，分析病例较少，尚不能形成可靠结论。关于恩格列净的RCT为了研究恩格列净在合并高血压的2型糖尿病患者中的降压效果，Hans团队进行了一项随机对照研究，证实了恩格列净在此人群中的显著降压效果。研究纳入825例患者，随机给予安慰剂、恩格列净10 mg及恩格列净25 mg，通过24小时动态血压监测观察恩格列净的降压效果。在随访的12周末，与安慰剂相比，10 mg恩格列净组的平均收缩压降幅为-3.34 mmHg，（95%CI：-4.78~-2.09mmHg，P＜0.001），25 mg恩格列净组的平均收缩压降幅为-4.16 mmHg（95%CI：-5.5~-2.83mmHg，P＜0.001)。▲恩格列净在研究中的降压幅度，恩格列净10 mg及25 mg 可以显著降低平均收缩压及舒张压小结由此，我们不难发现，高血压合并糖尿病并不是一道“加法题”，而是一道“乘法题”。在我们理解了两者合并带来了更多的心肾风险，以及糖尿病性高血压以“胰岛素抵抗为中心”可能机制后，在高血压合并糖尿病患者中，我们应当采用临床证据更加充分的药物——血管紧张素转换酶抑制剂及血管紧张素受体阻滞剂、盐皮质激素受体拮抗剂、SGLT2i、GLP1-RA，来管理这部分患者，以期获得更好的心肾保护作用。作者简介包丽雯复旦大学附属华山医院心内科副主任医师医学博士中国医学救援队队员华山医院内科学上海市住院医生规范化培训基地秘书中国高血压联盟理事，长三角心血管急重症联盟委员，中国微循环学会基层慢病管理委员会委员推荐阅读JAMA：治疗高血压，一针管半年！长效RNAi降压疗法联合用药，额外降压12 mmHg心血管死亡风险激增197%！最新研究发现，高血压合并糖尿病危害大，女性更需注意JAMA：强效降压近14 mmHg，66%患者血压达标！这种难治性高血压治疗药物值得关注站起来血压就升高？BMJ：强化降压有益于降低直立性高血压风险，无糖尿病获益更大全球13亿高血压患者新希望？新研究：降压潜在新选择，值得临床关注免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。分享，点赞，在看，传递医学新知

临床研究

2025-07-14

·FiercePharma

Bayer's Kerendia wins FDA label expansion to treat 2 types of heart failure

Already approved to reduce the risk of heart failure and other cardiovascular problems in patients with chronic kidney disease (CKD) associated with type 2 diabetes, Bayer's Kerendia has scored an FDA nod to treat patients with heart failure, regardless of whether they have CKD. The use of SGLT2 inhibitors has been a game-changer in the treatment of heart failure (HF). Now, another drug class has reached the market that could further alter the HF landscape.The FDA has expanded the label of Bayer’s Kerendia, a nonsteroidal selective mineralocorticoid receptor antagonist (MRA), to include treatment of patients with two types of heart failure. Kerendia can now be used by HF patients with either preserved ejection fraction (HFpEF) or mildly reduced ejection fraction (HFmrEF).The U.S. regulator originally approved Kerendia four years ago to reduce the risk of kidney function decline, kidney failure, cardiovascular death, non-fatal heart attacks, and hospitalization for heart failure in adults with chronic kidney disease (CKD) associated with type 2 diabetes.The new nod allows Kerendia to be given to HF patients who do not have CKD linked to type 2 diabetes.“Patients with heart failure with mildly reduced EF and heart failure with preserved EF historically have had very limited treatment options,” Alanna Morris-Simon, M.D., Bayer’s senior medical director of U.S. medical affairs, said in an interview. “We’re excited that Kerendia really hopefully will provide a benefit for a very large patient population—larger than we’ve seen based on our current indication.”HF patients are classified by the ability of their hearts to fill with and pump blood. The measurement tool is left ventricle ejection fraction (LVEF). Those with an LVEF of between 40% and 50% have HFmrEF. Those with an LVEF greater than 50% have HFpEF. With these patients, the heart muscle contracts properly but the ventricles don’t relax.Kerendia has not been approved for those with an LVEF of less than 40%. These patients have reduced ejection fraction (HFrEF), which means the heart muscle doesn’t contract properly. While treating HFrEF is relatively straightforward, developing effective medicines for those with HFpEF and HFmrEF has been more difficult. After decades of trial failures, the first drugs to show significant benefits in the more troublesome HF indications were the SGLT2 inhibitors, a group that includes Eli Lilly and Boehringer Ingelheim's Jardiance and AstraZeneca's Farxiga.“It takes sometimes more time for clinicians to recognize that this is heart failure when they’re dealing with a preserved ejection fraction,” Morris-Simon said. “One of the other reasons why we struggled as a scientific community is we took a lot of the medicines that worked really well in HFrEF—the reduced EF where the heart is weak—and said, ‘OK, let’s try those in HFpEF and see if they work.’ And in fact, they didn’t work.” Jardiance and Farxiga were originally approved to treat type 2 diabetes and then were later blessed for all types of HF. The added indications helped boost sales of the treatments to $12.4 billion and $7.7 billion, respectively, in 2024, according to Drug Discovery & Development.As for Bayer, the company is now projecting peak annual sales of Kerendia to reach $3 billion.As an MRA, Kerendia works as a diuretic, decreasing sodium reabsorption in the kidneys, which triggers increased water excretion and leads to lower blood pressure and a reduction in fluid around the heart.“When you have heart failure there are different hormones that circulate in your blood that kind of mess up the way that your heart and your kidney talk to each other,” Morris-Simon said. “A drug like Kerendia enables the heart and the kidneys to talk to each other in a much more efficient way by blocking one of those bad hormones.” Paving the way for Kerendia’s expansion was the FINEARTS-HF phase 3 trial, in which patients received the treatment or placebo on top of standard of care therapy. Kerendia showed a 16% reduction in the risk of cardiovascular death or an HF event compared with placebo. The results were comparable to risk reductions seen in the trials that led to label expansions for Jardiance and Farxiga. The results in the FINEARTS-HF study were consistent across all prespecified subgroups. It was particularly noteworthy that patients at baseline using an SGLT2 inhibitor—the only treatment option with a strong guideline recommendation in this population—saw the same primary outcome results as those not on one.

临床结果上市批准临床3期

2025-07-14

·药事纵横

同样是多肽，为什么司美格鲁肽可以口服，而胰岛素却不行

2019年9月20号，FDA批准口服版司美格鲁肽Rybelsus上市，标志着世界上第一款、也是唯一一款口服GLP-1类似物的诞生，根据诺德诺德年报显示，上市后Rybelsus 2020年到2022年的销售额分别为18.73亿、48.38亿以及112.99亿丹麦克朗，分别约合美金2.64亿、6.83亿以及15.95亿，年增长率均超100%。该药物的成功上市，不禁又让我们回忆起了口服多肽的心酸发展史：根据IQVIA的数据显示，2007年全球多肽药物市场规模约123.9亿美元，到2020 年达430 亿美元，每年增长率在10%-16%之间，并呈现逐年递增趋势。如此庞大的市场规模，对应的给药方式却非常单调，基本以注射为主，能够口服进行给药的多肽类药物寥寥无几，那么问题来了，口服多肽类药物在开发过程中到底面临着何种挑战？同样都是控制血糖的多肽类药物，为什么司美格鲁肽可以口服，而胰岛素却不行呢？口服多肽面临的障碍在聊口服司美格鲁肽和胰岛素之前，我们先来简单了解一下口服多肽面临的障碍，总结来说主要包括生物化学障碍、黏膜障碍和细胞转运障碍[1]。生物化学障碍中消化酶和pH值变化是主要的生物化学障碍：其实从多肽药物进入口腔开始就开始接触到各种各样的消化酶，但因为唾液淀粉酶作用时间较短，因此药物在口腔内基本不会降解。但当多肽进入胃内后，就会受到低pH值（PH=1 - 3）和各种胃蛋白酶的影响，而影响时间的长短主要取决于药物类型、胃内食物量、食物的粘度和蛋白含量等因素。而当多肽药物通过胃排空进入小肠后，又会受到小肠内各种蛋白酶的影响，如胰蛋白酶、糜蛋白酶、弹性蛋白酶、羧肽酶A和B等。因此如果要通过口服对多肽药物进行递送，则首先要保护多肽药物免受pH值及胃肠道各种蛋白酶的影响。黏膜障碍，则是指人体胃肠道表面覆盖的一层高度复杂的黏液层会对药物的吸收产生明显的阻碍，该黏液由杯状细胞分泌，主要由黏蛋白组成，负责润滑摄入的食物、维持上皮细胞的水化层以及防止病原体和外来物质进入上皮细胞。对于多肽类药物而言，药物分子只有穿透黏液层才能通过上皮细胞进行吸收，而药物在黏液层的穿透性主要由药物的颗粒大小和所带电荷决定。比如黏液层的孔隙率在25-200nm之间，且黏蛋白带有负电荷，因此尺寸在此范围内且带有正电荷的药物颗粒更易透过黏液层。而成功穿过黏液层的药物会以两种方式穿过上皮细胞：细胞旁转运和跨细胞转运。由于上皮细胞间存在紧密连接、粘附连接以及细胞桥粒，因此细胞旁转运只适合分子量相对较小（≤20 kDa）的多肽分子，且有研究证明带负电荷的分子更易通过细胞旁转运。而跨细胞转运中主要存在的障碍是多肽药物分子在进入小肠上皮细胞后可能会被当做是外来分子，从而被细胞内的蛋白酶水解，或被再次排出小肠细胞，这些情况都会对药物的生物利用度产生影响。口服司美格鲁肽Rybelsus司美格鲁肽是由一种30个氨基酸组成的多肽，分子量为4113.58 Da，与天然GLP-1序列同源性高达94%。诺和诺德通过对三个关键位置进行修饰来延长体内的半衰期：首先使用α-氨基异丁酸取代第8位的丙氨酸，从而使司美格鲁肽不易被二肽酶-4水解，其次在第26位的赖氨酸上连接了一个C18脂肪二酸侧链，并以谷氨酸作为连接头，目的是增加白蛋白的亲和力，避免药物被肾脏快速清除；最后使用精氨酸取代第34位的赖氨酸，目的是避免C-18脂肪酸链错位结合，提高侧链的稳定性。而司美格鲁肽口服剂型的成功开发，则离不开吸收促进剂-SNAC的功劳。SNAC是由美国Emisphere公司于20世纪90年代开发的一种具有两亲性的吸收促进剂，全称为Sodium N-(8-[2-hydroxybenzoyl]amino) caprylate。在SNAC成功合成之后Emisphere选取了一系列渗透性差的药物进行测试，这其中普通肝素的口服递送是SNAC第一个应用案例，然而令人遗憾的是，在Ⅲ期临床试验中口服配方相比于皮下注射而言并未显示出更优越的疗效，因此该产品最终并未上市。SNAC成功应用的第一个案例为2014年FDA批准上市的口服维生素B12（Eligen B12）。对于司美格鲁肽而言，由于其分子量低、半衰期长且效力较高，因此成为了SNAC口服配方的理想候选药物。其作用机制如下图所示：首先当司美格鲁肽药片在胃内崩解后，SNAC通过缓冲作用增加局部pH值，通过降低胃蛋白酶原向胃蛋白酶的转化来降低司美格鲁肽的降解；其次，溶解后的SNAC可以改变局部溶液的极性，从而减弱司美格鲁肽由于疏水相互作用而引起的寡聚化；最后SNAC可以通过流化胃上皮细胞细胞膜来促进司美格鲁肽的跨细胞膜转运[3]。Rybelsus的临床试验（PIONEER系列）结果如下图所示，从结果中我们可以看到，在控制血糖方面，不管是对于糖尿病早期病人、中期病人还是长期病人，与安慰剂相比口服3mg、7mg和14mg司美格鲁肽治疗26周之后均能有效的降低糖化血红蛋白（HBA1c）水平，并且降低幅度与剂量呈正相关，剂量越高降幅越大，同时与经典降糖药物恩格列净和西他列汀相比，口服14mg司美格鲁肽均显示出更优的降糖效果，如在PIONEER 7 Flex试验中，口服司美格鲁肽治疗52周之后HBA1c的降幅达1.3%，而对照组西他列汀只有0.8%；而在减重方面口服司美格鲁肽同样表现不俗，在PIONEER 1试验中，口服3mg、7mg和14mg司美格鲁肽可分别使体重降低1.5kg、2.3kg和3.7kg[3]。口服胰岛素1921年，Frederick等人在多伦多大学首次发现了胰岛素，随后科学家们便开启了漫长的口服给药研发之旅。根据文献的记载，就在胰岛素被发现的第二年Joslin博士便开启了一项由礼来公司为其准备的口服胰岛素的有效性研究，但结果发现随着口服胰岛素剂量的升高，该患者的新陈代谢却再次恶化，于是一周后Joslin博士便停止了该试验[4]。结构上胰岛素由两条肽链组成：其中A链由21个氨基酸组成，而B链由30个氨基酸组成，两条肽链由2个二硫键连接，分子量约为5808 Da。令人遗憾的是100多年过去了，尽管科学家们尝试了各种新型辅料和递送技术，但截至目前全球还未有任何一款口服胰岛素产品上市。与司美格鲁肽一样，初期SNAC也同样被用于开发口服胰岛素，因为根据部分文献报道，SNAC对于胰岛素的跨细胞转运同样具有促进作用：从下图中我们可以看到，在向配方中加入SNAC后，SNAC可以将胰岛素透过Caco-2单层细胞的渗透率增加约10倍，并且在基底侧并未发现明显的乳酸脱氢酶累计（Lactate Dehydrogenase，LDH），通常来说乳酸脱氢酶可作为细胞毒性的标识，这就初步说明SNAC可以促进胰岛素的细胞透过性，且不会引起细胞损伤。其次从图D中我们可以看到，SNAC的存在并不会引起甘露醇的增加，而甘露醇一般被作为细胞旁转运的标识，说明胰岛素基本都是通过跨细胞途径转运的[5]。基于上述的理论研究，Emisphere开展了一系列Ⅰ&Ⅱ临床试验，来证明通过Eligen技术口服递送胰岛素的安全性和有效性。与此同时，诺和诺德也看中了Eligen技术的潜在价值，与Emisphere签订了多个独家开发协议，用于诺和诺德胰岛素和GLP-1激动剂的口服开发。然而令人遗憾的是，在早期临床试验中Emisphere发现，与皮下注射相比口服胰岛素的吸收速度要快得多(Tmax分别是27min和161min)，并且口服胰岛素的清除速度也要快得多(2小时内)，说明口服胰岛素虽然起效快但作用时间却非常短，且口服的生物利用度仅为注射的3%。而在后续为期90天的Ⅱ期临床试验中，Emisphere发现口服胰岛素并不能改善2型糖尿病患者的代谢控制，因此暂时终止了口服胰岛素的开发[6]。因此总结来说，相比于司美格鲁肽而言，口服胰岛素存在的难点首先在于胰岛素分子量更高，更高的分子量就意味着细胞跨膜运输的难度将更高；并且由于胰岛素是由两条肽链组成的，具有一定空间构象，在口服过程胰岛素需要通过口腔、胃和小肠等一系列消化道，其中任何会引起构象改变的因素均会影响生物利用度。并且我们需要知道的是，即使是司美格鲁肽其口服的生物利用度也仅为0.8%，因此如何通过新技术与新辅料来进一步提高口服胰岛素的生物利用度，仍是摆在科研工作者面前的一道难题。参考文献：1. Jash A, Ubeyitogullari A, Rizvi S S H. Liposomes for oral delivery of protein and peptide-based therapeutics: challenges, formulation strategies, and advances[J]. Journal of Materials Chemistry B, 2021, 9.DOI:10.1039/D1TB00126D.2. Kalra S, Sahay R. A Review on Semaglutide: An Oral Glucagon-Like Peptide 1 Receptor Agonist in Management of Type 2 Diabetes Mellitus[J].Diabetes Therapy, 2020(9).DOI:10.1007/s13300-020-00894-y.3. Aroda V R, Blonde L, Pratley R E. A new era for oral peptides: SNAC and the development of oral semaglutide for the treatment of type 2 diabetes[J].Reviews in endocrine & metabolic disorders, 2022, 23(5):979-994.DOI:10.1007/s11154-022-09735-8.4. Heinemann L, Jacques Y. Oral Insulin and Buccal Insulin: A Critical Reappraisal[J].Journal of diabetes science and technology, 2009, 3(3):568-584.DOI:10.1177/193229680900300323.5. Dmitry Malkov, Robert Angelo, Huai-zhen Wang, Elizabeth Flanders, Heather Tang, Isabel Gomez-Orellana. Oral delivery of insulin with the eligen technology: mechanistic studies.[J].Current Drug Delivery, 2005, 2(2):-.DOI:10.2174/1567201053586001.6. Zijlstra E, Heinemann L, Plum-Morschel L. Oral Insulin Reloaded: A Structured Approach[J].Journal of Diabetes Science & Technology, 2014, 8(3):458-465.DOI:10.1177/1932296814529988.药事纵横投稿须知：稿费已上调，欢迎投稿

上市批准核酸药物

100 项与恩格列净相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10459	恩格列净	A10BK03	DB09038

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
心血管疾病	中国	Boehringer Ingelheim GmbH	2023-05-26
心血管疾病	中国	Boehringer Ingelheim International GmbH	2023-05-26
射血分数保留型心力衰竭	中国	Boehringer Ingelheim International GmbH	2022-08-30
射血分数保留型心力衰竭	中国	勃林格殷格翰（中国）投资有限公司	2022-08-30
射血分数降低的心力衰竭	中国	Boehringer Ingelheim GmbH	2022-06-10
射血分数降低的心力衰竭	中国	Boehringer Ingelheim International GmbH	2022-06-10
慢性心力衰竭	欧盟	Boehringer Ingelheim International GmbH	2014-05-22
慢性心力衰竭	冰岛	Boehringer Ingelheim International GmbH	2014-05-22
慢性心力衰竭	列支敦士登	Boehringer Ingelheim International GmbH	2014-05-22
慢性心力衰竭	挪威	Boehringer Ingelheim International GmbH	2014-05-22
慢性肾病	澳大利亚	Boehringer Ingelheim Pty Ltd.	2014-04-30
2型糖尿病	澳大利亚	Boehringer Ingelheim Pty Ltd.	2014-04-30
心脏衰竭	澳大利亚	Boehringer Ingelheim Pty Ltd.	2014-04-30

未上市

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适应症	最高研发状态	国家/地区	公司	日期
先天性心脏缺损	临床3期	加拿大	Boehringer Ingelheim GmbH	2025-05-01
肾性糖尿	临床3期	-	Tanta University	2023-01-01
精神分裂症	临床3期	-	Tanta University	2023-01-01
非酒精性脂肪性肝炎	临床3期	埃及	Tanta University	2022-11-01
低血糖	临床3期	瑞士	Boehringer Ingelheim GmbH	2022-03-11
急性心肌梗塞	临床3期	美国	Boehringer Ingelheim Pharma GmbH & Co., KG	2020-12-16
急性心肌梗塞	临床3期	美国	Boehringer Ingelheim International GmbH	2020-12-16
急性心肌梗塞	临床3期	美国	Eli Lilly & Co.	2020-12-16
急性心肌梗塞	临床3期	美国	Boehringer Ingelheim GmbH	2020-12-16
急性心肌梗塞	临床3期	中国	Eli Lilly & Co.	2020-12-16

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05262764 (Pubmed \| Expert Opin Drug Saf)	N/A	心脏衰竭 type 2 diabetes	-	Empagliflozin	觸憲網鹽鏇衊積襯獵壓(齋糧憲願蓋蓋製膚鏇醖) = 簾鏇獵膚壓膚簾鹹窪襯醖艱選夢蓋鬱繭齋壓醖 (憲鬱夢遞廠窪壓鹽醖鑰 ) 更多	积极	2025-06-18
NCT03753087 (Pubmed \| Cardiovasc Diabetol)	临床4期	2型糖尿病 \| 射血分数保留型心力衰竭 N-terminal pro-brain natriuretic peptide (NT-proBNP) \| sST2	70	Empagliflozin 10 mg	構窪鏇鬱簾鏇選廠壓鑰(願築餘壓夢網遞窪網膚) = 觸積鏇膚範鹹顧憲選積窪醖衊壓衊壓簾願膚繭 (衊鹽膚獵網醖觸醖鹽獵 )	积极	2025-05-09
				empagliflozin (Control Group)	構窪鏇鬱簾鏇選廠壓鑰(願築餘壓夢網遞窪網膚) = 獵鑰鹹窪齋獵願醖範襯窪醖衊壓衊壓簾願膚繭 (衊鹽膚獵網醖觸醖鹽獵 )
NCT05282121 (CTgov)	临床2期	甲型肝炎 \| 食管胃静脉曲张 \| 非酒精性脂肪性肝炎 ... 更多	90	Avenciguat (Patients With HBV - Avenciguat)	鹹齋顧鏇廠憲觸築構遞(鬱築窪顧艱顧壓構網膚) = 簾憲遞淵艱衊鑰遞夢顧顧糧膚襯製夢蓋繭網醖 (膚齋網糧簾蓋範膚選蓋, 6.66) 更多	-	2025-04-29
				Avenciguat (Patients With HCV - Avenciguat)	鹹齋顧鏇廠憲觸築構遞(鬱築窪顧艱顧壓構網膚) = 顧鹽網範蓋鹽壓憲餘選顧糧膚襯製夢蓋繭網醖 (膚齋網糧簾蓋範膚選蓋, 7.09) 更多
NCT03485092 (SUGAR-DM-HF, Pubmed \| Eur J Heart Fail)	临床4期	射血分数降低的心力衰竭	105	Empagliflozin 10 mg	觸糧製顧顧憲廠積製壓(蓋夢鬱艱壓觸廠積憲鏇) = 艱鏇窪遞遞繭鏇淵簾鑰鏇窪憲憲獵構鏇糧願鑰 (鹽範獵網壓壓範簾鏇繭, 2.5)	积极	2025-01-10
				Placebo	-
NCT04509674 (EMPACT-MI, CTgov)	临床3期	心脏衰竭 \| 急性心肌梗塞	6,522	Placebo (Placebo)	糧製製鑰鹹鑰繭鬱餘淵 = 遞醖網夢餘餘鹽積積鬱膚醖餘廠壓遞構觸艱憲 (獵獵獵鑰構鏇構窪鏇獵, 夢壓簾願壓製製蓋窪膚 ~ 襯夢鏇糧鹹憲淵窪選簾) 更多	-	2025-01-07
				Empagliflozin (Empagliflozin 10 mg)	糧製製鑰鹹鑰繭鬱餘淵 = 膚窪鹽壓憲築簾構鬱選膚醖餘廠壓遞構觸艱憲 (獵獵獵鑰構鏇構窪鏇獵, 構遞淵壓壓艱窪餘糧衊 ~ 製遞鬱範糧糧壓獵顧膚) 更多
NCT03594110 (EMPA-KIDNEY, Pubmed \| N Engl J Med)	临床3期	慢性肾病 estimated glomerular filtration rate (eGFR) \| urinary albumin-to-creatinine ratio	6,609	Empagliflozin 10 mg	積網醖遞憲觸憲鬱夢積(襯遞夢餘鹽觸獵壓蓋鬱) = 艱製窪願構鬱窪淵憲衊願壓繭醖鬱鑰築餘壓願 (齋範構鹽窪範淵繭壓築 ) 更多	积极	2024-10-25
				Placebo	積網醖遞憲觸憲鬱夢積(襯遞夢餘鹽觸獵壓蓋鬱) = 糧鬱醖遞範製範窪鏇範願壓繭醖鬱鑰築餘壓願 (齋範構鹽窪範淵繭壓築 ) 更多
NCT03087773 (EMMY, Pubmed \| Clin Res Cardiol)	临床3期	心肌梗塞	313	Empagliflozin	鬱鑰膚憲襯衊夢廠鹹艱(網願範遞鹹夢簾構夢遞) = parameters for diastolic function showed a distinct trend between groups but did not meet statistical significance in this cohort 餘襯築蓋醖餘選淵膚憲 (窪觸齋製繭醖網膚繭廠 ) 更多	积极	2024-09-16
				Placebo
NCT04509674 (EMPACT-MI, NEWS) 人工标引	临床3期	急性心肌梗塞	-	Empagliflozin	選積鹽餘窪獵製網鹹積(壓願膚鏇廠選艱壓餘顧) = 獵壓餘廠繭繭衊鹽製鏇範簾鏇繭鏇網獵糧淵積 (窪繭壓簾醖淵遞網鬱簾 )	积极	2024-09-09
				Placebo	選積鹽餘窪獵製網鹹積(壓願膚鏇廠選艱壓餘顧) = 艱鏇壓鬱糧衊艱製艱鬱範簾鏇繭鏇網獵糧淵積 (窪繭壓簾醖淵遞網鬱簾 )
ESC2024	N/A	-	-	Empagliflozin 25mg	餘膚簾淵鬱簾網衊構壓(鑰顧願糧艱選製遞遞鹽) = 13.3% experiencing mostly Level 1 hypoglycemia 範窪顧餘齋艱憲鬱獵簾 (壓範鏇淵繭簾簾積鹹顧 ) 更多	-	2024-09-02
ESC2024	N/A	-	-	Empagliflozin 10 mg	膚範淵積淵窪鏇醖餘簾(糧膚夢壓艱積繭憲鏇繭) = 膚糧廠鹽觸廠鏇糧鏇鑰顧願鹹繭顧壓糧範構遞 (繭糧鬱鬱築製網顧遞鹹, 6)	-	2024-09-02