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维格列汀--抗糖尿病新药
2007年9月28日，诺华公司宣布其口服抗糖尿病新药维格列汀(vildagliptin，商品名：Galvus)获得欧盟委员会批准，将在27个欧盟国家及挪威和爱尔兰上市。
其化学名为1-[[(3一羟基一l一金刚烷基)氨基]乙酰基]-2-氰基一(5)-四氢吡咯烷，分子式为c17H15N3O2，相对分子质量为303．
本品与默克公司2006年FDA批准上市的西他列汀(sitagliptin，Januvia)同属IV型二肽基肽酶(DPP_4)抑制剂。
药理作用
本品是一种具有选择性、竞争性、可逆的DPP_4抑制剂。葡萄糖依赖性促胰岛素多肽(GIP)和胰高血糖素样多肽．1(GLP．1)是维持体内葡萄糖浓度的重要激素，都具有肠促胰岛素作用。2型糖尿病患者GIP的促胰岛素分泌作用受损，仅有GLP·l能发挥促胰岛激素分泌作用，它通过作用于胰岛B细胞膜上的受体，促进胰岛素的分泌。GLP．1还可抑制胰高fliL糖素的分泌以及抑制胃排空从而增加饱足感(抑制食欲)。DPP4与蛋白结合存在于许多组织中，如肾、肝、小肠膜的刷状边缘、胰管、淋巴细胞、内皮细胞，其能通过水解GLP-1的N端第2位丙氨酸迅速使其失活。
本品通过与DPP一4结合形成DPP一4复合物而抑制该酶的活性，在提高GLP-l浓度，促使胰岛B细胞产生胰岛素的同时，降低胰高血糖素浓度，从而降低血糖。且对体重无明显影响。
药动学
健康人体药动学研究表明，口服本品吸收迅速，生物利用度约为85％。达峰时间为给药后1—2h，血浆半衰期为1．5—4．5h，蛋白结合率低(4％～17％)。其体内过程具有线性药动学特征，多次口服给药后未出现药物蓄积，其药动学参数不受食物影响。
本品代谢途径较多，大部分药物(55％)通过肝水解(氰基水解)灭活，主要代谢产物LAYl51无药理活性。很少一部分母体药物由CYP450酶系统代谢。本品主要通过尿排泄，尿中含有18％一22％的原型药物。
单次服用本品(25～200mg)可迅速抑制血浆中DPP．4活性，30～60min可抑制90％DPP4的活性。DPP-4抑制作用持续时间具有剂量依耐性，口服50和loomg本品后，12h内DPP4活性抑制可分别达70％和90％；口服100mg，24h仍可抑制40％的DPP4活性。肝功能异常患者使用本品无需调整剂量。
临床研究
单药治疗
Pratley等评估2型糖尿病患者单用本品治疗12周的疗效。纳入标准：年龄≥30岁，且先期仅通过饮食控制，空腹血糖浓度1．1—2．7g-L“(6．1一15mmo卜L。1)，糖基化血红蛋白(HbAh)值6．8％一11％，体重指数(BMI)为20一40kg·m～。随机分为本品25mg，bid组(凡=70)和安慰剂组(n=28)，口服给药。结果：12周后，本品组对脂水平无影响，空腹及餐后血糖浓度都显著下降，同时提高了B细胞的功能，且未引起体重的改变。两组在体重上无显著差异，不良反应发生率相似。
在另一个12周的双盲、剂量效应试验中，Ristic等评估了本品对HbA。。的作用效果、安全性以及耐受性。患者随机分为5组：本品25mg(qd)组(乃=51)，25mg(bid)组(，I=54)，50mg(qd)组(n=53)，100mg(qd)组(，l=63)及安慰剂组(n=58)．。结果表明，本品50mg和100mg(qd)组能有效降低HbA。值，且100mg(qd)组B细胞功能(B细胞分泌功能指数，HOMA—B)显著提高，并显示出良好的安全性和耐受性。表明更高剂量的本品降血糖作用可能与B细胞功能的提高有关。各组不良反应的发生率相似。
联合用药
与二甲双胍联用¨叫在一个随机、双盲、多中心对照试验中，纳入标准为：持续使用二甲双胍(剂量≥l500mg·d一)且血糖控制并不理想[HbA。。7．5％一11％]的2型糖尿病患者，分为3组：二甲双胍联合本品50mg·d“组(n=177)和100mg-dil组(n=185)，二甲双胍联合安慰剂组(，l=182)，治疗24周。结果表明：应用二甲双胍未能很好控制血糖的2型糖尿病患者加用本品能使空腹血糖和AIc均呈剂量相关性地降低，且耐受性良好。
另一项52周的研究评价了本品对B细胞功能的影响。2型糖尿病患者随机分为两组：本品(50mg，qd)联合二甲双胍组(n=31)，安慰剂联合二甲双胍组(，l=26)，二甲双胍剂量为1．5—3．0mg-d～。通过计算适应指数(评价p细胞功能敏感性的参数)评价B细胞功能。结果表明本品联合二甲双胍能提高2型糖尿病患者的B细胞功能及餐后胰岛素的敏感度。
与匹格列酮联用
一个24周多中心、随机双盲对照试验研究考察了本品与匹格列酮联合应用的有效性和耐受性。纳入463例先前单独使用匹格列酮(45mg·d。1)控制血糖无效的2型糖尿病患者，在加用本品(50或100mg·d。)和安慰剂后通过协变量分析的模式进行有效性参数分析。结果与安慰剂相比，本品两种剂量均能显著增加胰岛素的释放率。表明：本品与最大剂量的匹格列酮联用仍有效，耐受性良好，且并未增加低血糖的发生率。3．2．3与胰岛素联用¨引一个24周、多中心、随机双盲临床试验中，纳入使用胰岛素(>30u·d“)治疗，且HbA，，值为7．5％一11％，在试验前3个月内未使用口服抗糖尿病药物的2型糖尿病患者，试验期间胰岛素剂量允许调整。随机分为两组：联合本品50mg(bid)治疗组(凡=125)和安慰剂治疗组(n=131)。结果表明：2型糖尿病患者特别是老年患者，尽管出现临床胰岛素抵抗，应用胰岛素联合本品能显著降低HbA，，值，且低血糖的发生率及严重性显著低于单用胰岛素，这可能与p细胞功能的改善有关，尚需进一步研究。
不良反应和药物相互作用
本品最常见的不良反应有头痛、鼻咽炎、咳嗽、便秘、头晕和增加出汗量等。低血糖的发生率与安慰剂相似。
Colleen等副报道，格列本脲10mg·d一与本品100mg(bid)联合服用28d，并无药物代谢方面的相互作用，且无低血糖报道。此外评估了吡格列酮45mg·d“和本品100mg·d。联合使用28d的安全性和药动学，通过测定联合治疗前与治疗期间吡格列酮和本品的血药浓度，发现两种药物的血药浓度在任何时间点均无显著改变。表明格列本脲或吡格列酮与本品联合应用都是安全的。
本品在临床试验中显示了相对的安全性，但DPP4酶存在于很多组织中，它作为人体多种激素和肽的酶作用底物，其长期抑制是否对这些物质有影响，还需进一步研究。
结语
综上所述，本品具有降低HbA1c、空腹及餐后血糖水平、餐后胰高血糖素分泌及提高B细胞功能的作用，为2型糖尿病患者的治疗提供了新选择。该药与其他药物联合使用的安全性和有效性，禁忌证、不良反应等还有待于更多的临床研究观察。
How does it work?
Galvus tablets contain the active ingredient vildagliptin, which is a type of medicine called a dipeptidyl peptidase-4 (DPP-4) inhibitor. It is used to treat type 2 or non-insulin dependent diabetes (NIDDM).
Vildagliptin works by increasing the amount of two incretin hormones found in the body, called glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These hormones are normally produced naturally by the body in response to food intake. Their function is to help control blood sugar (glucose) levels.
GLP-1 and GIP have two main actions that help to control blood glucose.
Firstly, they stimulate the pancreas to produce insulin in response to increasing levels of glucose in the blood. (Insulin is the main hormone responsible for controlling sugar levels in the blood. It causes cells in the body to remove sugar from the blood.)
GLP-1 also reduces the production of glucagon. (Glucagon is a hormone that normally increases glucose production by the liver.)
GLP-1 and GIP are normally broken down by an enzyme in the body called dipeptidyl peptidase-4 (DPP-4). Vildagliptin works by binding to this enzyme and preventing it from breaking down the GLP-1 and GIP. This increases the levels of these hormones in the body and so increases their effect on controlling blood sugar.
What is it used for?
Type 2 diabetes (non-insulin dependent diabetes).
Galvus is used for people with type 2 diabetes whose blood sugar is not sufficiently controlled by other antidiabetic medicines. It can be added to treatment with metformin; a sulphonylurea, for example gliclazide; or another type of antidiabetic medicine known as a thiazolidinedione, for example pioglitazone or rosiglitazone.
Warning!
Hypoglycaemia (low blood glucose) has been commonly reported when this medicine is used in combination with metformin or sulphonylurea medicines, eg glimepiride. Symptoms of hypoglycaemia usually occur suddenly and may include cold sweats, cool pale skin, tremor, anxious feeling, unusual tiredness or weakness, confusion, difficulty in concentration, excessive hunger, temporary vision changes, headache, nausea and palpitations. You should talk to your doctor or diabetes specialist about this and make sure you know what to do if you experience these symptoms.
Your ability to concentrate or react may be reduced if you have low blood sugar, and this can cause problems driving or operating machinery. You should take precautions to avoid low blood sugar when driving - discuss this with your doctor. This medicine may also cause dizziness or fatigue. If affected you should take care driving or operating machinery.
People with diabetes have a higher risk of developing foot ulcers and blistering of the skin. It is therefore important to have a good foot care routine. Consult your doctor if you get any new blisters or ulcers while taking this medicine.
Rare cases of inflammation of the liver (hepatitis) have been reported in people taking this medicine. For this reason, your liver function should be checked before starting treatment, every three months during the first year of treatment, and regularly thereafter. You should consult your doctor if you develop any of the following symptoms while taking this medicine, so that your liver can be checked: unexplained nausea, vomiting, abdominal pain, fatigue, loss of appetite, darkened urine or yellowing of the eyes or skin (jaundice).
Use with caution in
People over 75 years of age.
People with mild heart failure.
People taking ACE inhibitor medicines, eg captopril.
Not to be used in
Type 1 diabetes.
Diabetic ketoacidosis.
Decreased liver function.
Pregnancy.
Breastfeeding.
This medicine is not recommended for people receiving dialysis or who have moderate to severe kidney disease.
This medicine is not recommended for people with severe heart failure.
This medicine is not recommended for children and adolescents under 18 years of age because it has not been studied in this age group.
This medicine contains lactose and should not be taken by people with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
This medicine should not be used if you are allergic to one or any of its ingredients. Please inform your doctor or pharmacist if you have previously experienced such an allergy.
If you feel you have experienced an allergic reaction, stop using this medicine and inform your doctor or pharmacist immediately.
Pregnancy and breastfeeding
Certain medicines should not be used during pregnancy or breastfeeding. However, other medicines may be safely used in pregnancy or breastfeeding providing the benefits to the mother outweigh the risks to the unborn baby. Always inform your doctor if you are pregnant or planning a pregnancy, before using any medicine.
The safety of this medicine for use during pregnancy has not been established. It should not be used during pregnancy. Diabetes mellitus is usually controlled using insulin during pregnancy, because this provides a more stable control of blood sugar. If you get pregnant while taking this medicine, or are planning a pregnancy, you should seek medical advice from your doctor.
It is not known if this medicine passes into breast milk. The manufacturer states that it should not be used by breastfeeding mothers. Seek medical advice from your doctor.
Side effects
Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects that are known to be associated with this medicine. Just because a side effect is stated here does not mean that all people using this medicine will experience that or any side effect.
Common (affect between 1 in 10 and 1 in 100 people)
Tremor (when used with metformin or a sulphonylurea).
Headache (when used with metformin or a sulphonylurea).
Dizziness (when used with metformin or a sulphonylurea).
Low blood sugar levels (when used with metformin or a sulphonylurea).
Nausea (when used with metformin).
Feeling weak (when used with a sulphonylurea).
Weight gain (when used with a glitazone).
Swelling of the legs and ankles due to excess fluid retention (when used with a glitazone).
Uncommon (affect between 1 in 100 and 1 in 1000 people)
Fatigue (when used with metformin).
Constipation (when used with a sulphonylurea).
Headache (when used with a glitazone).
Feeling weak (when used with a glitazone).
Rare (affect between 1 in 1000 and 1 in 10,000 people)
Changes in liver function.
Inflammation of the liver (hepatitis).
Allergic reaction called angioedema, which may involve swelling of the face, tongue or throat, difficulty swallowing or breathing, rash or hives (stop taking this medicine and consult your doctor immediately if you experience these symptoms).
Very rare (affects less than 1 in 10,000 people)
Inflammation of the nose and throat, causing a blocked or runny nose and sore throat (nasopharyngitis).
The side effects listed above may not include all of the side effects reported by the medicine's manufacturer.
For more information about any other possible risks associated with this medicine, please read the information provided with the medicine or consult your doctor or pharmacist.
How can this medicine affect other medicines?
It is important to tell your doctor or pharmacist what medicines you are already taking, including those bought without a prescription and herbal medicines, before you start treatment with this medicine. Similarly, check with your doctor or pharmacist before taking any new medicines while taking this one, to ensure that the combination is safe.
Medicines that increase blood sugar levels as a side effect may make this medicine, and other antidiabetic medicines, less effective at controlling blood sugar. Medicines that can increase blood sugar levels include the following:
bronchodilators (beta agonists), eg salbutamol, terbutaline, salmeterol
corticosteroids, eg prednisolone
levothyroxine
thiazide diuretics, eg bendroflumethiazide.
Other medicines containing the same active ingredient
There are currently no other medicines available in the UK that contain vildagliptin as the only active ingredient.
Eucreas contains vildagliptin in combination with metformin.
Galvus (维格列汀片), 一种全新的、一天一次用于Ⅱ型糖尿病的口服药物，已获得欧盟的批准。Galvus是同类药物中唯一能与其它降糖药物广泛联合使用的药物。
在医生迫切需要全新药物与现有药物联合使用之际，Galvus作为全新的DPP-IV抑制剂获得了批准。
欧盟批准Galvus与最常用的口服降糖药：二甲双胍，噻唑烷二酮(TZD)或磺脲(SU)联合使用。
此批准适用于欧盟27个成员国以及挪威和冰岛。国际糖尿病联盟(IDF)Diabetes Atlas估计，在发达国家中约有2800万Ⅱ型糖尿病患者，其中一半以上的患者尽管使用药物治疗其血糖水平仍未控制达标。
“对欧洲几千万正在接受药物治疗但仍未将血糖控制达标的Ⅱ型糖尿病患者而言，Galvus的批准是一个极其重要的里程碑”，德国慕尼黑Ludwig-Maximilians大学的医学博士Burkhard G?ke说。
“Galvus能显著降低血糖水平，但不会导致现有药物像SU和TZD类药物常见的体重增加和低血糖等不良反应。有了Galvus，我们现在可以采用其他的治疗方式使患者达标”G?ke博士说。
与最常用的口服降糖药联合使用时，Galvus使绝大多数Ⅱ型糖尿病患者的血糖水平显著下降，包括各种种族的患者、老年患者和血糖水平控制不达标的患者。
“我们非常高兴Galvus在欧洲获准用于Ⅱ型糖尿病患者的治疗”，诺华制药公司负责全球研发的医学博士James Shannon说，“我们通过严格的临床试验证实Galvus有着可靠的疗效和安全性，它将为寻求新治疗的医生提供新的选择”。
此外，Galvus已在巴西和墨西哥获得批准。在2007年2月，诺华公司收到美国食品药品监督管理局(FDA)关于Galvus可批准的文件。诺华公司已向FDA递交在肾功能受损患者中关于药品耐受性的试验。
胰岛功能失常会导致Ⅱ型糖尿病患者的高血糖，而Galvus通过全新的作用机制直接针对胰岛功能失常，刺激胰岛素分泌和抑制胰升血糖素的过度分泌，从而控制血糖水平。胰岛功能失常和胰岛素抵抗是Ⅱ型糖尿病发病的根本原因。
临床试验证明，Galvus?良反应的总体发病率与安慰剂相似。最常见的不良反应包括鼻塞、头痛、头晕和上呼吸道感染。
糖尿病是一种进行性疾病。在绝大多数发达国家，糖尿病是第四大致死疾病。如果不治疗或治疗不达标，Ⅱ型糖尿病将导致心脏和肾脏疾病、失明以及血管和神经病变。
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产地国家: 美国
原产地英文商品名:
Galvus 50mg×112Tablets
原产地英文药品名:
vildagliptin
中文参考商品译名:
Galvus 50毫克×112片
中文参考药品译名:
维格列汀
生产厂家中文参考译名:
诺华制药公司
生产厂家英文名:
Novartis Pharmaceuticals Corporation
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产地国家: 美国
原产地英文商品名:
Galvus 50mg×56Tablets
原产地英文药品名:
vildagliptin
中文参考商品译名:
Galvus 50毫克×56片
中文参考药品译名:
维格列汀
生产厂家中文参考译名:
诺华制药公司
生产厂家英文名:
Novartis Pharmaceuticals Corporation
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