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2型糖尿病治疗新药Januvia(sitagliptin phosphate)

2009-11-03 19:45:35 作者：新特药房来源：中国新特药网浏览次数：2623 文字大小：【大】【中】【小】

简介： Sitagliptin phosphate (Januvia; Merck) 2006年10月获得FDA批准用于治疗2型糖尿病。这是一类称为DPP4抑制剂的第一个产品。作用机制两种肠促胰素（Incretins）-葡萄糖依赖性促胰岛素多肽(glucose- ...

关键字：2型糖尿病是 Januvia(sitagliptin phosphate)

Sitagliptin phosphate (Januvia; Merck) 2006年10月获得FDA批准用于治疗2型糖尿病。
这是一类称为DPP4抑制剂的第一个产品。

作用机制
两种肠促胰素（Incretins）-葡萄糖依赖性促胰岛素多肽(glucose-dependent insulinotropic polypeptide or gastric inhibitory peptide, GIP) 和胰高血糖素样多肽-1(glucagon-like peptide-1，GLP1)可以通过激活胰岛 -细胞的G蛋白偶联受体而促进胰岛素的释放。GLP1还可抑制胰高血糖素的分泌以及抑制胃排空从而诱导饱足感，因此使大部分接受治疗的患者体重减轻。只有在血糖升高的情况下才能刺激胰岛素的分泌，因此这类药物引起低血糖的风险较低。天然的GLP1虽然可以有效地降低血糖，但在体内迅速被二肽酰肽酶-4(dipeptidyl peptidase-4，DPP-4)降解。解决这个问题的方法之一是开发长效的，对DPP-4有抗性的GLP1类似化合物。2005年4月，FDA 批准了多肽GLP1受体激动剂exenatide (Byetta; Amylin)。另一个途径是开发DPP4的抑制剂。DPP4在多种细胞表面以跨膜蛋白形式存在，循环中也有可溶性DPP4存在。NVP DPP728是第一代的小分子DPP4抑制剂，在此基础上合成了一系列DPP4小分子抑制剂，包括sitagliptin。Sitagliptin是可口服的选择性DPP4抑制剂，是在对一系列β-氨基酸来源的DPP4抑制剂进行优化后获得的。每日口服一次即可持续降低DPP4活性。

临床疗效
4项有2000多名2型糖尿病患者参加的随机、安慰剂对照试验评价了sitagliptin单独或和其他降糖药联合使用的效果和安全性。评价指标主要是糖化血红蛋白(HbA1c) 较基线的改变值。HbA1c是过去3-4个月内血糖平均水平的一个标志指标。Sitagliptin（100或200mg）单独给药显著降低HbA1c水平，HbA1c水平的降低程度和HbA1c的起始水平成正比，24周单独治疗期间病人体重未见增加。Sitagliptin降低空腹和餐后血糖，提高前胰岛素原/胰岛素比例，改善胰岛素抵抗状态（通过HOMA-B进行评价)。
对于每天至少1500mg二甲双胍仍无法很好控制血糖的患者加用sitagliptin 100mg，有47%的患者达到HbA1C<7%的目标，而加用安慰剂的患者达到目标的比例只有18.3%。相对安慰剂组，sitagliptin组患者HbA1C平均降低了0.65%。Sitagliptin和二甲双胍联合使用作为初始治疗方案也显示有效。应用吡格列酮治疗而无法达到目标的患者（平均HbA1C水平为8.1%）加用sitagliptin 100mg，患者平均HbA1C水平降低了0.7%，和吡格列酮单独治疗组相比，更高比例的患者达到HbA1C<7%的目标(联合组和单独组分别为45.4%和23%)。

竞争优势与市场前景
二甲双胍被认为是治疗2型糖尿病最好的起始治疗药物，其有效性、安全性和低成本已为30年的临床应用所证实。但越来越多的医生呼吁起始治疗应至少包括2种药物，以避免单独药物的不足，同时延长二甲双胍的治疗周期。与二甲双胍联合使用的有多种药物，包括磺酰脲类、glitinides类、 -糖苷酶抑制剂类、噻唑烷二酮类和胰岛素。Exenatide和sitagliptin也可成为二甲双胍联合用药成分。但二甲双胍和上述哪一类或哪一种药物联合使用在有效性、安全性和长期顺应性方面更具优势，现在还没有答案。促胰岛素分泌剂如磺酰脲类和glitinides类虽然价格便宜，但可引起体重增加和低血糖，因此老年人使用的话不良反应多。 -糖苷酶抑制剂类有效而安全，但胃肠道不良反应常见，限制了应用。而噻唑烷二酮类可引起液体潴留和体重增加。Exenatide的安全性良好，但需要每日注射2次，还可引起轻到中度恶心，对于需要长期服药的糖尿病人来说，注射给药不是首选。

已有的数据显示二甲双胍单独治疗的效果要比sitagliptin或类似DPP4 抑制剂vildagliptin单独治疗好。但还没有数据阐明sitagliptin和其他药物在和二甲双胍联合使用时哪一个更好，也没有数据显示sitagliptin长期联合治疗的有效性和安全性。关于exenatide或sitagliptin是否可以预防2型糖尿病进展或减少心血管事件的发生也没有试验数据支持。作为新上市的药物，sitagliptin已被证实的优势是方便使用，不良反应少，低血糖风险低和不引起体重增加。但其他可能的优势还有待试验检验。

分析家预测Sitagliptin的峰销售额可在2010年达到10亿美元。75%来自于美国。诺华公司的类似药物vildagliptin在2007年2月将接受FDA的审评。而默克公司在2007年也将提交Sitagliptin/二甲双胍复方制剂的新药上市申请。Sitagliptin是二型糖尿病治疗的进步，但并不算突破性进展。其应用也主要集中于美国，而在欧洲，预计只有那些经过其他药物而不能达到目标的一小部分患者才会选择Sitagliptin。

Packaging: box 14 x 100mg film coated tablets
Shipped from: India

Description
Brand name: Janumet
Active substance: Sitagliptin and metformin hcl
Packaging: box 14 x 50mg Sitagliptin/ 1000mg metformin hcl
Shipped from: India

英文：sitagliptin，商品名Januvia

中文名为磷酸西格列汀片

生产商：美国默克（Merck）制药公司生产

治疗用途：FDA批准用于治疗2型糖尿病，这是一类被称为二肽基肽酶IV （dipeptidyl peptidase-4,DPP4）抑制剂的第一个产品。

GENERIC NAME: Sitagliptin Phosphate

BRAND NAME: Januvia

How does it work?

Januvia tablets contain the active ingredient sitagliptin, which is a type of medicine called a dipeptidyl peptidase 4 (DPP-4) inhibitor. It is used to treat people with type 2 or non-insulin dependent diabetes (NIDDM).

Sitagliptin 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 four 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 also reduce the rate at which food passes from the stomach into the intestines, which slows down the absorption of glucose from the gut into the bloodstream. Finally, they act on the brain to cause a feeling of fullness that reduces further food intake.

GLP-1 and GIP are normally broken down by an enzyme in the body called dipeptidyl peptidase 4. Sitaglipin 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.

Januvia 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.

Januvia 100mg tablet is taken once daily, with or without food. If you forget to take a tablet then it can be taken as soon as you remember. However, two tablets should not be taken on the same day.

What is it used for?

Type 2 diabetes (non-insulin dependent diabetes).
Use with caution in:

Decreased kidney function.
People over 75 years of age.
Not to be used in:

Type 1 diabetes.
Diabetic ketoacidosis.
This medicine is not recommended for people receiving dialysis or who have moderate to severe kidney disease.
Pregnancy.
Breastfeeding.
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 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. Because a side effect is stated here, it does not mean that all people using this medicine will experience that or any side effect.

Nausea.
Excess gas in the stomach and intestines (flatulence).
Low blood glucose levels (hypoglycaemia).
Headache.
Swelling of feet or ankles (peripheral oedema).
Inflammation of the nose and throat, causing a blocked or runny nose and sore throat (nasopharyngitis).
Upper respiratory tract infection.
Blocked nose.
Sore throat.
Pain in the arms or legs.
Osteoarthritis.
Constipation.
Abdominal pain.
Loss of appetite.
Diarrhoea.
Weight loss.
Dizziness.
Drowsiness.

The side effects listed above may not include all of the side effects reported by the drug'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.

Sitagliptin may cause a small increase in the amount of digoxin in the blood when both medicines are being taken together. If you are taking digoxin, your doctor may want you to have regular blood tests to monitor the amount of digoxin in your blood after you start treatment with this medicine.

Warning!

Hypoglycaemia (low blood glucose) has been commonly reported when this medicine is used in combination with sulphonylurea medicines, eg gliclazide or glibenclamide, or with glitazone medicines, such as rosiglitazone or pioglitazone. 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 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 uncommonly cause dizziness or drowsiness. If affected you should take care driving or operating machinery.