Active Substance: linagliptin / metformin
Common Name: linagliptin / metformin hydrochloride
ATC Code: A10BD11
Marketing Authorisation Holder: Boehringer Ingelheim International GmbH
Active Substance: linagliptin / metformin
Authorisation Date: 2012-07-20
Therapeutic Area: Diabetes Mellitus, Type 2
Pharmacotherapeutic Group: Drugs used in diabetes
Treatment of adult patients with type-2 diabetes mellitus:
- Jentadueto is indicated as an adjunct to diet and exercise to improve glycaemic control in adult patients inadequately controlled on their maximal tolerated dose of metformin alone, or those already being treated with the combination of linagliptin and metformin.
- Jentadueto is indicated in combination with a sulphonylurea (i.e. triple combination therapy) as an adjunct to diet and exercise in adult patients inadequately controlled on their maximal tolerated dose of metformin and a sulphonylurea.
What is Jentadueto?
Jentadueto is a medicine that contains the active substances linagliptin and metformin hydrochloride. It is available as tablets (2.5 mg/850 mg and 2.5 mg/1,000 mg).
What is Jentadueto used for?
Jentadueto is used in adults with type-2 diabetes to improve the control of blood glucose (sugar) levels. It is used in addition to diet and exercise in the following ways:
- in patients who are not satisfactorily controlled on metformin (an antidiabetes medicine) used on its own;
- in patients who are already taking a combination of linagliptin and metformin as separate tablets;
- in combination with a sulphonylurea (another type of antidiabetes medicine) in patients who are not satisfactorily controlled on this medicine and metformin.
The medicine can only be obtained with a prescription.
How is Jentadueto used?
Jentadueto is taken twice a day. The strength of tablet to use depends on the dose of the other antidiabetes medicines that the patient was taking before. If Jentadueto is taken with a sulphonylurea, the dose of the sulphonylurea may need to be lowered, to avoid hypoglycaemia (low blood sugar levels).
The maximum dose is 5 mg of linagliptin and 2,000 mg of metformin per day. Jentadueto should be taken with food to avoid any stomach problems caused by metformin.
How does Jentadueto work?
Type-2 diabetes is a disease in which the pancreas does not make enough insulin to control the level of glucose in the blood or when the body is unable to use insulin effectively. The active substances in Jentadueto, linagliptin and metformin hydrochloride, each have a different mode of action.
Linagliptin is a dipeptidyl-peptidase-4 (DPP 4) inhibitor. It works by blocking the breakdown of ‘incretin’ hormones in the body. These hormones are released after a meal and stimulate the pancreas to produce insulin. By prolonging the action of incretin hormones in the blood, linagliptin stimulates the pancreas to produce more insulin when blood glucose levels are high. Linagliptin does not work when the blood glucose is low. Linagliptin also reduces the amount of glucose made by the liver, by increasing insulin levels and decreasing the levels of the hormone glucagon. Together, these processes reduce blood glucose levels and help to control type-2 diabetes. Linagliptin has been authorised in the European Union (EU) as Trajenta since 2011.
Metformin works mainly by inhibiting glucose production and reducing its absorption in the gut. Metformin has been available in the EU since the 1950s.
As a result of the action of both active substances, blood glucose levels are reduced and this helps to control type-2 diabetes.
How has Jentadueto been studied?
The effects of Jentadueto were first tested in experimental models before being studied in humans.
The company presented the results of four studies with linagliptin in patients with type-2 diabetes, which were used to support the approval of Trajenta in the EU, comparing linagliptin given at 5 mg once per day with placebo (a dummy treatment). The studies looked at the effectiveness of linagliptin used on its own (503 patients), in combination with metformin (701 patients), with metformin plus a sulphonylurea (1,058 patients) or with another antidiabetes medicine pioglitazone (389 patients).
A new study was carried out involving 791 patients with type-2 diabetes, where the combination of linagliptin plus metformin given twice per day was compared with giving metformin alone, linagliptin alone or placebo. Linagliptin was given at 2.5 mg twice per day in the combination treatment and at 5 mg once per day in the single treatment. Metformin was given at either 500 mg or 1,000 mg twice per day, for both the combination and the single treatment.
A further study was carried out involving 491 patients with type-2 diabetes taking metformin twice per day, where placebo or linagliptin at either 2.5 mg twice per day or at 5 mg once per day was added to their treatment. The study compared the effects of adding linagliptin to metformin in these ways, since metformin needs to be taken at least twice per day.
In all studies, the main measure of effectiveness was the change in blood levels of a substance called glycosylated haemoglobin (HbA1c) after 24 weeks of treatment. This gives an indication of how well blood glucose is controlled.
What benefit has Jentadueto shown during the studies?
The studies with linagliptin showed that it was more effective than placebo at reducing HbA1c levels. When used on its own, linagliptin gave a reduction of 0.46 points compared with a rise of 0.22 points. When given in combination, linagliptin with metformin gave a reduction of 0.56 points compared with a rise of 0.10 points; linagliptin with metformin plus a sulphonylurea gave a reduction of 0.72 points compared with 0.10 points.
The study with the combination of linagliptin and metformin showed that it was more effective than linagliptin or metformin alone, as well as placebo, at reducing HbA1c levels. The combination gave a reduction of 1.22 points when metformin was given at 500 mg and a reduction of 1.59 points when metformin was given at 1,000 mg. This compared with a reduction of 0.45 with linagliptin alone, 0.64 with 500 mg metformin alone, 1.07 with 1,000 mg metformin alone, and 0.13 with placebo.
The study looking at adding linagliptin 2.5 mg twice per day or 5 mg once per day to metformin showed a similar reduction in HbA1c levels compared with placebo (0.74 and 0.80 points more than placebo respectively).
What is the risk associated with Jentadueto?
The most frequent side effect with the combination of linagliptin plus metformin was diarrhoea (seen in less than 1% of patients, with a similar rate seen in patients taking metformin plus placebo). When linagliptin and metformin were given with a sulphonylurea, hypoglycaemia was the most frequent side effect seen in around 23% of patients, compared with around 15% when placebo was given with metformin and a sulphonylurea. For the full list of all side effects reported with Jentadueto, see the package leaflet.
Jentadueto should not be used in people who may be hypersensitive (allergic) to linagliptin, metformin or any of the other ingredients. It must not be used in patients suffering diabetic ketoacidosis or diabetic precoma (a dangerous condition that can occur in diabetes), patients with moderate to severe kidney problems or suffering from acute (sudden) conditions which can affect kidney function, patients suffering from acute or chronic diseases which can cause tissue hypoxia (where the tissue is deprived of adequate oxygen supply) such as heart failure or difficulty breathing, and patients with liver problems, alcohol poisoning or alcoholism. For the full list of restrictions, see the package leaflet.
Why has Jentadueto been approved?
The CHMP concluded that the combination of linagliptin and metformin has been shown to be effective at lowering HbA1c levels, and that linagliptin 2.5 mg twice per day was as effective as 5 mg once per day, which is approved in the EU for use on its own and in combination with metformin and with metformin plus a sulphonylurea. The CHMP noted that fixed-dose combinations may increase the likelihood of patients taking their medicine correctly. With regard to side effects, the Committee considered that in general the risks seen were only slightly greater than those seen with placebo. Therefore the CHMP decided that Jentadueto’s benefits are greater than its risks and recommended that it be given marketing authorisation.
Other information about Jentadueto
The European Commission granted a marketing authorisation valid throughout the European Union for Jentadueto on 20 July 2012.
For more information about treatment with Jentadueto, read the package leaflet (also part of the EPAR) or contact your doctor or pharmacist.
Source: European Medicines Agency
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