Reason for request
Favourable opinion for reimbursement of XIGDUO, a fixed-dose combination of dapagliflozin/metformin in :
- patients insufficiently controlled on their maximally tolerated dose of metformin alone,
- patients insufficiently controlled at the maximum dose of metformin combined with a sulphonylurea or insulin,
- patients already being treated with the combination of dapagliflozin and metformin as separate tablets.
What therapeutic improvement ?
Therapeutic improvement, in the same way as FORXIGA (dapagliflozin), in the treatment of type 2 diabetes mellitus, as an adjunct to diet and exercise, for patients :
- insufficiently controlled on their maximally tolerated dose of metformin alone,
- insufficiently controlled at the maximum dose of metformin combined with a sulphonylurea or insulin,
- already being treated with the combination of dapagliflozin and metformin as separate tablets.
Role in the care pathway ?
The objective of treatment of type 2 diabetes is to prevent the numerous serious and disabling complications, such as microangiopathy (affecting the retina, nerves, heart and kidneys) and sudden complications of macroangiopathy, such as myocardial infarction, stroke, etc. Diabetes promotes the development of heart failure. The Committee also highlights the importance of ensuring patients are well informed and of their compliance with treatment for successful management of the disease. The initial management of type 2 diabetes is based on non-medicinal interventions and, in particular, the implementation of lifestyle and dietary measures. In the event of failure to meet the blood glucose target, medicinal treatment with metformin or, in the event of contraindications, a sulphonylurea is recommended as first-line therapy, in addition to these measures. Drug combinations are envisaged following the failure of monotherapy.
Role of the medicinal product in the care pathway
Following the failure of monotherapy with metformin or a sulphonylurea, a gliflozin, such as canagliflozin, dapagliflozin, empagliflozin, may be chosen as first-line treatment to reinforce and supplement the effect of the drug prescribed as monotherapy, or as second-line dual therapy with metformin or a sulphonylurea. A gliflozin may also be prescribed as third-line drug therapy in the context of triple therapy in combination with metformin and a sulphonylurea, as well as in combination with metformin and insulin.
The choice between the different drug families that can be used as second or third-line treatment (gliflozins, gliptins, alphaglucosidase inhibitors, GLP1 analogues and insulins) will notably be determined on the basis of the safety profile of the medicinal products, the availability of conclusive cardiovascular or renal morbidity and mortality study results and the preferences of patients after they have been given appropriate information.
Empagliflozin, dapagliflozin and canagliflozin present a specific benefit in type 2 diabetics at cardiovascular risk, as primary or secondary prevention, given the results of the EMPA-REG OUTCOME, DECLARE-TIMI 58 and CANVAS studies, having demonstrated the superiority of these drugs compared to placebo in the reduction of MACE for empagliflozin and canagliflozin, and in the reduction of the composite endpoint “cardiovascular death or hospitalisation for heart failure” for dapagliflozin.
Only canagliflozin 100 mg has been the subject of an assessment by the Transparency Committee for the treatment of T2D patients with stage 2 and 3 chronic kidney disease and albuminuria, in combination with standard treatment with ACE inhibitors or angiotensin receptor blockers.
The fixed-dose combination XIGDUO (dapagliflozin/metformin) has a role in the care pathway for type 2 diabetes :
- in patients insufficiently controlled on their maximally tolerated dose of metformin alone. It is reiterated that the use of metformin requires the maintenance of monotherapy, with the possibility of increasing doses up to 2,000 to 3,000 mg per day in the event of insufficient glucose control and good tolerability, before combination with another oral antidiabetic treatment,
- in patients insufficiently controlled at the maximum dose of metformin combined with a sulphonylurea or insulin,
- in patients already being treated with the combination of dapagliflozin and metformin as separate tablets. It is preferable to perform titration of the separate tablets in order to achieve the optimal dose of the treatments before using the fixed-dose combination.
The initiation of gliflozin treatment should be avoided in patients with factors identified as increasing the amputation risk, insofar as an excess amputation risk (mainly of the toe) was identified with canagliflozin versus placebo in the CANVAS programme. Although it was not detected in the clinical studies available, this excess risk cannot be excluded for other drugs in the class.
Potential predisposing factors for amputation are, in particular, a history of amputation, peripheral vascular disease or neuropathy. It is necessary to carefully monitor patients with a higher amputation risk, to inform them and support them to ensure the correct implementation of routine preventive foot care and the maintenance of adequate hydration. Gliflozin treatment must be discontinued in patients who develop events liable to precede an amputation, such as skin ulcers on the lower limbs, an infection or osteomyelitis.
The Committee highlights the fact that XIGDUO (dapagliflozin/metformin), like other gliflozins, is also liable to induce :
- ketoacidosis, requiring awareness-raising and patient information. Patients should self-monitor for its development, particularly in the event of non-specific symptoms, such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood glucose level. Patients should be able to test their blood ketone levels themselves if warning signs develop. In patients in whom diabetic ketoacidosis is suspected or diagnosed, treatment with XIGDUO (dapagliflozin/metformin) should be discontinued immediately.
- genital infections that may precede the development of Fournier’s gangrene.
- Fournier’s gangrene or necrotising fasciitis. The development of symptoms such as pain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise, are warning signs. Uro-genital infection or perineal abscess may precede necrotising fasciitis. If Fournier's gangrene is suspected, treatment with XIGDUO (dapagliflozin/metformin) should be discontinued and prompt treatment (including antibiotics and surgical debridement) should be instituted.
XIGDUO (dapagliflozin/metformin) is subject to annual initial prescription restricted to certain specialists (in diabetes, metabolic diseases, endocrinology, internal medicine); with renewal of prescriptions by any prescriber possible.
Given its safety profile, which involves warnings relative to the risk of amputations, ketoacidosis and genital infections, and the very rare but serious and class-specific risk of the development of Fournier's gangrene, the initiation of XIGDUO (dapagliflozin/metformin) requires not only a thorough assessment of the patient to make sure he/she does not present an excess risk of development of these events, but also the provision of complete and detailed information to the patient concerning the symptoms associated with each of these events.
The Committee raises the question of whether it might be appropriate to expand annual initial prescription of gliflozins to general practitioners, insofar as type 2 diabetes is a public health issue and its management also depends on these prescribers.
The Committee deems that the clinical benefit of XIGDUO (dapagliflozin/metformin) is substantial :
Clinical Added Value
The Committee considers that XIGDUO (dapagliflozin/metformin) provides a minor clinical added value (CAV IV), in the same way as FORXIGA (dapagliflozin), in the treatment of type 2 diabetes for patients :