BYETTA 5 - 10 microgrammes (exénatide)
Reason for request
The Committee reassessed nine proprietary medicinal products, including two fixed-dose combinations with insulins, containing five different GLP-1 analogues, indicated in the treatment of type 2 diabetes mellitus (see SMP), and recommended, for some of them, in specific situations:
- if the difference with respect to the target is > 1% HbA1c,
- and if the BMI ≥ 30 kg/m² or if weight gain under insulin or the occurrence of hypoglycaemic episodes are of concern,
- and only in combination with other medicinal products for the treatment of diabetes (as dual or triple therapy).
The Committee maintained a favourable opinion for maintenance of reimbursement in the indications previously recommended for the following GLP-1 analogues:
* dulaglutide (TRULICITY), except as dual therapy with a sulfonylurea,
* exenatide (BYDUREON / BYETTA), except as triple therapy with insulin and metformin for BYDUREON
* liraglutide (VICTOZA) and the fixed-dose liraglutide/insulin degludec combination (XULTOPHY)
* semaglutide for injection (OZEMPIC), except as dual therapy with a sulfonylurea and as triple therapy with insulin and metformin.
The clinical benefit of these proprietary medicinal products remains substantial, except for semaglutide for injection (OZEMPIC), which now has a moderate clinical benefit.
In the indications previously not recommended for reimbursement, the Committee maintained an unfavourable opinion for reimbursement as monotherapy or as dual therapy with insulin.
Finally, the unfavourable opinion for reimbursement of lixisenatide (LYXUMIA), of lixisenatide/insulin glargine (SULIQUA) and of oral semaglutide (RYBELSUS) was maintained.
What therapeutic improvement?
The proprietary medicinal products with a favourable opinion for reimbursement provide:
- a therapeutic improvement in the treatment of type 2 diabetes mellitus for TRULICITY (dulaglutide), VICTOZA (liraglutide) and XULTOPHY (liraglutide/insulin degludec).
- no clinical added value in the therapeutic strategy for type 2 diabetes mellitus for BYDUREON (exenatide), BYETTA (exenatide) and OZEMPIC (semaglutide).
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 sulfonylurea is recommended as first-line therapy, in addition to these measures. Drug combinations are envisaged following the failure of monotherapy.
Following the failure of monotherapy with metformin or a sulfonylurea, a new treatment line with an antidiabetic drug from a different therapeutic class will be added to the first-line treatment. The choice between the different drug families that can be used as second or third-line treatment (gliflozins, gliptins, alphaglucosidase inhibitors, GLP-1 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.
Role of the medicinal product in the care pathway
GLP-1 analogues are characterised by a substantial effect in terms of reducing HbA1c levels and an effect on weight loss. Only two substances from this class - dulaglutide and liraglutide - have demonstrated a clinical value in terms of cardiovascular benefit on the 3P-MACE cardiovascular composite endpoint (superiority versus placebo demonstrated in cardiovascular studies). The other substances only demonstrated non-inferiority versus placebo for this 3P-MACE endpoint. Although data from meta-analyses suggest a cardiovascular benefit for the entire analogue class, without formal evidence, this non-inferiority data only provides reassurance in terms of the cardiovascular safety of these substances without demonstrating a cardiovascular benefit. As regards semaglutide, the level of evidence provided by oral or injectable semaglutide is lower than for the other substances due to the choice of a non-inferiority margin of 1.8 instead of 1.3 as was the case for all the other substances.
Their safety profile is characterised by gastrointestinal events (nausea, vomiting, diarrhoea), headache, cholelithiasis and pain at the injection site.
In this context, five of the seven proprietary medicinal products with single substances re-evaluated - TRULICITY (dulaglutide), BYETTA (exenatide), BYDUREON (exenatide), VICTOZA (liraglutide) and OZEMPIC (semaglutide) - remain treatment options for type 2 diabetes mellitus in adults only as second or third-line medicinal treatment and recommended in specific situations: if the difference with respect to the target is > 1% HbA1c and if the BMI ≥ 30 kg/m² or if weight gain under insulin or the occurrence of hypoglycaemic episodes are of concern and the disease is inadequately controlled by metformin or a sulfonylurea as monotherapy, as an adjunct to diet and exercise, and in combination only:
- as dual therapy with metformin in the event of intolerance or contraindication to sulfonylureas,
- as dual therapy with a sulfonylurea, except for TRULICITY (dulaglutide) and for OZEMPIC (semaglutide), in the absence of conclusive data,
- as triple therapy in combination with a sulfonylurea and metformin,
- as triple therapy with metformin and insulin, except for BYDUREON (exenatide) and OZEMPIC (semaglutide), in the absence of conclusive data.
If prescription of a GLP-1 analogue is envisaged, given the results observed in terms of reduction of the 3P-MACE endpoint with dulaglutide in the REWIND study, and with liraglutide in the LEADER study, the choice should preferentially lean towards TRULICITY (dulaglutide) and VICTOZA (liraglutide) or its fixed-dose combination XULTOPHY (liraglutide/insulin degludec).
BYETTA (exenatide) and BYDUREON (exenatide) are therefore second-line GLP-1 analogues, due to the absence of a demonstrated cardiovascular benefit. Given the lower level of evidence provided by the cardiovascular study (with a non-inferiority margin of 1.8), OZEMPIC (semaglutide) should not be favoured within its class.
In the context of a specialised opinion, XULTOPHY, which enables administration of insulin degludec and liraglutide as a daily injection, has a role in the care pathway for type 2 diabetes, in combination with metformin, for patients not controlled by dual therapy with basal insulin and metformin. The Committee considers that it may be relevant to carry out a treatment optimisation phase for triple therapy with metformin + basal insulin + liraglutide as a free-dose combination before prescribing XULTOPHY (liraglutide/insulin degludec).
In the absence of conclusive new data, RYBELSUS (oral semaglutide), LYXUMIA (lixisenatide) and SULIQUA (lixisenatide/insulin glargine) have no role in the care pathway for type 2 diabetes.
In the absence of relevant clinical data as monotherapy and in combination with basal insulin alone, GLP-1 analogues have no role in the care pathway for type 2 diabetes in these treatment lines.
Liraglutide (VICTOZA) and dulaglutide (TRULICITY) may be prescribed in patients with mild, moderate or severe renal impairment, in contrast with prolonged-release exenatide (BYDUREON), which is not recommended in patients with moderate renal function impairment (creatinine clearance of 30 to 50 ml/min). Exenatide is not recommended in patients with end-stage renal disease or severe renal function impairment (creatinine clearance < 30 ml/min).
The Committee deems that the clinical benefit of BYETTA (exenatide) is substantial only in combination: with metformin, with a sulfonylurea, with metformin and a sulfonylurea and in adults having failed to achieve adequate glycaemic control at the maximum tolerated doses of these oral treatments.
The Committee deems that the clinical benefit of BYETTA (exenatide) is insufficient in combination with a basal insulin in adults having failed to achieve adequate glycaemic control with this medicinal product.
Clinical Added Value
|no clinical added value||
the Committee considers that BYETTA (exenatide) provides no clinical added value (CAV V) in the treatment of type 2 diabetes mellitus, as dual therapy with metformin, as dual therapy with a sulfonylurea, as triple therapy with metformin and a sulfonylurea and as triple therapy with metformin and insulin.