The benefit assessment of the fixed combination of saxagliptin and metformin was conducted in accordance with its approval status for the following therapeutic indications:
Combination of saxagliptin and metformin: “as an adjunct to diet and exercise to improve glycaemic control in adult patients aged 18 years and older with type 2 diabetes mellitus inadequately controlled on their maximally tolerated dose of metformin alone or those already being treated with the combination of saxagliptin and metformin as separate tablets”
Combination of saxagliptin and metformin in combination with insulin: (i.e., triple combination therapy) “as an adjunct to diet and exercise to improve glycaemic control in adult patients aged 18 years and older with type 2 diabetes mellitus when insulin and metformin alone do not provide adequate glycaemic control”
Combination of saxagliptin and metformin For the therapeutic indication “saxagliptin plus metformin”, the Federal Joint Committee (G-BA) specified the following appropriate comparator therapy (ACT):
Metformin in combination with a sulfonylurea (glibenclamide or glimepiride)
The company also cited metformin in combination with a sulfonylurea as ACT for this therapeutic indication, but without limitation to the drugs glibenclamide and glimepiride specified by the G-BA. It pointed out that the added benefit was to be derived on the basis of an approval study where the sulfonylurea glipizide had been used. However, as the company itself noted in its dossier, glipizide has not been approved in Germany since 2007 and is therefore unsuitable as ACT. Furthermore, the company justified the admissibility of a comparison with glipizide, instead of glibenclamide or glimepiride, particularly with the comparability of glipizide with these drugs. However, the data presented by the company were insufficient to support this assumption made by the company. In addition, the company cited the combination therapy of metformin plus other DPP-4 inhibitors as an alternative comparator therapy, namely for patients who cannot be treated with sulfonylurea or for whom sulfonylurea is unsuitable, but insulin therapy is not yet indicated. According to the information given by the company, this limitation of the patient population mainly refers to hypoglycaemias, the adverse event most commonly observed during treatment with sulfonylureas. Regarding this, the company cited several risk factors such as advanced age and pre-existing cardiovascular conditions. This rationale was not followed. According to the Summary of Product Characteristics (SPC) for glibenclamide there are no contraindications for the patient groups named by the company. Regarding elderly people it is pointed out that particular caution should be exercised when adjusting the dose; this does not mean however that sulfonylureas are unsuitable for these patients. Hence the company did not exclude elderly patients from the direct comparative study with glipizide. Patients with recent pre- existing cardiovascular conditions were excluded from the study, but this also applied to the placebo-controlled studies on saxagliptin, where sulfonylureas were not used at all. Moreover, the company did not submit any data to prove an added benefit of saxagliptin plus metformin versus the alternative ACT sitagliptin plus metformin the company had chosen.
In summary, the assessment was conducted for the therapeutic indication “saxagliptin plus metformin” in comparison with the ACT specified by the G-BA “metformin plus sulfonylurea (glibenclamide or glimepiride)”.
Combination of saxagliptin and metformin in combination with insulin Due to the lack of a consultation request, the G-BA had not specified an ACT in advance for the therapeutic indication “saxagliptin plus metformin in combination with insulin”. However, the company followed the ACT specified by the G-BA after explanations by the company during a consultation request for the individual substance saxagliptin for the same therapeutic indication:
Metformin + human insulin
This assessment followed the G-BA’s specification for the individual substance and therefore the company’s choice.
The assessment for both therapeutic indications was conducted based on patient-relevant outcomes.
Keywords: saxagliptin; metformin; diabetes mellitus, type 2; Benefit assessment.
Copyright © 2013 by the Institute for Quality and Efficiency in Healthcare (IQWiG).