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KOMBOGLYZE (metformine / saxagliptine)

Opinions on drugs - Posted on Aug 30 2021

Reason for request

Reevaluation

Key points

The Committee reassessed 12 proprietary medicinal products containing 5 different gliptin substances, including 6 as fixed-dose combinations with metformin. This re-evaluation concerns the indication in the treatment of type 2 diabetes mellitus in adults to improve glycaemic control in combination with other antidiabetic medicinal products and following the failure of diet and exercise followed by first-line medicinal treatment with metformin or a sulfonylurea. 

The Committee returned:

  • In the indications previously recommended for reimbursement by the Committee,
    • a favourable opinion for maintenance of reimbursement only in combination with other antidiabetic medicinal products (dual therapy in combination with metformin or a sulfonylurea or triple therapy in combination with metformin and a sulfonylurea or with metformin and insulin), for the following proprietary medicinal products:

      * alogliptin (VIPIDIA and VIPDOMET), except as triple therapy in combination with metformin and a sulfonylurea;

      * linagliptin (TRAJENTA and JENTADUETO)

     * saxagliptin (ONGLYZA and KOMBOGLYZE)

      * sitagliptin (JANUVIA/XELEVIA and JANUMET/VELMETIA)

     * and vildagliptin (GALVUS and EUCREAS).

Nonetheless, the clinical benefit of these proprietary medicinal products is now moderate in all the indications, except for saxagliptin (ONGLYZA) and its fixed-dose combination with metformin (KOMBOGLYZE) and for vildagliptin (GALVUS) and its fixed-dose combination with metformin (EUCREAS), for which it is low. Previously, the clinical benefit was substantial for all these proprietary medicinal products, except in a minority of clinical situations for which the clinical benefit was low or moderate.

  • In the indications previously not recommended for reimbursement, the Committee maintained:
    • an unfavourable opinion for reimbursement as monotherapy, except for sitagliptin (JANUVIA/XELEVIA) at the 25 mg and 50 mg strengths appropriate for patients with type 2 diabetes mellitus with moderate, severe or end-stage renal disease, which retains a favourable opinion for reimbursement (with a now moderate clinical benefit),
    • unfavourable opinion for reimbursement in the indication as dual therapy with insulin.

What therapeutic improvement?

No clinical added value in the therapeutic strategy for type 2 diabetes in the situations recommended for reimbursement.

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. Lifestyle and dietary measures must be maintained alongside medicinal treatment. 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.

Role of gliptins in the care pathway

Gliptins are characterised by a modest effect in terms of reducing HbA1c levels, a neutral effect on body weight and a low risk of occurrence of hypoglycaemia. In cardiovascular studies with alogliptin, linagliptin, saxagliptin and sitagliptin, none of these drug substances demonstrated any superiority compared to placebo.

The data from these studies is reassuring in terms of their cardiovascular safety profile (with only non-inferiority compared to placebo having been demonstrated for the 3P-MACE or 4P-MACE endpoint in cardiovascular studies). However, it is necessary to highlight a lower level of evidence based on a meta-analysis for vildagliptin, with demonstration of a lack of difference in terms of the number of cardiovascular events compared to placebo or other antidiabetic medicinal products with no formal demonstration of non-inferiority.

In the absence of demonstration of a superiority compared to placebo in these studies, these drug substances have not therefore demonstrated a clinical benefit in the prevention of cardiovascular events in type 2 diabetics at cardiovascular risk in primary and secondary prevention, in a context in which gliflozins and two GLP-1 analogues (dulaglutide, liraglutide) have demonstrated evidence of a clinical benefit in these at-risk populations (demonstrated superiority in cardiovascular studies versus placebo).

In addition, their safety profile remains favourable, with, however, an identified risk of pancreatitis and a rare but serious risk of bullous pemphigoid. For saxagliptin, the additional risk of hospitalisation due to cardiac failure suggested in the SAVOR-TIMI 53 study was not confirmed in subsequent data and study analyses and in the post-marketing follow-up data. 

In this context, the 5 drug substances re-evaluated - alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin - remain treatment options for type 2 diabetes in adults, only as second or third-line drug therapy, i.e. when 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
  • as dual therapy with a sulfonylurea (except for linagliptin, in the absence of conclusive data),
  • as triple therapy with a sulfonylurea and metformin (except for alogliptin, in the absence of conclusive data),
  • as triple therapy with metformin and insulin.

The fixed-dose combinations with metformin, VIPDOMET (alogliptin/metformin), JENTADUETO (linagliptin/metformin), JANUMET/VELMETIA (sitagliptin/metformin), EUCREAS (vildagliptin/metformin), must be used in the context of the recommended combinations.

If prescription of a gliptin is envisaged, the choice should be made on the basis of the efficacy data, the safety profile and the patient’s preferences. Demonstration of the cardiovascular safety of vildagliptin with a lower level of evidence than for the other gliptins is an element to be taken into consideration.

Given the suggested additional risk of hospitalisation due to cardiac failure with saxagliptin in the SAVOR-TIMI 53 study, caution is recommended when ONGLYZA (saxagliptin) or KOMBOGLYZE (saxagliptin/metformin) are used in patients with known risk factors for hospitalisation due to cardiac failure, such as a history of cardiac failure or moderate to severe renal failure. Patients must be informed of the symptoms characteristic of cardiac failure and immediately report any such symptoms.

Linagliptin, saxagliptin, sitagliptin and vildagliptin have an MA as monotherapy. However, in the absence of conclusive data, they still have no role in the care pathway at this stage, with the exception of sitagliptin at the 25 mg and 50 mg strengths, which retains a role in patients with renal failure, particularly in the event of failure of or contraindication to metformin and sulfonylureas and before the initiation of insulin.

It should be noted that, in combination with other antidiabetic medicinal products, ONGLYZA (saxagliptin), JANUVIA (sitagliptin), GALVUS (vildagliptin) and TRAJENTA (linagliptin) may be prescribed in the event of mild, moderate or severe renal failure, with adjustment of the dosage.

Finally, in the absence of conclusive clinical data, gliptins have no role in the care pathway for patients with type 2 diabetes mellitus as dual therapy in combination with insulin. The oral antidiabetic agents recommended in combination with insulin therapy are metformin or a sulfonylurea.

 


Clinical Benefit

Low

The Committee deems that the clinical benefit of KOMBOGLYZE (saxagliptin/metformin) is low in the MA indications.

Insufficient

Clinical Added Value

no clinical added value

Considering,

  • demonstration of the non-inferiority of saxagliptin only versus placebo (non-significant analysis for superiority), on a clinically relevant cardiovascular composite endpoint, i.e. reduction of the 3P-MACE composite endpoint including cardiovascular death, non-fatal myocardial infarction and non-fatal stroke, in the SAVOR-TIMI 53 study,
  • initial data having demonstrated a modest efficacy of saxagliptin, in combination with other antidiabetic agents, on reduction of the intermediate laboratory endpoint, HbA1c, compared to placebo or the non-inferiority compared to a sulfonylurea or sitagliptin, without any studies demonstrating a superiority compared to a clinically relevant comparator.
  • the safety profile of saxagliptin, which remains favourable, despite an identified risk of acute pancreatitis and bullous pemphigoid, a rare and serious event common to the gliptins,
  • the additional risk of hospitalisation due to cardiac failure suggested in the SAVOR-TIMI 53 study, which was not confirmed in subsequent data and study analyses and in the post-marketing follow-up data, 
  • the absence of clinical data specifically relating to the fixed-dose combination,
  • the unmet medical need to have access to antidiabetic medicinal products having shown evidence of a reduction in cardiovascular and renal morbidity and mortality, with improved patient compliance and adhesion to treatment, and with a satisfactory safety profile,

the Committee considers that KOMBOGLYZE (saxagliptin/metformin) provides no clinical added value (CAV V) in the treatment of type 2 diabetes.

 

 


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