JARDIANCE (ICC) (empagliflozine)

Key points

Favourable opinion for reimbursement as salvage therapy only, in addition to optimised standard of care therapy, in adults with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who remain symptomatic (NYHA class II to IV) despite this treatment. The Committee considers that optimisation of treatment prior to the prescription of JARDIANCE (empagliflozin) implies having used medicinal products in accordance with the recommended strategy and at the maximum tolerated dose, including the sacubitril/valsartan combination as a potential replacement for an ACE inhibitor or ARB, if their combination is compatible with the patient’s clinical profile.

Unfavourable opinion for reimbursement in other populations in the “chronic heart failure with reduced ejection fraction” indication, in particular as first-line treatment or in addition to non-optimised standard of care therapy including the sacubitril/valsartan combination.

What therapeutic improvement?

Therapeutic improvement in management of the disease (including FORXIGA (dapagliflozin)).

Role in the care pathway?

According to the European and international guidelines updated in 2021, in addition to lifestyle and dietary measures and control of cardiovascular risk factors, the management of adults with symptomatic (NYHA class II to IV) heart failure with reduced ejection fraction is based on optimised standard of care therapy, which includes:

•  either an angiotensin converting enzyme (ACE) inhibitor, or, in the event of intolerance to ACE inhibitors, an angiotensin receptor blocker (ARB), or a sacubitril/valsartan fixed-dose combination in ACE inhibitor naïve patients (i.e. de novo),
• a beta-blocker, in clinically stable patients, 
• a mineralocorticoid receptor antagonist (MRA) (spironolactone or eplerenone) in patients who remain symptomatic with an LVEF ≤ 35%, despite optimal ACE inhibitor (or ARB) + beta-blocker treatment,
• ± a loop diuretic in the event of signs and symptoms of congestion.

In the event of persistent symptoms and a LVEF ≤ 35% despite optimal ACE inhibitor (or ARB) + beta-blocker + mineralocorticoid receptor antagonist (MRA) treatment, the sacubitril/valsartan fixed-dose combination is recommended to replace of the ACE inhibitor (or ARB). It should be noted that the Committee considers that the proprietary medicinal product ENTRESTO (sacubitril/valsartan) may be proposed to patients with NYHA class II or III heart failure with an LVEF ≤ 35%, who remain symptomatic despite ACE inhibitor or ARB treatment and require treatment modification (opinion following the re-evaluation on 11 January 2017).

The addition of a sodium-glucose co-transporter 2 inhibitor (SGLT-2) (empagliflozin or dapagliflozin) to optimised standard of care therapy with an ACE inhibitor or ARB or sacubitril/valsartan fixed-dose combination + beta-blocker + mineralocorticoid receptor antagonist (MRA) is now recommended, in the absence of contraindications, irrespective of diabetes status.

Role of JARDIANCE (empagliflozin) in the care pathway 

The overall management of chronic heart failure with reduced ejection fraction is based on lifestyle and dietary measures, control of cardiovascular risk factors and an optimised medicinal strategy.

In the medicinal strategy, JARDIANCE (empagliflozin) 10 mg is a salvage therapy, which may be proposed in addition to optimised standard of care therapy, in adults with chronic heart failure with reduced ejection fraction (LVEF ≤ 40%) who remain symptomatic (NYHA class II to IV) despite this treatment.

The Committee considers that optimisation of treatment prior to the prescription of JARDIANCE (empagliflozin) implies having used medicinal products in accordance with the recommended strategy and at the maximum tolerated dose, including the sacubitril/valsartan combination as a potential replacement for an ACE inhibitor or ARB, if their combination is compatible with the patient’s clinical profile. It should be noted that in the EMPEROR-reduced study, only 19.5% of patients were previously treated with the sacubitril/valsartan combination.

In the absence of a comparison with FORXIGA (dapagliflozin), given its concomitant development, the role of JARDIANCE (empagliflozin) cannot be positioned in comparison with this medicinal product.

In other clinical situations of heart failure, in the absence of data, JARDIANCE (empagliflozin) has no role in the care pathway.

As regards safety signals such ketoacidosis, genital infections, lower limb amputations and Fournier's gangrene observed with gliflozins in the treatment of type 2 diabetes, in the EMPEROR-reduced study conducted in heart failure patients with or without concomitant type 2 diabetes, the following were observed:

• no ketoacidosis events reported in either of the two treatment groups,
• 31 genital infection events reported in the empagliflozin group, including 18 in diabetic patients, compared to 12 events in the placebo group, including 4 in diabetic patients. Serious forms were found in 6 patients in the empagliflozin group and 5 patients in the placebo group,
• 13 cases of amputation in the empagliflozin group and 10 cases in the placebo group, in diabetic or non-diabetic patients,
• one case of Fournier’s gangrene in the empagliflozin arm reported in a diabetic patient versus no cases in the placebo group.

The Committee therefore reiterates that it is necessary to conduct a detailed assessment of patients before initiating treatment with JARDIANCE (empagliflozin) in order to ensure that they present no risk factors for the occurrence of such events. It is necessary to provide the patient with comprehensive and precise information relative to the symptoms associated with each of these events, particularly if heart failure is combined with type 2 diabetes. The precautions relative to these events, particularly in diabetic patients, are highlighted in the re-evaluation opinion of 18 November 2020.

Assessment of renal function is recommended prior to initiation of treatment with JARDIANCE (empagliflozin) then periodically during treatment (at least yearly), and prior to initiation of any concomitant medicinal product that may have a negative impact on renal function.

Special recommendations

Given its safety profile, which involves warnings relative to the risk of lower limb amputations, ketoacidosis and genital infections, and the very rare but serious and SGLT-2 class-specific risk of the development of Fournier's gangrene, the initiation of JARDIANCE (empagliflozin) 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, particularly in heart failure patients with type 2 diabetes.

In the EMPEROR-reduced study, conducted in heart failure patients, 49.8% of patients had concomitant type 2 diabetes. The Committee reiterates that the safety profile of JARDIANCE (empagliflozin) requires warnings in patients with type 2 diabetes relative to the risks of amputation, ketoacidosis, genital infection, and the very rare but serious and SGLT-2 inhibitor class-specific risk of the development of Fournier's gangrene.