Abstract

• In early 2016, metformin monotherapy remains the treatment of choice for most patients with type 2 diabetes. There are several alternatives for patients in whom metformin is poorly tolerated or ineffective. However, dapagliflozin and canagliflozin have an unfavourable harm-benefit balance and should not be used to enhance the action of metformin.
   
• Empagliflozin is the third gliflozin to be authorised in the European Union for the treatment of type 2 diabetes.
   
• A randomised, double-blind, placebo-controlled trial of empagliflozin, in combination with other glucose-lowering drugs, involved 7020 patients with type 2 diabetes, an average glycated haemoglobin (HbA1c) concentration of about 8%, and a history of at least one cardiovascular event.
   
• After about 3 years of follow-up, overall mortality was lower with empagliflozin (5.7% versus 8.3%, p<0.001), mainly due to a reduction in cardiovascular mortality, particularly due to heart failure.
   
• This benefit does not seem due to efficacy in preventing the cardiovascular complications of diabetes, as there was no difference between the groups in terms of myocardial infarction or stroke. The most likely explanation is an effect in preventing other cardiovascular disorders, such as heart failure, in patients with a history of cardiovascular disorders. This is consistent with the diuretic effect of empagliflozin and its rapid impact on mortality (within a matter of months in the trial), as well as with lower exposure to cardiovascular drugs and reduction in the risk of hospital admission for heart failure.
   
• In seven comparative trials, empagliflozin had only a moderate glucose-lowering action: among patients with an average baseline HbA1c of about 8%, the HbA1c fell by about 0.5% more with empagliflozin than with placebo. An even smaller effect was reported in patients with renal impairment.
   
• Empagliflozin shares the adverse effects of other gliflozins, including genital infections, kidney failure, and diabetic ketoacidosis. Empagliflozin may also be hepatotoxic. A risk of cancer (especially bladder cancer) cannot be ruled out.
   
• Empagliflozin interacts with nephrotoxic drugs, which aggravate its adverse effects and decrease its hypoglycaemic potency. The diuretic action of empagliflozin can lead to volume depletion and a fall in blood pressure, especially during co-administration with other diuretics or antihypertensive drugs.
  
  
• In practice, empagliflozin was found to reduce mortality in a clinical trial involving patients with type 2 diabetes and significant cardiovascular risk factors. This benefit does not seem to be related to the hypoglycaemic effect of empagliflozin or to prevention of the cardiovascular complications of diabetes, but rather to prevention of heart failure in patients with history of cardiovascular disease. In early 2016, it is unclear which patients are most likely to derive a concrete benefit from empagliflozin therapy. Comparative evaluation must continue, especially in patients with heart failure.

©Prescrire 1 June 2016

"Empagliflozin (Jardiance°). Type 2 diabetes: no rush to use this drug" Prescrire Int 2016; 25 (172): 145-148. (Pdf, subscribers only)