Table 1

Possible mechanisms that could contribute to the reduction of CV mortality by empagliflozin in the EMPA-REG OUTCOME study

EffectLikelihoodReason
Metabolic actions
 Lowered plasma glucose concentrationUnlikelyHyperglycemia is a weak CV risk factor; benefit of HbA1c   reduction on CVD takes ∼10 years to observe
 Increased fax oxidationUnlikelyIncreased oxygen demand per ATP generated
 Increased plasma ketone concentrationUnlikelyIncreased oxygen demand per ATP generated
 Increased plasma uric acid concentrationUnlikelyCausal association with CVD not established
 Increased plasma glucagon concentrationUnlikelyPhysiological increase in glucagon has no effect on CV function
 Weight lossUnlikelyWeight loss is modest but may contribute to long-term   reduction in blood pressure
 Change in plasma electrolyte concentrationUnlikelyNo consistent changes observed
Hemodynamic actions
 Decrease in blood pressureLikelyRapid reduction in blood pressure correlates with early CV   benefit; proven CV protection in prior studies
 Diuretic effect and decrease in extracellular fluid volumeLikelyRapid reduction in extracellular fluid volume correlates with early CV benefit; proven protection against CHF in prior studies
 Impaired arterial elasticityPossibleArterial stiffness is a CV risk factor; empagliflozin reduces   arterial stiffness
 Direct effect on the myocardiumUnlikelyNo evidence
 Decreased sympathetic tonePossibleNo increase in heart rate despite decrease in blood pressure and extracellular fluid volume