Prof Juan Carlos Kaski, St George's University of London, UK

A recent paper by Zinman et al (1) reporting that the glucose-lowering agent empagliflozin reduced the relative risk for cardiovascular and all-cause mortality in patients with type 2 diabetes, has attracted the attention of physicians at both sides of the Atlantic. Indeed, the EMPA-REG OUTCOME trial (1) appears to have the potential to change the way DM is managed worldwide. The drug empagliflozin belongs to the the sodium glucose cotransporter 2 (SGLT2) inhibitors. This agent –according to the recently published results of EMPA-REG- appears to have achieved a goal that no other anti-diabetic agent has so far managed to achieve, namely improving major cardiovascular outcomes. Like other SGLT2 inhibitors, empagliflozin decreases reuptake of glucose by the kidney, which lowers serum glucose concentrations. The drug has been also shown to reduce body weight and blood pressure.

The exact mechanism (s) whereby this agent improves cardiovascular outcomes needs further investigation. Blood pressure and weight reduction are likely to play a role but it is likely that other mechanisms are also involved.

The results of the EMPA-REG OUTCOME trial have generated a series of questions that will require answers in the very near future; among these, the following are in my view of great importance:

  1. How prepared will be the medical community to embrace the use of these novel agents based on the results of a single (albeit large) study. Will guidelines change based on these findings?
  2. Will the health care services accept the financial challenge posed by the potentially massive use of SGLT2 inhibitors?
  3. Can similar results be achieved with the combined use of current anti-diabetic agents, statins, antihypertensive drugs and diuretics?
  4. Is the combined effect on body weight and blood pressure reduction responsible for the beneficial effect of empagliflozin on clinical outcomes?
  5. Would further longer term safety studies be required before current guideline recommendations are modified to include this agent among currently used compounds?


  1. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.
Cardio Debate Expert Comments

Empa Reg Outcome from a cardiologist’s point of view

EMPA-REG OUTCOME enrolled a population of patients at high cardiovascular risk with a long duration of diabetes and the presence of atherosclerotic cardiovascular disease at study entry. I this study, empagliflozin significantly reduced risk for the primary outcome of cardiovascular death, MI, and stroke compared with placebo with a hazard ratio of 0.86 (95% CI 0.74-0.99; p=0.038). This reduction of the primary outcome was mainly driven by a highly significant 38% reduction in cardiovascular death (HR 0.62; 95% CI 0.49-0.77; p<0.0001), with a very early separation of the curves evident as early as 2 months into the trial. There was a non-significant 13% reduction of non-fatal myocardial infarction (p=0.30) and a non-significant 24% increased risk for non-fatal stroke (p=0.16). In addition, in a secondary/exploratory analysis, empagliflozin led to a significant reduction of hospitalization for HF with a 35% risk reduction (HR 0.65; 95% CI 0.50-0.85; p<0.002), with separation of the curves evident almost immediately during trial observation, suggesting a very early effect of the SGLT2-inhibitor. Finally, empagliflozin reduced overall mortality by 32% (HR 0.68; 95% CI 0.57-0.82; p<0.0001), a highly significant effect translating into a number-needed-to-treat (NNT) of 39 over 3 years to prevent one death.

The results of EMPA-REG OUTCOME with a significant effect on cardiovascular mortality, overall mortality, and hospitalization for HF makes this trial a landmark trial in cardiovascular risk reduction for patients with type 2 diabetes. As such, EMPA-REG OUTCOME stands in line with trials such as the Scandinavian Simvastatin Survival Study (4S) and the Heart Outcomes Prevention Evaluation (HOPE) trial with regard to the magnitude of CV risk reduction. In the 4S trial, simvastatin versus placebo led to an NNT of 30 over 5.4 years to reduce 1 death. HOPE, in a population with about 25% of statin-treated patients, showed that ramipril versus placebo prevents 1 death if 56 patients are treated over 5 years. Finally, EMPA-REG OUTCOME in a population receiving statins in more than 75% of the patients ACE-inhibitors or ARBs in more than 80 % showed that 39 patients must be treated over 3 years to prevent 1 death.