EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) was the first clinical trial involving patients with type 2 diabetes (T2DM) and high cardiovascular (CV) risk to show that a glucose-lowering drug—in this case, the SGLT2 inhibitor empagliflozin—could lead to a net decrease in adverse CV outcomes.¹ Previously, studies with oral and injectable diabetes medications generally demonstrated an overall neutral effect. The sole exceptions included metformin, which has been linked to a reduction in CV complications but only in small trials and mostly in the pre-statin era. Also, the TZD drug pioglitazone reduced macrovascular events in the PROactive (PROspective pioglitAzone Clinical Trial in macroVascular Events) trial, but this was not the primary endpoint, and the benefits were counterbalanced by an increase in heart failure. So these new results involving empagliflozin will likely have a broad impact for our approach to the treatment of diabetes in patients with pre-existing CV disease.

The SGLT2 inhibitors block an important sodium-glucose transporter in the proximal nephron, and thereby increase renal glucosuria and reduce plasma glucose concentrations and HbA1c, the latter on the order of 0.6-0.8%. They also have modest benefits on body weight (approximately -2 kg) and blood pressure (about -4/-2 mmHg) and do not increase the risk of hypoglycemia. Accordingly, there was hope that this category of drugs might finally dispel the long-held notion that glucose-lowering does not improve CV outcomes.

This hope came to fruition in the EMPA-REG OUTCOME trial, which involved more than 7000 patients with T2DM and CVD randomized to one of two doses of empagliflozin (10, 25 mg) or to placebo on top of standard care. Over a mean follow-up of just over 3 years, active therapy was associated with a 14% reduction in major adverse CV events (MACE) (p = 0.04), an effect driven almost exclusively by a striking 38% reduction in CV mortality (p < 0.001). All-cause mortality was also reduced by 32% (p < 0.001). Non-fatal myocardial infarction (MI) and non-fatal stroke (the two other MACE components) were not significantly affected, with the former occurring slightly less frequently and the latter occurring slightly more frequently in the empagliflozin groups. Heart failure hospitalization was also decreased with the SGLT2 inhibitor, down 35% (p = 0.002),² as was the progression of kidney disease by 39% (p < 0.001).³ Both the CV mortality and HF hospitalization curves separated very early, suggesting that the benefit was driven by an abrupt hemodynamic effect (or, less likely, an abrupt metabolic effect). That is, the benefits did not appear to be the result of the traditional expectation of a glucose-lowering drug—namely, a reduction in atherosclerosis. This interpretation is also supposed by the fact that MI, stroke, and unstable angina were not significantly altered by the study drug. The only adverse effect observed in the trial was a tripling of genital infections, predominately due to candida, a well-recognized complication of glucosuria.

These results were very surprising, and some proposed that they were 'too good to be true.' However, they are now buttressed by newer data involving a second SGLT2 inhibitor, canagliflozin. In the CANVAS (Canagliflozin Cardiovascular Assessment Study) program, this SGLT2 inhibitor was associated with the exact same reduction in the hazard for the primary outcome (3-point MACE): 14% (p = 0.016).⁴ Also, the decreases in the risk for HF hospitalization and the progression of CKD was almost identical to those found in EMPA-REG OUTCOME. However, in CANVAS, while all three components of MACE moved in the right direction (i.e., HR <1.0), none actually achieved statistical significance, perhaps reflecting the fact that the study involved a sizable subgroup of patients who had no prior history of CVD. Importantly, two adverse effects seen in CANVAS (but not in EMPA-REG OUTCOME) included an increase in lower limb amputations and bone fractures in those assigned to canagliflozin.

The CANVAS study shows that the benefits of empagliflozin were not a fluke finding. The CV (and renal) effects of SGLT2 inhibitors are clearly real and likely to be game-changers in the field of diabetes. I would point out, however, that such enthusiasm should still be relegated to the treatment of T2DM in the context of established CVD. There is yet no evidence that the drugs are helpful (beyond lowering glucose) in a primary prevention population. Such individuals were simply not studied in EMPA-REG OUTCOME. As mentioned, in CANVAS, they were and constituted about one-third of the study's participants (i.e., had no overt CVD.) In this subgroup, the hazard ratio for the primary outcome was 0.98, suggesting that those without CVD do not experience the CV benefit as those with CVD.

So, in summary, the most recent introduction into the T2DM pharmacopeia, the SGLT2 inhibitors, show a clear and definite CV advantage in high-risk patients with T2DM and established macrovascular complications. The 'thumbprint,' however, of individual members of the class may be different with regard to not only individual components of MACE but also with regard to adverse effect profiles. The results of two ongoing CV outcome trials with other SGLT2 inhibitors in T2DM (dapagliflozin in DECLARE [Dapagliflozin Effect on CardiovascuLAR Events) and etrugliflozin in VERTIS CV [Cardiovascuar Outcomes Following Ertugliflozin Treatment in Diabetes Mellitus Participants With Vascular Disease]) are anticipated over the next several years. We will hopefully have a better understanding of these issues at that time.

The mechanistic underpinnings of the CV effects of SGLT2 inhibitors still remain to be full elucidated. They potentially pertain to the drug's glucoretic-natriuretic properties.⁵ Another school of thought points to the tendency for these agents to shift fuel metabolism in favor of the consumption of ketones (instead of glucose and free fatty acids).⁶ Such a change, it has been proposed, may provide an energy advantage for cardiomyocytes. Clearly, more mechanistic studies are needed to better understand these concepts, which might have implications for the management of CVD, and especially heart failure, in both diabetic as well as nondiabetic individuals. To this effect, there are several trials now underway to better assess the drug class' benefits in a HF population, and these do include patients without diabetes. These are EMPEROR (EMPagliflozin outcomE tRial in patients with chrOnic heaRt failure), which is studying the effects of empagliflozin in patients with either HF with reduced or preserved left ventricular function (HFrEF or HFpEF) and DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure), which is addressing the effects of dapagliflozin in HFrEF.

References

1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.
2. Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME trial. Eur Heart J 2016;37:1526-34.
3. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323-34.
4. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017. [Epub ahead of print]
5. Sattar N, McLaren J, Kristensen SL, Preiss D, McMurray JJ. SGLT2 inhibition and cardiovascular events: why did EMPA-REG outcomes surprise and what were the likely mechanisms? Diabetologia 2016;59:1333-9.
6. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes 2016;65:1190-5.

Keywords: Diabetes Mellitus, Type 2, Glycosuria, Renal, Metformin, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Blood Glucose, omega-Chloroacetophenone, Blood Pressure, Glucose, Glucose Transport Proteins, Facilitative, Sodium, Candida, Prospective Studies, Glucosides, Follow-Up Studies, Benzhydryl Compounds, Thiazolidinediones, Hypoglycemic Agents, Angina, Unstable, Heart Failure, Body Weight, Hypoglycemia, Atherosclerosis, Stroke, Nephrons, Hospitalization, Myocardial Infarction, Primary Prevention, Fractures, Bone, Amputation, Trematoda, Sodium-Glucose Transport Proteins, Lower Extremity, Renal Insufficiency, Chronic, Metabolic Syndrome

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