By what mechanism does empagliflozin reduce cardiovascular mortality? This question has puzzled scientists and clinicians since the surprising results of EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial were published in late 2015. The EMPA-REG OUTCOME trial was designed to demonstrate cardiovascular (CV) safety by showing non-inferiority in major adverse cardiac events versus the standard care.¹ One can only imagine the surprise and elation of the manufacturers and trial designers when a highly statistically significant 38% reduction in CV mortality was observed. CV mortality was not the trial's primary endpoint; however, the validity of the result is strengthened by the fact that both the 10 mg and 25 mg empagliflozin arms of the study had a CV mortality benefit.

With such an unexpected result, the obvious question is what is the mechanism of action (MOA)? This is of particular importance, as there are signs the unclear MOA has held back widespread adoption of empagliflozin. One endocrinologist at the FDA advisory committee meeting voted against giving empagliflozin a label stating the drug improved CV mortality since they could not explain the MOA.² Ultimately, the committee narrowly voted 12-11 to support an indication that empagliflozin reduces the incidence of CV death among those with type 2 diabetes. Yet, despite being the only approved oral therapy for type 2 diabetes mellitus with a CV mortality benefit, sales and prescriptions of empagliflozin are significantly less than sitagliptin, which has conclusively shown no CV benefits.

It remains highly likely that mechanisms beyond glucose lowering or diuresis are behind the dramatic reduction in CV morality. There have been provocative animal studies of SGLT-2 inhibitors showing reductions in oxidative stress, improvement in endothelial function, neurohormonal modulation and anti-inflammatory effects.^3,4 It has been postulated that reduction in plasma volume without neurohormonal activation, or possibly a change in metabolic fuel sources away from glucose oxidation to free fatty acid (FFA) and ketone bodies may play a role in improving myocardial efficiency and function.^5,6 Still others hypothesize the main driver of benefit may derive from the specific effects on renal sodium and glucose handling, leading to improvements in diabetes-related maladaptive afferent renal arteriolar vasoconstriction.⁷ While many of these biologically plausible mechanisms have potential to explain the CV benefits, little concrete evidence exists to support them.

Inzucchi et al. conducted a post hoc mediation analysis of the EMPA-REG OUTCOME trial to assess the extent to which changes in covariates during the trial contributed to CV death reduction.⁸ To mediate an effect, the treatment (empagliflozin) must have an effect on the variable of interest (hematocrit, BMI, blood pressure, eGFR, etc.) over time, and the change in the variable over time must have an effect on the outcome (CV mortality). Inzucchi et al. found changes in hematocrit and hemoglobin mediated 51.8% and 48.9%, respectively, of the effect of empagliflozin in reducing CV death. Changes in albumin and uric acid mediated 25.5% and 24.6%, respectively. The other potential mediators investigated, including HbA1c, FPG, weight, BMI, SBP and DBP, LDL and HDL cholesterol, triglycerides, free fatty acids, eGFR and UACR, had no or negligible effects in these analyses. In multivariable analysis change in hematocrit in those patients on empagliflozin continued to be the most powerful predictor of CV mortality.

It is well known that patients with higher hemoglobin/hematocrits have improved CV outcomes, both in the setting of ischemic heart disease and heart failure (HF).⁹ Empagliflozin raised hematocrits 4% in EMPA-REG OUTCOME compared to placebo and Inzucchi's work convincingly demonstrates that the improvement in anemia correlates with reduced CV mortality. However, why SGLT-2 inhibition would have such a profound effect on hematocrit is a provocative question in and of itself. The seemingly obvious answer is volume reduction and hemoconcentration. However, even patients with acute decompensated HF and undergoing diuresis with loop diuretics and tolvaptan fail to have such profound and consistent hemoconcentration.¹⁰ Improvements in renal function along with volume reduction with empagliflozin appear more likely contribute to the dramatic increase hematocrit. SGLT-2 inhibitors significantly improve estimated glomerular filtration rate (eGFR), erythropoietin levels and a number of biomarkers of renal function.^11,12 Though eGFR was a variable in the analysis, there is concern its ability to mediate CV mortality may be underestimated in the model. Similar to ACE-inhibitors, empagliflozin initially worsens eGFR, though over the long term it improves. Each variable was analyzed as a time-dependent covariate in Cox regression models, but one cannot help but wonder that since eGFR worsened and improved in the same patients that it was more difficult to accurately model. It is thus likely that the increase in hematocrit, which appears to be mediating the CV mortality reduction in the EMPA-REG OUTCOME trial, is related to improved renal function and erythropoiesis along with volume reduction.

As the mystery of how empagliflozin reduces CV mortality continues to unfold there is still much work to be done. Inzucchi's analysis provides a valuable clue, and draws attention to the remarkable hematocrit increase caused by SGLT-2 inhibition. While many questions remain unanswered, the paucity of mechanistic and biomarker data will be short lived. Three large outcomes trials of patients with well phenotyped HF are currently ongoing. The EMPEROR-PRESERVED (EMPagliflozin outcome tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction) and EMPEROR-REDUCED (EMPagliflozin outcome tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) trials, DAPA-HF (Study to Evaluate the Effect of Dapagliflzoin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) and several smaller randomized clinical trials are evaluating the effects of SGLT-2i on biomarkers, health status, CV outcomes and filling pressures in patients with various phenotypes of HF. This additional randomized data will include over 30,000 patients with numerous biomarker, proteomic, imaging, and hemodynamic sub studies which will be linked to outcomes. This influx of data over the next 2-3 years should allow us to confirm and elaborate on Inzucchi's findings, and hopefully confirm the CV benefits of empagliflozin solve this mystery of MOA.

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. Husten L. CardioBrief: Specialty Rift Brewing Over Empagliflozin. MedPage Today. Jul 6, 2016. Accessed Jun 19, 2018. https://www.medpagetoday.com/cardiology/cardiobrief/58907.
3. Oelze M, Kroller-Schon S, Welschof P, et al. The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity. PLoS One 2014;9:e112394.
4. Lin B, Koibuchi N, Hasegawa Y, et al. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol 2014;13:148.
5. Inzucchi SE, Zinman B, Wanner C, et al. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res 2015;12:90-100.
6. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care 2016;39:1115-22.
7. 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.
8. Inzucchi SE, Zinman B, Fitchett D, et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care 2018;41:356-63.
9. O'Meara E, Clayton T, McEntegart MB, et al. Clinical correlates and consequences of anemia in a broad spectrum of patients with heart failure: results of the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program. Circulation 2006;113:986-94.
10. Ter Maaten JM, Valente MA, Damman K, et al. Combining diuretic response and hemoconcentration to predict rehospitalization after admission for acute heart failure. Circ Heart Fail 2016;9.
11. Wanner C, Inzucchi SE, ZInman B. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:1801-2.
12. Ferrannini E, Bladi S, Frascerra S, et al. Renal handling of ketones in response to sodium-glucose cotransporter 2 inhibition in patients with type 2 diabetes. Diabetes Care 2017;40:771-6.

Keywords: Diabetes Mellitus, Type 2, Sodium Potassium Chloride Symporter Inhibitors, Hematocrit, Uric Acid, Fatty Acids, Nonesterified, Blood Pressure, Glycated Hemoglobin A, Cholesterol, HDL, Plasma Volume, Angiotensin-Converting Enzyme Inhibitors, Sodium, Glucose, Erythropoiesis, Ketone Bodies, Glomerular Filtration Rate, Proteomics, Body Mass Index, Stroke Volume, Vasoconstriction, Glucosides, Benzhydryl Compounds, Hypoglycemic Agents, Benzazepines, Heart Failure, Myocardial Ischemia, Anemia, Diuresis, Biomarkers, Albumins, Cardiovascular Diseases, Oxidative Stress, Phenotype, Erythropoietin, Triglycerides

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