PracticeUpdate Cardiology March 2019

EXPERT OPINION 16

Practical Considerations and Utility of SGLT2 Inhibitors in Improving CV Outcomes Interview with Silvio E. Inzucchi MD

Dr. Inzucchi is Professor of Medicine (Endocrinology), Clinical Director of the Section of Endocrinology, Director of the Yale Diabetes Center, and Director of the Endocrinology and Metabolism Fellowship at Yale School of Medicine in New Haven, Connecticut.

What are the potential mechanisms by which SGLT2 inhibitors reduce CV mortality? Dr. Inzucchi: Well, the SGLT2 inhibitors have many effects on cardiovascular risk. They lower glucose without hypoglycemia. They lower blood pressure. They lower body weight and there have been some beneficial effects on certain lipid param- eters as well. We conducted a mediation analysis recently that was published in Diabetes Care to try to determine which of the covariants that we influenced in EMPA-REG-OUTCOME actually drove the risk reduction specifically for cardiovascu- lar mortality. Interestingly, very few of the factors that we were able to modulate with empagliflozin actually translated to the cardiovascular benefit with one exception, which was the change in hematocrit. It’s interesting to note that when you use an SGLT2 inhibi- tor, hematocrit actually increases by about 3 to 4 absolute percentage points. We take this to mean a reduction in plasma volume so there is hemo-concentration and that explained about 50% of the benefit from empagliflozin on cardiovascular mortality. We think that this means that by reducing plasma volume in patients either with heart failure or at risk for heart failure, there can be an offloading of the ventricle allowing for more efficient function. Very contro- versial. We don’t have any direct data to support that hypothesis, but this is what we found in the specific statistical analysis.

There have been other theories. Some feel that there is a minor increase in the ketone beta hydroxybutyrate and that might pro- vide a more efficient fuel source for the heart and other mechanisms have been discussed recently as well. I think this is a critically important issue, very controversial but it’s going to take us a few more years to figure it out. Prior studies have shown improvements in renal risk factors such as hypertension, albu- minuria, and hyperfiltration, with use of SGLT2 inhibitors. What is the role of SGLT2 inhibitors in the management of patients with kidney disease? Dr. Inzucchi: Well, there are two important issues here. The first is that in EMPA-REG- OUTCOME with empagliflozin and CANVAS with canagliflozin the reduction in the pro- gression of CKD was on the order of 40%. The second issue is that the drugs actually should not be used in those patients with more advanced renal disease so there’s a bit of a clinical conundrum here.

" I usually follow the guidelines so we’re using SGLT2 inhibitors not as monotherapy. We almost always start with metformin but it’s a good add-on drug after metformin, especially in those patients that have cardiovascular disease and I tend to favor them over GLP-1 receptor agonists in those patients who are either at risk for heart failure or already have heart failure. " PRACTICEUPDATE CARDIOLOGY