SGLT2 Inhibitors: A Class Effect?

Have you felt as if nearly every time you surf the Web or open up a journal there is a new update on SGLT2 inhibitors? From the results of EMPA-REG to adverse effects, we are continually encountering news about this class of agents. These and other topics await further data from clinical trials as well as experience in prescribing to larger numbers of patients. So, what do we make of all of this information?

We know that the 3 currently available sodium-glucose co-transporter 2 (SGLT2) inhibitors — canagliflozin (Invokana, Janssen), dapagliflozin (Farxiga, AstraZeneca), and empagliflozin (Jardiance, Boehinger Ingelheim and Lilly) — yield statistically significant reductions in HbA1c as well as produce modest decreases in weight and blood pressure.

However, in September 2015, intriguing and surprising results emerged at the annual European Association for the Study of Diabetes (EASD) meeting. Diabetologists and journalists heard audible gasps and multiple rounds of applause from among the approximately 5000 individuals in attendance when the results from the EMPA-REG Outcome study were presented.

These reactions are definitely not what you would usually expect from such a meeting, which begs the question: Why? Perhaps it was because the findings prompted the following questions.

1. Researchers reported an unprecedented effect on cardiovascular (CV) outcomes.^1,2 How was this effect achieved?

   Empagliflozin is the first type 2 diabetes therapeutic agent to show improved CV outcomes in patients at high risk for CV disease (CVD). The EMPA-REG Outcome study strikingly demonstrated a 38% relative risk reduction in CV death and a 32% relative risk reduction in all-cause mortality.^1,2 This clinical trial had a total of 7020 patients with type 2 diabetes and established CVD (myocardial infarction [MI], cerebrovascular accident [CVA], or peripheral artery disease [PAD]) who were on standard-of-care medications for both hypertension and dyslipidemia. They had a BMI greater than 45, and an estimated glomerular filtration rate (eGFR) greater than 30 mL/min/1.73m². Participants were randomly assigned on a 1:1:1 basis to 1 of 2 doses of empagliflozin (10 mg or 25 mg) or placebo.

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   As impressive as these results were, we are left with many significant questions. Chief among them: What exactly is the mechanism underlying this impact? The short answer is that we do not know yet. Is it the decrease in HbA1c, weight, or blood pressure? The CV effects began very early, approximately within 3 to 6 months of starting empagliflozin. Silvio E. Inzucchi, MD, one of the study authors, observed, “The cardiovascular effects occurred too early … it may have been mediated through the osmotic diuresis that empagliflozin induces. That is, we are helping heart failure (HF) patients.”²

   But how, you may ask, is that the case when only 10% of the study participants had HF at baseline? Dr Inzucchi, and others, including Vivian Fonseca, MD, and Edward S. Horton, MD, explained that a potential explanation is the fact that empagliflozin may have had an impact on subclinical HF.²

2. Is it too early to speculate on whether this a class effect?

   As intriguing as it as it is to think, “If the putative mechanism of osmotic diuresis causing the CV changes holds true, would it be too large of a leap to extrapolate this to the other 2 SGLT2 inhibitors? Hold on and wait a bit, many clinicians and researchers have cautioned. I agree that we cannot — and should not — draw conclusions until we see the data for canagliflozin and dapagliflozin. Next year, it is anticipated that the results from the Canagliflozin Cardiovascular Assessment Study (CANVAS) will be reported. This trial is studying approximately 4000 patients with type 2 diabetes on canagliflozin 100 mg or 300 mg daily or placebo. Also, the DECLARE-TIMI 58 study of dapagliflozin will randomly assign more than 17 000 patients with type 2 diabetes to dapagliflozin 10 mg per day or placebo, and is slated for completion in 2019.

3. Does this study have implications for where empagliflozin is placed in the armamentarium of diabetes agents?

   Some endocrinologists, such as Anne Peters, MD, answer with a resounding “yes.” She initially moved this agent from fourth-line to third-line therapy, and in light of EMPA-REG, has now placed empagliflozin as early as second-line treatment after metformin.

   In a commentary on Medscape, she remarks, “With the EMPA-REG trial, I am really convinced that there are additional benefits in addition to just lowering glucose … For now, what I know is that empagliflozin produced this reduction in mortality, so empagliflozin is the one that I know can cause these benefits. Clinically, if I am starting a patient who has established cardiovascular disease on an SGLT2 inhibitor, I put them on empagliflozin.”³ Will the guidelines change as a result of this and future studies? We will have to wait and see.

It should also be noted that EMPA-REG Outcome was a secondary — not a primary — prevention trial so whether or not low-risk patients would experience similar benefits is unknown.

Also, as with every medication or procedure in medicine, there are potential risks. In light of the reports of cases of euglycemic diabetic ketoacidosis, to what degree do they affect our use of these agents? Look for more on this and other potential disadvantages in a future column.

Like my fellow clinicians, I will continue following and learning about the developments for this class of medications with great interest.

References

1. Zinman B, Wanner C, Lachin JM, et al; for the EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720.
2. Empagliflozin cuts cardiovascular deaths in landmark trial. National Diabetes Education Initiative website. http://www.ndei.org/conference-coverage-empa-reg-outcome-trial-empagliflozin-reduces-cardiovascular-deaths-SGLT2-inhibitor-EASD-congress-2015.aspx. Published September 2015. Accessed March 26, 2016.
3. Peters AL. How EMPA-REG has changed my practice. Medscape. http://www.medscape.com/viewarticle/853875. Published November 9, 2015. Accessed March 26, 2016.