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How I Use SGLT2 Inhibitors in T2D for Cardiovascular and Renal Disease

Martin J. Abrahamson, MD, FACP

Associate Professor of Medicine
Harvard Medical School
Director, Division of CME
Beth Israel Deaconess Medical Center
Boston, Massachusetts

Martin J. Abrahamson, MD, FACP, has disclosed that he has received consulting fees from Novo Nordisk.

View ClinicalThoughts from this Author

Released: November 10, 2020

The management of type 2 diabetes (T2D) has evolved from primarily focusing on lowering A1C to now considering the whole person. Lowering A1C is still important, of course, but we also consider other health risks and comorbidities—in particular, cardiovascular and renal disease.

Here’s my take on how SGLT2 inhibitors can be used to mitigate cardiovascular and renal comorbidities in patients with T2D and how I approach treatment selection in various clinical scenarios.

Treatment Selection
There are 3 key areas where SGLT2 inhibitors have an expanding role in preventing poor outcomes:

  • First, there are 3 SGLT2 inhibitors that, like GLP-1 receptor agonists, have good evidence for secondary prevention of cardiovascular disease (CVD): canagliflozin, dapagliflozin, empagliflozin. Anyone with T2D and either established atherosclerotic cardiovascular disease (ASCVD) or high risk for ASCVD should receive one of these 3 SGLT2s and/or a GLP-1 receptor agonist, regardless of their A1C.
  • Second, these 3 SGLT2 inhibitors significantly slow progression of kidney disease, even in people who have lower estimated glomerular filtration rates (eGFRs).
  • Third, as a class, all 4 of the FDA-approved SGLT2 inhibitors lower the risk of hospitalization for heart failure (HF). 

Below, I discuss some of the subtleties of when I recommend these SGLT2 inhibitors in certain clinical scenarios.

Chronic Kidney Disease (CKD)
American Diabetes Association (ADA) guidelines recommend SGLT2 inhibitors in the setting of T2D and CKD with urinary albumin-to-creatinine ratio > 30 mg/g, particularly > 300 mg/g. And the studies that showed the benefit of SGLT2 inhibitors on renal outcomes included patients with urinary albumin-to-creatinine ratio as low as 300 mg/g in CREDENCE and 200 mg/g in DAPA-CKD.

But what about patients without albuminuria? Is there a cutoff below which we would not expect this benefit?

Personally, the presence or absence of albuminuria does not affect my choice of treatment in the setting of T2D and CKD. Even though the evidence for benefits is strongest in albuminuria, studies have demonstrated that the primary outcome was still positive with use of an SGLT2 inhibitor regardless of the severity of albuminuria.

Low eGFR
ADA guidelines also recommend SGLT2 inhibitors in the setting of T2D and CKD with eGFR 30-60 mL/min/1.73m2. So how does eGFR affect my treatment choice?

We have data indicating that at least some of the SGLT2 inhibitors slow progression of kidney disease and continue to offer some benefit to people with a lower eGFR. Canagliflozin has been approved for patients with an eGFR as low as 30 mL/min/1.73 m2, the EMPA-REG study of empagliflozin also included patients with eGFRs as low 30 mL/min/1.73 m2, and the DAPA-CKD study of dapagliflozin included patients with eGFRs as low as 25 mL/min/1.73 m2. In fact, in CREDENCE and DAPA-CKD, there was still benefit in the primary composite outcome of renal and cardiovascular endpoints for individuals with an eGFR < 45 mL/min/1.73 m2.

I hope we will soon have more information on this population from subgroup analyses, as it remains unknown whether there is benefit from using SGLT2 inhibitors in people with an eGFR < 30 mL/min/1.73 m2.

All told, this benefit in CKD explains why patients with T2D and CKD should receive an SGLT2 inhibitor, regardless of their need for glucose control. But what about glucose control? We know that at low eGFRs the glucose‑lowering effect of these drugs is minimized, so at these eGFRs, I am clear with patients that I recommend SGLT2 inhibitors for their cardiorenal protection, not necessarily for glucose control. The lower the eGFR, the more we should be ready to add another glucose-lowering agent.

Heart Failure
ADA guidelines also recommend using SGLT2 inhibitors in the setting of HF, particularly with reduced ejection fraction. In fact, the EMPEROR-Reduced trial of empagliflozin and the DAPA-HF trial of dapagliflozin showed the benefit of these SGLT2 inhibitors in improving cardiovascular and HF outcomes even in patients without diabetes.

What about other forms of HF? We currently lack data on use of SGLT2 inhibitors in patients with T2D and HF with preserved ejection fraction. Clinical trials to date have only examined SGLT2 inhibitors in patients with T2D and HF with reduced ejection fraction. 

Your Thoughts?
How would you approach treatment selection in these scenarios? Please share your thoughts in the comments box. And, to see what a panel of 5 experts would recommend, I encourage you to visit the online decision support tool, “Diabetes Consult” that I developed with my colleagues, Zachary T. Bloomgarden, MD, MACE; Anne Peters, MD; Richard E. Pratley, MD; and Robert S. Zimmerman, MD. In this decision support tool, you can enter the details of your case and see how we would proceed.

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This activity is supported by an independent educational grant from
Boehringer Ingelheim Pharmaceuticals, Inc.

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