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Professor of Medicine
Division of Endocrinology
Department of Medicine
Duke University Medical Center
Duke Clinical Research Institute
Durham, North Carolina
Jennifer B. Green, MD: consultant/advisor/speaker: Bayer.
Care of people with type 2 diabetes (T2D) and chronic kidney disease (CKD) has gone through tremendous change in the past 5 years or so as management has shifted away from reliance on angiotensin-converting–enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) alone. Sodium glucose cotransporter 2 (SGLT2) inhibitors are now standard care in this population and provide the opportunity to intervene to preserve kidney function and reduce the risk of the cardiovascular (CV) complications that so often accompany CKD. Glucagon-like peptide-1 receptor agonists also offer a means of reducing CV risk in patients with T2D and CKD.
Clinical Trials of SGLT2 Inhibitors
The first CV outcomes trials of SGLT2 inhibitors enrolled patients with T2D who had atherosclerotic cardiovascular disease (ASCVD) or were at very high risk for ASCVD but who, generally, did not have CKD, although there was some overlap. Subsequent trials have shown that in addition to reducing CV risk in patients with T2D and CKD, SGLT2 inhibitors significantly reduce the risk of progressive kidney disease. We now know from the CREDENCE trial of canagliflozin and the DAPA‑CKD trial of dapagliflozin that these drugs significantly reduce the risk of progression to composite kidney outcomes, including worsening kidney function, end-stage kidney disease, and CV-related or kidney-related death. The SGLT2 inhibitors significantly reduce the risk of those endpoints occurring in people with diabetic kidney disease and reduce the risks of other CV complications, such as hospitalization for heart failure.
Screening for CKD in T2D
Physicians who are not nephrology specialists should feel empowered by this evidence to use these therapies to preserve kidney function, reduce the need for dialysis or kidney transplantation, and keep our patients with T2D healthy and out of the hospital. Unfortunately, we know that even people who have obvious CKD based on low estimated glomerular filtration rate (eGFR) commonly remain undiagnosed and miss the opportunity to benefit from available treatment. We need to ensure that we are screening for CKD and taking action in anyone who has a sustained eGFR <60 mL/min, which is common in people with T2D in the United States.
Of course, eGFR is only half of the story—we also need to check the urine albumin-to-creatinine ratio (UACR) in people with T2D at least once a year. Put simply, an elevated UACR is an indication of kidney damage. People with either a sustained eGFR <60 mL/min for ≥3 months or a UACR that is elevated above normal for ≥3 months have CKD. However, we know that only approximately one half of people with diabetes in the United States receive annual UACR testing, despite this having been recommended by the American Diabetes Association (ADA) and other medical societies for decades. Clearly, we need to increase our awareness of CKD among our patients with T2D.
The ADA now recommends using an SGLT2 inhibitor in patients with established CKD to reduce their risk of progressive kidney dysfunction, in addition to background ACE inhibitor or ARB therapy. At present, that benefit has been most clearly demonstrated in people with CKD and significant albuminuria, meaning a UACR of ≥200 mg/g. Patients with CKD who have a less significant elevation—or even no elevation in UACR—but who do have an eGFR <60 mg/dL will still benefit from use of an SGLT2 inhibitor, but the main benefit will be to reduce the risk of CV complications, which still warrants intervention.
Prevention of CKD
The effects of SGLT2 inhibitors in people with T2D without kidney or CV complications has not been well studied in interventional, randomized, controlled, and prospective trials. A large observational study from the United Kingdom of people with T2D who received SGLT2 inhibitors has reported a reduced risk of CV events with SGLT2 inhibitors compared with treatment using other classes of drugs, which suggests that these drugs may be effective in primary prevention of CV disease. Those data are imperfect, but SGLT2 inhibitors are approved for glucose control and will have a glucose‑lowering effect in people with T2D without complications as long as their eGFR is above approximately 40‑45 mg/dL. Therefore, SGLT2 inhibitors can certainly be selected for glycemic management of lower-risk patients with T2D. There are many other benefits to use of SGLT2 inhibitors: They’re not associated with hypoglycemia, and they can be associated with weight loss, although it is usually fairly modest. We would hope that might provide a CV and kidney benefit over the long run, but it is not possible to say that with confidence at present.
Prescribing SGLT2 Inhibitors
When SGLT2 inhibitors are prescribed, particularly to people with established CKD, there will be a decrease in their eGFR almost immediately after they start the medication, which is not indicative of kidney damage. In fact, it is probably indicative of an immediate and favorable change to hemodynamics in the kidney. Subsequently, there is a plateauing and less of a decline in eGFR over time.
Occasionally people who started on an SGLT2 inhibitor may have a very significant deterioration in kidney function. I am very careful to assess patients’ volume status when starting an SGLT2 inhibitor. If it looks depleted and, in particular, if they are receiving preexisting diuretic therapy or their blood pressure is low, I will make changes to their background medications. In these cases, I preemptively decrease the dosage of their diuretic. I often discontinue thiazides, or if they are not receiving a diuretic I may reduce one of their other blood pressure medication dosages in anticipation that they are going to have some volume contraction when they start the SGLT2 inhibitor. I know that when they come back to see me, I can readjust their medication if they have volume overload or their blood pressure is higher than optimal. Although, frankly, I do not often need to do that. I have had very good results with this proactive approach, and I would strongly recommend it. It is much easier to prevent a problem than to take action after a problem has occurred.
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