Sodium glucose cotransporter-2 (SGLT2) inhibitors currently approved by the US Food and Drug Administration include empagliflozin (Jardiance), canagliflozin (Invokana), dapagliflozin (Farxiga), and ertugliflozin (Steglatro). Combination formulations are also available: empagliflozin/metformin (Synjardy), canagliflozin/metformin (Invokamet), dapagliflozin/metformin (Xigduo XR), and ertugliflozin/metformin (Segluromet).
For this year’s Kidney Watch, we look once again at the diabetic kidney disease (DKD) space as these agents enter the world of nephrology (1).
On September 30, 2020, the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2) was published. There continues to be increased discussion surrounding the use of SGLT2 inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors. These novel agents are particularly notable for being strongly supported by several studies that looked at primary outcomes, e.g., major adverse cardiovascular events (MACE) or CKD progression and kidney outcomes [effects on albuminuria or albuminuria-containing composite outcomes and effects on estimated glomerular filtration rate (eGFR) loss]. Interestingly, there have been several more publications that did not make it to the KDIGO guideline document but nevertheless, are worthy of mention because they will influence how we will use these agents in our respective clinical practices.
EMPEROR-Reduced (3)
This was a multicenter, double-blind randomized controlled trial (RCT) that enrolled 3730 patients with heart failure and a left ventricular ejection fraction (LVEF) 40% or less who were receiving recommended therapy for heart failure. The primary outcome was a composite of cardiovascular (CV) death or hospitalization for worsening heart failure. This study demonstrated that in patients with or without diabetes, those who received empagliflozin had significantly lower rates of CV death or hospitalization for heart failure (as compared to those who received placebo), hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.65–0.86, p < 0.001.
VERTIS CV (4)
This study is a multicenter, double-blind (non-inferiority) RCT that enrolled 8246 patients who were randomized to receive 5 mg or 15 mg of ertugliflozin or placebo once daily. Note that as compared to other studies cited in this article, this one, in particular, only had CV endpoints [MACE: a composite of death from CV causes, non-fatal myocardial infarction (MI), or non-fatal stroke]. This study showed that among patients with type 2 diabetes and atherosclerotic CV disease (ASCVD), ertugliflozin was non-inferior with regard to MACE.
DAPA-CKD (5)
This is another RCT that enrolled 4304 patients with CKD [eGFR 25–75 and urine albumin-to-creatinine ratio (UACR) 200–5000 mg/g]. With the primary outcome being a composite of a sustained decline in eGFR (at least 50%), end-stage kidney disease (ESKD), or death from causes related to the kidneys or CV disease, this trial was stopped early because of efficacy. The primary outcome event occurred in 9.2% (197/2152) of the dapagliflozin group vs. placebo 14.5% (312/2152), HR 0.61, 95% CI 0.51–0.72, p < 0.001.
SCORED (6)
This is a multicenter, double-blind RCT that enrolled 10,584 patients with type 2 diabetes (A1C ≥ 7%), CKD (eGFR 25–60), and risks for CV disease. Interestingly, the primary endpoint was changed to the composite of the total number of deaths from CV causes and hospitalizations’ urgent visits for heart failure. This study showed that those patients with diabetes and CKD (with or without albuminuria) who received sotagliflozin (first dual SGLT1/SGLT2 inhibitor approved for diabetes) had a lower rate of deaths from CV causes (2.2/100 patient-years vs. 2.4/100 patient-years, HR 0.74, 95% CI 0.73–1.12, p < 0.35). However, there was a signal for adverse events, namely diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis (DKA).
This trial ended early due to funding issues.
FIDELIO-DKD (7)
This is a double-blind, multicenter, international RCT that enrolled 5734 patients who were randomized in a 1:1 ratio to receive finerenone (a non-steroidal mineralocorticoid antagonist) or placebo. Eligibility criteria included the following: CKD (eGFR 25 to <60 and UACR 30 to <300 mg/g) and type 2 diabetes with diabetic retinopathy or CKD (eGFR 25 to <75 and UACR 300–5000 mg/g). The primary composite outcome was kidney failure, a sustained decrease in eGFR (at least 40% from baseline), or death from causes related to the kidneys. It occurred in 17.8% (504/2833) patients who received finerenone vs. placebo 21.1% (600/2841), HR 0.82, 95% CI 0.73–0.93, p = 0.001. Although the frequency of adverse events was similar in the finerenone and placebo groups, there was a higher incidence of hyperkalemia-related discontinuation in the former (2.3% vs. 0.9%).
Certainly, there are more studies down the road that will further shape how physicians use these agents in their respective clinical practices. The question now that all of these guidelines have officially come out, and additional randomized clinical trials continue to be published, is: Are we nephrologists willing to step up to the plate and be the champions for the use of these novel agents?
References
- 1.↑
Neuen BL, et al.. Kidney Watch 2019: SGLT2 inhibitors and cardiorenal outcomes. ASN Kidney News 2019; 11:14–15. https://www.asn-online.org/publications/kidneynews/archives/2019/KN_2019_02_feb.pdf
- 2.↑
Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int 2020; 98:S1–S115. doi: 10.1016/j.kint.2020.06.019
- 3.↑
Packer M, et al.. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020; 383:1413–1424. doi: 10.1056/NEJMoa2022190
- 4.↑
Cannon CP, et al.. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med 2020; 383:1425–1435. doi: 10.1056/NEJMoa2004967
- 5.↑
Heerspink HJL, et al.. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020; 383:1436–1446. doi: 10.1056/NEJMoa2024816
- 6.↑
Bhatt DL, et al.. Sotagliflozin in patients with diabetes and chronic kidney disease [published online ahead of print November 16, 2020]. N Engl J Med doi: 10.1056/NEJMoa2030186; https://www.nejm.org/doi/full/10.1056/NEJMoa2030186
- 7.↑
Bakris GL, et al.. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes [published online ahead of print October 23, 2020]. N Engl J Med doi: 10.1056/NEJMoa2025845; https://www.nejm.org/doi/full/10.1056/NEJMoa2025845
