The role of the proximal tubule and the sodium glucose cotransporter 2 (SLC5A2) in glucose homeostasis was discovered by exploring the antiglycemic effect of phlorizin (a natural compound in unripe apples) and the molecular basis of familial renal glucosuria. Inhibitor of the sodium glucose cotransporter 2 (SGLT2i) was introduced in the early 2010s as a new class of antiglycemic medications. The Food and Drug Administration mandates cardiovascular outcomes randomized controlled trials (RCTs) for all antiglycemic agents. These trials (1–234) provided suggestive clinical evidence that SGLT2is may improve hard cardiovascular and kidney outcomes in diabetic CKD.
The first cardiovascular trial to be reported was empagliflozin’s EMPA-REG OUTCOME (1). Cardiovascular benefit was documented for the primary (MACE-3: a composite of cardiovascular death, nonfatal myocardial infarction, or stroke) outcome: hazard ratio (HR), 0.86; 95% confidence interval, 0.74 to 0.99; P=0.04 for superiority. Soon after, it was reported that canagliflozin (2) was associated with a beneficial reduction in MACE-3: HR, 0.86; 95% confidence interval, 0.75 to 0.97; P=0.02 for superiority. On the other hand, dapagliflozin (3) and ertugliflozin (4), while being noninferior to placebo for the MACE-3 outcome, did not achieve superiority in their respective cardiovascular safety trials, DECLARE-TIMI-58 and VERTIS-CV. All four SGLT2i safety trials reported consistent reductions in hospitalizations for congestive heart failure, with HR falling in the very narrow range of 0.65–0.73, and P values that were all considerably smaller than 0.001. The same cardiovascular safety trials showed improvements in variably defined composite kidney-specific outcomes of worsening kidney function (doubling serum creatinine and/or sustained reductions in eGFR>40 ml/min per 1.73 m2), ESKD (defined as need for dialysis, transplantation, and/or eGFR<15 ml/min per 1.73 m2), or kidney death, with HR between 0.53 and 0.81. Currently, the only publicly reported trial with a prespecified primary kidney-specific outcome is the CREDENCE (5) double-blinded RCT of canagliflozin in patients with persistent macroalbuminuria while receiving maximal therapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. CREDENCE confirmed the cardiorenal benefit of SGLT2is as a class by showing that the primary composite outcome of ESKD (dialysis, transplantation, or a sustained eGFR <15 ml/min per 1.73 m2) or death from cardiovascular or kidney disease was 30% lower in patients receiving canagliflozin.
In this issue of CJASN, Levin et al. (6) return to the “scene of the crime” to conduct a post hoc analysis of the EMPA-REG OUTCOME trial data and examine the cardiovascular and kidney outcomes of empagliflozin against the cardiorenal risk of study participants. The latter was defined according to the 2012 Kidney Disease Improving Global Outcomes (KDIGO) two-dimensional CKD classification, which takes into account the degree of kidney filtration (eGFR) and the severity of kidney damage (albuminuria). Analyses in multiple cohorts (7) have shown that this simple classification system, which assigns higher risk to patients with low eGFR or severe albuminuria (assessed by the urine albumin-to-creatinine ratio [UACR]), can predict the risk of mortality as well as cardiovascular- and kidney-specific (loss of kidney function, need for KRT, i.e., dialysis or transplant or AKI) outcomes. In our present era in which approximately 40% of patients with diabetes and kidney disease do not have overt albuminuria, the KDIGO risk allows clinicians to approach patients uniformly, in terms of their total cardiorenal risk rather than the individual laboratory components contributing to the risk. The paper thus goes beyond the conventional eGFR and UACR subgroup analyses previously reported for empagliflozin and canagliflozin in the EMPA-REG OUTCOME (8) and CREDENCE (5) trials by considering the extent of both benefit and harm according to individual risk. This is a more clinically relevant way to conduct subgroup analyses for prescribers who are considering the initiation of SGLT2i for their patients.
In the EMPA-REG OUTCOME trial, nearly 75% of the recruited patients had eGFR>60 ml/min per 1.73 m2 (approximately 17.7% with eGFR=45–59 ml/min per 1.73 m2, 7.7% with eGFR=30–44 ml/min per 1.73 m2), while approximately 60% of patients had UACR<30 mg/g, and 11% had UACR>30 mg/g. Considering the contribution of both laboratory tests to risk, a rather different classification of participants emerges: approximately 47%, 29%, 15%, and 8% would be classified as low, moderately increased, high, and very high KDIGO risk, respectively. Levin et al. (6) examined whether the KDIGO risk modified the benefit of empagliflozin against the prespecified MACE-3 and its individual components of myocardial infarction, stroke and cardiovascular death, congestive heart failure, and all-cause mortality. They also examined the prespecified outcome of incident or worsening nephropathy (composite of progression to macroalbuminuria, doubling of serum creatinine accompanied by eGFR<45 ml/min per 1.73 m2, and initiation of dialysis) and the composite of doubling of serum creatinine, initiation of KRT, or death from kidney causes.
What did the analysis of Levin et al. (6) show? Excitedly for the clinician but unsurprisingly for anyone who has followed the SGLT2i saga since the first translational science paper in diabetic kidney disease >20 years ago (9), empagliflozin worked equally well across KDIGO risk categories with no evidence of effect modification by KDIGO risk in tests of statistical interaction. Stated in less technical terms, the numerically variable results obtained for MACE-3 and nephropathy (Figure 1, A and B) within the four risk categories are due to statistical noise. Both clinicians who still classify patients with two numbers (eGFR and albuminuria) and those who prefer a global risk assessment can communicate the benefits of empagliflozin to their patients using the primary study results: 14% and 39% risk reductions in major cardiovascular events and new or worsening kidney disease or failure, respectively. In terms of safety, serious adverse events associated with the use of empagliflozin did not seem to differ according to baseline risk category; interestingly enough, the incidence rates of all adverse events were lower with empagliflozin than placebo, except for genital infections.
Do the results of this paper imply that one may procrastinate in the decision to use SGLT2i? To answer this question, one must pay attention to the nuance hidden in the eGFR slope, which Levin et al. (6) modeled within risk categories in a fashion analogous to the earlier global analysis of eGFR slopes in EMPA-REG OUTCOME (10). These analyses may be casually read in a qualitative fashion by noting that the slope patterns were similar across risk categories: empagliflozin was associated with acute worsening eGFR (slope more negative than placebo) in the first 4 weeks after initiation, followed by stabilization of eGFR (slopes either close to zero or less negative than placebo) in the chronic phase. However, the quantitatively oriented reader will appreciate the nuance in the absolute eGFR slopes during chronic use of empagliflozin. The latter were essentially identical to zero in the low, moderate, and high risk categories of patients (i.e., empagliflozin stabilized eGFR, which was the major determinant of KDIGO risk in this analysis).
The “average” patient in these categories may expect to postpone kidney failure by a very large, potentially infinite time (dividing by zero is a tricky business!). In the very high risk category, the rate of loss of eGFR was lower (−0.756 ml/min per 1.73 m2 per year) with empagliflozin than with placebo (−3.024 ml/min per 1.73 m2 per year). For a patient with a pretherapy eGFR () in the very high risk KDIGO category, we can translate the slope into years of postponed kidney failure (eGFR approximately 15 ml/min per 1.73 m2) according to the formulaWe plot this formula in Figure 1C for the range of eGFRs in EMPA-REG OUTCOME; there is a striking dependency of the years of postponed dialysis on the pretherapy eGFR. Hence, even though the risk reduction for this outcome may not differ according to baseline eGFR, the absolute benefit a patient may derive will be larger if an SGLT2i is started sooner rather than later. These slope analyses may be easily communicated to patients in the very risk category as: “After we start the drug, the eGFR will decline somewhat, but the kidney function will be the same as if you had never started the drug after 1 year (point to 52-weeks time point of figure 4 in Levin et al. ). Afterward, the average patient may be able to postpone kidney failure and possibly avoid dialysis by X (result of Equation 1) years.”
How comfortable should one be in applying the results of this paper to daily clinical practice? One may rightfully point out that the post hoc, exploratory nature of this analysis and the low number of patients in the high/very high risk category are major limitations. Hence, one may decide to wait before prescribing SGLT2i until further dedicated studies are reported in peer reviewed publications (in particular, DAPA-CKD and EMPA-KIDNEY, both of which are pushing the envelope of SGLT2i by examining patients with CKD with or without diabetes and even patients without proteinuria). Or one may simply shrug these limitations away and meta-analyze the kidney-specific outcomes in the cardiovascular safety, CKD, and heart failure trials (Figure 1D). Across trials, SGLT2is reduce the clinically meaningful end point of worsening kidney function/ESKD/kidney death by 38% with little statistical heterogeneity among the different SGLT2is and a prediction interval about the results of future SGLT2i RCT of 0.40–0.97. The inescapable conclusion from this back-of-envelope meta-analysis and the paper by Levin et al. (6) is that all nephrologists should make discussing the SGLT2i option with their patients their main New Year's resolution for 2021.
C. Argyropoulos reports receiving personal fees from Baxter Healthcare for serving on the advisory board about the Theranova Dialyser; personal fees from Bayer for media strategy about finerenone; grants from Dialysis Clinic, Inc. for epidemiology of CKD; and personal fees from Health Services Advisory Group for activities related to the Medical Board of ESRD Network 15, outside the submitted work. The remaining author has nothing to disclose.
The content of this article reflects the personal experience and views of the author(s) and should not be considered medical advice or recommendations. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or CJASN. Responsibility for the information and views expressed herein lies entirely with the author(s).
1. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators: Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373: 2117–2128, 2015 26378978
2. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group: Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377: 644–657, 2017 28605608
3. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johansson PA, Langkilde A-M, Sabatine MS; DECLARE–TIMI 58 Investigators: Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 380: 347–357, 2019 30415602
4. American College of Cardiology: Cardiovascular outcomes following ertugliflozin treatment in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease, 2020. Available at: https://www.acc.org/education-and-meetings/image-and-slide-gallery/media-detail?id=307A7E103BC04A588A3370709253FC35&_ga=2.169043750.628506905.1596648172-2020666806.1596648172
. Accessed August 5, 2020
5. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu P-L, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW; CREDENCE Trial Investigators: Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 380: 2295–2306, 2019 30990260
6. Levin A, Perkovic V, Wheeler DC, Hantel S, George J, von Eynatten M, Koitka-Weber A, Wanner C; EMPA-REG OUTCOME Investigators: Empagliflozin and cardiovascular and kidney outcomes across KDIGO risk categories: Post hoc
analysis of a randomized, double-blind, placebo-controlled, multinational trial. Clin J Am Soc Nephrol 15: 1433–1444, 2020
7. Levey AS, de Jong PE, Coresh J, El Nahas M, Astor BC, Matsushita K, Gansevoort RT, Kasiske BL, Eckardt K-U: The definition, classification, and prognosis of chronic kidney disease
: A KDIGO controversies conference report. Kidney Int 80: 17–28, 2011 21150873
8. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B; EMPA-REG OUTCOME Investigators: Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 375: 323–334, 2016 27299675
9. Vallon V, Richter K, Blantz RC, Thomson S, Osswald H: Glomerular hyperfiltration in experimental diabetes mellitus: Potential role of tubular reabsorption. J Am Soc Nephrol 10: 2569–2576, 1999 10589696
10. Wanner C, Heerspink HJL, Zinman B, Inzucchi SE, Koitka-Weber A, Mattheus M, Hantel S, Woerle H-J, Broedl UC, von Eynatten M, Groop P-H; EMPA-REG OUTCOME Investigators: Empagliflozin and kidney function decline in patients with type 2 diabetes: A slope analysis from the EMPA-REG OUTCOME trial. J Am Soc Nephrol 29: 2755–2769, 2018 30314978