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1
Prescribing SGLT2 Inhibitors in Patients 52
2 Q2 With CKD: Expanding Indications 53
3 54
4
Q1 and Practical Considerations 55
5 56
6
Q24 Kevin Yau1,2,3, Atit Dharia1,2,3, Ibrahim Alrowiyti1,2 and David Z.I. Cherney1,2 57
7 1
Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada; and 2Department of 58
8 Medicine, University of Toronto, Toronto, Ontario, Canada 59
9 60
10 Q5Q6 SGLT2 inhibitors have emerged as a key disease-modifying therapy to prevent the progression of chronic 61
11 kidney disease (CKD). These agents prevent decline in kidney function through reduction in glomerular 62
12 hypertension mediated through tubuloglomerular feedback independent of their effect on glycemic con- 63
13 trol. The proliferation of clinical trials on SGLT2 inhibitors has rapidly expanded the approved clinical 64
indications for these agents beyond patients with diabetes mellitus (DM). We review the current in- 65
14 dications for SGLT2 inhibitors in patients with and without diabetic kidney disease, including new evidence
15 for use in patients with heart failure with or without reduced ejection fraction, stage 4 CKD, and chronic 66
16 glomerulonephritis. The EMPA-KIDNEY trial was recently stopped early for efficacy suggesting that SGLT2 67
17 inhibitors may soon be indicated for patients with CKD without albuminuria. We review practical con- 68
18 siderations for prescription of SGLT2 inhibitors, including the anticipated acute decline in estimated 69
glomerular filtration rate (eGFR) on initiation, initiating the lowest dosage used in clinical trials, volume 70
19
status considerations, and adverse event mitigation. Combination therapy in patients with DM may be
20 71
considered with agents, including glucagon-like peptide-1 receptor agonists (GLP-1-RAs), novel mineral-
21 ocorticoid receptor antagonists, and selective endothelin receptor antagonists to reduce residual albu- 72
22 minuria and cardiovascular risk. 73
23 Kidney Int Rep (2022) -, -–-; https://doi.org/10.1016/j.ekir.2022.04.094 74
24 KEYWORDS: chronic kidney disease; diabetes; diabetic kidney disease; glomerulonephritis; heart failure; SGLT2 75
25 inhibitors 76
26 ª 2022 Published by Elsevier, Inc., on behalf of the International Society of Nephrology. This is an open access article 77
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
27 78
28 79
29 80
n 2008, the US Food and Drug Administration apparent shortly after drug initiation suggesting
30
31
I mandated that new glucose-lowering therapies un-
dergo cardiovascular outcome trials (CVOTs).1 This
mechanisms independent of glycemic control.6 On the
basis of emerging evidence, SGLT2 inhibitors are now
81
82
32 83
led to the approval of SGLT2 inhibitors, of which transforming the management of heart failure and CKD 84
33
4—canagliflozin, dapagliflozin, empagliflozin, and ertu- in patients with and without T2DM.7–9 Despite these 85
34
gliflozin—are available in North America, whereas proven clinical benefits, the mechanisms of benefit 86
35
sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, is from SGLT2 inhibitors have not been fully elucidated. 87
36
approved in Europe, and other specific agents are avail- Nephrologists now play a key role in prescribing 88
37
able in Japan. SGLT2 inhibitors as nephroprotective agents in our 89
38
SGLT2 inhibitors have revolutionized the treatment effort to reduce the global burden of kidney disease. 90
39
of patients with type 2 DM (T2DM) with established or We will provide an overview of SGLT2 inhibitors, their 91
40
at risk for atherosclerotic cardiovascular disease current indications and practical considerations in 92
41
(ASCVD) and patients with diabetic kidney disease.2–5 prescribing these agents. 93
42
The beneficial effects from SGLT2 inhibitors are 94
43
44 Systemic Effects and Mechanisms of Action 95
45 SGLT2 inhibitors have been found to reduce hemo- 96
46 Correspondence: David Z.I. Cherney, Division of Nephrology, globin A1c (HbA1c) level by 0.6% to 1% in patients 97
47 Department of Medicine, Toronto General Hospital, 585 Univer-
with T2DM and preserved renal function.10,11 This 98
Q3Q4 sity Avenue, 8N-845, Toronto, Ontario, M5G 2N2, Canada. E-mail:
48 david.cherney@uhn.ca effect is primarily mediated by glucosuria resulting 99
49 3
KY and AD contributed equally as co-first authors. from blockade of the SGLT2 channel predominantly 100
50 localized to the S1 segment of the proximal convoluted 101
Received 11 March 2022; revised 8 April 2022; accepted 25 April
51 2022 tubule, which is responsible for >90% absorption of 102

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103 filtered glucose.12 The resulting glucosuria can exceed hypokalemia (<3.5 mmol/l) and the need for new po- 157
104 100 g/d in individuals with T2DM and 50 to 60 g/d in tassium binder usage in those treated with canagliflozin 158
105 nondiabetics. The glucose-lowering effect of SGLT2 by 22%.32 159
106 inhibitors is attenuated in patients with eGFR <60 ml/ 160
Dual SGLT1 and SGLT2 Inhibitors
107 min per 1.73 m2 and minimal when eGFR is <30 ml/min 161
Sotagliflozin is the first dual SGLT1 and SGLT2 inhib-
108 per 1.73 m2.13 Caloric loss from glucosuria typically 162
itor and is approved in Europe for both type 1 DM and
109 results in 1 to 3 kg weight loss,14 most of which is 163
T2DM. It has been postulated that SGLT1 inhibition
110 fat,15,16 and greater weight loss is observed in patients 164
delays intestinal glucose absorption and reduces post-
111 with higher baseline HbA1c.17 165
prandial glucose levels.33–35 Furthermore, SGLT1 con-
112 166
Mechanisms of Action for End-Organ Protection tributes to distal proximal tubular glucose reabsorption
113 167
SGLT2 inhibitors are associated with a sustained following SGLT2 inhibition when tubular glucose
114 168
Q7 modest reduction in systolic blood pressure (BP) of concentrations are increased, which may result in
115 169
approximately 3 to 6 mm Hg and diastolic BP of additional glucosuric effects in patients with more
116 170
approximately 1 to 2 mm Hg.18,19 BP lowering is advanced CKD.36 In the SCORED trial, 10,584 patients
117 171
mediated through natriuresis and associated plasma with T2DM, eGFR 25 to 60 ml/min per 1.73 m2 with or
118 172
volume contraction,20 reduction in arterial stiffness,21 without albuminuria were enrolled. However, this trial
119 173
and improvement in endothelial function.22 Reduction ended early at 16 months because of loss of funding.
120 174
in BP is generally observed irrespective of hyperten- The primary end point (cardiovascular death, heart
121 175
sion status23 and is also achieved in patients with lower failure hospitalizations, and urgent heart failure visits)
122 176
eGFR level.24 was reduced by 26% with sotagliflozin despite the
123 177
In patients with diabetes, decreased sodium delivery relatively short trial duration (hazard ratio [HR] 0.74,
124 178
to the macula densa results in increased proximal 95% CI 0.63–0.88).37 In the SOLOIST-WHF trial,
125 179
tubular sodium reabsorption and afferent arteriolar initiation of sotagliflozin before or shortly following
126 180
vasodilatation by tubuloglomerular feedback leading to discharge reduced cardiovascular hospitalization or
127 181
glomerular hypertension and hyperfiltration.25 The death and urgent heart failure visits.35 SGLT1 inhibi-
128 182
primary mechanism by which SGLT2 inhibitors are tion may result in increased rates of diarrhea, and the
129 183
thought to be nephroprotective is through increasing additional benefit of SGLT1 blockade to SGLT2 inhi-
130 184
distal sodium delivery and inhibiting tubuloglomerular bition is not yet fully understood, although sotagli-
131 185
feedback resulting in afferent vasoconstriction and flozin does reduce hyperglycemia even in patients with
132 186
reduction in intraglomerular pressure.26,27 A marker of CKD stage 4.38
133 187
134 this reduction in intraglomerular pressure is the 188
reduction in albuminuria, which is largely independent Current Indications for SGLT2 Inhibitors
135 189
of concomitant changes in metabolic parameters or Indications for SGLT2 inhibitors have expanded based
136 190
eGFR.28 on growing evidence from randomized controlled trials
137 191
Other putative mechanisms through which SGLT2 and fall broadly into the following 5 categories: gly-
138 192
inhibitors may be beneficial include reduction in in- cemic control/metabolic risk, reduction in ASCVD,
139 193
140 flammatory mediators, including interleukin-6, nuclear heart failure, diabetic kidney disease with albuminuria,
194
factor-kB, and profibrotic factors, such as transforming nondiabetic CKD with albuminuria, and ejection frac-
141 195
growth factor-ß.24,29 In addition, by conserving energy tion (Table 1).
142 196
143 required to reabsorb the filtered load of glucose and Kidney Outcomes From CVOTs 197
144 associated sodium, SGLT2 inhibition may attenuate CVOTs including EMPA-REG OUTCOME, CANVAS, 198
145 renal hypoxia and is simultaneously associated with a DECLARE-TIMI-58, VERTIS CV, and SCORED revealed 199
146 rise in hematocrit level.24,30,31 the benefit of SGLT2 inhibitors in improving cardio- 200
147 SGLT2 Inhibitors and Potassium vascular outcomes in patients with T2DM with varying 201
148 Hyperkalemia is a frequent clinical challenge in the risks for ASCVD.2–5,37 On the basis of the results of 202
149 care of patients with CKD and may prohibit uptitration CVOTs, the 2020 Kidney Disease: Improving Global 203
150 of renin-angiotensin-aldosterone system (RAAS) in- Outcomes Diabetes Management in CKD Guideline now Q8 204
151 hibitor blockade. SGLT2 inhibitors may enhance supports SGLT2 inhibitors or metformin as first-line 205
152 kaliuresis by increasing distal delivery of sodium and treatment for T2DM for glycemic control.39,40 206
153 stimulating aldosterone.25 In CREDENCE, which Secondary analysis of renal outcomes from CVOTs 207
154 included patients with T2DM and CKD on RAAS was the first to suggest potential benefit in patients 208
155 blockade, canagliflozin reduced the incidence of with kidney disease. In EMPA-REG OUTCOME which 209
156 hyperkalemia (K $ 6.0) by 23% without causing included 7020 patients with T2DM with established 210
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211 Table 1. Current indications for SGLT2 inhibitors 265

212 Indication Criteria Kidney function 266
213 Congestive heart failure
NYHA classes II–IV
eGFR >20 ml/min per 1.73 m
2 267
214
Elevated NT-pro BNP 268

All ejection fractions
215 269
Glycemic control or metabolic risk
Type 2 diabetes mellitus
eGFR $60 ml/min per 1.73 m
2
216
First-line for glycemic control (along with
Anticipated HbA1c Y: 0.6%–0.9%
270
217 metformin)
Anticipated weight Y: 2–3 kg 271
218 272
2

eGFR 45–59 ml/min per 1.73 m

Anticipated HbA1c Y: 0.3%–0.5%
219
Anticipated weight Y: 1–2 kg 273
220
eGFR < 45 ml/min per 1.73 m
2
274

Anticipated HbA1c Y: minimal
221
Anticipated weight Y: 1–2 kg
275
222 Reduction in ASCVD
Type 2 diabetes mellitus
eGFR $ 30 ml/min per 1.73 m
2 276
223
Established ASCVD or high risk for ASCVD
a
277
224 Diabetic kidney disease
Type 2 diabetes mellitus
eGFR $25 ml/min per 1.73 m
b
2
278

UACR 200–5000 mg/g
225 279
Nondiabetic kidney disease
Etiology of kidney disease: ischemic ne-
eGFR $ 25 ml/min per 1.73 m
2
226 phropathy, IgA nephropathy, FSGS, chronic
UACR 200–5000 mg/g
b 280
227 pyelonephritis, chronic interstitial nephritis 281
228
No immunosuppression in prior 6 mo
282
229 ASCVD, atherosclerotic cardiovascular disease; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate (CKD-EPI); FSGS, focal 283
segmental glomerular sclerosis; HbA1c, hemoglobin A1c; LDL, low-density lipoprotein; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; UACR,
230 urine microalbumin-to-creatinine ratio.
a
284
231 Atherosclerotic cardiovascular disease is defined as ischemic heart disease, ischemic cerebrovascular disease, or peripheral artery disease. High risk for atherosclerotic cardio-
vascular disease is defined as age $55 years in men and $60 years in women and one or more of the following risk factors: hypertension, dyslipidemia (LDL >130 mg/dl or use of lipid-
285
232 lowering therapies), or tobacco use.
b
286
The EMPA-KIDNEY trial was stopped early for efficacy and included patients with diabetic kidney disease and nondiabetic kidney disease with eGFR 20 to 45 ml/min per 1.73 m2
233 regardless of UACR or eGFR 45 to 90 ml/min per 1.73 m2 with UACR $200 mg/g; however, results have not yet been presented or published. 287
234 288
235 289
236 ASCVD and enrolled patients with eGFR $30 ml/min 0.66).2 Despite the positive outcomes, CVOTs were not 290
237 per 1.73 m2, the renal composite outcome of end-stage powered for kidney-related outcomes and patients with 291
238 kidney disease (ESKD) and doubling of serum creati- CKD comprised <30% of the study cohorts but 292
239 nine was 0.54 (95% CI 0.40–0.75), with a reduction in informed subsequent dedicated trials for patients with 293
240 ESKD (HR 0.45, 95% CI 0.21–0.97) and doubling in kidney disease.41 In VERTIS CV, ertugliflozin was 294
241 serum creatinine (HR 0.56, 95% CI 0.39–0.79).4 As a associated with preservation of eGFR decline by >0.75 295
242 consequence of the reduction in intraglomerular hy- ml/min per 1.73 m2 per year with greater benefit in 296
243 pertension and other protective pathways discussed reducing heart failure hospitalizations in those with 297
244 previously, albuminuria decreases by 30% to 50% more advanced CKD.5,42–44 In SCORED, which included 298
245 regardless of baseline albuminuria within the span of patients with CKD with eGFR 25 to 60 ml/min per 1.73 299
246 weeks in response to SGLT2 inhibition. For example, in m2, a secondary kidney end point was not significantly 300
247 EMPA-REG OUTCOME, patients taking empagliflozin different between sotagliflozin and placebo (HR 0.71, 301
248 had a reduction in albuminuria of 7% in those with 95% CI 0.46–1.08), although the trial was terminated 302
249 normoalbuminuria, 25% with microalbuminuria, and early and likely not of a sufficient duration to detect 303
250 32% with macroalbuminuria, which was sustained these differences in composite end points.37 304
251 when measured at follow-up at 164 weeks.28 On stop- 305
252 ping these agents, albuminuria increases within weeks CKD Trials 306
253 suggesting a contribution from underlying hemody- CREDENCE and DAPA-CKD are seminal randomized 307
254 namic mechanisms. controlled trials which specifically evaluated the effect 308
255 In the CANVAS Program, which enrolled patients of SGLT2 inhibitors on a primary kidney end point and 309
256 with T2DM with high cardiovascular risk and eGFR ultimately provide the strongest evidence for use in 310
257 >30 ml/min per 1.73 m2, the renal composite outcome patients with CKD. CREDENCE included 4401 patients 311
258 was also lower with canagliflozin (HR 0.53, 95% CI aged $30 years with T2DM with albuminuria (micro- 312
259 0.33–0.84).3 DECLARE-TIMI 58, which only included albumin-to-creatinine ratio [ACR] 300–5000 mg/g), 313
260 patients with T2DM with established or multiple risk eGFR 30 to 90 ml/min per 1.73 m2, HbA1c 6.5% to 314
261 factors for ASCVD and eGFR >60 ml/min per 1.73 m2, 12%, on maximal tolerated RAAS blockade. The trial 315
262 similarly favored SGLT2 inhibitor use, which reduced was stopped early after a median follow-up of 2.62 316
263 the composite renal outcome of sustained eGFR decline years because of benefit found in the interim analysis. 317
264 of $40%, ESKD, or renal death (HR 0.53, 95% CI 0.43– The primary composite of doubling of creatinine, 318
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319 ESKD, and death from renal or cardiovascular causes SGLT2 Inhibitors in Heart Failure 373
320 was reduced by 30% with canagliflozin. Benefit was Subsequent to the consistent benefits in heart failure 374
321 consistent across renal end points with lower risk of hospitalization risk reported in CVOTs,2–4 in patients 375
322 doubling serum creatinine (HR 0.60, 95% CI 0.48–0.76) with established heart failure with reduced left ven- 376
323 and ESKD (HR 0.68, 95% CI 0.54–0.86). Decline in tricular ejection fraction (#40%), a reduction in the 377
324 eGFR was lower in the canagliflozin group (3.19 ml/ composite of heart failure hospitalizations or cardio- 378
325 min per 1.73 m2 per year) in comparison to 4.71 ml/ vascular death was observed in both DAPA-HF and 379
326 min per 1.73 m2 per year in the placebo group. This EMPEROR-Reduced, independent of diabetes status.7,47 380
327 finding was observed despite only modest changes in The DAPA-HF trial compared dapagliflozin with pla- 381
328 blood glucose, weight, and BP. Extrapolating between- cebo in adults with heart failure with left ventricular 382
329 group differences in eGFR loss to the average 63-year- ejection fraction #40%, elevated N-terminal-pro B- 383
330 old patient from CREDENCE with an eGFR of 56 ml/min type natriuretic peptide, and eGFR $30 ml/min per 384
331 per 1.73 m2 would result in a delay in progression to 1.73 m2 on a background standard of care. The primary 385
332 ESKD by as much as 15 years.45 composite outcome of cardiovascular death, heart fail- 386
333 DAPA-CKD enrolled 4304 adults with both diabetic ure hospitalization, or urgent heart failure visit was 387
334 and nondiabetic kidney diseases with eGFR 25 to 75 reduced by 26%. In EMPEROR-Reduced, which 388
335 ml/min per 1.73 m2, ACR 200 to 5000 mg/g on maximal included adults with chronic heart failure left ven- 389
336 tolerated RAAS blockade and followed them for a tricular ejection fraction #40%, New York Heart As- 390
337 median of 2.4 years.8 Dapagliflozin reduced the pri- sociation II to IV, elevated N-terminal pro B-type 391
338 mary composite outcome of sustained decline in the natriuretic peptide, on appropriate heart failure ther- 392
339 estimated GFR by >50%, ESKD, and renal or cardio- apy with eGFR >20 ml/min per 1.73 m2, dapagliflozin 393
340 vascular death by 39% with a number need to treat of reduced the primary composite outcome by 25%. The 394
341 19. Importantly, the effects of dapagliflozin were composite kidney outcome ($50% sustained decline in 395
342 similar in patients with T2DM (HR 0.64, 95% CI 0.52– eGFR, ESKD, and renal death) was reduced with 396
343 0.79) or without T2DM (HR 0.50, 95% CI 0.35–0.72). dapagliflozin (HR 0.71, 95% CI 0.44–1.16). Annual 397
344 All individual components of the renal end point had change in eGFR was 3.10 ml/min per 1.73 m2 in the 398
345 benefit with the risk of ESKD reduced by 36% and placebo group versus 2.05 ml/min per 1.73 m2 per 399
346 50% eGFR decline reduced by 47%. The risk for year in the dapagliflozin group (95% CI 2.36 400
347 hospitalization for heart failure or cardiovascular was to 1.75) with no difference by diabetes status. 401
348 reduced by 29% similar to previous CVOTs. The par- Historically, therapies have been lacking in pa- 402
349 ticipants had a mean baseline eGFR of 43 ml/min per tients with heart failure with preserved ejection 403
350 1.73 m2, and the slope of eGFR decline from baseline to fraction (>40%). However, in the EMPEROR- 404
351 30 months was 2.86 ml/min per 1.73 m2 for dapagli- Preserved trial, which enrolled patients with left 405
352 flozin and 3.79 ml/min per 1.73 m2 per year for pla- ventricular ejection fraction >40% and included 406
353 cebo, resulting in a between-group difference of 0.93 patients with eGFR >20 ml/min per 1.73 m2, empa- 407
354 ml/min per 1.73 m2 per year (95% CI 0.61–1.25). Both gliflozin reduced the combined risk of cardiovascular 408
355 CREDENCE and DAPA-CKD represent a strong win for death or hospitalization for heart failure (HR 0.79, 409
356 the field of nephrology, collectively revealing impres- 95% CI 0.69–0.90) regardless of the presence or 410
357 sive benefit of SGLT2 inhibitors on hard renal end absence of diabetes.9 In EMPEROR-Preserved, 50% of 411
358 points in patients with CKD with albuminuria regard- participants had eGFR <60 ml/min per 1.73 m2 and 412
359 less of diabetes status. similar benefit for the primary outcome (HR 0.78, 413
360 From a safety perspective, similar to CVOTs, a higher 95% CI 0.66–0.91). Similarly, consistent benefit on 414
361 incidence of genital mycotic infection (GMI) noted was heart failure end points was observed in subgroups 415
362 also observed, although reassuringly, no increase in analysis of patients with eGFR <60 ml/min per 1.73 416
363 serious volume depletion, hypotension, or hypoglyce- m2 in DAPA-HF and EMPEROR-Reduced.48 Together, 417
364 mia was observed in CREDENCE or DAPA-CKD.8,46 In these trials provide the evidence to safely support 418
365 CREDENCE, the incidence of diabetic ketoacidosis SGLT2 inhibitor use in all patients with heart failure 419
366 (DKA) was higher with canagliflozin treatment, irrespective of ejection fraction, down to an eGFR of 420
367 although absolute rates were low (2.2 vs. 0.2 per 1000 20 ml/min per 1.73 m2. The recently completed 421
368 patient-years). In DAPA-CKD, no cases of DKA were EMPULSE trial revealed clinical benefit with in- 422
369 reported with dapagliflozin treatment; however, all hospital empagliflozin treatment among patients 423
370 patients should receive counseling regarding “sick admitted with acute heart failure regardless of left 424
371 day” medication management on SGLT2 inhibitor ventricular ejection fraction. In this trial, empagli- 425
372 prescription. flozin was well tolerated with renal failure occurring 426
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427 in 7.7% in those receiving empagliflozin in compar- patients with glomerular disease (n ¼ 1669) and hy- 481
428 ison to 12.1% with placebo.49 pertensive/renovascular disease (n ¼ 1444).58 The pri- 482
429 Real-World Effectiveness Studies mary outcome of this trial was a sustained $40% 483
430 Real-world effectiveness studies have confirmed that decline in eGFR, ESKD, or death from renal or cardio- 484
431 the benefits of SGLT2 inhibitors extend to routine vascular causes. The EMPA-KIDNEY trial was stopped 485
432 clinical practice. CVD-REAL 3, a multinational obser- early in March 2022 for efficacy suggesting that CKD 486
433 vational cohort study, assessed kidney outcomes in patients without albuminuria also benefit from SGLT2 487
434 35,561 patients initiating SGLT2 inhibitors propensity inhibitors and will soon markedly expand the popu- 488
435 matched to other glucose-lowering agents and found lation eligible for therapy.59 489
436 that SGLT2 inhibitors reduced eGFR decline by 1.53 490
437 ml/min per 1.73 m2 per year (95% CI 1.34–1.72). SGLT2 Inhibitors in Glomerulonephritis 491
438 Similar to randomized controlled trials, the composite Although patients with glomerulonephritis most often 492
439 outcome of 50% decline in eGFR or progression to require immunosuppressive therapy, those who 493
440 ESKD was lower with SGLT2 inhibitors.50–52 From a develop CKD secondary to chronic damage or scar- 494
441 safety perspective, similar to results of clinical trials,53 ring may share a common final pathway mediated by 495
442 in real-world evidence studies, SGLT2 inhibitors hyperfiltration, which may be amenable to SGLT2 496
443 reduce the risk of acute kidney injury compared with inhibition. In the TRANSLATE study, short-term 497
444 other glucose-lowering agents,54 potentially as a result treatment with dapagliflozin did not significantly 498
445 of improved kidney oxygenation and kidney alter renal hemodynamics or reduce proteinuria in 10 499
446 perfusion.55 patients with focal segmental glomerular sclerosis 500
447 (FSGS).60 Similarly, the DIAMOND trial first evalu- Q9 501
448 Stage 4 CKD ated this hypothesis in patients without diabetes CKD 502
449 The most robust evidence for use of SGLT2 inhibitors with eGFR > 25 ml/min per 1.73 m2 and 500 to 3500 503
450 in stage 4 CKD is a prespecified analysis of DAPA-CKD mg/d proteinuria, including patients with IgA ne- 504
451 in 624 of 4304 patients (14%) with baseline eGFR 25 to phropathy (n ¼ 25) and FSGS (n ¼ 11).61 Dapagli- 505
452 30 ml/min per 1.73 m2. Consistent with results from the flozin was associated with an acute dip in eGFR on 506
453 overall trial, a 27% reduction in the primary composite initiation suggestive of a beneficial hemodynamic ef- 507
454 end point (50% sustained decline in eGFR, ESKD, or fect, but it did not result in a significant reduction in 508
455 kidney/cardiovascular death) was observed. Dapagli- proteinuria compared with placebo in a 6-week 509
456 flozin resulted in a 28% reduction in the risk for ESKD, treatment period, and the 17% reduction in UACR 510
457 with an eGFR slope decline in 2.15 ml/min per 1.73 m2 also did not reach significance.61 511
458 in the dapagliflozin group in comparison to 3.38 ml/min DAPA-CKD was the largest trial studying use of 512
459 per 1.73 m2 in the placebo group with separation of the SGLT2 inhibitors in patients with chronic glomerulo- 513
460 eGFR curves evident by 16 months. No difference in nephritis (n ¼ 695) to date, although patients with a 514
461 adverse events, including renal related or volume history of immunosuppression in the prior 6 months 515
462 depletion, was noted. Furthermore, no significant het- were excluded.8,62 DAPA-CKD included 270 partici- 516
463 erogeneity by diabetes status or albuminuria was pants with IgA nephropathy, of whom 254 (94%) had 517
464 observed. Although evidence for kidney-related end pathologic confirmation by kidney biopsy. The mean 518
465 points remains limited for patients with eGFR <25 ml/ eGFR of participants was 43.8 ml/min per 1.73 m2 with 519
466 min per 1.73 m2, it should be emphasized that SGLT2 a median ACR 900 mg/g, who were followed for a 520
467 inhibitors may be continued until patients are on median of 2.1 years. In a prespecified analysis of IgA 521
468 dialysis. nephropathy participants, the primary composite kid- 522
469 Patients With CKD Without Albuminuria ney outcome was lower for patients with dapagliflozin 523
470 Meta-analysis of CVOTs has revealed that the benefits (HR 0.29, 95% CI 0.12–0.73) with a mean annual rate of 524
471 of SGLT2 inhibitors on delaying CKD progression are eGFR decline of 3.5 ml/min per 1.73 m2 with dapagli- 525
472 consistent regardless of baseline albuminuria.2–4,46,56 flozin and 4.7 ml/min per 1.73 m2 with placebo. 526
473 To definitively determine benefits in patients with Furthermore, dapagliflozin resulted in a 26% reduction 527
474 low eGFR and low urine ACR (UACR), the EMPA- in albuminuria in comparison to placebo. Interestingly, 528
475 KIDNEY trial included adults with or without dia- the primary outcome event rate was more than double 529
476 betes with eGFR 20 to 45 regardless of albuminuria or in the placebo group (24% at 32 months), compared 530
477 eGFR 45 to 90 ml/min per 1.73 m2 with UACR $ 200 with what would have been predicted for the average 531
478 mg/g on maximally tolerated RAAS blockade.57 This DAPA-CKD patient using the international IgA ne- 532
479 study enrolled 6609 patients with a mean eGFR of 37.5 phropathy risk prediction tool, suggesting a high-risk 533
480 ml/min per 1.73 m2. Notably, this cohort includes group of participants. Nevertheless, the overall 534
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535 findings were supportive of SGLT2 inhibitor use in IgA Heightened vigilance for infectious complications 589
536 nephropathy.61 should also be considered in those receiving immuno- 590
537 For FSGS, a prespecified analysis of DAPA-CKD suppression given that those receiving immunosup- 591
538 included 115 individuals with FSGS, of which 105 pression were excluded from clinical trials. Patients 592
539 (90%) were biopsy proven.63 The primary composite with lupus nephritis and antineutrophil cytoplasmic 593
540 kidney outcome did not reach statistical significance autoantibody–associated vasculitis have also not been 594
541 (HR 0.62, 95% CI 0.17–2.17). However, participants studied to date because of the relapsing and remitting 595
542 treated with dapagliflozin had 26.1% reduction in nature of the disease processes, but future use may 596
543 albuminuria compared with 9.9% in placebo which consider whether there is role for SGLT2 inhibitors in 597
544 persisted after a year. Furthermore, the annual mean those who have achieved remission and are considered 598
545 rate of eGFR decline was lower in those receiving to have stable or inactive disease.65 599
546 dapagliflozin (1.9 ml/min per 1.73 m2, 95% CI 3.0 600
547 to 0.9) in comparison to placebo (4.0 ml/min per Adverse Effects and Mitigation 601
548 1.73 m2, 95% CI 4.9 to 3.0). Although SGLT2 inhibitors are generally well tolerated 602
549 Reduction in albuminuria has been used as a useful by most patients, clinicians should take potential 603
550 surrogate marker in clinical trials for FSGS, and adverse effects into consideration when prescribing 604
551 although the primary outcome in DAPA-CKD was not these agents. Patients should be counseled regarding 605
552 significant in participants with this condition, attenu- potential adverse events, as the risk may be reduced 606
553 ation of eGFR decline with dapagliflozin supports long- when appropriate mitigation strategies are followed. 607
554 term benefit in patients with FSGS. For example, by Infectious Complications 608
555 modifying the eGFR slope, a hypothetical DAPA-CKD Owing to glucosuria, SGLT2 inhibitors are associated 609
556 patient with a mean baseline eGFR of 43 ml/min per with a 2- to 4-fold increased risk for GMIs.66–68 610
557 1.73 m2 would have an 8-year delay in reaching eGFR Furthermore, the increased risk of GMIs versus pla- 611
558 of 10 ml/min per 1.73 m2. It may also be relevant that cebo was similar across all SGLT2 inhibitors.69 A 612
559 FSGS is a heterogeneous disease entity, and the exclu- retrospective analysis found that GMIs were most 613
560 sion of recent immunosuppression suggests that most common in the first months after initiating SGLT2 in- 614
561 patients with FSGS in DAPA-CKD may have had sec- hibitors and are more common in women and those 615
562 ondary etiologies. In patients with both IgA nephrop- with prior GMIs.70 Strategies to reduce this risk 616
563 athy and FSGS, SGLT2 inhibitors were well tolerated include counseling the patient to maintain genital hy- 617
564 with no cases of major hypoglycemia or DKA in those giene, including keeping the genital region dry. Prior 618
565 receiving dapagliflozin. history of GMI is not a contraindication to treatment, 619
566 In a prespecified analysis of DAPA-CKD, patients and prophylactic topical treatment with antifungal 620
567 with T2DM had a 35.1% reduction in UACR in com- agents can be considered in high-risk individuals. If a 621
568 parison to 14.8% in nondiabetics suggesting attenuated patient develops an uncomplicated fungal infection, 622
569 reduction in intraglomerular hypertension in non- this may be easily treated with a single dose of an oral 623
570 Q10 diabetics. However, dapagliflozin had similar effects on agent, such as 150 mg of fluconazole, and discontinu- 624
571 kidney outcomes regardless of DM status suggesting ation the SGLT2 inhibitor is typically not required.71 625
572 kidney protective effects of SGLT2 inhibitors in Fournier’s gangrene is an extremely rare, life- 626
573 nondiabetic patients may be partially mediated by threatening condition associated with necrotizing fas- 627
574 mechanisms beyond inhibiting tubuloglomerular ciitis of perineal soft tissue. In 2018, US Food and Drug 628
575 feedback, such as reduction in tubular workload, Administration identified 55 unique cases of Fournier’s 629
576 increased autophagy, and anti-inflammatory or anti- gangrene in patients receiving SGLT2 inhibitors,72 and 630
577 fibrotic effects.64 a meta-analysis involving 84 trials and including 631
578 In both DIAMOND and DAPA-CKD,8,61 patients >42,000 patients receiving SGLT2 inhibitors found no 632
579 were required to be on the maximal tolerated dose of difference in the risk of Fournier’s gangrene with 633
580 RAAS blockade. Given the positive findings from SGLT2 inhibitor use.73 Although earlier studies sug- 634
581 DAPA-CKD in patients with chronic glomerulone- gested that SGLT2 inhibitors were associated with 635
582 phritis, in patients with IgA nephropathy and FSGS, possible increased risk for urinary tract in- 636
583 SGLT2 inhibitors should be considered as a component fections,10,74,75 subsequent randomized controlled trials 637
584 of “conservative care” for those with proteinuria. have revealed no association.2–4,46 However, in patients 638
585 However, it should be emphasized that despite the with a history of complicated or recurrent urinary tract 639
586 benefit of SGLT2 inhibitors in IgA nephropathy and infections including those with chronic indwelling 640
587 FSGS, these therapies should not be used in lieu of Foley catheters, SGLT2 inhibitors should be used with 641
588 immunosuppression when clinically indicated. caution. 642
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643 Amputation may be typically resumed 24 to 48 hours following 697

644 The CANVAS Program raised a concern regarding an recovery. 698
645 association between canagliflozin and minor and major 699
646 amputations.3 However, CREDENCE reported similar Practical Considerations 700
647 incidences of amputation in both the canagliflozin and Accepting the Acute “Dip” in eGFR 701
648 placebo groups.46 A real-world meta-analysis The major mechanism by which SGLT2 inhibitors are 702
649 comparing canagliflozin and other antihyperglycemic thought to delay CKD progression is through reduction 703
650 agents did not find any association with amputation, in glomerular hyperfiltration and tubuloglomerular 704
651 and the black box warning for amputation was feedback. SGLT2 inhibitors are well recognized to 705
652 removed in 2020.76 No subsequent trials have revealed result in an acute transient reduction in GFR through a 706
653 any association between other SGLT2 inhibitors and reduction in glomerular hypertension analogous to the 707
654 amputation risk.77,78 In clinical practice, routine foot mechanism of RAAS blockade. The dip in eGFR 708
655 care is recommended in all patients with diabetes, and following SGLT2 inhibitor frequently elicits concern 709
656 it is also important to identify patients who may have among clinicians, which may lead to inappropriate 710
657 an indication for SGLT2 inhibition on the basis of discontinuation of an effective therapy. The urge to 711
658 having peripheral vascular disease, which was an in- discontinue the SGLT2 inhibitor because of a rise in 712
659 clusion criterion for the CVOTs. serum creatinine should be resisted in most patients 713
660 and efforts should be made to maintain patients on 714
661 Fractures SGLT2 inhibitors given their cardiorenal benefits. In 715
662 The CANVAS Program reported a link between cana- fact, a larger magnitude of dip in eGFR correlates with 716
663 gliflozin and increased risks of fractures.3 However, in greater long-term benefit and therefore should be 717
664 other studies involving canagliflozin, including viewed as evidence of a positive hemodynamic effect.87 718
665 CREDENCE, no such safety signal was detected.46,79 Furthermore, concerns regarding the incidence of acute 719
666 Meta-analyses including canagliflozin, dapagliflozin, kidney injury with SGLT2 inhibitors have been allayed 720
667 empagliflozin, and ertugliflozin66,80,81 have found no by meta-analyses from clinical trials and propensity- 721
668 significant association with fracture.82 matched observational studies, which have found 722
669 that SGLT2 inhibitors are associated with lower rates of 723
670 Diabetic Ketoacidosis acute kidney injury.54,56,88 724
671 SGLT2 inhibitors are rarely associated with euglycemic It remains uncertain whether it is necessary to 725
672 DKA resulting in a US Food and Drug Administration monitor serum creatinine changes shortly after SGLT2 726
673 warning in 2015. The frequency of DKA reported in inhibitor initiation; however, it is reasonable to 727
674 CVOTs in patients with T2DM receiving SGLT2 in- monitor kidney function 1 month after initiation in 728
675 hibitors was low,2–5 but occurred in 4% to 6% of pa- higher risk patients, including those with a history of 729
676 tients with type 1 DM.83,84 Reports analyzing the US prior acute kidney injury, advanced CKD, or in those in 730
677 Food and Drug Administration Adverse Events whom there is increased concern regarding volume 731
678 Reporting System found 7-fold higher rate of DKA with depletion. Traditionally, an increase in serum creati- 732
679 SGLT2 inhibitors in patients with T2DM when nine level by up to 30% from baseline is considered 733
680 compared with dipeptidyl peptidase-4 inhibitor ther- acceptable. If the level rises beyond this threshold, the 734
681 apy, of which 71% had euglycemia.85 The risk factors patient should undergo a careful reassessment of vol- 735
682 of SGLT2 inhibitor-associated ketoacidosis include ume status and a decision made about whether to hold 736
683 >20% insulin dose reduction, lean body habitus, the SGLT2 inhibitor temporarily and then consider 737
684 women, surgical stress, trauma, intercurrent illness, rechallenging the patient once appropriate (Figure 1). 738
685 alcohol abuse, and patients with latent autoimmune Consideration of Diuretic Effect and Volume Status 739
686 diabetes of adulthood.86 All patients being initiated on SGLT2 inhibitors result in an osmotic diuresis that 740
687 SGLT2 inhibitor must be counseled regarding risk of seems to be additive to loop diuretics. Favorable 741
688 DKA. It is recommended that SGLT2 inhibitors be held properties in comparison to loop diuretics include a 742
689 2 to 3 days before scheduled surgery. Strategies to reduction in serum uric acid and that hypokalemia or 743
690 reduce the risk of DKA include avoiding >20% hypomagnesemia is uncommon.89,90 Although precise 744
691 reduction in insulin dose, careful monitoring following quantification of additional diuresis is challenging, in 745
692 insulin dose changes, and discontinuation of SGLT2 RECEDE-HF patients with T2DM and heart failure with 746
693 inhibitors during episodes of acute illness, vomiting, reduced ejection fraction taking regular loop diuretic 747
694 diarrhea, or inability to eat or drink. In high-risk cir- and empagliflozin 25 mg daily had a mean increase in 748
695 cumstances, monitoring of urine ketones can be 24-hour urine volume of 535 ml 3 days after initiation 749
696 considered. Following acute illness, SGLT2 inhibitors and 545 ml by 6 weeks.91 Correspondingly, in patients 750
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751 805
752 Consideration of SGLT2 inhibitor 806
753 807
754 Type 2 Diabetes Mellitus: If eGFR > 60 ml/min per 1.73 m2 808
755 consider decreasing insulin by 10%–20% or decreasing
sulfonylurea dose in collaboration with Endocrinologist if
809
756 HbA1c <7% or history of hypoglycemia 810
757 811
758 Assess Volume Status and
Blood Pressure 812
759 813
760 Euvolemic/Hypervolemic Hypovolemic 814
761 815
762 Start SGLT2 inhibitor (empagliflozin 10 mg,
Decrease blood pressure medications,
816
763 dapagliflozin 5 mg, canagliflozin 100 mg,
ertugliflozin 5 mg daily)
reduce diuretic agents 20%–30%, and/or 817
liberalize fluid intake
764 818
765 Continue baseline ACE Inhibitor/ARB/ARNI/MRA in 819
766 most patients. In normotensive, euvolemic patient
consider decreasing loop diuretic by 20%–50% and up-
Start SGLT2 inhibitor when 820
euvolemic
767 titrate as required 821
768 822
769 "Sick Day" Counselling 823
770 824
771 Follow-up bloodwork (electrolytes, bicarbonate,
825
772 creatinine) as per local guidelines in 1 mo–3 mosa 826
773 827
774 828
775 Expect up to 30% increase
in serum creatinine
>30% increase in
serum creatinine
829
776 830
web 4C=FPO

777 831
778 Re-assess blood pressure and volume status,
and consider reducing diuretics, liberalizing
832
779 fluid intake, or holding SGLT2 inhibitor 833
780 834
781 Figure 1. Proposed algorithm for SGLT2 inhibitor initiation. *Consider earlier bloodwork in higher risk: stage $3B CKD, prior episode(s) of acute 835
782 kidney injury, or at risk for volume depletion. ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; ARNI, angiotensin 836
783 receptor-neprilysin inhibitor; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; MRA, mineral- 837
ocorticoid receptor antagonist.
784 838
785 on maintenance loop diuretics, reduction in diuretic patients may be initiated on the lowest SGLT2 inhibitor 839
786 dosage should be considered with SGLT2 inhibitor if dose available: canagliflozin 100 mg daily, dapagliflozin 840
787 they are not volume overloaded on clinical examina- 10 mg daily, empagliflozin 10 mg daily, or ertugliflozin 841
788 tion. This should also be considered in patients initi- 5 mg daily. 842
789 ating on medications with even modest diuretic effects, 843
790 including mineralocorticoid receptor antagonists or Combination With GLP-1 Receptor Agonists 844
791 angiotensin receptor-neprilysin inhibitors. Patients Although SGLT2 inhibitors offer a clear benefit in 845
792 taking SGLT2 inhibitors may be at risk of volume slowing progression of CKD, GLP-1-RAs were also 846
793 depletion, during episodes of acute illness associated found to have cardiorenal benefit in patients with 847
794 with nausea, vomiting, or diarrhea. Correspondingly, diabetic kidney disease. The GLP-1-RA agonists are 848
795 patients should be provided with sick day advice, optimal agents for patients with established ASCVD 849
796 whereby patients are advised to hold their SGLT2 in- and act by increasing glucose-dependent insulin 850
797 hibitor until resolution of symptoms. Some patients secretion, decreasing glucagon secretion, and delaying 851
798 including those with heart failure may require liber- gastric emptying.92 GLP-1-RAs are an established 852
799 alization of fluid intake if they are euvolemic when disease-modifying treatment for T2DM with known 853
800 initiating SGLT2 inhibitors. beneficial effects on glycemic control, weight loss, BP 854
801 control, and reduction in cardiovascular events. The 855
802 Specific Agents and Dose Considerations proposed mechanisms of benefit on kidney disease 856
803 In clinical trials, a dose–response relationship has not progression include natriuresis through inhibition of 857
804 been observed for cardiorenal outcomes. Therefore, proximal tubular NHE3-dependent sodium 858
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859 Table 2. Characteristic of patients with CKD in SGLT2 inhibitor CKD trials Q21 913
860 Characteristics CREDENCE DAPA-CKD SCORED EMPA-KIDNEY 914
861 Number of participants 4401 4304 10584 6609 915
862 Mean age (yr) 63 61.8 69 63.8 916
863 Female (%) 1494 (33.9) 1425 (33.1) 4754 (44.9) 2192 (33) 917
864 UACR (mg/g)
Median (IQR)
927 (463–1833) 949.3 74 (17–481) 412 (94–1190)
918
865 eGFR (ml/min per 1.73 m2) 56.2 (18.2) 43.1 (12.4) 44.5 37.5 (14.8) 919
866 mean (SD) 920
867 eGFR categories (%) 921
$45 ml/min per 1.73 m2
868 3035 (69) 1782 (41.4) 5116 (48.3) 1424 (22)
922
$30–44 ml/min per 1.73 m2 1191 (27.1) 1898 (44.1) 4655 (43.9) 2905 (44)
869 <30 ml/min per 1.73 m2 174 (3.9) 624 (14.5) 813 (7.8) 2280 (34)
923
870 Prior DM (%) 4401 (100) 2888 (67.1) 10,584 (100) 3039 (46) 924
871 Baseline RAAS inhibitor (%) 4395 (99) 4224 (98.1) 9365 (88.5) 5613 (84.9) 925
872 Primary kidney disease (%) 926
873 Diabetic kidney disease 4401 (100) 2510 (58.3) 10,584 (100) 2057 (31)
927
Ischemic/hypertensive nephropathy 687 (16) 1445 (22)
874 928
Glomerular disease 695 (16.1) 1669 (25)
875 IgA nephropathy 270 (6.3) 817 (12)
929
876 Focal segmental glomerulosclerosis 115 (2.7) 195 (3.0) 930
877 Membranous nephropathy 43 (1.0) 96 (1.0) 931
878 Minimal change disease 11 (0.3) 14 (<1) 932
879 Other glomerular disease 256 (5.9) 547 (8.0)
933
Unknown 214 (5) 630 (10)
880 Other 198 (4.6) 808 (12)
934
881 935
CKD, chronic kidney disease; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate (CKD-EPI); IQR, interquartile
882 range; RAAS, renin-angiotensin-aldosterone inhibitor; UACR, urine microalbumin-to-creatinine ratio. 936
883 937
884 938
885 reabsorption and reduction in albuminuria by analysis which evaluated the combination of SGLT2 939
886 decreasing renal inflammation or antioxidative inhibitors and once-weekly exenatide, improvements 940
887 effects.93,94 in all-cause mortality and major adverse cardiovascular 941
888 On the basis of available data, SGLT2 inhibitors are event were observed in addition to a nominal signifi- 942
889 clearly favored for preventing progression of CKD cant improvement in preventing decline in eGFR in 943
890 (with or without cardiovascular disease) and in patients comparison to patients not on SGLT2 inhibitors.98 944
891 with heart failure.39,40 In comparison, GLP-1-RAs may Although SGLT2 inhibitors are preferred to delay 945
892 be preferred in patients with obesity/obesity-related progression of CKD, patients with residual albuminuria 946
893 complications or established ASCVD, including may benefit from the addition of a GLP-1-RA to reduce 947
894 stroke, particularly given that SGLT2 inhibitors have this risk further. Furthermore, GLP-1-RA may be use- 948
895 not been found to reduce the incidence of stroke.95 ful in low eGFR settings, where SGLT2 inhibitor or 949
896 On the basis of complementary mechanisms of action RAAS blocker titration is not possible. In clinical 950
897 and metabolic effects, combination of SGLT2 inhibition practice, patients with T2DM may have indications for 951
898 plus GLP-1-RA therapy is an attractive option to both agents, and sequential prescription can be 952
899 enhance weight loss and reduce major adverse cardio- considered. The ongoing FLOW trial (NCT03819153) 953
900 vascular events in selected patients. Data on combina- will determine whether the GLP-1-RA semaglutide 954
901 tion therapy have, however, been sparse. The delays CKD progression in T2DM patients with eGFR 955
902 DURATION-8 study evaluated the use of SGLT2 inhi- 50 to 75 ml/min per 1.73 m2 and UACR 300 to 5000 mg/ 956
903 bition (dapagliflozin) and GLP-1-RA (once-weekly g or eGFR 25 to 50 ml/min per 1.73 m2 and ACR 100 to 957
904 exenatide), which reduced HbA1c <0.4%, but found 5000 mg/g on a background of RAAS blockade. 958
905 an additive BP reduction (4.2 mm Hg). An additive 959
906 effect on weight loss was also observed in AWARD-10, Combination With Mineralocorticoid Receptor 960
907 which studied the GLP-1-RA dulaglutide versus pla- Antagonists and Endothelin Receptor Antagonists 961
908 cebo in patients already on SGLT2 inhibitors with 0.9 The nonsteroidal, selective mineralocorticoid receptor 962
909 kg additional weight loss,96 although SUSTAIN-9 antagonist finerenone exhibits beneficial effects on 963
910 found that semaglutide superimposed on SGLT2 inhi- reducing fibrosis and inflammation and was found in 964
911 bition resulted in 3.8 kg of additional weight loss and a the FIDELIO-DKD trial to reduce albuminuria, CKD 965
912 reduction of HbA1c of 1.42.97 In EXSCEL, a post hoc progression, and cardiovascular events in T2DM 966
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967 patients with eGFR 25 to 60 ml/min per 1.73 m2 and from Janssen, Boehringer Ingelheim, Eli Lilly, Sanofi, 1021
968 UACR 30 to 300 mg/g or eGFR 25 to 75 ml/min per 1.73 AstraZeneca, and Merck & Co Inc. All the other authors 1022
969 m2 and UACR 300 to 5000 mg/g. The FIGARO-DKD trial declared no competing interests. 1023
970 further revealed similar benefit in a broader population 1024
971 including stages 2 to 4 CKD with moderately elevated ACKNOWLEDGMENTS Q12
1025
972 albuminuria (30–300mg/g UACR) or stages 1 to 2 CKD IA is supported by King Abdulaziz University, Jeddah, 1026
973 with severely elevated albuminuria (300–5000 mg/g). A Saudi Arabia. DZIC is supported by a Department of 1027
974 recent subgroup analysis of DAPA-CKD in 229 patients Medicine, University of Toronto Merit Award, and receives 1028
975 found similar safety and effectiveness in reducing support from the Canadian Institutes of Health Research, 1029
976 kidney end points with combination therapy with Diabetes Canada, and the Heart & Stroke/Richard Lewar Q23 1030
977 SGLT2 inhibitors and mineralocorticoid receptor an- Centre of Excellence in Cardiovascular Research. Q22
1031
978 tagonists, although further studies on added benefit of 1032
979 combination therapy are needed.99 AUTHOR CONTRIBUTIONS 1033
980 The SONAR trial evaluated the selective endothelin 1034
KY, AD, IA, and DZIC all contributed to the writing of the
981 A receptor antagonist atrasentan in adults with T2DM 1035
manuscript, provided critical edits, and reviewed and
982 with eGFR 25 to 75 ml/min per 1.73 m2 and UACR 300 1036
approved the final manuscript.
983 to 5000 mg/g on maximally tolerated RAAS blockade 1037
984 carefully selected to have 30% reduction in UACR and 1038
985 no clinically significant fluid retention during an REFERENCES 1039
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