Presentation given to our fellowship program about diabetic kidney disease. 2022 update discussing SGLT2i, MRA (e.g. finerenone), health economics and beyond

1. Diabetic Kidney
Disease- 2022
CHRISTOS ARGYROPOULOS MD, MS, PHD, FASN

2. Disclosures
Site investigator for TRIDENT (Transformative Research In Diabetic
Nephropathy), an Investigator Initiated Study (Sponsor: University of
Pennsylvania)
Research support (access to preclinical data of RNA biomarkers of acute
kidney injury) from Pfizer
Site PI for the PRO2TECT Phase 3 of the investigational agent
vadadustat for anemia of CKD
Consultation from Bayer, Otsuka, Baxter, Quanta

3. Learning Objectives
1. Epidemiology, clinical presentation and
pathogenesis of Diabetic Kidney Disease (DKD)
2. Standard of Care in DKD (2022)
3. Pharmacological Interventions to reduce
Cardiorenal Risk in Patients with DM2
4. Population Health Challenges in DKD

4. Diabetic Nephropathy
in the 21st century
EPIDEMIOLOGY, CLINICAL PRESENTATION AND
PATHOGENESIS

5. Diabetic CKD (DKD) is common …
NHANES PARTICIPANTS WITH EGFR <60
ML/MIN/1.73 M2
NHANES PARTICIPANTS WITH URINE
ALBUMIN/CREATININE RATIO ≥30 MG/G
2016 Annual Data Report, Vol 1, CKD, Ch 1

6. JAMA. 2016;316(6):602-610
… despite improvements in care

7. Diabetic CKD + Cardiovascular Disease =
Hospitalization + Death
2016 ANNUAL DATA REPORT, VOL 1, CKD, CH 3
Data source: Medicare 5 percent sample. January 1, 2014 point prevalent patients aged 66 and
older. Adj: age/sex/race. Ref: all patients, 2014. Abbreviations: CKD, chronic kidney disease;
CVD, cardiovascular disease; DM, diabetes mellitus.
Death Hospitalization

8. Progression of DKD
Kidney disease progression and all-cause mortality across estimated glomerular filtration rate and albuminuria categories among
patients with vs. without type 2 diabetes | BMC Nephrology | Full Text (biomedcentral.com)

9. DM is becoming a non-proteinuric state in the US
JAMA. 2016;316(6):602-610.
J. Clin. Med. 2015, 4, 1761-1773
RR of albuminuria (adjusted for eGFR): 0.73 vs 1988-1994
Diabetes Metab. 2012 Oct;38(4):291-7
Adv Chronic Kidney Dis. 2014 May;21(3):256-9

10. JAMA. 2016;316(6):602-610.
The prevalence of DKD in T2DM has
increased over the last 25 years
T2DM : Type 2 Diabetes

11. … and a substantial % of DKD is
now non-proteinuric
Diabetes Metab. 2012 Oct;38(4):291-7 JAMA. 2016;316(6):602-610
NHANES prevalence of non-proteinuric DKD : ~48%

12. Risk Factors for DKD
Clin J Am Soc Nephrol 12: 2032–2045, 2017 Am J Kidney Dis. 71(6):884-895,2018

13. Diabetic Glomerulopathy
Clin J Am Soc Nephrol 12: 2032–2045, 2017 Am J Kidney Dis. 71(6):884-895,2018

14. Tubulointerstitial and Arterial
Changes in DKD
Clin J Am Soc Nephrol 12: 2032–2045, 2017 Am J Kidney Dis. 71(6):884-895,2018

15. International Pathologic
Classification System of DKD
GLOMERULAR LESIONS
VASCULAR AND
TUBULOINTERSTITIAL LESIONS
Clin J Am Soc Nephrol 12: 2032–2045, 2017 Am J Kidney Dis. 71(6):884-895,2018

16. Glomerular Hyperfiltration initiates DKD
Normal state Diabetes
Clin J Am Soc Nephrol 12: 2032–2045, 2017 Am J Kidney Dis. 71(6):884-895,2018

17. DOI:10.1016/j.tips.2010.11.011
SGLT2 (high capacity) and SGLT1(high
affinity) transport glucose in the nephron

18. Hyperfiltration in experimental
diabetes is reduced by SGLT2i
SGLT2 and hyperfiltration in experimental diabetes
Diabetes vs control Diabetes vs control under phlorizin
Glomerular Hyperfiltration in Experimental Diabetes Mellitus | American
Society of Nephrology (asnjournals.org)

19. From Hyperfiltration to Molecular
Pathways in DKD
Clin J Am Soc Nephrol 12: 2032–2045, 2017 Am J Kidney Dis. 71(6):884-895,2018
.
Am J Physiol. 1985 Sep;249(3 Pt 2):F324-37

20. SGLT2i is NOT going to
be the end of (D)CKD
Am J Physiol Renal Physiol 304: F156–F167, 2013.

21. Renin – Angiotensin – Aldosterone:
Beyond the ENAC chronicles
https://www.frontiersin.org/articles/10.3389/fphys.2022.770375/full

22. A brief history of aldosterone time
https://doi.org/10.1093/eurheartj/ehaa736

23. Aldosterone, inflammation and fibrosis
https://academic.oup.com/ajh/article/34/1/15/5895247

24. Kidney &
Cardiovascular
diseases as
disorders of MR
activation
https://academic.oup.com/ajh/article/34/1/15/5895247 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1827836

25. Standard of Care of
DKD (2022)

26. Components of renal consultation in
patients with DM
AIMS
 Securing the diagnosis
Cardiovascular (CV) risk
reduction
Renal risk reduction
OBJECTIVES
Glycemic goals (with
renal+CV disease in mind)
Blood pressure control (with
renal+CV disease in mind)
Initiate and sustain evidence-
based pharmacological
therapy

27. Diagnosis of DKD
Impaired eGFR (<60 ml/min/1.73m2)
Albuminuria (UACR> 30 mg/g creatinine)
Spot sample to calculate the ratio of Albumin to Creatinine (morning
sample preferred)
Annual screening for DKD
5 years after the diagnosis of Type 1 diabetes
Upon diagnosis of Type 2 diabetes
Am J Kidney Dis. 71(6):884-895,2018

28. When to consider non-DKD and/or pursue a kidney biopsy
Atypical Presentation of renal disease in DM
Absence of retinopathy (T1D)
Albuminuria developing <5 or >25 the onset of
disease (T1D)
Immunological markers or active urinary
sediment
Acute/sudden onset macroalbuminuria or the
nephrotic syndrome
Nephritic syndrome
Hematuria
Rapid decline in renal function
Significant reduction in eGFR (>30%) after
initiation RAASi
Acute Kidney Injury
J Clin Med. 2015 May; 4(5): 998–1009 NDT. 32(1): 97–110, 2017

29. https://www.ajkd.org/article/S0272-6386(21)00924-0/fulltext

30. Statins for CV risk reduction (in CKD)?
Lancet Diabetes Endocrinol. 2016 Oct;4(10):829-39
Subject level meta-analysis 28 studies, ~183k pts

31. Glycemic Targets in Diabetes
Note: Vascular complications includes DKD
https://diabetesjournals.org/care/article/45/Supplement_1/
S83/138927/6-Glycemic-Targets-Standards-of-Medical-
Care-in

32. Individualize Glycemic Goals!
EVERYONE
Providers might reasonably suggest
A1C < 7% if this can be achieved without
significant hypoglycemia
If using CGM, a parallel goal is time in
range of >70% and time below range <4%
 A1c< 8% for patients with severe
hypoglycemia, limited life expectancy,
advanced microvascular complications, or
long standind diabetes
OLDER ADULTS (>65)
< 7.0 - 7.5% with few coexisting chronic
illnesses and intact cognitive function and
functional status
8-8.5% multiple coexisting chronic illnesses,
cognitive impairment, or functional
dependence
Goals should be reassessed and
individualized
CGM may be used to avoid hypoglycemia
6. Glycemic Targets: Standards of Medical Care in Diabetes—2021 (diabetesjournals.org)

33. Continuous Glucose Monitoring (CGM)
https://diabetesjournals.org/care/article/45/Supplement_1/S83/138927/6-Glycemic-Targets-Standards-of-Medical-Care-in

34. Key Glycemic Control Trials
Am J Kidney Dis. 71(6):884-895,2018
JACC 53(3): 298–304,2009
Cochrane Database Syst Rev. 2017 Jun 8;6:CD010137. doi:
10.1002/14651858.CD010137.pub2.

35. Role of the kidney in glucose homeostasis &
hypoglycemia during intensive glycemic targeting
1. Gluconeogenesis (cortex) mainly for utilization in the medulla
◦ Fasting post-absorptive state:
◦ 20-25% of the glucose released into the circulation is derived from the kidneys (12-55g)
◦ Kidneys use about 10% of the entire glucose pool (25-35g)
◦ Post-prandial state (4-5 hours after a meal):
◦ Kidneys responsible for 60% of endogenous glucose release (70g)
◦ Renal release of glucose x30% in pts with T2D
2. Reabsorption of filtered glucose by the proximal tubule
◦ GFR of 125 ml/min x 90-100 mg/dL = 160-180g filtered
◦ Nearly all of it is reabsorbed
◦ Primary renal contribution to glucose homeostasis
3. Insulin is cleared by the kidneys
DOI: 10.1152/ajpendo.00116.2001
DOI: 10.1113/JP271904
DOI: 10.1016/j.diabres.2017.07.033
DOI: 10.1152/physrev.00055.2009
DOI:10.1016/j.tips.2010.11.011
DOI: 10.1016/j.metabol.2014.06.018

36. Antiglycemics in CKD
https://www.ajkd.org/article/S0272-6386(21)00924-0/fulltext

37. Glucose-
lowering
medication
in DM2:
2022
version
9. Pharmacologic Approaches to
Glycemic Treatment: Standards of
Medical Care in Diabetes—2022 |
Diabetes Care | American Diabetes
Association (diabetesjournals.org)

38. FDA Label Change for Metformin in
Diabetes and CKD : April 2016
1. Measure eGFR
Before starting metformin
At least annually
2. eGFR < 30 ml/min/1.73m2
Metformin is contraindicated
3. eGFR between 30-45 ml/min/1.73m2
It is not recommended to initiate metformin
If eGFR falls in this range, re-assess risk-benefit
4. Discontinue metformin with iodinated contrast
eGFR between 30 and 60 mL/minute/1.73 m2
liver disease
alcoholism
 heart failure
intra-arterial iodinated contrast.
5. Re-evaluate eGFR 48 hours after contrast
restart metformin if renal function is stable.
https://www.fda.gov/Drugs/DrugSafety/ucm493244.htm Diabetes Care 2018;41:547–553
Prospective PK studies in advanced CKD
Therapeutic Metformin level: 1-4 / peak not to exceed 5, average 2.5
Off-label

39. Conflicting guidelines:
130/80 (KDIGO/ADA/EASD)
140/90 (JNC-8,ESH-ESC)
Data driven by lack of efficacy in
ACCORD
Higher (renal) adverse events with
intensive therapy
Blood Pressure Goals
N Engl J Med 2010;362:1575-85.

40. Single, not dual RAASi (ACEi+ARB)
should be used in DKD
Am J Kidney Dis. 71(6):884-895,2018

41. Lowering Cardiorenal
Risk in Patients with
CKD and DM2

42. https://cjasn.asnjournals.org/content/clinjasn/17/7/1092.full.pdf

43. Take home points for this section
1. Patients may be selected for further therapies based on UACR
2. SGLT2i have broad cardiovascular, renal and heart failure benefits
3. Cardiorenal benefits of SGLT2i are likely to be class, rather than agent specific
4. Effects of SGLT2i on CKD don’t differ between diabetic and non-diabetic forms of
CKD
5. Successful roll out of SGLT2i is likely to have the same population level effects that
ACE/ARBs had
6. Selective, non-steroidal MRAs have the same effects on cardiorenal outcomes as
SGLT2i
7. Don’t ask who will prescribe the SGLT2i/MRA for your patient, but when YOU will
prescribe SGLT2i/MRA and how you will do it like royalty

44. Urine Albumin to Creatinine Ratio: the
Piss Prophet of Renal Risk in RENAAL
https://jasn.asnjournals.org/content/21/8/1355.long

45. Residual albuminuria, Albuminuria Delta
after ARB predict kidney outcomes
1.36 (1.31-1.42)
1.43 (1.36-1.51)
https://doi.org/10.1111/j.1523-1755.2004.00653.x

46. https://onlinelibrary.wiley.com/doi/epdf/10.1002/clc.23508
https://bitbucket.org/chrisarg/sglt2imetanalysis/

47. Snapshot of the
SGLT2i trials

48. SGLT2i reduce all cause and
cardiovascular death by 15%

49. SGLT2i reduce major cardiovascular events
by 10% and heart failure events by 30%

50. SGLT2i reduced rates of ESKD by 37%
and the composite kidney outcome of
worsening kidney function/ ESKD by 39%

51. Biphasic eGFR changes upon initiation of SGLT2i
Canagliflozin (CREDENCE) Dapagliflozin (DAPA-CKD) Empagliflozin (EMPA-REG)

52. Renal Benefits of SGLT2i are observed across
demographics and levels of eGFR
https://doi.org/10.2215/CJN.10140620
http://www.nejm.org/doi/10.1056/NEJMoa2024816

53. Renal benefits
of SGLT2i are
observed
irrespective of
the presence of
diabetes type 2
https://doi.org/10.1038/s41581-020-00391-2

54. Safety
events
in
SGLT2i
trials

55. Effects of SGLT2i
on biomarkers and
clinical variables
(meta-analysis)
DOI: 10.1111/dom.13648

56. SGLT2i vs RASi
PAYING FOR NEW THERAPIES
SGLT2i ARB
Canagliflozin
(CREDENCE)
Dapagliflozin
(DAPA – CKD)
Losartan
(RENAAL)
Irbesartan
(IDNT)
All-Cause Mortality (Q1) 0.83
(0.68 – 1.02)
0.69
(0.53 – 0.88)
0.98
(0.73 – 1.19)
0.92
(0.69 – 1.23)
Composite Kidney Outcome
(Q2)
0.66
(0.53-0.81)
0.56
(0.45 – 0.68)
0.79
(0.66 – 0.95)
0.71
(0.59 – 0.86)
End Stage Kidney Disease (Q2) 0.68
(0.54 – 0.86)
0.64
(0.50 – 0.82)
0.78
(0.58 – 0.89)
0.77
(0.57 – 1.03)
Heart Failure Hospitalizations
(Q4)
0.61
(0.47- 0.80)
0.51
(0.34 – 0.76)
0.74
(0.55 – 0.98)
0.72
(0.52 – 1.00)
Composite Kidney Outcome: doubling creatinine/End Stage Kidney Disease/decrease in eGFR >
40% (doubling of serum creatinine in the Angiotensin Receptor Blocker Trials)

57. Aldosteronism Antagonism (MRA) for the
reduction of cardiorenal risk across the
spectrum of DKD
https://doi.org/10.1093/eurheartj/ehab827

58. https://doi.org/10.1093/eurheartj/ehab777
Cardiovascular and kidney
outcomes with finerenone in
patients with type 2 diabetes
and chronic kidney disease:
the FIDELITY pooled analysis

59. Effects of Finerenone reduced loss of
eGFR and had modest effects on BP
https://www.nejm.org/doi/10.1056/NEJMoa2025845
Change in SBP < 3 mmHg
throughout FIDELIO-CKD

60. Do MRA/SGLT2i interfere with each other?
MRA IN DAPA-CKD SGLT2I IN THE FIDELIO-DKD TRIAL
https://doi.org/10.1016/j.ekir.2021.12.013 https://www.kireports.org/article/S2468-0249(21)01467-4/fulltext
No evidence of effect modification based on limited and
subject to selection effect post hoc subgroup data

61. Role of combination MRA/SGLT2i in CKD?
OF RODENTS … AND HUMANS …
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619789/
Empa vs
Finerenone vs
Empa+Finerenone

62. Management of hyperkalemia for diabetic
and non-diabetic CKD
Hypekalemia will occur with ACEi/ARB and MRAs (can’t escape ENAC!)
Hyperkalemia will occur irrespective of the the diabetic (or not) nature of CKD
Management of hyperkalemia will allow the safe use of ACEi/ARB/MRAs
Continued use of these agents is required to deliver their cardiovascular and kidney benefits
Potential strategies to manage the hyperkalemia risk by any RAASi are:
• Measure the potassium (it never makes sense to “stop the count”)
• Stop the RAASi or reduce the dose (temporarily)
• “Convince” the kidneys to get rid of potassium (diuretics/SGLT2 inhibitors)
• Use a potassium binder (patiromer/ZS9)

63. 63
GLP1RA in diabetic Kidney Disease
Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the
REWIND randomised, placebo-controlled trial - The Lancet
Liraglutide and Renal Outcomes in Type 2 Diabetes | NEJM
Dulaglutide Liraglutide
Semaglutide:
Composite Kidney HR 0.64 (95% CI 0.46 – 0.88)
mostly driven by progression to
macroalbuminuria: HR 0.54 95% CI (0.37 – 0.77)
Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes | NEJM

64. Wrapping up!

65. DKD Nephrology Encounters in 2022
1. Establish the absence of a non-diabetic lesion!
2. Initiate, optimize and sustain evidence- based pharmacological therapy
ACEi/ARB/SGLT2i / MRAs
Guideline Directed Medical Therapy utilizing UACR/Albuminuria to select pts for further therapy
? What to do with non-proteinuric (D)CKD (EMPA-KIDNEY stopped early for efficacy)
3. Treat the complications that endocrinologists/PCPs don’t treat
Hyperkalemia (diuretics/patiromer/ZS-9/SGLT2!!)
Volume overload
CKD complications
Hypertension management
4. Consult referring physicians about renal safety/efficacy/dosing of anti-glycemic
therapies
Metformin/SGLT2i/GLP-1RA/DPP-4i

66. Which anti-glycemic/antifibrotic agents to
recommend to referring providers?
1. Patient’s cardiorenal risk
2. Cardiovascular and renal end-points
◦ Medical literature
◦ Regulatory submission documents
3. Safety profile
4.Level of renal function
5.What the insurance will pay
6.The copay the patient can afford

67. American
exceptionalism: the
high clinical value but
poor value
proposition of SGLT2i

68. Medicare expenditures by DM, CHF, CKD status
U.S. Medicare
Population
Total Spending
(millions, U.S. $)
PPPY (U.S. $), with
Parts A & B coverage
PPPY (U.S. $), with
Parts A, B, & D
coverage Population (%) Spending (%)
ALL 24,561,980 $295,655 $12,453 $14,090 100.0 100.0
No CKD 21,350,400 $225,146 $10,842 $12,302 86.9 76.2
All CKD (+/- DM & HF) 3,211,580 $70,509 $23,691 $25,769 13.1 23.8
All DM (+/- CKD & HF) 5,935,000 $103,744 $18,321 $20,103 24.2 35.1
All HF (+/- DM & CKD) 2,280,040 $62,445 $30,510 $32,737 9.3 21.1
No CKD or DM or HF 16,120,660 $141,419 $8,976 $10,217 65.6 47.8
With CKD or DM or
HF
8,441,320 $154,235 $19,312 $21,002 34.4 52.2
CKD only (- DM & HF) 1,210,720 $19,507 $16,916 $18,237 4.9 6.6
DM only (- HF & CKD) 3,853,240 $51,261 $13,690 $15,051 15.7 17.3
HF only (- DM & CKD) 905,540 $19,744 $23,696 $25,271 3.7 6.7
CKD and DM only (-
HF)
1,097,320 $21,023 $20,167 $22,130 4.5 7.1
CKD and HF only (-
DM)
390,060 $11,241 $33,274 $34,994 1.6 3.8
DM and HF only (-
CKD)
470,960 $12,722 $29,393 $31,676 1.9 4.3
CKD and DM and HF 513,480 $18,738 $42,318 $45,516 2.1 6.3
CKD and DM (+/-HF) 1,610,800 $39,761 $26,771 $29,288 6.6 13.4
CKD and HF (+/- DM) 903,540 $29,979 $38,404 $41,080 3.7 10.1
DM and HF (+/- CKD) 984,440 $31,460 $35,929 $38,688 4.0 10.6
Annual Data Report | USRDS

69. Recommendations Indication Implementation Rate, % Implications
Albuminuria testing by
UACR (1,16)
• Annually in type 2
diabetes
• After 5 yr of type 1
diabetes
• 3–6 mo after initiation or
dose change in ACE
inhibitor or ARB
10–40 (7,14,15)
• Underdiagnosis of DKD
• Low usage rates of DKD
therapies
• Inadequate therapeutic
monitoring and dose
adjustments
ACE inhibitor or ARB
(1,2,16)
• UACR >300 mg/g
irrespective of
hypertension
• UACR >30–299 mg/g
with hypertension
• Consideration for UACR
>30–299 mg/g without
hypertension
25–40 (14,17)
• Most patients in typical
health care settings are
not given standard-of-care
therapies to prevent DKD
progression, kidney
failure, and cardiovascular
risk
SGLT2 inhibitor (1,2)
• Initiate with eGFR ≥25
ml/min per 1.73 m2
• Initiate with eGFR ≥20
ml/min per 1.73 m2 if used
for heart failure
(empagliflozin)
• SGLT2 inhibitors may be
continued until onset of
kidney failure
13 (27)
• Patients are not given
therapies that
substantially reduce risk of
DKD progression, kidney
failure, cardiovascular
risk, and all-cause
mortality on top of
standard of care
• Early in the
implementation phase for
SGLT2 inhibitors, with first
drug approval for DKD in
2019
GLP-1 receptor agonist
(1,2)
• Use for glucose lowering
and atherosclerotic
cardiovascular risk
reduction with eGFR ≥15
ml/min per 1.73 m2
17 (27)
• Patients rarely are given
therapies that effectively
and safely lower glucose
and reduce major adverse
cardiovascular events with
eGFR <60 or ≥60 ml/min
per 1.73 m2
Nonsteroidal MRA (2)
• UACR >30 mg/g and
eGFR ≥25 ml/min per 1.73
m2 (finerenone)
• Not recommended if
serum potassium is >4.8
mEq/L prior to initiation or
>5.5 mEq/L on treatment
Not yet known • To be determined
https://cjasn.asnjournals.org/content/clinjasn/17/7/1092.full.pdf

70. Backup slides

71. Acute and chronic effects of SGLT2
blockade in experimental DKD
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349378/
Chronic and acute fx of SGLT2i on
proximal reabsorption are similar
Hyperglycemia major driver of
hyperfiltration & urine flow
Chronic effects of
SGLT2i on TGF are
expected to be
reduced but not
abolished

72. Normal
Hyperglycemia
Early diabetic
kidney disease
Glomerular Hyperfiltration in Experimental Diabetes
Mellitus | American Society of Nephrology
(asnjournals.org)

73. GLOMERULAR HYPERFILTRATION IN DM
AS A PRIMARY TUBULAR EVENT
Annu. Rev. Physiol. 2012. 74:351–75
Salt Paradox: the
inverse relationship
between
dietary NaCl and
GFR in DM ->
Due to changes in
the Na in macula
densa

74. Patient is a candidate for one of the sodium glucose cotransporter two
inhibitors (i.e. Jardiance 10mg a day, Invokana 100mg a day, Steglatro 5
mg a day or Farxiga 10 mg a day) given chronic kidney disease, long
standing Type 2 Diabetes/hypertension and pre-existing cardiovascular
disease and/or heart failure).
Benefits of SGLT2i include:
a) reduction in total and cardiovascular mortality by 15-20%,
b) decrease in the risk for dialysis 40%
c) hospitalization for heart failure by 30%
d) reduction in the rate of Acute Kidney Injury by 25% with no
symptomatic hypoglycemia.
e) decrease in systolic BP by about 2-4 mmHg
f) decrease in body weight by about 2-3 kgr
Currently, Jardiance/Farxiga/Invokana have cardiovascular and heart
failure FDA indications , while Invokana has an FDA indication for
diabetic kidney disease. However, the aforementioned effects are class
effects so any SGLT2i insurance would cover would be an appropriate
choice for the patient.
After starting SGLT2i,
a) eGFR will decline between 5-8 ml/min because of the mechanism of
action of these drugs; this acute decline is not progressive and is fully
reversible upon stopping the drugs. Recommend a kidney function
check in 4 weeks to establish the patient's new baseline, and/or monitor
more severe decline (anything over 10-15 ml/min should prompt one to
look for potential reversible causes of acute renal deterioration and
revisit the entire cardiorenal regimen, including the SGLT2i)
b) patients receiving insulin may experience an improvement in
glycemic control and/or need for less insulin (up to 30%).
Most common side effect is yeast infection. In addition to optimizing
diabetes care and weight reduction in overweight/obese patients.
Personal hygiene education is recommended in all patients at the
initiation of an SGLT2i. Yeast infections may be minimized by cleaning
the genital area before and after going to the bathroom and before
bedtime with water. Women should be advised to wear cotton
underwear to reduce their potential risk for vaginal candidiasis. Other
risks like diabetic ketoacidosis are rare (about 1/500 patients) and the
risk may be reduced by temporarily holding the SGLT2i during acute
illness in which access to fluids is impaired and then restarting it once
the episode has resolved. SGLT2i should be held prior to scheduled
surgery to minimize risk for euglycemic DKA (4 days for ertugliflozin,
others 3 days). The patient has no active peripheral arterial disease
(with ischemia at rest or ulcers), so very unlikely to develop symptoms of
PAD needing amputation (risk was seen in only one trial of SGLT2i).
https://docs.google.com/docu
ment/d/1l1FyXHPCvBJdcCnyJg-
NGtElwlAfQ6fgL0jQdosflSs/edit
?usp=sharing .

75. Intensive glycemic control in pts with CKD in the
ACCORD trial
ALL CAUSE MORTALITY HYPOGLYCEMIC EPISODES
Kidney International (2015) 87, 649–659;

76. Are MRAs our next weapon in
the fight against the
cardiovascular and kidney
sequelae of CKD ?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094274

77. MRA improves
proteinuria in
CKD
 Uncertain effects on
1. Kidney failure
2. Death
3. CV events
 MRA may decrease blood
pressure: MD -4.98 mmHg,
95% CI -8.22 to -1.75, I2 = 87%
https://www.ncbi.nlm.nih.gov/
pmc/articles/PMC8094274
Nearly all studies used spironolactone

78. Nonselective MRA is associated with hyperkalemia and
gynecomastia
HYPERKALEMIA GYNECOMASTIA
Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD007004.
DOI: 10.1002/14651858.CD007004.pub3.
Hyperkalemia Gynecomastia
41 14.1
Numbers Needed To Harm

79. RAASi to prevent microalbuminuria
in diabetes?
TYPE 1 DIABETES TYPE 2 DIABETES
DOI: 10.1177/1470320316652047
Multiple negative studies
1. RASS
2. DIRECT
3. DIRECT-PROTECT-1
No effect in mortality
N Engl J Med 2009;361:40-51. Am J Kidney Dis. 71(6):884-895,2018

80. How to Read
a CGM report
https://diabetesjournals.org/care/article/45/Supplement_1/S83/138927/6-Glycemic-Targets-Standards-of-Medical-Care-in

81. Intensifying
Injectable
Therapies 2022
version
American Diabetes Association Diabetes Care 2019;42:S90-S102 Reference - material
9. Pharmacologic Approaches to Glycemic Treatment:
Standards of Medical Care in Diabetes—2022 | Diabetes
Care | American Diabetes Association
(diabetesjournals.org)

82. The importance of harmonizing
(kidney) outcomes in RCTs
PRIMARY ANALYSIS OF VERTIS-CV
HARMONIZED DEFINITION IN
VERTIS-CV
Cardiovascular Outcomes with Ertugliflozin in Type 2
Diabetes | NEJM
Effects of ertugliflozin on kidney composite
outcomes, renal function and albuminuria in patients
with type 2 diabetes mellitus: an analysis from the
randomised VERTIS CV trial | SpringerLink

83. Laboratory outcomes with selective MRAs not included
in the Cochrane meta-analysis
ESAXERENONE APARARENONE
https://cjasn.asnjournals.org/content/15/12/1715.long https://pubmed.ncbi.nlm.nih.gov/32974732/

84. Kidney Outcomes of Finerenone in more severe
Diabetic Kidney Disease: a 30,000 ft view
https://www.karger.com/Article/FullText/503713

85. FIDELIO CKD : Inclusion, exclusion
& statistical analysis
Pts with T2D and CKD :
UACR > 300 mg/g & eGFR in 25-75 ml/min/1.73m2
UACR in 30-300 mg/g & eGFR in 25-60 ml/min/1.73m2
Serum potassium level ≤ 4.8 meq/l
Prior treatment with ACEi or ARB
Excluded pts currently receiving
eplerenone/spironolactone/renin inhibitor/K-sparing
diuretic
Excluded A1c > 12% or UACR >5,000 mg/g
Dialysis dependent AKI within 12 wks of study run-
in visit
Poorly controlled hypertension (BP > 170/110
mmHg)
NYHA Class II-IV or indication 1A for MRA
https://www.karger.com/Article/FullText/503713

86. Finerenone reduces hard kidney and
cardiovascular outcomes in moderate DKD
https://www.nejm.org/doi/10.1056/NEJMoa2025845
Event Finerenone Placebo
(N=2827) (N=2831)
no. of patients (%)
Any adverse event 2468 (87.3) 2478 (87.5)
Adverse event related to trial regimen 646 (22.9) 449 (15.9)
Adverse event leading to discontinuation of trial regimen 207 (7.3) 168 (5.9)
Any serious adverse event 902 (31.9) 971 (34.3)
Serious adverse event related to trial regimen 48 (1.7) 34 (1.2)
Serious adverse event leading to discontinuation of trial
regimen
75 (2.7) 78 (2.8)
Investigator-reported hyperkalemia 516 (18.3) 255 (9.0)
Hyperkalemia related to trial regimen 333 (11.8) 135 (4.8)
Serious hyperkalemia 44 (1.6) 12 (0.4)
Hospitalization due to hyperkalemia 40 (1.4) 8 (0.3)
Permanent discontinuation of trial regimen due to
hyperkalemia
64 (2.3) 25 (0.9)
Investigator-reported hypokalemia 28 (1.0) 61 (2.2)
Investigator-reported renal-related adverse events
Acute kidney injury 129 (4.6) 136 (4.8)
Hospitalization due to acute kidney injury 53 (1.9) 47 (1.7)
Discontinuation of trial regimen due to acute kidney injury 5 (0.2) 7 (0.2)
Hospitalization due to acute renal failure 70 (2.5) 71 (2.5)
Discontinuation of trial regimen due to acute renal failure 31 (1.1) 36 (1.3)
Adverse events affecting ≥5% of patients in either group
Hyperkalemia 446 (15.8) 221 (7.8)
Nasopharyngitis 241 (8.5) 250 (8.8)
Hypertension 212 (7.5) 273 (9.6)
Anemia 209 (7.4) 191 (6.7)
Peripheral edema 186 (6.6) 304 (10.7)
Diarrhea 184 (6.5) 189 (6.7)
Upper respiratory tract infection 181 (6.4) 189 (6.7)
Glomerular filtration rate decreased 179 (6.3) 133 (4.7)
Urinary tract infection 179 (6.3) 192 (6.8)
Back pain 175 (6.2) 175 (6.2)
Hypoglycemia 151 (5.3) 194 (6.9)
Dizziness 146 (5.2) 153 (5.4)
Arthralgia 142 (5.0) 149 (5.3)
Bronchitis 134 (4.7) 151 (5.3)
Constipation 131 (4.6) 163 (5.8)
Pneumonia 128 (4.5) 181 (6.4)

87. Cardiovascular Outcomes of Finerenone
in less severe Diabetic Kidney Disease:
the FIGARO-DKD trial
https://www.nejm.org/doi/full/10.1056/NEJMoa2110956
Pts with T2D and CKD :
 UACR > 300 mg/g & eGFR > 60ml/min/1.73m2
 UACR in 30-300 mg/g & eGFR in 25-90 ml/min/1.73m2
Serum potassium level ≤ 4.8 meq/l
Prior treatment with ACEi or ARB
Excluded pts currently receiving
eplerenone/spironolactone/renin inhibitor/K-sparing
diuretic
Excluded A1c > 12% or UACR >5,000 mg/g
Dialysis dependent AKI within 12 wks of study run-in visit
Poorly controlled hypertension (BP > 170/110 mmHg)
NYHA Class II-IV or indication 1A for MRA
 SAE: 31.4% (Finerenone) vs 33.2% (placebo)
 Incidence of hyperkalemia was higher with finerenone
than with placebo (10.8% vs. 5.3%)

88. Management of hyperkalemia in
Fidelio DKD
https://jasn.asnjournals.org/content/33/1/225

89. Predictors of
treatment
emergent
hyperkalemia in
FIDELIO-DKD
https://jasn.asnjournals.org/content/33/1/225

90. MRA v.s. SGLT2i in the management of CKD
ARE MRAS LESS POTENT?
OR DID THE TRIALS JUST RECRUIT
PATIENTS WITH SOMEWHAT DIFFERENT
RISK PROFILES ?
Eye-balling HRs
Network meta-analysis (statistical eye-
balling) SGLT2i vs MRA:
1. Kidney Failure Progression: HR 0.78,
95% CI 0.67–0.90
2. HHF: HR 0.71, 95% CI 0.55–0.92
3. MACE: HR 0.95, 95% CI 0.71–1.27
https://doi.org/10.1093/ndt/gfab336
https://www.frontiersin.org/articles/10.3389/fphar.2021.751496/