This document discusses diabetic kidney disease (DKD). It provides information on the epidemiology, clinical presentation, pathogenesis, standard of care, and pharmacological interventions to reduce cardiorenal risk in patients with type 2 diabetes. Regarding standard of care, it outlines glycemic and blood pressure targets, the use of RAAS inhibitors and statins, and glucose-lowering medications. It then discusses how SGLT2 inhibitors have shown benefits in reducing cardiovascular, renal, and heart failure outcomes as well as slowing kidney disease progression in patients with DKD and type 2 diabetes.

1. Diabetic Kidney
Disease- 2021
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 (investigational agents for DKD)

3. Learning Objectives
1. Epidemiology, clinical presentation and
pathogenesis of Diabetic Kidney Disease (DKD)
2. Standard of Care in DKD (2021)
3. Pharmacological Interventions to reduce
Cardiorenal Risk in Patients with DM2

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. 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

9. 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)

10. 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

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

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

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

14. 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

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

16. 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)

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

18. 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

19. 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

20. 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

21. Standard of Care of
DKD (2021)

22. 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

23. 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

24. 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

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

26. Glycemic Targets in Diabetes
Note: Vascular complications includes DKD
6. Glycemic Targets: Standards of Medical Care in
Diabetes—2021 | Diabetes Care (diabetesjournals.org)

27. 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)

28. Continuous Glucose Monitoring
(CGM)
6. Glycemic Targets: Standards of Medical Care in
Diabetes—2021 (diabetesjournals.org)

29. Glucose-
lowering
medication
in DM2:
2021
version
9. Pharmacologic Approaches to
Glycemic Treatment: Standards
of Medical Care in Diabetes—
2021 | Diabetes Care
(diabetesjournals.org)

30. 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

31. 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.

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

33. The combination of RAASi + Aldosterone antagonists
improves proteinuria and blood pressure control
PROTEINURIA SYSTOLIC BLOOD PRESSURE
Diastolic BP: -1.73 [ -2.83, -0.62 ]
Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD007004.
DOI: 10.1002/14651858.CD007004.pub3.
eGFR -2.55 [ -5.61, 0.51 ] (favors SPL, NS)

34. The combination of RAASi + Aldosterone antagonists
causes hyperkalemia and gynecomastia
HYPERKALEMIA GYNECOMASTIA
Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD007004.
DOI: 10.1002/14651858.CD007004.pub3.
Hyperkalemia Gynecomastia
7.2 14.1
Numbers Needed To Harm

35. 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

36. Lowering Cardiorenal
Risk in Patients with
CKD and DM2

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

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

39. Residual Renal Risk in RCTs
ALBUMINURIA REDUCTION BLOOD PRESSURE REDUCTION
Kidney International (2014) 86, 40–49; doi:10.1038/ki.2013.490

40. Snapshot of the
SGLT2i trials

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

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

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

44. 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

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

46. 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

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

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

49. 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)

50. GLP-1R & DPP-
4 are widely
distributed in the
kidney
doi:10.1038/nrneph.2017.123
GLP-1R & DPP-4 may be relevant
to the pathogenesis of DKD

51. 61
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

52. Wrapping up!

53. DKD Nephrology Encounters in 2021
1. Establish the absence of a non-diabetic lesion!
2. Initiate, optimize and sustain evidence- based pharmacological
therapy
ACEi/ARB/SGLT2i / ? Aldo antagonists
3. Treat the complications that endocrinologists/PCPs don’t treat
Hyperkalemia (diuretics/patiromer/ZS-9)
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

54. Which anti-glycemic 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

55. 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 .

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