Update on diabetic kidney disease given at the New Mexico Academy of Physician Assistant Conference on 9/23

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 (finerenone)

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

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

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

12. 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

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

14. Standard of Care of
DKD (2021)

15. 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

16. 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

17. 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

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

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

20. 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)

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

22. 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.

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

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

25. 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

26. 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 in these studies
(“creatinine bumps”)
Blood Pressure Goals
N Engl J Med 2010;362:1575-85.

27. Blood Pressure Goals - Continued
AMERICAN HEART ASSOCIATION
For adults with confirmed hypertension
and known stable CVD or ≥10% 10-year
ASCVD risk, a BP target of <130/80 mm
Hg is recommended.
In patients with diabetes, antihypertensive
drug treatment should be initiated at a BP
≥130/80 mm Hg with a treatment goal of
<130/80 mm Hg.
CKD: BP goal should be <130/80 mm Hg.
AMERICAN DIABETES ASSOCIATION
For patients with diabetes and hypertension,
blood pressure targets should be
individualized through a shared decision-making
process that addresses CV risk, potential adverse
effects of antihypertensive medications, and
patient preferences. (C)
For individuals with diabetes and hypertension
at higher CV risk (existing ASCVD or 10-year
ASCVD risk >15%), a blood pressure target of
,130/80 mmHg may be appropriate, if it can be
safely attained. (C)
For individuals with diabetes and hypertension
at lower risk for CVD (10-year ASCVD risk
<15%), treat to a blood pressure target of <140/90
mmHg.A
GUIDELINE TARGETS WILL LIKELY DECLINE TO <125/75 NOW THAT THE STEP TRIAL HAS BEEN PUBLISHED

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

29. 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)

30. 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

31. 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

32. Lowering Cardiorenal
Risk in Patients with
CKD and DM2

33. 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. GLP1s appear to have kidney protective effect (off-label use for this indication)
6. Selective non-steroidal mineralocorticoid antagonists (finerenone) improve outcomes
in diabetic kidney disease

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

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

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

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

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

39. Adverse events of SGLT2i in meta-analysis
Volume depletion : increased by 18%
Acute kidney injury: decreased by 25%
Genital mycotic infections: increased by x4
UTI: increased by 9%
Hypoglycemia: not observed
Fractures: increased 12% (driven by CANVAS)
Amputations: increased 22% (driven by CANVAS)
Diabetic ketoacidosis: increased by 2.5x

40. 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)

41. 45
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

42. Clinical Outcomes of Finerenone in
Diabetic Kidney Disease of T2D

43. Meta-analysis of
finerenone trials

44. Wrapping up!

45. 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 / GLP1RA/ MRA
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

46. 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

47. 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 .