Q1 2019 Update of my diabetic nephropathy talk. Incorporates the ADA 2019 guidelines and data tables

1. Update on Diabetic
Nephropathy - 2019
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 fees Momenta Pharmaceuticals (investigational agents for
immune related renal disease)

3. Learning Objectives
1. Epidemiology, clinical manifestations and
pathogenesis of Diabetic Kidney Disease (DKD)
2. Standard of Care in DKD (2019)
3. Outcome trials and clinical studies for emerging
therapies in diabetic kidney disease and its
complications

4. Diabetic Nephropathy
in the 21st century
BURDEN, CLINICAL MANIFESTATIONS, 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. 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

7. ESRD incidence is increasing because of DM
Adjusted prevalence of ESRD in the US 1996-2014 .. but certain states have it worse than others
2016 Annual Data Report, Vol 2, ESRD, Ch 1 Fig 1.16
BMC Nephrol. 2018 Feb 27;19(1):47. doi:
10.1186/s12882-018-0842-4.

8. Data Source: Medicare 5% sample. Abbreviations: CKD, chronic kidney disease; CHF,
congestive heart failure; DM, diabetes mellitus; PPPY, per patient per year costs.
Medicare expenditures by DM, CHF, CKD status
U.S. Medicare
Population
Total Costs (millions,
U.S. $)
PPPY Costs
(U.S. $)
Population (%) Costs (%)
All 24,496,020 $254,356 $10,803 100.00 100.00
With CHF or CKD or DM 8,140,540 $130,220 $17,013 33.23 51.20
CKD only (- DM & CHF) 1,023,220 $15,109 $15,673 4.18 5.94
DM only (- CHF & CKD) 4,093,320 $47,846 $12,116 16.71 18.81
CHF only (- DM & CKD) 893,760 $16,955 $20,733 3.65 6.67
CKD and DM only (- CHF) 847,220 $14,856 $18,610 3.46 5.84
CKD and CHF only (- DM) 340,300 $8,829 $30,395 1.39 3.47
DM and CHF only (- CKD) 515,500 $12,599 $26,758 2.10 4.95
CKD and CHF and DM 427,220 $14,025 $38,561 1.74 5.51
No CKD or DM or CHF 16,355,480 $124,136 $7,812 66.77 48.80
All CKD (+/- DM & CHF) 2,637,960 $52,819 $21,857 10.77 20.77
All DM (+/- CKD & CHF) 5,883,260 $89,327 $16,003 24.02 35.12
All CHF (+/- DM & CKD) 2,176,780 $52,409 $26,975 8.89 20.60
CKD and DM (+/- CHF) 1,274,440 $28,882 $24,854 5.20 11.36
CKD and CHF (+/- DM) 767,520 $22,854 $34,935 3.13 8.99
DM and CHF (+/- CKD) 942,720 $26,625 $31,902 3.85 10.47
2016 Annual Data Report, Vol 1, CKD, Ch 3

9. Conventional Natural History Model
of DKD
Kidney International, Vol. 63 (2003), pp. 225–232
T1D : ~20-30%
T2D : ~40%

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

12. … 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%

13. JAMA. 2016;316(6):602-610
Incidence of DKD ↑, while care improves

14. Does RAASi therapy completely account
for this emerging pattern of DKD?
Kidney International (2014) 86, 50–57; doi:10.1038/ki.2014.98

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

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

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

18. 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

19. 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

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 (2019)

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
American Diabetes Association. 6. Glycemic targets: Standards of Medical
Care in Diabetes 2019. Diabetes Care 2019; 42(Suppl. 1):S61–S70
Note: Vascular complications includes DKD

27. Individualize Glycemic Goals!
EVERYONE
➢Providers might reasonably suggest
A1C < 6.5% if this can be achieved
without significant hypoglycemia or other
adverse effects of treatment (i.e.,
polypharmacy).
➢ A1c< 8% for patients with severe
hypoglycemia, limited life expectancy,
advanced microvascular complications, or
long standind diabetes
OLDER ADULTS (>65)
➢< 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 over time
American Diabetes Association. 6. Glycemic targets: Standards of Medical
Care in Diabetes 2019. Diabetes Care 2019; 42(Suppl. 1):S61–S70, S139-147

28. 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.

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

30. 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

31. Anti-glycemictherapyin
patientswithtype2diabetes
Agents that reduce major adverse
cardiovascular events/mortality
Agent ASCVD CHF
Metformin Potential Benefit Neutral
SGLT2i Canagliflozin
Empagliflozin
Canagliflozin
Empagliflozin
GLP-1RA Liraglutide Neutral
Thiazolidinediones Potential Benefit
(pioglitazone)
Higher Risk
DPP4i Neutral Potential Risk
saxa/alogliptin
Diabetes Care 2018;41(Suppl. 1):S73–S85
ASCVD: atherosclerotic cardiovascular disease
CHF: Congestive Heart Failure
2018 version

32. Glucose-lowering medication in DM2: 2019 version
American Diabetes Association Diabetes Care 2019;42:S90-S102

33. American Diabetes Association Diabetes Care 2019;42:S90-S102
IntensifyingInjectable
Therapies2019version
For self-reference only

34. 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

35. ➢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.

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

37. 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)

38. 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

39. 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

40. Emerging Therapies
In Diabetic Kidney
Disease
(THESE ARE ALL APPROVED OR “REPURPOSED” DRUGS
THAT ONE CAN PRESCRIBE NOW)

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

42. Proteinuria reduction predicts improved renal
function in late but not in early diabetic nephropathy
TYPE 1 DIABETES TYPE 2 DIABETES
Am J Nephrol. 2008;28(4):614-27
Early
Late
Early, normal BP
Early, hypertensive
Late, hypertensive

43. Back to the basics: hyperfiltration
and renal glucose handling in DKD
DOI:10.1016/j.tips.2010.11.011 Am J Kidney Dis. 72(2): 267-277.

44. Distal Tubule Bias
in Nephrology
Research
& the 20 lost years
in DKD
https://jasn.asnjournals.org/cont
ent/10/12/2569.long
https://www.ncbi.nlm.nih.gov/pm
c/articles/PMC3349378/
The dawn of
the SGLT2
inhibitors

45. 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

46. Hemodynamics across the age span in T1D
(the forgotten arteriole)
doi: 10.1053/ j.ajkd.2018.12.034
As we age:
GFR, RPF, Intraglomerular Pressures ↓
Intrarenal vascular resistances ↑

47. Effects of SGLT2i in human DKD
➢Future use of any antidiabetic therapy will be colored by their CVOT outcomes data
➢Data from cardiovascular safety trials (nearly all completed)
➢Data from the entire development program (including Phase 1,2 studies)
➢Data from dedicated renal studies (all of them currently ongoing)
➢General rules of thumb:
➢Regulators (FDA) have access to patient level data and report their own patient – level meta-
analyses in the regulatory documents: BEST SOURCE OF INFORMATION
➢Journal articles: heavily influenced by agendas of companies and authors (lots of information
are hidden in supplements or spread over publications)
➢Meta-analyses: can be used to create “optical” illusions based on how the data are cut (almost
no articles published to date include patient level data)
➢Guideline tables: good for eye-balling reality (usually equally (un)influenced in this space

48. Cardiovascular effects of SGLT2i:
published clinical studies v.s. patient level
meta-analyses reviewed by the FDA
MACE Published FDA
Empagliflozin 1
MACE-3
MACE-4
0.86 (0.74 – 0.99)
0.89 (0.78 – 1.01)
–
0.74 (0.57 – 0.96)
Canagliflozin (MACE-4) 2 0.86 (0.75 – 0.97) 0.91 (0.68 – 1.22)
Dapagliflozin
MACE-3 3
MACE-4 4
0.93 (0.82 – 1.04)
–
–
0.78 (0.55 – 1.11)
1 https://www.fda.gov/downloads/AdvisoryCommittees/UCM508422.pdf
2 https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000MedR.pdf
3 DECLARE-TIMI-58 (NCT01730534) http://care.diabetesjournals.org/content/table-104-update
4 https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/202293Orig1s000MedR.pdf (uCI 1.83 in 2 unpublished high CV RCTs)

49. DPP-4 inhibitors GLP-1 receptor agonists SGLT2 inhibitors
SAVOR-TIMI 53
(n = 16,492)
EXAMINE
(n = 5,380)
TECOS
(n = 14,671)
ELIXA
(n = 6,068)
LEADER
(n = 9,340)
SUSTAIN-6
(n = 3,297)
EXSCEL
(n = 14,752)
EMPA-REG
OUTCOME
(n = 7,020)
CANVAS
(n = 4,330)
CANVAS-R
(n = 5,812)
DECLARE-
TIMI-58
(n=17,160)
Intervention
Saxagliptin
/placebo
Alogliptin
/placebo
Sitagliptin
/placebo
Lixisenatide
/placebo
Liraglutide
/placebo
Semaglutide
/placebo
Exenatide
QW/placebo
Empagliflozi
n
/placebo
Canagliflozin
/placebo
Dapagliflozin
/placebo
Inclusion
criteria
Type 2 diabetes
and history of or
multiple risk
factors for CVD
Type 2 diabetes and
ACS within 15–90
days before
randomization
Type 2 diabetes
and preexisting
CVD
Type 2 diabetes
and history of
ACS (<180 days)
Type 2 diabetes
and preexisting
CVD, kidney
disease, or HF at
≥50 years of age
or
cardiovascular
risk at ≥60 years
of age
Type 2 diabetes and
preexisting CVD, HF,
or CKD at ≥50 years
of age or
cardiovascular risk
at ≥60 years of age
Type 2 diabetes
with or without
preexisting CVD
Type 2
diabetes and
preexisting
CVD
Type 2 diabetes and
preexisting CVD at ≥30
years of age or >2
cardiovascular risk factors
at ≥50 years of age
Type 2
diabetes and
established
ASCVD or
multiple risk
factors
MACE-3
1.00
(0.89–1.12)
0.96
(95% UL ≤1.16)
0.98
(0.89–1.08)
1.02
(0.89–1.17)
0.87
(0.78–0.97)
0.74
(0.58–0.95)
0.91
(0.83–1.00)
0.86
(0.74–0.99)
0.86
(0.75–0.97)
0.93
(0.84-1.03)
ACM
1.11
(0.96–1.27)
0.88
(0.71–1.09)
1.01
(0.90–1.14)
0.94
(0.78–1.13)
0.85
(0.74–0.97)
1.05
(0.74–1.50)
0.86
(0.77–0.97)
0.68
(0.57-0.82)
0.87 (0.74–1.01)
0.90 (0.76–1.07)
0.93
(0.82-1.04)
Diabetes Care 2019;42(Suppl. 1): S103–S123
ADA Summary of CVOT Data

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

51. Current (2019) indications for SGLT2i
Canagliflozin
◦ as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
◦ to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial
infarction and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular
disease (CVD)
Dapagliflozin
◦ as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
Empagliflozin
◦ as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
◦ to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and
established cardiovascular disease.
Ertugliflozin
◦ as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

52. Renal function has a substantial
effect on dosing of SGLT2i
eGFR range Canagliflozin Dapagliflozin Empagliflozin Ertugliflozin
>60 ml/min/1.73m2 100-300 mg/d 5-10 mg/d 10-25 mg/d 5-15 mg/d
45-60
ml/min/1.73m2
Not to exceed
100 mg/d
Do not initiate 10-25 mg/d Not recommended
<45 ml/min/1.73m2 Do not initiate Do not initiate Do not initiate Not recommended
<30 ml/min/1.73m2 Contraindicated Contraindicated Do not initiate Contraindicated
Adjustments
during therapy
Not recommended
when eGFR
declines persistently
below 45
ml/min/1.73m2
Not recommended
when eGFR
declines persistently
between 30-60
ml/min/1.73m2
Discontinue if
eGFR persistently
falls below 45
ml/min/1.73m2
Not recommended
when eGFR
declines persistently
between 30-60
ml/min/1.73m2

53. Warnings & Precautions in the PI of marketed
SGLT2i (current label)
Empagliflozin
Canagliflozin
Dapagliflozin Ertugliflozin

54. Acute Kidney Injury And Changes In Renal
Function: Network meta-analysis
DOI: 10.1111/dom.12917
SUCRA (Surface Under the Cumulative Ranking): parameter used to rank treatments
based on their probability of ranking 1st, 2nd, etc.
Empa < Luseo < NonSGLT2 antiDM < Cana < Dapa

55. UTIs and genital infections
DOI 10.1111/dom.12825
Category
Effect
Dose effect
UTI
Genital Infections
Genital infections: higher with empa, dapa, cana. UTI: only with dapa
Genital Infections
UTI
Higher risk of Dapa over other SGLT2i also shown in more recent meta-analysis
BMJ Open 2019;9:e022577. doi:10.1136/bmjopen-2018-022577

56. What about ketoacidosis?
Meta-analysis of RCTs
Market Claims Data – Propensity Matching
DOI: 10.1016/j.diabres.2017.04.017
DOI: 10.1056/NEJMc1701990
HR ~ 2x
HR ~ 1x

57. Back to the basics: sensing food and
gearing up for a calorie load
ENTERO-ENDOCRINE SYSTEM GUT – NONGUT ORGAN AXES
doi:10.1038/nrneph.2017.123

58. 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

59. Renal outcomes of DM2 therapies
(worsening nephropathy: loss of
eGFR/worsening proteinuria/dialysis)
DPP4i GLP1-RA SGLT2i
Saxagliptin Liraglutide Semaglutide Cana Dapa Empa
1.08
(0.88–1.32
0.78
(0.67–0.92)
0.64
(0.46–0.88)
0.60
(0.47 – 0.77)
0.53
(0.43 – 0.66)
0.61
(0.53 – 0.70)
Diabetes Care 2019;42(Suppl. 1): S103–S123
ARB Hazard Ratio
IDNT composite 0.60 (0.66 – 0.97)
RENAAL
composite
0.84 (0.72 – 0.98)
ARB meta ESRD1 0.78 (0.67 – 0.91)
ARB meta x2SCr1 0.79 (0.68 – 0.91)
1doi: 10.1038/ajh.2008.206

60. Outpatient
Nephrology consults
for DKD in 2019
NO LONGER YOUR FELLOWSHIP’S ACEI/ARB STANDARD
NOTE

61. The role of the nephrologist in the
changing landscape of DKD therapeutics
1. Initiate and sustain evidence- based pharmacological therapy
➢ACEi/ARB / ? Aldo antagonists
2. Treat the complications that endocrinologists/PCPs don’t treat
➢Hyperkalemia (diuretics/patiromer)
➢Volume overload
➢CKD complications
3. Consult referring physicians about renal safety/efficacy/dosing
of anti-glycemic therapies
➢Metformin/SGLT2i/GLP-1RA/DPP-4i

62. What about Blood Pressure?
Diabetes Care 2019;42(Suppl. 1): S103–S123

63. 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

64. Should SGLT2i be put into the water ?
NOT YET
Patients in the existing SGLT2i
trials had very high
cardiovascular risk
Proportion of real world patients
with the same cardiovascular risk
profile as in EMPA-REG:
◦ ~15.7% in the UK
◦ 11.1% among new SGLT2i users
SWEETEN MY PEE PLEASE
Outcome NNT
Nephropathy/CV
Death
14
Nephropathy 16
Albuminuria
progression
20
X2 SCr/eGFR<45 91
X2
SCr+eGFR<45/R
RT/Renal Death
71
RRT 333
DOI 10.1007/s13300-017-0254-7

65. My personal approach to antiglycemic
pharmacotherapy in DKD
➢Old therapies:
◦ I push for metformin AND dose escalate (off label) with PK (level of drug) and PD (lactate)
monitoring
➢New therapies (bias since 2016, now with evidence support)
o Empagliflozin > Canagliflozin ~ Liraglutide > Dapagliflozin
o If insurance will not pay for any of the above, I attempt ertugliflozin (no outcomes data to date,
but half the price)
➢ Monitoring of glycemic control:
o A1c is not a good marker of glycemic control in CKD
o I advocate for CGMs or flash CGM

66. Are the SGLT2i the end of DKD?
Am J Physiol Renal Physiol 304: F156–F167, 2013.

67. TRIDENT
Transformative
Research in
Diabetic
Nephropathy
Vision
• Identify human-derived testable hypotheses for
future intervention trials, with the goal of providing
transformative therapies for the patients suffering
from diabetic nephropathy
Strategy
• Identify pathways associated with rapid (>5cc/year)
and slow (<5cc/year) progression of renal functional
decline in diabetic patients, through integration of their
epigenetic, genetic, genomic, histologic, clinical, and
biomarker profile
Structure
• Precompetitive Pharma-Academia Partnership
• UPenn + 16 active recruiting sites
• 4 pharma partners: Boehringer Ingelheim, Gilead,
GSK, Regeneron

68. TRIDENT: Study Design
Whole exome
sequencing