Speaker

Diabetic Kidney Disease - How Can We Improve Outcomes ?

Vivian A. Fonseca, MD, FRCP

Professor of Medicine, Assistant Dean for Clinical Research
Tullis-Tulane Alumni Chair in Diabetes
Chief, Section of Endocrinology
Tulane University Medical Center, New Orleans, Louisiana
 Disclosures

Research Support (to Tulane): Grants

from Fractyl

Consulting: Asahi, Fractyl, Sanofi

Stock: BRAVO4Health, Insulin

Algorithms
 Goals
• Understand the scale and risks of diabetes and chronic kidney
disease (CKD).
• Recognize the new guideline directed medical therapies (GDMT)
for diabetes and CKD.
• Comprehend the importance of CKD detection in diabetes and
team care as key strategies to implement GDMT.
Diabetic Nephropathy versus Diabetic Kidney Disease
and CKD in Diabetes
• Diabetic nephropathy has been traditionally used to specify
classic glomerular lesions identified on kidney biopsy.
• Diabetic kidney disease (DKD) refers to glomerular and non-
glomerular kidney damage attributable to diabetes.
• CKD in diabetes is a clinical diagnosis of albuminuria, low
estimated glomerular filtration rate (eGFR), or both
irrespective of known cause.
 The Enormity of Diabetes and CKD

Tuttle KR et al. CJASN 2022;17:1092-1103

 Development of CKD in Diabetes
A Serious Matter
• Diabetes prevalence in patients with end stage kidney disease
(ESKD) is 66-86% in the United States (US)
• US prevalence of ESKD >doubled to ~800,000 in 2000-2019,
primarily driven by diabetes
• Most of diabetes-related excess risk for all-cause and CVD
mortality occurs in people with CKD

Burrows NR et al. MMWR Morb Mortal Wkly Rep

2022;71:412-415
Alicic RZ, Tuttle KR et al. CJASN 2017;12:2032-2045
Afkarian M et al. JASN 2013;24:302-308
CKD Incidence in Diabetes at Providence and UCLA Health
CURE-CKD 2015-2020 (N=654,459)

Tuttle KR et al. N Engl J Med 2022;387:1430-1431

 Holistic Approach for Patients with
Diabetes and CKD

8 de Boer IH et al. Diabetes Care 2022; Kidney Int 2022 online ahead of print
 Angiotensin Receptor Blockade
in Type 2 Diabetes and CKD
Doubling of serum creatinine, ESKD, or death
RENAAL IDNT

Risk reduction, 20%

P = 0.02

Absolute residual risk

Absolute residual risk with irbesartan: ~40%
with losartan: ~40%

Brenner B, et al. N Engl J Med. 2001;345(12):861-869.

Brenner B, et al. N Engl J Med 2001;345:861–869 Lewis EJ, et al. N Eng J Med. 2001;345:851-860
 Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors
Cardiovascular Trials in Type 2 Diabetes
• Reduce risk of major adverse CVD Events.
• Heart failure (empagliflozin, canagliflozin, dapagliflozin)
• Atherosclerotic CVD (3-point MACE: myocardial infarction, stroke, CVD death)
• CVD death (empagliflozin, dapagliflozin)
• Decrease macroalbuminuria, eGFR decline, and kidney failure.
• CVD and CKD benefits are present in patients with CKD.
 Benefits of SGLT2 inhibitors on Kidney and Heart
Failure Outcomes in People with and without Diabetes

Kang A, Jardine MJ. Nat Rev Nephrol 2021;17:83-84

 SGLT2 Inhibition Across Ranges of
eGFR and Albuminuria in Type 2 Diabetes
Proportion of patients with eGFR <60 mL/min/1.73 m2 Proportion of patients with normoalbuminuria
and ≥60 mL/min/1.73 m2 1–7 and micro-/macroalbuminuria1–7
100 100

80 80
Patients (%)

Patients (%)
60 60
eGFR ≥60 Normo
40 40

20 20

00 00

20 20
Patients (%)

Patients (%)
40 40
Micro/
eGFR <60
60 macro 60

80 80

100 100
EMPA-REG CANVAS DECLARE- CREDENCE EMPA-REG CANVAS DECLARE- CREDENCE
OUTCOME program TIMI 58 OUTCOME program TIMI 58
Zinman B et al. N Engl J Med 2015;373:2217–2128; Kluger AY et al. Rev Cardiovasc Med 2018;19:41–49; Wanner C et al. J Am Soc Nephrol 2018;29:2755–2769;
Wanner C et al. N Engl J Med 2016;375:323–334; Neuen BL et al. Circulation 2018;138:1537–1550; Raz I et al. Diabetes Obes Metab 2018;20:1102–1110;
Wiviott SD et al. N Engl J Med 2019;380:347–357
 DAPA-CKD
DKD and Non-Diabetic CKD
• Participants with eGFR 25-75
mL/min/1.73m2 and UACR 200-
5000 mg/g (n=4304).
• Dapagliflozin 10 mg daily versus
placebo.
• Primary endpoint (eGFR decline
>50%, ESKD, kidney or CVD
death) reduced by 39%.
• Outcomes were similar in
participants with or without
type 2 diabetes.

Heerspink HJL et al. for the DAPA-CKD Trial Committees and Investigators. N Eng J Med 2020;383:1436-1446
 DAPA-CKD
Dapagliflozin and Outcomes by CKD Diagnosis
Fast track, Breakthrough, Priority approval granted by FDA – A first in the field of Nephrology
April 30, 2021

Wheeler DC et al. Lancet Diabetes Endocrinol 2021;9:22-31

 EMPA-REG and CREDENCE
eGFR over Time in Type 2 Diabetes

Wanner C et al. N Engl J Med 2016;375:323-334 Perkovic V et al. N Eng J Med 2019;380:2295-2306
The Kidney–Heart Connection for Organ
Protection by SGLT2 Inhibitors

Alicic RZ, Johnson EJ, Tuttle KR. Am J Kidney Dis 2018;72:267-277

Tuttle KR et al. Am J Kidney Dis. 2021;77:94-109
Braunwald E. N Engl J Med 2022;386:2024-2034
 Glucagon Like Peptide-1 (GLP-1) Receptor Agonists
Cardiovascular Outcomes Trials in Type 2 Diabetes
• Reduce risk of major adverse CVD events.
• Atherosclerotic CVD (3-point MACE: myocardial infarction, stroke, CVD death)
• CVD death (liraglutide, semaglutide)
• Decrease macroalbuminuria and eGFR decline from early- to
late-stage CKD (liraglutide, dulaglutide, semaglutide)
• CVD and CKD benefits are present in patients with CKD.
 AWARD-7: Dulaglutide versus Insulin Glargine in
Type 2 Diabetes and Moderate-to-Severe CKD

Tuttle KR et al. Lancet Diabetes Endocrinol 2018;6:605-617

 eGFR Slope with Semaglutide versus Placebo
in SUSTAIN-6 and PIONEER-6

eGFR estimated treatment difference (ETD) >0.75 mL/min/1.73m2 per year

Tuttle KR et al. Kidney Int 2022 (In revision) predicts significantly lower risk of kidney failure by treatment versus placebo
Inker LA et al. J Am Soc Nephrol 2019;30:1735-1745
 AWARD 7: ≥40% eGFR Decline or ESKD with
Dulaglutide versus Insulin Glargine
Overall Macroalbuminuria
12
1 0 .8 %
e x p e r ie n c in g c o m p o s ite o u tc o m e

n /N = 21/194
10
P r o p o rtio n o f p a tie n ts (% )

8 .4 %
p = .0 4 6
8 n /N = 16/190
v s . g la r g in e

6 5 .2 %
n /N = 10/192

0
In s u l i n D u la g lu tid e D u la g lu tid e
g la rg in e 0 .7 5 m g 1 .5 m g

Dulaglutide 1.5 mg versus insulin glargine HR (95% CI): 0.25 (0.10-0.68); p=0.006
Tuttle KR et al. Kidney 360 2021;2:254-262 Dulaglutide 0.75 mg versus insulin glargine HR (95% CI): 0.72 (0.36-1.43); p=0.34
 AWARD-7: Comparable HbA1c Reduction,
Larger Weight Loss, Less Hypoglycemia
Dulaglutide 1.5 mg Dulaglutide 0.75 mg Insulin Glargine
Baseline mean HbA1c= 8.58%
Baseline mean weight = 88.9 kg
Symptomatic
HbA1c Body Weight Hypoglycemia
0 0 2 (≤70 mg/dL)
70

Incidence of Hypoglycemia, %
* 63.4%
-0.2 1 60
-5 #

HbA1c, mmol/mol
-0.4 50 48.1%
0 ##
HbA1c, %

Weight, kg
-0.6 40
40.5%
-10 -1
-0.8 30
-1 -2
-15 20
-1.2 **
-3 10
-3.13 (-3.92, -2.34)##a
-1.4
** ** -20 **
** 0.02 (-0.18, 0.22)‡a -4 -3.92 (-4.73, -3.11)##a
0 n=77 n=91 n=123
Rate (events/patient/year), mean ± SD:
4.4 ± 12.2 4.3 ± 9.3 9.6 ± 17.7
-0.05 (-0.26, 0.15)‡, ‡‡a

Tuttle KR et al. Lancet Diabetes Endocrinol 2018;6:605-617

 GLP-1 Receptor Agonists
in Discovery and Pre-Clinical Science

Kidney GLP-1 receptors

• Intrinsic cells
• Endothelial
• Proximal tubular cells?
• Infiltrating cells
Tanaka T et al. Kidney Int 2014; 86:701–711 • Macrophages
Alicic RZ, Cox EJ, Neumiller JJ, Tuttle KR. Nature Reviews Nephrology 2021;17:227-244 • T lymphocytes
 FLOW: Study Design
Kidney Disease Outcomes Trial in Type 2 Diabetes

ClinicalTrials.gov Identifier: NCT03819153

 Next-Generation Dual Incretin Agonist: Glucose-
Dependent Insulinotropic Polypeptide (GIP) and GLP-1
GLP-1
• GLP-1 has direct actions in
CNS, pancreas, and
stomach • ↓ Food intake
• ↑ Insulin secretion • Delayed gastric
• ↓ Glucagon secretion emptying
• GIP has potential actions in
CNS, adipose, and pancreas
• A GIP/GLP-1 receptor dual
agonist may augment
glycemic and weight • ↑ Insulin
• ↓ Appetite sensitivity
management and possibly • ↓ Food intake
• ↑ Insulin secretion
• ↑ Glucagon secretion
organ protective effects • ↑ Energy expenditure

GIP
Müller TD et al. Mol Metab 2019;30:72-130. Seino Y et al. J Diabetes Investig 2010;10:1-20. Fukuda M et al. Diabetes 2021;70:8-23. Nauck MA et al. Diabetes Obes
Metab 2021 (online ahead of print). Samms RJ et al. Trends Endocrinol Metab 2020;31:410-421. Bastin M et al. Diabetes Metab Syndr Obes 2019;12:1973-1985.24
CNS = central nervous system
 ADA 2022: Tirzepatide Reduces Risk of
the Composite Kidney Disease Endpoint
Incidence of Composite Kidney Disease Endpoint Consistent effects in SGLT2 inhibitor
and ACE inhibitor/ARB subgroups

Component Treatment N HR
(%) (95%CI)
38
eGFR decline TZP (3.8%) 0.87
≥40% from 45 (0.56,1.33)
baseline iGLAR (4.5%)
TZP 0
Renal death -
iGLAR 0

TZP 0
Progression to
5 -
ESKD
iGLAR (0.5%)
25
New onset TZP (2.5%) 0.41
macroalbuminuria 61 (0.26,0.66)
a
iGLAR (6.1%) *

Heerspink HJL et al. Lancet Diab Endocrinol 2022 online ahead of print
 ADA 2022: eGFR and UACR
During Treatment and Safety Follow-up

Heerspink HJL et.al. Lancet Diab Endocrinol 2022 online ahead of print
 New Drugs for Diabetic Kidney Disease:
“Convergence”

Jackson Pollock Circa 1952

Mineralocorticoid
Receptors in the
Diabetic Kidney
• Homeostatic regulation of
electrolyte transport occurs
in the cortical collecting
duct
• Mineralocorticoid receptors
upregulate inflammatory
and fibrotic pathways in
non-epithelial cells

Rationale for Non-Steroidal Mineralocorticoid Antagonist (MRA)

Ghuman J, Tuttle K. Kidney 360 2022;3:744-748
 FIDELIO-FIGARO-FIDELITY
Finerenone in CKD and Type 2 Diabetes
Finerenone 10/20 mg daily versus placebo
Standard-of-care with ACE inhibitor or ARB use

FIDELIO FIGARO
eGFR decline 40%, kidney failure, kidney disease death MI, stroke, heart failure hospitalization, CVD death
FIDELITY Meta-Analysis
• 13,026 patients followed for median of 3.0 years
Bakris GL et al. N Engl J Med 2020;383:2219-2229
Pitt B et al. N Engl J Med 2021;385:2252-2263
• CVD outcome HR 0.86; 95% CI 0.78–0.95
Filippato G et al. European Heart J, 2022;43:474-484 • Kidney disease outcome HR 0.77; 95% CI 0.67–0.88
• Similar risk reductions in SGLT2 inhibitor users (5-10%)
 A Menu of Therapies for
Personalized Heart-Kidney Protection
• 75-year-old woman with hypertension and type 2 diabetes
• Originally from rural Alabama, moved to the Northwest 40 years ago
with the US Airforce
• Hospitalized 3 times in 4 months for congestive heart failure
Medications: furosemide, metoprolol, ACE inhibitor, metformin
• Presents to primary care physician with worsening dyspnea
• BP 124/68 mm Hg, bilateral rales, 1+ edema to mid-calf
• Labs: Serum K 5.2 mEq/L, serum creatinine 1.5 mg/dL/eGFR 34
mL/min/1.73m2 (CKD-EPI 2021), UACR 800 mg/g, HbAc1 6.8%
• LVEF 36% by echocardiogram, heart failure with reduced ejection
fraction (HFrEF)

Microsoft Office stock image

Type 2 Diabetes with CKD and HFrEF

Type 2 Diabetes with CKD and HFrEF

What pillars of therapy can be initiated to optimize care of

this patient?

a) SGLT2 inhibitor with proven benefit (dapagliflozin,

canagliflozin, empagliflozin)
b) Sacubitril/valsartan in place of ACE inhibitor
c) Thiazide for diuretic synergy
d) a and b
Type 2 Diabetes with CKD and HFrEF

What pillars of therapy can be initiated to optimize care of

this patient?

a) SGLT2 inhibitor with proven benefit (dapagliflozin,

canagliflozin, empagliflozin)
b) Sacubitril/valsartan in place of ACE inhibitor
c) Thiazide for diuretic synergy
d) a and b
 Reduced Risks of Edema and Hyperkalemia with
Empagliflozin in Type 2 Diabetes and CKD

Tuttle KR et al. Diabetes Care 2022;45:1445-1452

Type 2 Diabetes with CKD and HFrEF
An MRA was initially avoided due to hyperkalemia. At a clinic
visit 4 weeks later, her dyspnea was better, but she still had
trace pedal edema. Serum K 4.6 mEq/L, serum creatinine 1.7
mg/dL/eGFR 31 mL/min/1.73m2 (CKD-EPI 2021), UACR 420
mg/g. What is the preferred next step?

a) Add thiazide diuretic

b) Increase furosemide
c) Start finerenone
d) a and b
Type 2 Diabetes with CKD and HFrEF
An MRA was avoided due to hyperkalemia. At a clinic visit 4
weeks later, her dyspnea was better, but she still had trace
pedal edema. Serum K 4.6 mEq/L, serum creatinine 1.7
mg/dL/eGFR 31 mL/min/1.73m2 (CKD-EPI 2021), UACR 420
mg/g. What is the preferred next step?

a) Add thiazide diuretic

b) Increase furosemide
c) Start finerenone
d) a and b
 Finerenone and Reduced Rates of Hyperkalemia
with SGLT 2 Inhibitor Use in FIDELIO-DKD

Rossing P et al. Kidney Int Rep 2022;7:36-45

Risks of CKD Progression and CVD Events,
Monitoring Frequency, and Actions

37

de Boer IH et al. Diabetes Care 2022; In press

 Albuminuria/Proteinuria Monitoring in CKD
CURE-CKD (N=606,064)
All CKD CKD/DM/PDM/HTN CKD/HTN CKD/DM/PDM CKD Alone

Tuttle KR et al. JAMA Netw Open 2019;2:e1918169

Albuminuria/Proteinuria Monitoring in Medicare
Beneficiaries >66 Years Old
 Medication Use in CKD Stages 3-5 ND
CURE-CKD (N=606,064)
Providence and UCLA Health

Diabetes with
CKD and
hypertension:
ACE Inhibitor or
ARB use 25%

Tuttle KR et al. JAMA Netw Open 2019;2:e1918169

 GDMT in Diabetes and CKD
CURE-CKD 2019-2020 (N=39,158)
SGLT2 Inhibitor Use ACE Inhibitor/ARB Use
• Baseline 70.7%
• Baseline 5.7%
• 90 days persistence 40.5%
• 90 days persistence 4.7%

Providence and UCLA Health

Nicholas SB et al ASN Kidney Week 2022
 Glucose Lowering Agents in Diabetes and CKD
Commercially Insured Population

Harris ST et al. Diabetes Care 2021;44:2293-2301

 Multidisciplinary Team Care for
Diabetes and CKD
Team Players
• Physicians
• Nurses
• Pharmacists
• Educators
• Advanced Practitioners
• Dietitians
• Physical therapists
• Exercise specialists
• Dentists
• Podiatrists
• Optometrists
• Mental health professionals

43 de Boer IH et al. Diabetes Care 2022; In press

 Take Home Points
• SGLT2 inhibitors, GLP-1 receptor agonists, and a non-steroidal
MRA, along with an ACE inhibitor or an ARB, are now codified as
GDMT for diabetes and CKD.
• Lack of CKD detection is an important barrier to implementation of
GDMT in persons with diabetes.
• Multidisciplinary team care and education can improve GDMT
implementation for CKD in persons with diabetes.
Back-up slides