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The Diabetic Kidney
Paul P. Doghramji, MD, FAAFP
Family Practice Physician
Collegeville Family Practice & Pottstown Medical Specialists, Inc.
Medical Director of Health Services, Ursinus College – Collegeville, PA
Attending Family Practice Physician, Pottstown Memorial Medical Center – Pottstown, PA
Learning Objectives
▪ Appropriately screen for the presence of chronic kidney
disease in patients with T2DM
▪ Identify chronic kidney disease at an early stage in
patients with T2DM
▪ Individualize evidence-based therapy to slow the
progression of kidney disease in patients with T2DM
and chronic kidney disease
Chronic Kidney Disease Is Common
▪ US: ~12% of the population has diabetes
▪ Up to 25% of these individuals may be undiagnosed
▪ 20% of adults have hypertension
▪ Diabetic kidney disease (DKD) affects about 20% of patients
with diabetes1
▪ 45% of new cases of ESRD are due to diabetes2
▪ 48% of those with severely reduced kidney function but not on
dialysis are not aware of having CKD1
1. US Centers for Disease Control and Prevention. https://www.cdc.gov/diabetes/pubs/pdf/kidney_factsheet.pdf. Accessed February 4, 2020.
2. United States Renal Data System. https://www.usrds.org/2017/download/2017_Volume_2_ESRD_in_the_US.pdf. Accessed February 4, 2020.
CKD = chronic kidney disease; ESRD = end-stage renal disease
End-Stage Renal Disease, United States
87
147
238
312
370379
369358
350341
0
50
100
150
200
250
300
350
400
19
80
19
85
19
90
19
95
20
00
20
05
20
10
20
15
20
16
20
17
Incid
ence p
er
mill
ion/y
ear, s
tandard
ized
Year
Incidence Rate of ESRD
United States Renal Data System. https://usrds.org/2019/download/USRDS_2019_ES_final.pdf. Accessed February 4, 2020.
End-Stage Renal Disease, United States, 2017 (cont)
124,500
108,131
12,572
3,666
0
25,000
50,000
75,000
100,000
125,000
Total ESRD Hemodialysis Peritoneal Dialysis Transplant
Nu
mb
er
of n
ew
ca
se
s
Incidence, 2017
United States Renal Data System. https://usrds.org/2019/download/USRDS_2019_ES_final.pdf. Accessed February 4, 2020.
Pathophysiology of DKD1
▪ Multiple mechanisms involving microvascular and macrovascular changes
▪ These changes lead to albuminuria, decreased glomerular filtration, or both
▪ Incidence is approximately 2% of patients with diabetes per year classically progresses from microalbuminuria (30 to 300 mg per day) to macroalbuminuria (more than 300 mg per day)
▪ Affects 25% of patients within 10 years of a type 2 diabetes diagnosis
▪ These changes may correlate chronologically with the development of diabetic retinopathy
▪ Rates of cardiovascular morbidity and mortality rise dramatically with the progression of renal disease
▪ For patients who develop macroalbuminuria, in any given year the risk of mortality (4.6%) is higher than the risk of progression to ESRD (2.3%)
1Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR; UKPDS Group. Development and progression of nephropathy in type 2 diabetes: the United
Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 2003;63(1):225–232.
Factors Affecting the Rate of Diabetic Kidney Disease Onset and Progression
Nonmodifiable
▪ Age at diagnosis
▪ Family history
▪ Level of formal education
▪ Male sex
▪ Type 1 vs. type 2 diabetes mellitus
Potentially modifiable
▪ Alcohol use
▪ Hyperglycemia
▪ Hyperlipidemia
▪ Hypertension
▪ Obesity
▪ Physical activity
▪ Social network at baseline
Macisaac RJ, Ekinci EI, Jerums G. Markers of and risk factors for the development and progression of diabetic kidney disease. Am J Kidney Dis.
2014;63(2 suppl 2):S39–S62.
Prognosis of CKD by Stage
Urine Albumin-to-Creatinine Ratio (UACR)
A1 A2 A3
NL-Mildly Moderately Severely
<30 mg/g 30-300 mg/g >300 mg/g
eGFR
(m
L/m
in/1
.73
m2)
G1 Normal/High ≥90 Low risk Moderate risk High risk
G2 Mildly 60-89 Low risk Moderate risk High risk
G3a Mildly-Moderately 45-59 Moderate risk High risk Very high risk
G3b Moderately-Severely 30-44 High risk Very high risk Very high risk
G4 Severely 15-29 Very high risk Very high risk Very high risk
G5 Kidney failure <15 Very high risk Very high risk Very high risk
Reprinted from Kidney International Supplements, volume 3/issue 1, KDIGO, KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of
Chronic Kidney Disease, chapter 1: Definition and classification of CKD, pages 19-62, Copyright 2012, with permission from KDIGO. KDIGO. Kidney Int Suppl
(2011). 2013;3(1):19-62.
eGFR = estimated glomerular filtration rate
Prognosis
▪ Patients are more likely to develop ESRD if they have
persistent and severely increased levels of albuminuria
(300 mg per g or higher)
American Diabetes Association. Microvascular complications and foot care: standards of medical care in diabetes—2019. Diabetes Care.
2019;42(suppl 1):S124–S138.
Prevalence is Increasing in Adults with Diabetes and Low eGFR in the Absence of Albuminuria
0
0.5
1
1.5
2
2.5
3
UACR <30 mg/g UACR 30-299 mg/g UACR ≥300 mg/g
Po
pu
latio
n e
stim
ate
(m
illio
ns)
Persons with Diabetes and eGFR <60 mL/min/1.73 m2
1988-1994 1999-2002 2003-2006 2007-2010
Kramer H, et al. Diabetes Care. 2018;41:775-781. UACR = urine albumin-to-creatinine ratio
Mortality is Increasing in Adults with Diabetes and Low eGFR in the Absence of Albuminuria
35
51
0
10
20
30
40
50
60
Mort
alit
y r
ate
per
1,0
00 p
ers
on
-years
Mortality Rate in Persons with Diabetes with eGFR <60 mL/min/1.73 m2 and UACR <30 mg/g
1988-1994 2003-2006
Kramer H, et al. Diabetes Care. 2018;41:775-781.
From 1988-1994 to 2003-2006, the mortality rate in adults with diabetes
and low eGFR in the absence of albuminuria has increased.
Risk Factors for CKD
▪ Diabetes mellitus (uncontrolled)
▪ Hypertension (uncontrolled)
▪ Obesity
▪ Heart failure
▪ Age > 60 years
▪ Tobacco use
▪ Family history
▪ Ethnicity
▪ Prior history of acute kidney injury
Gatwood J, et al. PLoS One. 2018;13(2):e0192712.
All-Cause Mortality Based on eGFR and UACR
0
1
2
3
4
5
6
7
8
9
15-30 30-45 45-60 60-75 75-90 90-105 >105
Rela
tive r
isk
eGFR (mL/min/1.73 m2)
<10 10-29 30-299 300+
UACR (mg/g)
KDIGO. Kidney Int Suppl (2011). 2013;3(1):19-62. UACR = urine albumin-to-creatinine ratio
Cardiovascular Mortality Based on eGFR and UACR
0
1
2
3
4
5
6
7
8
9
15-30 30-45 45-60 60-75 75-90 90-105 >105
Rela
tive r
isk
eGFR (mL/min/1.73 m2)
<10 10-29 30-299 300+
UACR (mg/g)
KDIGO. Kidney Int Suppl (2011). 2013;3(1):19-62.
Cognitive Impairment in CKD
Chronic Kidney Disease
Reduced
● Processing
● Attention
● Response speed
● Short-term memory
Early stage
Deficits in
● Executive functioning
● Verbal fluency
● Logical memory
● Orientation
● Concentration
Moderate stage
Early stage +
Moderate stage +
Deficits in
● Cognitive control
● Delayed/Immediate memory
● Visuospatial impairment
● Overall cognition
End stage
Brodski J, et al. J Int Neuropsychol Soc. 2019;25(1):101-114.
Case Study - Carlos
▪ Carlos is a 63-yo male diagnosed
with T2DM x 7y
▪ A1c had ranged from 6.8% to
7.4% since diagnosis
▪ Now 7.8%
▪ PMH: angina pectoris x 2y; stable
▪ Vital signs WNL
▪ eGFR 64 mL/min/1.73 m2
▪ UACR 90 mg/g
▪ Current meds:
▪ Metformin 1 g BID
▪ Pioglitazone 45 mg qAM
▪ Atorvastatin 40 mg qPM
▪ Ramipril 10 mg qPM
▪ Aspirin 81 mg qPM
▪ NTG 0.3 mg SL prn
What change would you make to his antidiabetic therapy?
Intensive Therapy Results in Reduced Nephropathy
0
5
10
15
20
25
30
35
40
At 4 Years At 8 Years Post-Trial At 13 Years At 13 Years
Num
ber
of P
atie
nts
Intensive Therapy
Conventional Therapy
Diabetic Nephropathy ESRD
Requiring
Dialysis
HR 0.44
95% CI: 0.25-0.77
P=0.004
P=0.04
▪ Patients with T2DM and
persistent microalbuminuria
▪ 160 randomized
▪ 130 continued follow-up
▪ Intensive* or conventional
therapy for 7.8 y
▪ Follow-up for 5.5 y
Gaede P, et al. N Engl J Med. 2008;358:580-591.
*To achieve A1c <6.5%, total cholesterol <175 mg/dL,
triglyceride <150 mg/dL, BP <130/80 mmHg; included
renin-angiotensin-aldosterone inhibitor, low-dose aspirin
Effect of Intensive Glucose Lowering vs Standard Therapy on Renal Outcomes
Risk Ratio(intensive vs
standard therapy)
95% CI P
Microalbuminuria 0.86 0.76-0.96 0.009
Macroalbuminuria 0.74 0.65-0.85 0.001
Doubling of the SCr 1.06 0.92-1.22 0.44
ESRD 0.69 0.46-1.05 0.09
Death from renal disease 0.99 0.55-1.79 0.98
Systematic review of 7 trials involving 28,065 adults; 2-15 years of follow up
Target A1C (or FPG) in the intensive group in each trial: A1c <7; 7.1; <6; ≤6.5; <6 and 1.5% less than standard; FPG <6 mg/dL; FPG <6 mg/dL
Target A1C (or FPG) in the standard group in each trial: A1c 7-7.9; <9 and 1.5% higher than intensive; FPG 6.1-15 mg/dL; 6.1-15 mg/dL; not
reported; local standards; avoidance of excessive hyperglycemia
Coca SG, et al. Arch Intern Med. 2012;172(10):761-769.
Screening for DKD1
▪ Can be completed in three ways
1. 24-hour collection with creatinine, allowing for simultaneous measurement of creatinine clearance
2. Timed (four-hour or overnight) collection
3. Random spot collection measurement of the albumin/creatinine ratio (preferred)
▪ UAC ratio can be elevated independent of kidney damage, so consideration should be given to the possibility of other causes
▪ Congestive heart failure
▪ Exercise within 24 hours of testing
▪ Fever
▪ Infection
▪ Marked hyperglycemia
▪ Menstruation
▪ Because of variability in UAC, 2 of 3 specimens collected over a 3-6 month period must be abnormal (30-300 mg albumin/g creatinine) before diagnosis of microalbuminuria can be made
1American Diabetes Association. Microvascular complications and foot care: standards of medical care in diabetes—2019. Diabetes Care.
2019;42(suppl 1):S124–S138.
Screening for CKD in Diabetes
Adults Children/Adolescents
Who? T1DM: Duration ≥5 years
T2DM: All
Comorbid hypertension: All with T1DM or T2DM
At puberty or age >10 years,
whichever is earlier, once the child
has had diabetes ≥5 years
How? Urinary albumin (eg, spot UACR)
and
eGFR
Urinary albumin (morning preferred)
with spot UACR
When? At least once a year At least once a year
American Diabetes Association. Diabetes Care. 2019;42(Suppl 1):S124-S138.
American Diabetes Association. Diabetes Care. 2019;42(Suppl 1):S148-S164.
This is correct regarding screening for kidney
dysfunction in patients with type 2 diabetes:
Measure estimated glomerular filtration rate and urine albumin-to-creatinine
ratio at least annually.
Diabetic CKD vs non-Diabetic CKD
Non-DKD DKD
Onset of proteinuria Rapid Gradual
Progression of CKD Rapid Gradual
Duration of diabetes <5 years >10 years
UrinalysisActive sediment
(hematuria, pyuria, casts)
Bland sediment
(crystals, protein, hyaline casts)
Retinopathy Absent Usually present
Republished with permission of American Society of Nephrology from Diagnosis and Management of Type 2 Diabetic Kidney Disease, Doshi SM, Friedman
AN, volume 12, © 2017; permission conveyed through Copyright Clearance Center, Inc.
Doshi SM, et al. Clin J Am Soc Nephrol. 2017;12:1366-1373.
Characteristics of CKD* in Adults with T2DM
45%
19%
28%30%
0%
20%
40%
60%
80%
100%
Microalbuminuria Macroalbuminuria Retinopathy No retinopathy ormicro/macroalbuminuria
Perc
ent of P
atie
nts
with C
KD
*eGFR <60 mL/min/1.73 m2
13% (171/1197) of patients with T2DM had CKDKramer HJ, et al. JAMA. 2003;289:3273-3277.
n=171
Management Goals for DKD
▪ Identify patients at risk for CKD/DKD
▪ Intervene early
▪ Prevent further deterioration in kidney function
Treatment Principles for DKD
▪ Control blood glucose, blood pressure, blood lipids
▪ Tobacco cessation
▪ Manage diet/lifestyle - reduce salt intake
▪ Consider RAAS inhibitor (ACE-I or ARB)
▪ Consider referral, especially for dialysis/transplantation
▪ Monitor potentially nephrotoxic medications
▪ Monitor medications cleared by the kidney
▪ Implement shared decision-making
▪ Provide patient education
American Diabetes Association. Diabetes Care. 2019;42(Suppl 1):S124-S138.
DKD Management
Therapeutic Option Recommendation
Glycemic control A1c ≤7% reduces risk or slow the progression of CKD
Consider SGLT-2i or GLP-1RA shown to reduce CKD progression, CV events, or both
BP control 10-y ASCVD risk <15%: <140/90 mmHg
10-y ASCVD risk >15%: <130/80 mmHg
RAAS blockade ACE-I or ARB (nonpregnant with diabetes + HTN)
- recommended if UACR 30-299 mg/24 h
- strongly recommended if UACR ≥300 mg/24 h and/or eGFR <60 mL/min/1.73 m2
- not recommended for 1° prevention if normal BP, UACR, eGFR
Weight loss Demonstrated benefit
Close monitoring for disease progression and treatment-related complications is advised
American Diabetes Association. Diabetes Care. 2019;42(Suppl 1):S124-S138.
Doshi SM, et al. Clin J Am Soc Nephrol. 2017;12:1366-1373.
Glycemic Control
American Diabetes Association Recommended
A1C Targets
< 6.5% Adults tolerating therapy without hypoglycemia or other
complication (long life expectancy)
< 7% Optimal goal for many adults
< 8% Advanced renal disease; Elderly or frail; Extended duration of
disease; High risk of hypoglycemia; Limited life expectancy;
Significant medical comorbidities
Qaseem A, Wilt TJ, Kansagara D, Horwitch C, Barry MJ, Forciea MA; Clinical Guidelines Committee of the American College of Physicians. Hemoglobin A1c
targets for glycemic control with pharmacologic therapy for nonpregnant adults with type 2 diabetes mellitus: a guidance statement update from the American
College of Physicians. Ann Intern Med. 2018;168(8):569–576.
Glycemic Control (cont’d)
▪ 2018 guideline from the American College of Physicians suggests that a target of 7% to 8% may be more appropriate
▪ A lower A1C target (e.g., less than 6% vs. 7% to 8%) has been associated with a reduction in DKD but at the cost of more hypoglycemic events, polypharmacy, and increased mortality
▪ NB: A1C measurements in CKD stage 4 or 5 may be falsely low
▪ Due to shortened red-cell survival time and associated chronic anemia
▪ Routine glucose monitoring may be more accurate for testing and treatment planning
Recommended BP Goals in Various Guidelines
PATIENTS JNC-8 ACC/AHA ADA
Target BP for patients with
diabetes mellitus< 140/90 mm Hg < 130/80 mm Hg < 140/90 mm Hg
Target BP for patients with
CKD stage 3 or beyond< 140/90 mm Hg < 130/80 mm Hg Not specified
Special populations
Patients > 65 years with
CKD or diabetes should
still have goal < 140/90
mm Hg
Shared decision-making
for patients > 65 years
with multimorbidity; risks
of intensive control may
outweigh benefits
Patients with multiple risk
factors may benefit from
more intensive control with
goal < 130/80 mm Hg or
even < 120/80 mm Hg
American Diabetes Association. Cardiovascular disease and risk management: standards of medical care in diabetes—2019. Diabetes Care.
2019;42(suppl 1):S103–S123.
James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members
appointed to the Eighth Joint National Committee (JNC 8) [published correction appears in JAMA. 2014;311(17):1809]. JAMA. 2014;311(5):507–520.
More about Blood Pressure
▪ One large trial of patients with diabetes found no significant difference
in adverse cardiovascular outcomes between standard control (BP less
than 140/90 mm Hg) and intensive control (target BP less than 120/80
mm Hg)
▪ Higher rates of adverse outcomes in the intensive therapy arm,
including significant reductions in eGFR and increases in
macroalbuminuria (number needed to harm = 47), suggest that the
risks of aggressive BP control may outweigh any benefits
▪ Dietary sodium restriction (less than 2,300 mg per day)
Cushman WC, Evans GW, Byington RP, et al.; ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus.
N Engl J Med. 2010;362(17):1575–1585.
American Diabetes Association. Cardiovascular disease and risk management: standards of medical care in diabetes—2019. Diabetes Care.
2019;42(suppl 1):S103–S123.
Selected Antihypertensive Agents in DKD
INTERVENTION MECHANISM OF ACTION CLINICAL EVIDENCE PRACTICAL TIPS
ACE inhibitors
Dilate vessels; promote sodium
and water excretion by inhibiting
aldosterone secretion; dilate renal
arterioles
Delay progression from normo-
albuminuria to microalbuminuria
and macroalbuminuria. Decrease
risk of mortality. Decrease
progression of DKD in
normotensive patients with
microalbuminuria
Monitor for hyperkalemia. Unsafe
in pregnancy. No benefit to
combining with ARB; may
increase risk. For patients with
renal impairment (CrCl < 30 mL),
start with lower initial doses; titrate
slowly
Aldosterone antagonists
Bind to receptors in distal tubules,
resulting in increased excretion of
sodium, chloride, and water;
increased retention of potassium
and hydrogen.
Alter testosterone clearance and
estradiol production
Reduce proteinuria and blood
pressure in patients with mild to
moderate CKD already on an ACE
inhibitor or ARB Studies were
small and generally
underpowered to detect patient-
centered outcome; not clear if
they reduced risk of major CVD
event or progression to ESRD
Increase potassium
(hyperkalemia); particularly for
patients with reduced renal
clearance. Can cause
gynecomastia. Dose reduction of
spironolactone may be necessary
in patients with CrCl < 50.
ARBs
Block binding of angiotensin to
receptors; inhibit the
vasoconstrictive and aldosterone-
secreting effects of angiotensin
Decrease albuminuria compared
with placebo
Monitor for hyperkalemia Unsafe
in pregnancy No benefit in
combination with ACE inhibitors
Lv J, Perkovic V, Foote CV, Craig ME, Craig JC, Strippoli GF. Antihypertensive agents for preventing diabetic kidney disease. Cochrane Database Syst Rev.
2012;(12):CD004136.
Calcium channel blockers and thiazide diuretics have
been shown to exhibit cardioprotection, but they do
not appear to have the same degree of benefit on
preventing progression of DKD
Bangalore S, Fakheri R, Toklu B, Messerli FH. Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and
meta-analysis of randomized trials [published correction appears in BMJ. 2016;352:i525]. BMJ. 2016;352:i438
RAAS Blockade
From The New England Journal of Medicine, Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P, The Effect of Irbesartan on the
Development of Diabetic Nephropathy in Patients with Type 2 Diabetes, volume 345, pages 870-878, Copyright © 2001 Massachusetts Medical Society.
Reprinted with permission from Massachusetts Medical Society.
Parving HH, et al. N Engl J Med. 2001;345(12):870-878.
*P=0.08 vs placebo
**P<0.001 vs placebo
*
**
RAAS Blockade (cont)
From The New England Journal of Medicine, Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinin SM, Zhang Z, Shahnifar
S, Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy, volume 345, pages 861-869, Copyright © 2001
Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Brenner BM, et al. N Engl J Med. 2001;345(12):861-869.
Lipid Management
▪ DKD alters lipid metabolism, leading to increased LDL
▪ Statin therapy does not significantly alter the
progression of DKD
▪ Many statins are metabolized by the kidneys
▪ Doses should be reduced if a patient has significantly
decreased eGFR
▪ Atorvastatin (Lipitor) doses do not need to be adjusted
Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic kidney disease: a report from an ADA Consensus Conference. Am J Kidney Dis. 2014;64(4):510–533.
Dietary Modification
▪ Dietary modification has the potential for preventing progression of DKD
▪ However, the evidence for specific interventions is mixed
▪ ADA recommends a protein-restricted diet (0.8 g per kg per day) in patients with DKD
▪ Studies show that this can slow the decline of GFR and progression to ESRD
▪ A Mediterranean diet and the dietary approaches to stop hypertension (DASH) diet can have beneficial outcomes
American Diabetes Association. Lifestyle management: standards of medical care in diabetes—2019. Diabetes Care. 2019;42(suppl 1):S46–S60.
Management Issues Clinicians Should Master
▪ Screen using eGFR and UACR
▪ Utilize glucose-lowering medications shown to reduce cardiovascular risk
▪ Consider SGLT2i > GLP-1RA, DPP-4i depending on CV risk factor
▪ Achieve and maintain good control of blood glucose, blood pressure, blood lipids
▪ Consider renin-angiotensin-aldosterone inhibitor therapy
▪ Facilitate/support tobacco cessation
▪ Early referral to nephrology (at chronic kidney disease stage 3 or 4) may help improve DKD outcomes and should be considered
Considerations for Referral to Nephrology
▪ Acute kidney injury or abrupt sustained fall in eGFR
▪ eGFR <30 mL/min/1.73 m2 (G4-G5)
▪ Consistent UACR ≥300 mg/g or AER ≥300 mg/24h
▪ Progression of CKD
▪ Urinary red cell casts, RBC >20 hpf sustained and not readily explained
▪ CKD and HTN refractory to ≥4 antihypertensive agents
▪ Persistent abnormalities of serum K+
▪ Recurrent or extensive nephrolithiasis
▪ Hereditary kidney disease
▪ Progressive CKD with risk of kidney failure within 1 y ≥10% to 20%
KDIGO. Kidney Int Suppl (2011). 2013;3(1):19-62. AER = albumin excretion rate; hpf = high-power field; HTN = hypertension
Considerations for Referral to Nephrology (cont)
Urine Albumin-to-Creatinine Ratio (UACR)
A1 A2 A3
NL-Mildly Moderately Severely
<30 mg/g 30-300 mg/g >300 mg/g
eG
FR (
mL/
min
/1.7
3 m
2) G1 Normal/High ≥90 Monitor Refer*
G2 Mildly 60-89 Monitor Refer*
G3a Mildly-Moderately 45-59 Monitor Monitor Refer
G3b Moderately-Severely 30-44 Monitor Monitor Refer
G4 Severely 15-29 Refer* Refer* Refer
G5 Kidney failure <15 Refer Refer Refer
*Referring clinicians may wish to discuss with their nephrology service depending on local arrangements regarding monitoring or referring.
Reprinted from Kidney International Supplements, volume 3/issue 1, KDIGO, KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of
Chronic Kidney Disease, chapter 1: Definition and classification of CKD, pages 19-62, Copyright 2012, with permission from KDIGO.
KDIGO. Kidney Int Suppl (2011). 2013;3(1):19-62.
Results of CV Outcomes Trials
CV Safety
▪ Non-inferiority
▪ Not more than 30% increase in CV
risk compared to placebo as part of
standard therapy
CV Benefit
▪ If non-inferiority is demonstrated,
can look for superiority
▪ Superiority - CV risk significantly
reduced compared to placebo as
part of standard therapy
*Will no longer be available as of December 2019.
CV
Safety
CV
Benefit
Renal
Benefit
Dipeptidyl peptidase-4 inhibitors
Alogliptin
Linagliptin
Saxagliptin
Sitagliptin
Glucagon-like peptide-1 receptor agonists
Albiglutide*
Dulaglutide
Exenatide BID NR
Exenatide QW
Liraglutide
Lixisenatide
Semaglutide
Sodium glucose cotransporter-2 inhibitors
Canagliflozin
Dapagliflozin
Empagliflozin
Ertugliflozin
Saxagliptin Improves UACR
84% 82%
29% 23%
4% 3%
15% 17%
60%60%
28%23%
1% 1%
12% 17%
68% 74%
0%
20%
40%
60%
80%
100%
Saxagliptin Placebo Saxagliptin Placebo Saxagliptin Placebo
Change in categorical UACR from baseline to end of treatment by baseline UACR category
<30 30-300 >300
P=0.021* P<0.001** P=0.049***
UACR mg/g at end of treatment:
UACR <30 mg/g at baseline UACR 30-300 mg/g at baseline UACR >300 mg/g at baseline
*P value is based on a 2-tailed normal distribution approximation test for the proportion of patients who worsened.
**P value is based on a 2 test for independence.
***P value is based on a 2-tailed normal distribution approximation test for the proportion of patients who improved.Mosenzon O, et al. Diabetes Care. 2017;40:69-76.
GLP-1 Receptor Agonists -
Liraglutide
Rate/100
patient-yearsHazard
Ratio(95% CI)
P
Active Placebo
New onset of persistent
macroalbuminuria or a doubling of
SCr and eGFR ≤45 mL/min/1.73 m2,
need for continuous renal-
replacement therapy, or death from
renal disease
1.5 1.9 0.78(0.67-0.92)
0.003
New onset of persistent
macroalbuminuria 0.9 1.21 0.74(0.60-0.91)
0.004
Marso SP, et al. N Engl J Med. 2016;375(4):311-322.
Mann JFE, et al. N Engl J Med. 2017;377(9):839-848.
Effect of GLP-1 Receptor Agonists on Renal Endpoints
GLP-1 Receptor Agonists -
Semaglutide
Rate/100
patient-yearsHazard
Ratio(95% CI)
P
Active Placebo
Persistent macroalbuminuria or a
doubling of SCr and eGFR ≤45
mL/min/1.73 m2, need for continuous
renal-replacement therapy1.86 3.06 0.64
(0.46-0.88)0.005
Marso SP, et al. N Engl J Med. 2016;375(19):1834-1844.
Effect of GLP-1 Receptor Agonists on Renal Endpoints
Canagliflozin CREDENCE Trial
▪ 4,401 patients with T2DM
▪ Age ≥30 y
▪ A1c 6.5% to 12.0%
▪ eGFR 30 to <90 mL/min/1.73 m2
▪ UACR >300 to 5000 mg/g
▪ Stabilized on ACE-I or ARB therapy
▪ 2-week, single-blind, placebo run-in
▪ Randomized (1:1) to (stratified
by eGFR):
▪ Canagliflozin 100 mg or placebo daily
Perkovic V, et al. N Engl J Med. 2019;380(24):2295-2306.
▪ Treatment continued until:
▪ Trial completion
▪ Initiation of dialysis
▪ Kidney transplantation
▪ Occurrence of diabetic ketoacidosis
▪ Pregnancy
▪ Receipt of disallowed therapy
▪ Results included that there was
no difference in amputation risk
or fracture risk between
canagliflozin and placebo
Effect of SGLT-2 Inhibitors on Renal Endpoints
SGLT-2 Inhibitors –
Canagliflozin
Rate/100
patient-yearsHazard
Ratio(95% CI)
P
Active Placebo
Dialysis, transplantation, sustained eGFR <15
mL/min/1.73 m2, doubling of SCr, or renal or
CV death
4.32 6.12 0.70(0.59-0.82)
0.00001
Doubling of SCr 2.07 3.38 0.60(0.48-0.76)
<0.001
ESRD 2.04 2.94 0.68(0.54-0.86)
0.002
ESRD, doubling of SCr, or renal death 2.70 4.04 0.66(0.53-0.81)
<0.001
Dialysis, kidney transplantation, or renal death 1.36 1.86 0.72(0.54-0.97)
–
Perkovic V, et al. N Engl J Med. 2019;380(24):2295-2306.
Canagliflozin in T2DM and Pre-existing Nephropathy: CREDENCE
N=4401 patients with T2DM, eGFR 30 to <90
mL/min/1.73 m2 and UACR >300 to 5000 mg/g
Median follow-up 2.62 y
NNT=22 for primary composite
NNT=28 for renal-specific composite
NNT=43 for ESKD
From The New England Journal of Medicine, Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM,
Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C,
Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW, Canagliflozin and Renal Outcomes in
Type 2 Diabetes and Nephropathy, volume 380, pages 2295-2306, Copyright © 2001 Massachusetts Medical Society.
Reprinted with permission from Massachusetts Medical Society. Perkovic V, et al. N Engl J Med. 2019;380(24):2295-2306.
SGLT-2 Inhibitors -
Dapagliflozin
Kaplan-Meier
event rate (4 y)Hazard
Ratio(95% CI)
P
Active Placebo
Sustained decrease in eGFR ≥40% to <60
mL/min/1.73 m2, ESRD, or CV or renal death4.2% 5.3% 0.76
(0.67-0.87)<0.0001
Sustained decrease in eGFR ≥40% to <60
mL/min/1.73 m2, ESRD, or renal death1.5% 2.6% 0.53
(0.43-0.66)<0.0001
Sustained decrease in eGFR ≥40% to <60
mL/min/1.73 m2 1.4% 2.5% 0.54(0.43-0.67)
<0.0001
ESRD 0.1% 0.2% 0.31(0.13-0.79)
0.013
ESRD or renal death 0.1% 0.3% 0.41(0.20-0.82)
0.012
Mosenzon O, et al. Lancet. Diabetes Endocrinol 2019;doi:10.1016/S2213-8587(19)30180-9.
Effect of SGLT-2 Inhibitors on Renal Endpoints
SGLT-2 Inhibitors -Empagliflozin
Rate/100patient-years
Hazard Ratio(95% CI)
P
Active Placebo
Doubling of SCr, ESRD, or renal death 0.63 1.15 0.54 <0.001
Doubling of SCr and eGFR ≤45 mL/min/1.73 m2 0.55 0.97 0.56(0.39-0.79)
<0.001
Doubling of SCr and eGFR ≤45 mL/min/1.73 m2,
initiation of renal-replacement therapy, or renal death0.63 1.15 0.54
(0.40-0.75)<0.001
Initiation of renal-replacement therapy 0.10 0.21 0.45(0.21-0.97)
0.04
Progression to macroalbuminuria 4.18 6.49 0.62(0.54-0.72)
<0.001
Incident or worsening nephropathy 4.78 7.60 0.61(0.53-0.70
<0.001
Wanner C, et al. N Engl J Med. 2016;375(4):323-334.
Effect of SGLT-2 Inhibitors on Renal Endpoints
As a class of medications, dipeptidyl peptidase-4 inhibitors
are supported by little, if any, evidence demonstrating a cardiovascular benefit in a
patient with T2DM and chronic kidney disease.
Updated Prescribing Information to Reflect CV Outcomes Trials
MACE FDA Labeling Regarding CV Risk
GLP-1 Receptor Agonists
Albiglutide* –
Dulaglutide –
Exenatide
once-weekly
Liraglutide …to reduce the risk of major adverse CV events (CV death, non-fatal myocardial infarction, or non-fatal stroke)
in adults with T2DM and established CV disease
Lixisenatide
Semaglutide –
SGLT-2 Inhibitors
Canagliflozin
…to reduce the risk of major adverse CV events in adults with T2DM and established CV disease
…to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death,
and hospitalization for heart failure in adults with T2DM and diabetic nephropathy with albuminuria ˃ 300 mg/d
Dapagliflozin…to reduce the risk of hospitalization for heart failure in adults with T2DM and established CV disease or multiple
CV risk factors
Empagliflozin …to reduce the risk of CV death in adults with T2DM and established CV disease
Ertugliflozin
*No longer
available as of
December 2019
Tanzeum [package insert]. Research Triangle, NC: GlaxoSmithKline; December 2017. Trulicity [package insert]. Indianapolis, IN: Eli Lilly and Co.; January 2019. Bydureon
[package insert]. Wilmington, DE: Astrazeneca Pharmaceuticals LP; February 2019. Victoza [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; September 2019. Adlyxin
[package insert]. Bridgewater, NJ: Sanofi-aventis U.S., LLC; January 2019. Ozempic [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; April 2019. Invokana [package
insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; October 2019. Farxiga [package insert]. Wilmington, DE: Astrazeneca Pharmaceuticals LP; October 2019. Jardiance
[package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; January 2019. Steglatro [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme
Corp.; October 2018.
American Diabetes Association. Diabetes Care. 2019;42(Suppl 1):S90-S102. American Diabetes Association. Standards of medical care in diabetes-2019, American Diabetes
Association, 2019. Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association.
New Paradigm in T2DM Treatment
Patients with T2DM and
Established ASCVD or CKD
American Diabetes Association. Diabetes Care. 2019;42(Suppl 1):S90-S102.
American Diabetes Association. Standards of medical care in diabetes-2019,
American Diabetes Association, 2019. Copyright and all rights reserved. Material from
this publication has been used with the permission of American Diabetes Association.
Implications for Patient Care
▪ CKD is common in patients with T2DM causing significant increases in:
▪ CV mortality
▪ All-cause mortality
▪ Annual screening for CKD in patients with T2DM is critical
▪ Measure both eGFR and UACR
▪ Controlling blood glucose, blood pressure, and blood lipids is critical
▪ Recent clinical trial evidence demonstrates reduced renal events with several SGLT-2 inhibitors and GLP-1 receptor agonists
▪ Presents an additional opportunity to individualize therapy
▪ Patient affordability may be a limiting factor
