Management of Advancing Diabetic Nephropathy - Medical College ...

Management of Advancing Diabetic
Nephropathy
6 th Annual Diabetes Symposium of Wisconsin
May 16, 2013
Mark E. Molitch, M.D.
Division of Endocrinology, Metabolism & Molecular Medicine
Northwestern University Feinberg School of Medicine
Chicago, Illinois

Disclosures
• Research Support
– Novartis
– Novo Nordisk
– Eli Lilly
– Reata
– Sanofi-Aventis
• Consulting
– Novartis
– Novo Nordisk
– Eli Lilly
– Abbott
– Janssen

Incident counts & adjusted rates,
by primary diagnosis
Incident ESRD patients; rates adjusted for age, gender, & race.
USRDS - 2008

Adjusted five-year survival, by modality
& primary diagnosis: 1997-2001
incident dialysis patients & patients receiving a first transplant in the calendar year. All probabilities adjusted for age, gender, &
race; overall probabilities also adjusted for primary diagnosis. All ESRD patients, 2005, used as reference cohort. Modality
determined on first ESRD service date; excludes patients transplanted or dying during the first 90 days. Five-year survival
probabilities noted in parentheses. Dialysis patients followed from day 90 after initiation; transplant patients followed from the
transplant date.
USRDS - 2008

Is the Answer More Available Kidneys
for Transplantation?

Or
Can We Decrease the Number of People with
End Stage Diabetic Kidney Disease?
• Prevent the development of diabetes
– The DPP has shown that it is possible
• Decrease the proportion of people with
diabetes who develop nephropathy
• Decrease the rate of progression of
nephropathy

Incidence of Diabetic End-Stage
Renal Disease per 100,000 People
with Diabetes, U.S., 1980 - 2008
National Diabetes Surveillance System, U.S. Renal Data System, National Health Interview Survey

GFR (ml/min/m
Urinary albumin
(mg/24h)
2
140
120
100
80
60
40
20
0
Natural History of Diabetic
Nephropathy
GFR
Albumin
Albuminuria
Microalbuminuria
0 5 10 15 20 25 30
Duration of Diabetes (years)
600
500
400
300
200
100
0
Microalbuminuria – 30 – 299 mg/g creatinine (spot) or 30-299 mg/24h
Albuminuria - > 300 mg/g creatinine (spot) or > 300 mg/24h

Kramer et al., JAMA 2003;289:3273
Frequency of Albuminuria and Retinopathy in
Subjects with GFR above and below
60 ml/min/m 2 in Subjects with Type 2 Diabetes
> 40 Years of Age (NHANES III)
GFR > 60 GFR < 60
Microalbuminuria 32% 45%
Macroalbuminuria 5% 19%
Retinopathy 15% 28%
No retinopathy or
albuminuria
30%

Albumin Excretion Rates Preceding Diagnosis
of Impaired Kidney function ([Sustained] GFR
< 60 ml/min/1.73m 2 ) in DCCT/EDIC Subjects
39%
N=203 N=89

Estimates of the mean levels of eGFR at each DCCT-EDIC
follow-up year among subjects currently with normal AER, or
microalbuminuria or albuminuria at that time
Normal
Allbuminuria
Microalbuminuria
Molitch et al., Diabetes Care 2010; 33:1536

Equations for Estimating GFR
Abbreviated MDRD Study Equation
GFR (mL/min/1.73 m 2 ) = 186.3 SCr -1.154 Age -0.203
0.742 (if female) 1.210 (if African American)
Cockcroft-Gault Equation
C cr =
(mL/min)
(140 – Age) Weight in kg
72 SCr
0.85 if female
MDRD = Modification of Diet in Renal Disease; C cr = creatinine clearance.
Levey et al. Ann Intern Med. 2003;139:137-147.

GFR Calculator
(just type MDRD
Into search space
In Google)
The formula used to estimate GFR in this application is appropriate for adults only.
Available at: www.kidney.org/kls/professionals/gfr_calculator.cfm/

CKD Progresses in Stages Defined by
Kidney Function: GFR
CKD
Stage
Description
GFR
(mL/min/1.73 m 2 )
1 Kidney damage with normal
or GFR
2 Kidney damage with
mild GFR
3a
3b
90
60-89
Moderate GFR 45-59
30-44
4 Severe GFR 15-29
5 Kidney failure

Good Glycemic Control (Lower HbA 1c )
Reduces Complications
DCCT
Kumamoto
UKPDS
HbA 1c
9 7%
9 7%
8 7%
Retinopathy
76%
69%
17-21%
Nephropathy
54%
70%
24-33%
Neuropathy
60%
-
-
Macrovascular
disease
41%*
-
16%*
* not statistically significant
DCCT Study Group: N Engl J Med 329:977-86, 1993
Ohkubo Y: Diabetes Res Clin Prac 28:103-17, 1995
UKPDS Study Group: Lancet 352:837-53, 1998

Cumulative Incidence of Albuminuria* in Type 1
Diabetes in the DCCT/EDIC Study and the Pittsburgh
Epidemiology of Diabetes Complications Study
25%
17%
9%
*>300 mg/24h
DCCT/EDIC Research Group. Arch Intern Med 2009;169:1307

Relative Risk
DCCT
Relationship of HbA 1c to Risk of Microvascular
Complications
15
13
11
9
Retinopathy
Nephropathy
Neuropathy
Microalbumin
7
5
3
1
6 7 8 9 10 11 12
HbA 1c (%)
Skyler. Endocrinol Metab Clin. 1996;25:243-254, with permission.
3-3

Cumulative Incidence of Impaired eGFR
(sustained

Primary & Secondary GFR Outcomes
Number of Events
Relative Risk Reduction
Intensive
Therapy
Conventional
Therapy
Risk Reduction
(%, 95% CI)
P-
value
Impaired GFR* 24 46 50 (18, 69) 0.006
eGFR < 45 mL/min/1.73m 2 24 39 40 (1, 64) 0.045
eGFR < 30 mL/min/1.73m 2 13 23 44 (-9, 72) 0.088
End stage renal disease 8 16 51 (-14, 79) 0.098
Impaired GFR* or death 53 80 37 (10, 55) 0.011
• Sustained eGFR < 60 mL/min/1.73m 2 (primary outcome of this study)
• Risk reduction is relative difference in risk of impaired GFR (in percent) comparing
intensive to conventional diabetes therapy
N Engl J Med 2011;365:2366

GFR (ml/min)
Management of Progressing Diabetic
Kidney Disease and Its Complications
140
120
100
80
60
40
↑Glucose
CVD
↑ BP
↑ LDL
2 HPT
Anemia
20
0
0 2 4 6 9 10 12 14 16 18 20
ESRD
Years

Annual Transition Rates In Patients with
Type 2 Diabetes in the UKDPS
No Nephropathy
2.0%
Microalbuminuria
2.8%
Albuminuria
2.3%
Elevated Creatinine or
Renal Replacement Rx
1.4%
3.0%
4.6%
19.2%
Death
Adler et al., Kidney Intl 2003;63:225

Estimated Event Rate (%)
Cardiovascular Outcomes Worsen With CKD
Progression: 3-Y Follow-Up by eGFR Levels
60
50
P

Control of BP Slows Decline of
GFR in Patients with Diabetic
110
Nephropathy
100
ΔGFR: 0.94 ml/min/month
GFR (min/1.73m 2
90
80
70
Before
Start of antihypertensive
treatment
ΔGFR: 0.29
ml/min/month
60
During
-2 -1 0 1 2 3
Years
Parving et al., 1987

GFR (ml/min/year)
Relationship Between Achieved BP and GFR
MAP (mm Hg)
0
-2
-4
-6
-8
-10
-12
-14
95 98 101 104 107 110 113 116 119
130/80 140/90
r=0.69; p

Pohl et al., JASN 2005;16:3027
Relative Risk of Reaching
a Renal End Point
(doubling of serum
creatinine or SCr > 6.0 or
RRT) and All Cause
Mortality by Level of
Achieved SBP in the
Irbesartan Diabetic
Nephropathy Trial (IDNT)

Pohl et al., JASN 2005;16:3027
Relative Risk of Reaching
a Renal End Point
(doubling of serum
creatinine or SCr > 6.0 or
RRT) and All Cause
Mortality by Level of
Achieved SBP in the
Irbesartan Diabetic
Nephropathy Trial (IDNT)

ACCORD BP Study:
Primary and Secondary Outcomes
• Patients with T2D and hypertension (N = 4733)
• Random assignment
• Intensive therapy: target SBP < 120 mm Hg
• Standard therapy: target SBP < 140 mm Hg
• 1 outcome: nonfatal MI, nonfatal stroke, death from CV causes
• Mean follow-up = 4.7 y
Outcome Intensive Standard HR P-value
SBP after 1 year (mmHg) 119.3 133.5 NR NR
1 outcome (annual rate) 1.87 2.09 0.88 .20
Death from any cause
(annual rate)
1.28 1.19 1.07 .55
Stroke (annual rate) 0.32 0.53 0.59 .01
AEs (rate) 3.3 1.3 NR

ADA Standards of Care 2013:
Recommendations for Managing
Hypertension in Diabetes
• Control BP to prevent or slow CVD and CKD in
people with diabetes
• BP goal: < 140/80 mm Hg
• Therapy
– SBP 130–139
• Lifestyle therapy alone
– SBP ≥ 140 or DBP ≥ 80 mm Hg
• Pharmacologic and lifestyle therapy
• Include ACE-I or ARB
• Add more drugs if necessary
• Multiple drug therapy generally required
Diabetes Care. 2013;36(suppl 1):S11- S66.

Effects of ACE Inhibitors and ARBS on Mortality and Renal
Outcomes in Diabetic Nephropathy: Systematic Review
• ACE Inhibitors compared to placebo: 20 Trials with 2838
patients
– All cause mortality: RR 0.79 (CI 0.63-0.99)
• ACE Inhibitors compared to placebo: 9 Trials with 1907
patients
– ESRD: RR 0.64 (0.40-1.03)
– Doubling of Creatinine: RR 0.60 (0.34-1.05)
– Progression micro- to macroalbuminuria: RR 0.45 (0.28-0.71)
• ARBs compared to placebo: 4 trials with 3329 patients
– All cause mortality: RR 0.99 (0.85-1.17) (LIFE Study not included)
• ARBs compared to placebo: 3 trials with 3251 patients
– ESRD: RR 0.78 (0.67-0.91)
– Doubling of Creatinine: RR 0.79 (0.67-0.93)
– Progression micro- to macroalbuminuria: RR 0.49 (0.32-0.75)
Strippoli et al., BMJ 2004:329:828-828

Lack of Benefit of Enalapril (20mg) or Losartan (100mg) in
Preventing the Initial Development of Microalbuminuria in
Normotensive Subjects with Type 1 Diabetes
Mauer M et al. N Engl J Med 2009;361:40-51

Lack of Benefit of Candesartan (32mg) in Preventing the
Initial Development of Microalbuminuria in Normotensive
Subjects with Type 1 and Type 2 Diabetes (DIRECT Studies)
Bilous, R. et. al. Ann Intern Med 2009;151:11

Average Number of Antihypertensive Medications
Needed per Patient to Achieve Target Systolic Blood
Pressure (SBP) Goals in Various Trials
TRIAL (SBP Achieved)
ALLHAT (138 mmHG)
IDNT (138 mmHg)
RENAAL (141 mmHg)
UKPDS (144 mmHg)
ABCD (132 mmHg)
MDRD (132 mmHg)
HOT (138 mmHg)
AASK (128 mmHg)
0 1 2 3 4
Number of Antihypertensive Medications
Bakris, Am J Med 2004;116(Suppl5A):30S

Event Rates Plotted against LDL Cholesterol Levels
during Statin Therapy in Secondary-Prevention Studies
LaRosa, J. C. et al. N Engl J Med 2005;352:1425

Heart Protection Study
Cardiovascular Benefits of Simvastatin in those
with Normal and Abnormal Renal Function
% of Patients with Cardiac Events
50
45
40
35
30
25
20
15
10
5
0
Placebo
Simvastatin
23.9 24.3
19.5 19.1
44.6
34.5
37.5
26.4
168 142 515 504
Diabetes No Diabetes Diabetes No Diabetes
Creatininine
Creatinine
< 1.24 mg/dl
1.24 (1.47) – 2.26 mg/dl
(GFR >47)
GFR 47(52) – 23 (32)
< 1.47 mg/dl (GFR >52)
HPS Collaborative Group: Lancet 2003;361:2005

Cumulative incidence (%)
4D Study: Primary Composite End Point (Cardiac
Death, Nonfatal MI & Stroke)
1255 subjects with Type 2 diabetes receiving hemodialysis
60
50
Relative Risk Reduction 8 %
(95 % CI: 0.77-1.10, P=0.37)
Placebo
40
30
20
10
Atorvastatin 20 mg
Placebo
Atorvastatin
0
0 1 2 3 4 5 5.5 years
Placebo 636 532 383 252 136 51 29
Atorvastatin 619 515 378 252 136 58 19
Median follow-up time of 4 years
Years from Randomization
Wanner et al., NEJM 2005;353:238

Aurora Study
2776 Patients with ESRD (19.2% with DM) assigned to Rosuvastatin 10 mg
vs. Placebo, Primary Endpoint: CVD death, nonfatal MI or nonfatal stroke
43% reduction in LDL
Fellstrom B et al. N Engl J Med 2009;360:1395-1407

SHARP: Major Atherosclerotic Events
by renal status at randomization
Eze/simv
(n=4650)
Placebo
(n=4620)
Risk ratio & 95% CI
Non-dialysis (n=6247) 296 (9.5%) 373 (11.9%)
Dialysis (n=3023) 230 (15.0%) 246 (16.5%)
Any patient 526 (11.3%) 619 (13.4%) 16.5% SE 5.4
reduction
(p=0.0022)
No significant heterogeneity between
non-dialysis and dialysis patients (p=0.25)
0.6 0.8 1.0 1.2 1.4
Eze/simv
better
Placebo
better

Summary of Lipids and CKD
• Patients with diabetes and CKD are at very high risk of
CVD
• CVD events can be significantly reduced with statins in
patients with diabetes
• CVD events can be significantly reduced with statins in
patients with CKD prior to dialysis
• CVD events cannot be significantly reduced with
statins in patients with diabetes undergoing dialysis
– Does this mean we should stop statins when
patients go on dialysis? Probably not
– But no evidence to support the NEW institution of
statins in a dialysis patient
• The LDL goal for treatment of patients with diabetes
and CKD prior to dialysis should be 70 mg/dl
• Risks of rhabdomyolysis with statins are low -

Vitamin D and Kidney Disease
OH
OH
HO
HO
HO
OH
Vitamin D 3
25-Hydroxyvitamin D 3
25(OH)D
Storage Form
1,25-Dihydroxyvitamin D 3
1,25(OH) 2 D 3 or Calcitriol
Active Form

Mineral Metabolism and Secondary HPT
in Patients With CKD
Reduced Renal Mass
Decreased Serum
1,25(OH) 2 D
Increased Serum
Phosphate
Hypocalcemia
Increased PTH Secretion
Decreased
Vitamin D
Receptors
Decreased
Ca-sensing
Receptors
Parathyroid Glands
CKD = chronic kidney disease; HPT = hyperparathyroidism; PTH = parathyroid hormone; 1,25(OH) 2 D = calcitriol.

Prevalence of Abnormal PTH, Hyperphosphatemia
and Hypocalcemia by eGFR
90
80
70
60
50
40
30
20
10
0
PTH > 65 pg/mL
Phosphorus > 4.6 mg/dL
Calcium < 8.4 mg/dL
>80 79-70 69-60 59-50 49-40 39-30 29-20

Percentage of Patients
Prevalence of 1,25(OH) 2 D 3 and 25(OH)D 3
Deficiency/Insufficiency
100%
80%
25(OH) Vitamin D

Bone Mineral Density, Z-Score
Evidence of Renal Osteodystrophy:
Bone Loss in CKD Stages 2-4
0.00
PTH 120 pg/mL
Spine Hip Arm
-0.25
-0.50
-0.75
-1.00
-1.25
-1.50
-1.75
*
*
-2.00
-2.25
*P

Observed/Expected
Incidence of Hip Fracture*
Hip-Fracture Rate in Patients on Dialysis:
Comparison With the General Population
100
80
Overall
Male relative risk = 4.4x
Female relative risk = 4.4x
60
40
20
0

Additional Factors Influencing Renal
Osteodystrophy in Patients
With Chronic Kidney Disease
• Glucocorticoid therapy
• Female Hypogonadism (Estrogen Deficiency)
• Menopause
• Male hypogonadism
• Metabolic acidosis
Eknoyan et al for the NKF. Am J Kidney Dis. 2003;42(4 suppl 3):1-201.

Recommended Goals for Hormone and
Mineral Metabolism in CKD Stages 3 and 4
Parameter
Recommendation
iPTH (pg/mL) 35-70 in CKD Stage 3; 70-110 in CKD Stage 4
Ca (mg/dL) Within normal range of your lab (8.5-10.2)
P (mg/dL) 2.7-4.6
Ca P (mg 2 /dL 2 )

Activated Vitamin D Compounds for the
Treatment of Secondary Hyperparathyroidism
H 3 C
CH 3
OH
First Generation
(discovery 1971)
HO
CH 2
OH
Calcitriol
CH 3
Second Generation
(discovery 1974)
H 3 C
HO
CH 2
OH
CH 3
CH 3
H 3 C
HO
CH 3
CH 3
CH 2
OH
Alfacalcidol*
H 3 C
CH 3 CH 3
CH OH
3
Doxercalciferol
Third Generation
(discovery 1985)
Paricalcitol
*Not available in the United States. Dusso et al. Semin Nephrol. 2004;24:10
HO
OH

Change in iPTH 1-84 (%)
Change in Spine (%)
Vitamin D Compound Alfacalcidol* Suppresses
PTH and Improves BMD in CKD Stages 3 and 4
100
80
6
Alfacalcidol (n = 16)
Placebo (n = 15)
60
4
40
20
2
† †
0
-20
-40
-60
†
†
†
†
‡
‡
‡
‡
0 3 6 9 12 15 18
0
-2
-4
0 6 12 18
Follow-Up (mo)
BMD = bone mineral density; *Alfacalcidol is available outside the United States; † Significant differences
between groups; ‡ Significant changes from baseline in each group.
Rix et al. Nephrol Dial Transplant. 2004;19:870-876.

Secondary Hyperparathyroidism: New Paradigms
Old Paradigm:
If Ca low or P high,
check PTH
Chronic Renal Failure
New Paradigm:
Monitor PTH regularly
Old Paradigm:
Phosphate
Retention
• Treat with dietary P
restriction and Ca as
binder and supplement
• Use limited amounts of
active D due to risk of
elevation of Ca and P
Hypocalcemia
HPT
Low Levels of
Calcitriol
New Paradigm:
• Active D is crucial to
maintain bone health,
and related to CV health
• Active D analogs can be
used at higher doses with
minimal effects on Ca
and P metabolism
Courtesy of Daniel Coyne, MD.

Glycemic Control and Progressing
Diabetic Nephropathy
• In the patient who is developing a progressive fall
in GFR, several things need to be considered:
– Decreased insulin sensitivity
– Decreased renal gluconeogenesis
– Decreased clearance of insulin
– Decreased clearance of oral agents
– Changes in body composition
• Anorexia, gastroparesis, weight loss

Role of the Kidney in Insulin Metabolism
• Kidney accounts for 30 – 80% of insulin
removal from the circulation
– 60% via glomerular filtration
– 40% via proximal tubular reabsorption and
intracellular degradation
• As CKD progresses, there is a decline in
kidney extraction of insulin
– There is also a uremic depression of insulin
degradation at extra-renal sites
• Can be improved by hemodialysis
Rabkin et al., Diabetologia 1984;;27:351

Type 1 DM
Decreased
Insulin
Requirements
(U/kg) in Relation
to GFR
Type 2 DM
CrCl T1DM T2DM
80 0.72 0.68
10 0.45 0.33
Biesenbach et al., Diabetic
Medicine 2003;20:642

Incidence Rate Ratios
Risk of Hypoglycemia in 243,222 Veterans with and
without CKD (GFR < 60) and Diabetes
9
8
7
6
Glucose

Halving of Insulin Doses when
eGFR Is < 45 ml/min/1.73m 2
• Prospective trial of 107 inpatients at Rush, Loyola and NMH
with T2DM and eGFR < 45 ml/min/1.73m 2 randomized to
0.5U/kg vs. 0.25 U/kg total daily dose of insulin
• Insulin: 50% glargine as basal insulin and 50% glulisine
divided into 3 premeal injections
• Glucose targets:
– Premeal 100 – 140 mg/dL
– Post meal < 180 mg/dL
• Primary Outcome: % glucose levels 100-180 mg/dL
• Secondary Outcome: % glucose levels < 70 mg/dL
Baldwin , et al., Diabetes Care 2012;35:1970

Halving of Insulin Doses when
eGFR Is < 45 ml/min/1.73m 2
0.5U/kg
0.25U/kg
Glucose in 100 – 180 range, Day 1 30% 33%
Glucose in 100 – 180 range, Last Day 46% 56%
Hypoglycemia (

• Glyburide
Sulfonylurea Use in CKD
– Glyburide clearance not affected but renal clearance of
metabolites is reduced with CKD
– Risk of hypoglycemia high with CKD and should not be used
with eGFR < 60
• Glimepiride
– Glimepiride clearance not affected but renal clearance of
metabolites is reduced with CKD
– Risk of hypoglycemia increased and should be used with
caution with eGFR < 60 and avoided with eGFR < 30
• Glipizide
– Less than 10% renally cleared
– Use with caution with eGFR < 30
Balant et al., Diabetologia 1973;9:331 Holstein et al., Eur J Clin Pharmacol 2003;59:91
Rosencranz et al., Diabetologia 1996;39:1617 Ferreira et al., Diabetes Care 2012 doi:10.2337/dc12-1365/-/DC1

Guideline
Guidelines for Metformin Use in
FDA (package insert)
National Institute for Health &
Clinical Excellence (NICE- UK)
Australian Diabetes
Association
Patients with CKD
Recommendation
Serum Cr

Risk of Metformin-Associated
Lactic Acidosis
• Cochrane review of 347 trials/studies of 70,490
patient-years of metformin use and 55,451
patient-years of non-metformin use
– No cases of fatal or nonfatal lactic acidosis
• UK General Practice Research Database
– Metformin: 3.3 cases per 100,000 patient years
– Sulfonylureas: 4.8 cases per 100,000 patient years
Saltpeter et al., Cochrrane Database Syst Rev 2010;4:CD002967
Bodmer et al., Diabetes Care 2008;31;2086

14 Cases of Metformin-Associated
Lactic Acidosis
• All 14 patients had decreased GFR
• 10/14 had metformin accumulation with creatinine
ranging 3.05 – 11.8 mg/dL (eGFR 21.4 – 4.8
ml/min/1.73m 2 )
– 7/10 in shock
– 3/10 not in shock
• Serum creatinine: 5.1, 8.0, and 12.3 mg/dL (eGFR 7.2, 14.3,
and 7.2 ml/min/1.73m 2 )
• 4/14 had no metformin accumulation
– 4/4 in shock
– Serum creatinine 1.6, 1.9, 2.2, 4.0 (eGFR 34.1, 36.5, 22.9,
16.2 ml/min/1.73m 2 )
Lalau et al., Diabetes Care 1995;18;779

eGFR (ml/min/1.73m 2
Metformin Dosing
What to Do?
Metformin Dosing
> 60 No limitation of dosing
> 45 – 30 -

Thiazolidinediones and CKD
• Rosiglitazone
– ? Increased CVD – essentially no longer used
• Pioglitazone
– Clearance not affected by kidney function
• No dose reduction needed in CKD
– Potential problems with fluid retention
– Bone disease - ? Additive to renal osteodystrophy
– Slight increased risk of bladder cancer (?)
Budde et al., Br J Clin Pharmacol 2003;55:368 Colmers et al., CMAJ 2012;184:E675
Panchapakesan et al., Nephrology 2009;14:298 Betteridge, Diabetic Medicine 2011;28:759

Alpha-Glucosidase Inhibitors
Acarbose and Miglitol
• Acarbose
- Minimal absorption with < 2% of drug and active metabolites
appearing in urine
- Package insert states that in patients with eGFR < 25
ml/min/1.73m 2 , the peak concentration is increased 6x and the
AUC is increased 5X but no long-term trials in patients with
serum creatinine > 2 mg/dL
- Should not be used if serum creatinine > 2 mg/dL
• Miglitol
- 50-70% absorption with >95% excreted in urine
- Package insert states that in patients with eGFR < 25
ml/min/1.73m 2 , the peak concentration is increased 2x and no
long-term trials in patients with serum creatinine > 2 mg/dL
- Should not be used if serum creatinine > 2 mg/dL

Incretins
• GLP-1 receptor agonists
– Exenatide – discontinue for eGFR < 30
– Liraglutide – no dose adjustments
necessary for progressing CKD
• DPP4 Inhibitors
Sitagliptin Saxagliptin Alogliptin Linagliptin
GFR > 50 100 mg/d 10 mg/d 25 mg/d 5 mg/d
GFR 30 – 50 50 mg/d 5 mg/d 12.5 mg/d 5 mg/d
GFR < 30 25 mg/d 2.5 mg/d 6.25 mg/d 5 mg/d

SGLT2 Inhibitors
• Increase urinary glucose excretion, thereby
lowering blood glucose
• Less effective with eGFR < 60 ml/min/1.73m 2
• Possibly more adverse effects (volume loss,
hyperkalemia) with eGFR < 45 ml/min/1.73m 2
– For eGFR < 60 ml/min/1.73m 2, Canagliflozin should
be kept at 100 mg/day and higher dose (300 mg)
avoided
– Canagliflozin currently not approved for use with
eGFR

Management of Diabetic Nephropathy
Parameter
Improve glycemia
Lower BP
Block RAAS
Lower LDL cholesterol
Anemia management
Endothelial protection
Increased PTH
Target
A1c

Thank you
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