of diabetic patients with ckd - mediquest.in 2/management of diabetic patients...management of...

MANAGEMENT OF DIABETIC PATIENTS WITH CKD

Roberto Pecoits-Filho, MD, PhD, FASN, FACP

PUCPR, Curitiba, BRAZIL

KDIGO Diabetes Conference | February 5-8, 2015 | Vancouver, Canada

Disclosure of Interests

Honoraria

Astra Zeneca, Novartis

Trial participation and research grants

Amgen, Genzyme, Jansen, Astra Zeneca

Consultoria

Jansen, Astra Zeneca, Abbvie

1. International Diabetes Federation. IDF Diabetes Atlas. 6th ed.

http://www.idf.org/diabetesatlas. Published 2013. Accessed January 2, 2014.

2. Gilmer TP, O’Connor PJ. Strategies to reduce the cost of renal complications

in patients with type 2 diabetes. Diabetes Care. 2011;34:2486-2487.

Cerebrovascular Disease Retinopathy (18.9%)

Myocardial infarction (9.8%)

Angina (9.5%)

Coronary heart disease (9.1%)

Nephropathy (27.8%)

Neuropathy

Peripheral Vascular Disease

Ulceration/amputation

(22.9%)

I

Hyperfiltration

GFR

UAE

0 5 10 20

Duration of diabetes (years)

15 25

150

120

90

60

30

0

GF

R (

mL

/min

/1.7

3 m

2)

30

10

1

0.1

0.01

0

Lo

g U

AE

(g/2

4h

)

II

Silent DN

III

Incipient DN

IV

Overt DN

V

ESRD

Natural history of diabetic nephropathy

• DN, diabetic nephropathy; ESRD, end-stage renal disease; GFR, glomerular filtration rate; UAE, urinary

albumin excretion

• Pugliese G. Acta Diabetol 2014;51:905–915

Non-albuminuric renal impairment in Type 2 diabetes The Third National Health and Nutrition Examination Survey (NHANES III)

• A total of 1197 patients with Type 2 diabetes

Kramer HJ, et al. JAMA 2003;289:3273–3277

36%

Albuminuria

45%

19%

0

20

40

60

80

Pre

va

len

ce

(%

)

13%

Renal

impairment*

Normo Micro Macro

Risk of progression to proteinuria in the STENO-2 trial

CI, confidence interval; RR, relative risk

Fioretto P, et al. Nat Rev Endocrinol 2010;6:19–25

Conventional

treatment

Intensive

treatment

60

40

20

0

P=0.01

24

10

39

20

46

25

Residual

risk

3.8 7.8 13.3

Duration of follow-up (years)

RR: 0.44

(95% CI: 0.25, 0.77)

P=0.004

Pa

tie

nts

(%

)

Multifactorial intervention failed to eliminate

the risk of new-onset diabetic nephropathy in

patients with Type 2 diabetes

Trends in diabetes-related complications among

US adults with diagnosed diabetes 1990–2010

ESRD, end-stage renal disease

Gregg EW, et al. N Eng J Med 2014;370:1514–1523

150

125

100

75

50

25

4 2 0

Eve

nts

pe

r 1

0,0

00

ad

ult

po

pu

lati

on

wit

h d

iag

no

se

d d

iab

ete

s

1990 1995 2000 2005 2010

Acute myocardial infarction

Stroke

Amputation

ESRD

Death from hyperglycaemic crisis

Year

Incident counts and adjusted rates of ESRD, by

primary diagnosis

ESRD, end-stage renal disease; GN, glomerulonephritis; USRDS, United States Renal Data System

USRDS annual data report 2014

Diabetes

Hypertension

GN

Cystic

kidney

Rate

per

mil

lio

n p

op

ula

tio

n

0

50

100

15

0

200 Rates

81 84 87 90 93 96 99 02 05 08 11

Year

Diabetes

Hypertension

GN

Cystic

kidney

Nu

mb

er

of

pati

en

ts (

in t

ho

usa

nd

s)

0

1

0

2

0

3

0

4

0

5

0

Counts

8

1

8

4

8

7

9

0

9

3

9

6

9

9

0

2

0

5

0

8

11

Year

Brazil

France

Germany

United States

Study design Target ≈ 12,000 CKD patients

Census • CKD stage 3b to 5 (non dialysis, non-renal

transplant) patients

• ≥18 yrs old

• All causes of CKD

Inclusion • 60–90 per clinic with eGFR <60

mL/min/1.73 m2

Follow-up • 3 years (up to 5 years in France)

• Before and after starting RRT

Data

collection

(longitudinal)

• Abstraction from medical records

• Nephrologist survey

• Patient questionnaire

32 clinics

(target=30)

40 clinics

(target=40) 29 clinics

(target=40)

20 clinics

(target=20)

Japan 30 clinics

(target=30)

CKDopps protocol and countries (2016)

CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; RRT, renal replacement therapy.

Prevalence of hypertension and diabetes

• PRELIMINARY: From CKDopps census (all clinic patients); N=14,769 (France), 925

(Germany), 1897 (Brazil), 3221 (USA); eGFR <60 mL/min/1.73m2

100

0

80

60

40

20

93

87 86

93

50

41 38

43

Hypertension * Diabetes

Brazil France Germany USA

* Among sampled patients

% o

f p

ati

en

ts

Age distribution

eGFR, estimated glomerular filtration rate

• PRELIMINARY: From CKDopps census (all clinic patients); N=14,769 (France), 26,093

(Germany), 1328 (Brazil), 2851 (US); eGFR <60 mL/min/1.73m2

Median

age

Brazil 68 yrs

Germany 74 yrs

France 73 yrs

USA 71 yrs

50

0

40

30

20

10

4

18–44 45–64 65–74 75–84 ≥85

8

13 15

10

28

44

32

25

31

24

28 29

27

15

22

31

2

5 7


Age (years)

% o

f p

ati

en

ts

Reported causes of chronic kidney disease

100

75

50

25

0


563 3043 1028 859 Number of patients:

% o

f p

ati

en

ts

Other Hypertension Glomerulonephritis Diabetes

22

33

8

46

19

16

30

39

9

20

35

6

37

19 22

39

J Am Coll Cardiol 2008; 52:1527-39

Anorexia induced decrease in cfood intake

Dietary restriction-induced food intake

Decrease in insulin metabolization

Interferance in pharmacokinetics of hypoglicemic drugs

Decreased renal gluconeogenesis

Increase in insulin half life

Diabetes mellitus

Decrease in renal glucose excretion

Uremic toxicity –induced insulin resistance

Accumulation ofvcounterbalance hormones

Insulin resistance

Hypoglicemia Hyperglicemia

Inflammation-induced insulin resistance

Pecoits-Filho et al. Diabetology & Metabolic Syndrome, 2016

Risk of severe hypoglycaemia is increased in CKD

1

1.21

1.66

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

Creatinine (µmol/L)

Hazard

Rati

o

<88 88-115 >115

*P<0.001 Miller ME, et al. BMJ 2010;340:b5444

*

*

ACCORD study

eGFR (ml/min) >60 30-59 15-29 <15 dialysis)

Metformin

Glimepiride

Gliblenclamide

Pioglitazone

Vildagliptin

Sitagliptin

Saxagliptin

Linagliptin

Exenatide

Liraglutide

Insulin

Dapagliflozin

Canagliflozin

Empagliflozin

Figure 2 HbA1c levels and mortality in patients on dialysis

Abe, M. & Kalantar-Zadeh, K. (2015) Haemodialysis-induced hypoglycaemia and glycaemic disarrays

Nat. Rev. Nephrol. doi:10.1038/nrneph.2015.38

Permission obtained from Wiley © Rhee, C. M. et al. Semin. Dial. 27, 135–145 (2014)

Questions and Answers

Which of the following clinical presentation in diabetes were not significantly improved over the last 3 decades?

a. Myocardial infarction

b. Stroke

c. End stage kidney disease

d. Amputation

Clinical case

70 years old man, type 2 DM for 12 years

• PA 150/90mmHg (Amlodipine 10mg/day)

• LDL 120mg/dL (Simvastatin 20mg/day)

• TG 245mg/dL

BMI 29

Metformin 1.5g/day and gliblencamide 5mg/day

HbA1C 7.9

1.4

52

70


How would you best stratify the risk(s) of this patient?

a. Patient at low risk of progression to end stage kidney disease

b. Patient at high risk for a cardiovascular event

c. Patient at high risk of progression to end stage kidney disease

d. Patient at very high risk of progression to end stage kidney disease and cardiovascular disease


Lifestyle & Dietary Potential

Dietary – Restrict dietary salt

– Fruit and vegetables

– Mediterranean diet

– Dietary fibre

– Calorie control

– Limited cola

beverages

Physical exercise

Weight reduction

Smoking cessation

Alcohol reduction

Increase fitness

Improve blood pressure

Improve glycemic

control

Reduce albuminuria

Improve survival,

vascular health,

etc.

What can we do?

What should we do?


Modulators of the lipid pattern

• Proteinuria & Nephrotic syndrome

• Peritoneal dialysis & uremic toxins & NS

• Hemodialysis & Heparin administration

• Immunosuppression & polypharmacy

• Insulin resistance


4D 216 125 34 224

AURORA 175 100 45 156

SHARP 189 107 43 203

ALERT 249 158 52 192

Pattern of dyslipidemia

TC LCL-C HDL-C TG

mg/dl

32.6

Lp(a)


PLANET I

Prospective EvaLuation of ProteinuriA and KidNey

Function in diabetic (PLANET I) and non-diabETic

(PLANET II) Patients with progressive Kidney Disease

Renal effects of atorvastatin and rosuvastatin in patients with diabetes

who have progressive renal disease (PLANET I): a randomised clinical

trial

•The Lancet Diabetes & Endocrinology, Available online 4 February 2015,

http://www.sciencedirect.com/science/article/pii/S2213858714702463




































Rosuvastatin 10 mg

Rosuvastatin 40 mg

Atorvastatin 80 mg

0.6

0.8

1.0

1.2

1.4

Pro

tein

/cre

ati

nin

e (

mg

/g)

on

-tre

atm

en

t/b

aseli

ne r

ati

o

0 26 52 Weeks

LOCF

325 patients with T1- or T2-Diabetes

Primary Endpoint: Proteinuria

No. of patients

R10 107 98 91 107

R40 116 108 103 116

A80 102 92 81 102


Ch

an

ge f

rom

baselin

e e

GF

R

mL

/min

/1,7

3m

2

0 26 52 Weeks

LOCF

-12

0

4

8

12

-8

-4

* *

Rosuvastatin 10 mg

Rosuvastatin 40 mg

Atorvastatin 80 mg

Secondary Endpoint: Change in eGFR

No. of patients

R10 107 100 93 107

R40 116 111 103 115

A80 102 92 84 101

Kidney Disease: Improving Global Outcomes

Fibrates in CKD

J Am Coll Cardiol. 2012;60:2061-71

Cardiovascular eventseGFR 30-59.9 ml/min/1.73m2

Cardiovascular death

Stroke

Events

32

Total

199

Events

49

Total

200 0.66 (0.44-0.98), p=0.04

Fibrate Placebo

Risk Ratio; 95% CIFavours Fibrate

Favours Placebo

(I² = 0.0%, p for hetero=0.72)eGFR ≥60 ml/min/1.73m2

VA-HIT

FIELD 57 295 60 224 0.72 (0.53-0.99), p=0.04

Overall 89 494 109 424 0.70 (0.54-0.89), p=0.004

265 1065 329 1067 0.81 (0.70-0.93), p=0.002

(I² = 40.4%, p for hetero=0.195)

VA-HIT

FIELD 555 4600 623 4676 0.91 (0.81-1.01), p=0.07

Overall 820 5665 952 5743 0.86 (0.77-0.96), p=0.009

0.5 0.7 1 1.5 2

eGFR 30-59.9 ml/min/1.73m2

10 199 13 200 0.77 (0.35-1.72), p=0.529


VA-HIT

FIELD 18 295 26 224 0.53 (0.30-0.94), p=0.028

Overall 28 494 39 424 0.60 (0.38-0.96), p=0.032

37 309 50 329 0.79 (0.53-1.17), p=0.002

(I² = 70.3%, p for hetero=0.066)

VA-HIT

FIELD 122 4600 101 4676 1.23 (0.95-1.59), p=0.07

Overall 159 4909 151 5005 1.01 (0.66-1.56), p=0.966

eGFR 30-59.9 ml/min/1.73m2

6 199 15 200 0.40 (0.16-1.02), p=0.054


VA-HIT

FIELD 23 295 20 224 0.87 (0.49-1.55), p=0.643

Overall 29 494 35 424 0.65 (0.31-1.36), p=0.250

52 1065 61 1067 0.85 (0.60-1.22), p=0.002

(I² = 0.0%, p for hetero=0.868)

VA-HIT

FIELD 135 4600 155 4676 0.89 (0.71-1.11), p=0.07

Overall 187 5665 216 5743 0.88 (0.72-1.06), p=0.178

All-cause mortality

eGFR 30-59.9 ml/min/1.73m2

22 199 22 200 1.01 (0.58-1.76), p=0.986


VA-HIT

FIELD 43 295 41 224 0.80 (0.54-1.18), p=0.254

Overall 65 494 63 424 0.86 (0.62-1.18), p=0.355

176 1065 198 1067 0.89 (0.74-1.07), p=0.218

(I² = 72.9%, p for hetero=0.055)

VA-HIT

FIELD 313 4600 282 4676 1.13 (0.97-1.32), p=0.129

Overall 489 5665 480 5743 1.01 (0.80-1.27), p=0.948

P for hetero b/teGFR subgroups

p=0.12

p=0.11

p=0.44

p=0.43

Cardiovascular eventseGFR 30-59.9 ml/min/1.73m2

Cardiovascular death

Stroke

Events

32

Total

199

Events

49

Total

200 0.66 (0.44-0.98), p=0.04

Fibrate Placebo

Risk Ratio; 95% CIFavours Fibrate

Favours Placebo


VA-HIT

FIELD 57 295 60 224 0.72 (0.53-0.99), p=0.04

Overall 89 494 109 424 0.70 (0.54-0.89), p=0.004

265 1065 329 1067 0.81 (0.70-0.93), p=0.002

(I² = 40.4%, p for hetero=0.195)

VA-HIT

FIELD 555 4600 623 4676 0.91 (0.81-1.01), p=0.07

Overall 820 5665 952 5743 0.86 (0.77-0.96), p=0.009

0.5 0.7 1 1.5 2

eGFR 30-59.9 ml/min/1.73m2

10 199 13 200 0.77 (0.35-1.72), p=0.529


VA-HIT

FIELD 18 295 26 224 0.53 (0.30-0.94), p=0.028

Overall 28 494 39 424 0.60 (0.38-0.96), p=0.032

37 309 50 329 0.79 (0.53-1.17), p=0.002

(I² = 70.3%, p for hetero=0.066)

VA-HIT

FIELD 122 4600 101 4676 1.23 (0.95-1.59), p=0.07

Overall 159 4909 151 5005 1.01 (0.66-1.56), p=0.966

eGFR 30-59.9 ml/min/1.73m2

6 199 15 200 0.40 (0.16-1.02), p=0.054


VA-HIT

FIELD 23 295 20 224 0.87 (0.49-1.55), p=0.643

Overall 29 494 35 424 0.65 (0.31-1.36), p=0.250

52 1065 61 1067 0.85 (0.60-1.22), p=0.002

(I² = 0.0%, p for hetero=0.868)

VA-HIT

FIELD 135 4600 155 4676 0.89 (0.71-1.11), p=0.07

Overall 187 5665 216 5743 0.88 (0.72-1.06), p=0.178

All-cause mortality

eGFR 30-59.9 ml/min/1.73m2

22 199 22 200 1.01 (0.58-1.76), p=0.986


VA-HIT

FIELD 43 295 41 224 0.80 (0.54-1.18), p=0.254

Overall 65 494 63 424 0.86 (0.62-1.18), p=0.355

176 1065 198 1067 0.89 (0.74-1.07), p=0.218

(I² = 72.9%, p for hetero=0.055)

VA-HIT

FIELD 313 4600 282 4676 1.13 (0.97-1.32), p=0.129

Overall 489 5665 480 5743 1.01 (0.80-1.27), p=0.948

P for hetero b/teGFR subgroups

p=0.12

p=0.11

p=0.44

p=0.43


What would be your preferred approach to the dyslipidemia in the case presented?

a. Keep the treatment with simvastatin

b. Add a fibrate

c. Associate ezetimibe to simvastatin

d. Change to rosuvastatin

Lipid control

LDLc <70 mg/dl or a 50% reduction

• Statins are safe and efficient for CV protection

- SHARP

• Atorvastatin e fluvastatin don’t require adjustment

• Sinvastatin, pravastatin, rosuvastatin, pitavastatin require

• Fibrates may be important in a subgroup of patients

Crude rates of thromboembolism OFF warfarin therapy by category of eGFR

among adults with nonvalvular AF.

Go A S et al. Circulation 2009;119:1363-1369 Copyright © American Heart Association

AFIB/CKD/ATRIA Study

HOT- bleeding by Kidney function

Hazard

ratio (

95%

CI)

20 30 45 60 90 120

0.6

1.0

2.0

4.0

8.0

Any bleeding

6.0

p for trend =0.0005

HR 1.77 (1.09-2.86) per halving of GFR

*

* Reference

eGFR (ml/min/1.73 m2)

Bleeding with warfarin in AF

Jun et al, BMJ 2015

Major Regulatory Agency

Recommendations for Novel Oral

Anticoagulants in Patients with CKD

Hart RG et al. Nat Rev Nephrol. 2012; 8(10):569-78

Anticoagulation and platelet antiaggregation therapy

Progressive increased risk of bleeding

• individualize treatment


Relationship Between Achieved BP and Decline in

Kidney Function from Primary Renal Endpoint Trials

Update from Kalaitzidis R and Bakris GL In: Handbook of Chronic Kidney Disease Daugirdas J (Ed.) 2011

Normal decline in GFR

Nondiabetes

MDRD. N Engl J Med. 1993

AIPRI. N Engl J Med. 1996

REIN. Lancet. 1997

AASK. JAMA. 2002

Hou FF, et al. N Engl J Med. 2006

Parsa A et.al. NEJM 2013

Diabetes

Captopril Trial. N Engl J Med.

1993

Hannadouche T, et al. BMJ. 1994

Bakris G, et al. Kidney Int. 1996

Bakris G, et al. Hypertension.

1997

IDNT. NEJM. 2001

RENAAL. NEJM. 2001

ABCD. Diabetes Care (Suppl).

2000


Data from the ADVANCE trial Zoungas S, et.al. Diabetes Care 2009;32 (11):2068-2074


Summary of Guideline Goal BP and Initial Therapy in

Kidney Disease to Reduce CKD Progression?

Group Goal BP

(mmHg) Initial Therapy

2014 Expert Panel (2014)

ADA (2015)

<140/90

<140/90

ACE Inhibitor/ARB

ACE Inhibitor/ARB*

KDIGO/KDOQI (NKF) (2012)

<140/90

(130/80 if

proteinuric)

ACE Inhibitor/ARB

ESH (2007+ 2009) <130/80 ACE Inhibitor/ARB*

KDOQI (NKF) (2004) <130/80 ACE Inhibitor/ARB*

JNC 7 (2003) <130/80 ACE Inhibitor/ARB*

Am. Diabetes Assoc (2003) <130/80 ACE Inhibitor/ARB*

Canadian HTN Soc. (2002) <130/80 ACE Inhibitor/ARB*

Natl. Kidney Foundation (2000) <130/80 ACE Inhibitor*

JNC VI (1997) <130/85 ACE Inhibitor

Hipertension

Risk factor for the progression of diabetic kidney diasease

• KDIGO recomendation: <130/90mmHg if albuminuria

Unique features in diabetes:

• Volume related (diuretics and sodium restriction often needed)

• Frequent nocturnal and mask hypertension

• Consider ABPM

SPRINT / ACCORDEON

ACEs or ARBs mandatory

Glycemic control

No important comorbidities, GFR higher than - 6.5-7%.

Longer diabetes duration, eGFR lower than 60ml/min – 7-8%.


What is the degree of kidney dysfunction currently recommended for metformin discontinuation?

a. Serum creatinine higher that 1.5mg/dL

b. Creatinine clearance lower then 30ml/min

c. eGFR lower than 45ml/min

d. eGFR lower than 30ml/min

eGFR (ml/min) >60 30-59 15-29 <15 dialysis)

Metformin

Glimepiride

Gliblenclamide

Pioglitazone

Vildagliptin

Sitagliptin

Saxagliptin

Linagliptin

Exenatide

Liraglutide

Insulin

Dapagliflozin

Canagliflozin

Empagliflozin


Which of the following hypoglycemic drugs have shown a reduction in the risk of progression to ESRD

a. Insulin

b. Metformin

c. Pioglitazones

d. SGLT2 inhibitors

10

8

6

4

2

0

6 0 12 18 24 30 36 42 48 54

HR: 0.78

95% CI (0.67, 0.92)

P=0.003

Liraglutide

Placebo

4668

4672

4635

4643

4561

4540

4492

4428

4400

4316

4304

4196

Liraglutide

Placebo

Patients at risk

4210

4094

4114

3990

1632

1613

454

433

Pa

tie

nts

wit

h a

n e

ve

nt

(%)

Time since randomisation (months)

LEADER: Time to first renal event Macroalbuminuria, doubling of serum creatinine, ESRD, renal death

The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard

regression model; the data analyses are truncated at 54 months because less than 10% of the patients had an observation time beyond 54 months

CI, confidence interval; ESRD, end-stage renal disease; HR, hazard ratio

Marso SP, et al. N Eng J Med 2016; June 13 [Epub ahead of print]

Vlado Perkovic et al (2015): Renal effects of canagliflozin in type 2 diabetes mellitus, Current Medical Research and Opinion

66

Ad

juste

d m

ea

n (

SE

) e

GF

R

(mL

/min

/1.7

3m

2)

70

72

74

76

78

68

0 4 12 28 52 66 80 94 108 122 136 150 164 178 192 206

Empagliflozin 10 mg

Empagliflozin 25 mg

Placebo

Weeks

Placebo

Empagliflozin 10 mg

2323

2322

2322

2295

2290

2288

2267

2264

2269

2205

2235

2216

2121

2161

2156

2064

2114

2111

1927

2012

2006

1981

2064

2067

1763

1839

1871

1479

1540

1563

1262

1314

1340

1123

1180

1207

977

1024

1063

731

785

838

448

513

524

171

193

216 Empagliflozin 25 mg

After initial decrease, long term weekly

changes of:

EMPA (10 mg): +0.48±0.04 mL/min

EMPA (25 mg): +0.55 ±0.04 mL/min

PBO: –0.04 ±0.04

P<0.001 for both

EMPA groups vs

placebo

EMPA-REG: Change in eGFR over time

eGFR, estimated glomerular filtration rate; SE, standard error

Wanner C. N Engl J Med 2016; June 14 [Epub ahead of print]

0.13 0.25 0.50 1.00 2.00

Favours placebo Favours empagliflozin

P value

<0.0001

<0.0001

0.0009

0.0409

N with event/n analysed

Empagliflozin Placebo HR (95% CI)

525/4124

459/4091

388/2061 0.61 (0.53, 0.70)

330/2033 0.62 (0.54, 0.72)

70/4645 60/2323 0.56 (0.39, 0.79)

13/4687 14/2333 0.45 (0.21, 0.97)

New onset or

worsening of

nephropathy

New-onset

macroalbuminuria

Doubling of

serum creatinine

Initiation of

renal

replacement

therapy

EMPA-REG: New onset or worsening of

nephropathy

CI, confidence interval; HR, hazard ratio


Pa

tien

ts w

ith

eve

nt

(%)

7

6

5

3

2

0

1

6 12 18 24 30 36 42 48 0

4

HR: 0.54

(95% CI: 0.40, 0.75)

P=0.0002

Placebo

Empagliflozin

Months

4645

2323

4500

2229

4377

2146

4241

2047

3729

1771

2715

1289

Empagliflozin

Placebo

No. of patients

2280

1079

1496

680

360

144

EMPA-REG: Doubling of serum creatinine,

initiation of renal replacement therapy or death

due to renal disease


Sodium–glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the

emerging role of natriuresis

Kidney International, Volume 89, Issue 3, 2016, 524–526

http://dx.doi.org/10.1016/j.kint.2015.12.038

Back to our patient: what changes in the management when kidney

disease is present?

• Start an ACEi or ARB – target <130/90mmHg

• Aspirin

• Warfarin

• Simvastatin/Ezetimibe – target LDLc 70mg/dL

• Reduce the metformin dose to half

• Add a SGT2i target HbA1C 7%

– Weight, BP, albuminuria, eGFR

GLP-1 agonist

DPP inhibitors

PPARγ agonist

SGL2i

Glucose lowering

AGE inhibitors

RAGE antagonists

PKC inhibitors

e.g. ruboxistaurin

TGF-β or CTGF

Antibodies

Pirfenidone

Glucose

AGEs and RAGE

PKCα and PKC β

Other

Blood pressure

All

ET-1

Other

Growth factors

CTGF

TGF-β

VEGF

Fibrosis Inflammation Albuminuria

Diabetic nephropathy

Antihypertensives

ACE inhibitors

Or ARBs

Endothelin

Receptor blockers

e.g. atrasentan

VEGF antibodies

Fineberg D, et al. Nat Rev Endocrinol 2013;9:713–723

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