Pavan Chava DO, FACE January 25, 2020 · Introduction • Currently 9-10% of the population has diabetes • Diabetes is the leading cause of chronic kidney disease and ESRD • 2013-

Diabetes and the Kidney

Pavan Chava DO, FACE

January 25, 2020

Disclosures

• Novo Nordisk- Speaker Bureau

• Janssen- Speaker Bureau

• Pfizer- Advisory Board- historical

Introduction

• Currently 9-10% of the population has diabetes

• Diabetes is the leading cause of chronic kidney

disease and ESRD

• 2013- 51,000 new cases of renal failure related

to diabetes

• 413 per 1 million- rate of ESRD in LA

– # 49

– MS- 428 per million

• 25-30% with diabetes had CKD

http://nccd.cdc.gov/CKD

Diabetes Trends

https://www.cdc.gov/diabetes/data/center/slides.html

1994 2005 2015

ESRD

National Kidney Foundation

Diabetic Kidney Disease

• Renal disease from DM was previously referred

to as diabetic nephropathy

– This was based on initial thoughts on progression of

renal disease

• Various forms of renal disease that can occur in

patients with diabetes

• DKD

– Albuminuria

– Decreased eGFR

Type 1 vs Type 2

• Patients with Type 1 are more likely to have

diabetes as the cause of renal disease

• Patients with Type 2 may have a multifactorial

cause for renal disease

Risk Factors

Alicic et al. Clin J Am Soc Nephrol 12: 2032–2045, December, 2017

Pathogenesis

• Heterogeneous disease and variation by

individual

• Advanced Glycosylation end products

• Inflammation

• Fibrosis

• Change in glomerular hemodynamic

– Initial Hyperfiltration- 120-140 mL/min

Type 1 > Type 2

Pathophysiology


Progression Model


Screening

• Once yearly assessment of urine albumin (B)

• Once yearly assessment of eGFR (B)

• Type 1: > 5 years after diagnosis

• Type 2: When diagnosed

• If urine albumin > 30 mg/g Cr and/or < 60 mg/g

Cr- Monitor twice annually (C)

2020 ADA Standards of Care

Urine Albumin Screening

• Usually done as spot collection

• If positive, should be repeated over a 3-6 month period-

2-3 specimens

• Vigorous exercise can increase urine albumin

– May need to avoid vigorous exercise x 24 hrs

• Can be overestimated in patients with reduced muscle

mass

• False +– Uncontrolled HTN

– Hyperglycemia

– Infection/Fever

– Heart Failure


Urine Albumin

• Normal: urine albumin <30 mg/day

• 30-300 mg/day

– Moderately increased albuminuria

– microalbuminuria

• > 300 mg/day

– Severely increased albuminuria

– macroalbumin

Diagnosis of DKD

• Diagnosis is clinical

– Albuminuria

– Reduced eGFR

– Absence of other known renal disease

• Consideration of other causes

– Short duration of diabetes without other microvascular

disease- Type 1

– Hematuria

– Rapid decline in eGFR or increase in albuminuria

• Rarely biopsy may be required

Urine Albumin after Diagnosis

• Debate on monitoring once diagnosed

• Assessment to response in therapy

• Assess progression

• Ability to assess for adherence

• Titration to urine albumin < 300 mg/g Cr?

2020 ADA Standards of care

BLOOD PRESSURE

Blood Pressure Management

• NEPHRON-D Trial

– 1448 patients in VA with proteinuric DKD

– Prim Endpoint: Decline eGFR, ESRD, death

– F/U 2.2 yrs

Leehey et al. Clin Am J Neph. 2015 Dec 7;10(12):2159-69

Blood Pressure Management

• ACE Inhibitor– MICRO-HOPE substudy- ramipril

– 3577 patients-

– 4.5 yrs- Stopped early

– Reduction in nephropathy- 24% (p=0.027)

• ARB– 590 pt w/ HTN, DM 2, Microalbuminuria

– Irbesartan

– Primary Outcome- time to onset of nephropathy

– Placebo: 14.9%

– 150 mg: 9.7%

– 300 mg: 5.2%

– Similar BP in each group

Lancet. 2000 Jan 22;355(9200):253-9

Parving et al. NEJM 2001; 345:870-878

https://www.ncbi.nlm.nih.gov/pubmed/10675071

Early use of ACE or ARB

• 285 patients with Type 1 DM- 5 years

• Normotensive and normal albumin

• Losartan (L) 100 mg or enalapril (E) 20 mg or placebo

(P)

• Primary end point- Change in fraction glomerular volume

(biopsy)

• No difference between groups

• Incidence of microalbuminuria: P (6%), L (17%), E (4%)

Mauer et al. NEJM 2009; 361:40-51

Blood Pressure Goals

• DM and high ASCVD risk (>15%): < 130/80

mmHg (C)

• DM and low ASCVD risk (<15%): <140/90

mmHg (A)

• ACE or ARB preferred 1st line agents

– Urine Alb 30-299 mg/g Cr (B)

– Urine Alb >300 mg/g Cr or eGFR < 60 mL/min (A)

– HTN without DKD- unclear benefit of ACE/ARB 1st

line




Glycemic Management

Glycemic control

• Intensive control has been shown to delay onset

and progression

– DCCT- intensive therapy (Median A1c 7.2 vs 9.1)

reduced occurrence of microalbuminuria by 39% and

albuminuria by 54

– EDIC- microalbuminuria 7% in intensive arm vs 16%

in conventional

– EDIC 16 yr f/u- 3.9 in intensive arm and 7.6% in

conventional achieved eGFR < 60 mL/min

Nathan et al. NEJM 1993; 329 (14):977

De Boer et al. NEJM 2011:365(25):2366

Glycemic control

• UKPDS- DM 2

– Microvascular disease- 25% decrease

– Renal and Retinopathy measures

– 10 yr f/u showed 24% risk reduction

• Kumamoto Study- Nephropathy Progression

7.7% vs 28% for primary prevention

• ACCORD trial- HR 0.85 for renal outcomes

Craven et al. Lancet 2010;376(9739):419

Ohkobu et al. Diab Res Clin Pract 1995;28(2):103

Lancet 1998;352(9131):837

CREDENCE Trial

• Double Blind Randomized Trial– Cana 100 mg vs placebo

• Type 2 Diabetes in patients with albuminuric

chronic kidney disease

• Patient Eligibility– Age > 30

– A1c 6.5%-12%

– CKD

eGFR 30 to < 90 ml/min

And Albuminuria- urine albumin/cr > 300 to 5000

60% of participants had eGFR 30-60 ml/min

– Stable dose of ACE or ARB x 4 weeks

Perkovic et al. n engl j med 380;24

CREDENCE Trial

• Exclusion

– DKA

– Type 1

– Any history of Renal transplant

– Any history of dialysis

• Primary Outcome composite

– End stage Kidney disease or eGFR < 15 ml/min

– Doubling Serum Cr

– Death renal or CV cause


CREDENCE Trial

• 4401 patients randomized

• Median f/u 2.62 years

• 14.8% had CHF

• DM Duration 15.8 years

• 50.4% had CV disease

• 5.3% had amputation

• Avg A1c 8.3%

• Avg eGFR 56.2 mL/min

• Median urine alb/cr ratio 927

• Trial stopped early at interim analysis due to positive

results





CREDENCE Trial

• Hosp Heart Failure HR 0.61- P value < 0.001

• No difference in risk of limb amputation

– 12.3 vs 11.2 in 1000 pt years

– Black box warning remains

• Fracture rate similar

• DKA risk

– 2.2 vs 0.2 in 1000 pt years.

• NNT- 1000 pt for 2.5 yrs

– 22: Prim Composite outcome (ESKD, DBL Cr, Renal or CV

Death)

– 28: Composite of ESKD, DBL Cr, or Renal Death

– 46: Hosp for Heart Failure


Canagliflozin Indication for Use

• Adjunct to diet and exercise in adults with DM 2

• Reduce the risk of major adverse cardiovascular

events in adults with type 2 diabetes AND

established CV disease

• Reduce the risk of ESKD, doubling serum Cr,

CV death, hospitalization for heart failure in

adults with DM 2 AND nephropathy with

albuminuria

• Lower limb amputation warning remains

Canagliflozin Indication for Use

• Dose can be increased to 300 mg if eGFR > 60

• Contraindicated if ESRD

• ADA:

– DM 2 + DKD

– SGLT 2: Consider use with > 30 mL/min and urine alb

> 30mg/g Cr

– Consider strongly if urine Alb >300 mg/g Cr (A)


Current Studies

• EMPA-KIDNEY- 2022

• Empagliflozin on renal Function in patients with

Decompensated Heart Failure- 2021

• Dapagliflozin in patients with CKD- 2020

• Dapagliflozin in patients without DM and with

Proteinuria- active

Liraglutide

• LIRA-RENAL

• 26 week trial with 279 patients

• A1c 7-10%

• Mod renal impairment: eGFR 30-59 mL/min

• Lira 1.8 mg vs placebo

Davies Diabetes Care 2016; 39:222-230

LIRA-RENAL

Davies Diabetes Care 2016; 39:222-230

Liraglutide and Renal Outcomes

• Secondary outcomes of the LEADER trial

• 9340 patients with DM 2 and CV disease

• Median f/u 3.8 years

• Secondary renal Composite outcome

– New onset persistent macroalbuminuria

– Persistent doubling of serum Cr

– ESRD

– Death due to renal disease

Mann et al NEJM 2017; 377:839-848

Liraglutide and Renal Outcomes

• 9340 patients

– Liraglutide 4668

– Placebo 4672

• Median f/u 3.84 years.

• Mean BP 136/77 mm Hg

• Mean eGFR 80 mL/min

• 20 % had eGFR 40-59 mL/min

• Microalbuminuria- 26%

• Macroalbuminuria 10.5%

Mann et al. N Engl J Med 2017;377:839-48.

Renal Outcomes

Mann et al NEJM 2017; 377:839-848

Renal Outcomes

Mann et al NEJM 2017; 377:839-848

Renal Outcomes with Dulaglutide

• REWIND Trial

• Patients with CVD or at risk

• 3 point MACE- Nonfatal MI, Non fatal stroke, CV

death

• 9901 patients

– 31% with CVD

• Median F/U 5.4 years

Gerstein et al Lancet. 2019;394(10193):131.


• Baseline

– 7.9% had macroalbuminuria

– Mean eGFR 76 mL/Min

• Renal outcome-

– 1st occurrence of new macroalbuminuria

– sustained decline in eGFR (>30%)

– chronic renal replacement



• Renal outcome

– Dulaglutide: 17.1%

– Placebo: 19.6%

– HR 0.85 (p value = 0.0004)

• New macroalbuminuria: HR 0.77 (P value

<0.0001)

• Sustained decline eGFR: HR 0.89 (P value

0.066)

• Chronic renal Replacement: HR 0.75 (p value

0.39)


GLP-1

• Consider use in patients with CKD and

increased risk of CV events (C)

• May decrease progression of albuminuria


Questions

Documents

Pavan Chava DO, FACE January 25, 2020 · Introduction • Currently 9-10% of the population has diabetes • Diabetes is the leading cause of chronic kidney disease and ESRD • 2013-