relationship of type 2 diabetes and chronic kidney disease: … · 2020. 9. 22. · 29‐15%

Provided by ASHP Sponsored by AstraZeneca Pharmaceuticals

Relationship of Type 2 Diabetes and Chronic Kidney Disease: Opportunities for Prevention, Intervention, and Mitigation

Presented as a Live Webinar Thursday, September 17, 2020 1:00 p.m. – 2:00 p.m. ET

On-demand Activity Release Date: September 24, 2020 Expiration Date: March 31, 2021

This webinar is not accredited for continuing education.

FACULTY Kelley Doherty Sanzen, Pharm.D., PAHM, CDOE Clinical Pharmacist Specialist Brown Medicine Division of Kidney Disease and Hypertension Providence, Rhode Island

View faculty bio at https://www.ashpadvantage.com/t2d/ckd/

Any referenced figures, tables and graphs are copyrighted works of their respective owners; used with permission.

https://www.ashpadvantage.com/t2d/ckd/

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Relationship of Type 2 Diabetes and Chronic Kidney Disease:Opportunities for Prevention, Intervention, and Mitigation

Relationship of Type 2 Diabetes and Chronic Kidney Disease: Opportunities for Prevention, Intervention, and Mitigation

Kelley Doherty Sanzen, Pharm.D., PAHM, CDOE

Brown Medicine Division of Kidney Disease and HypertensionProvidence, Rhode Island

Provided by ASHP Sponsored by AstraZeneca Pharmaceuticals

All planners, presenters, reviewers, ASHP staff, and others with an opportunity to control content report no financial relationships relevant to this activity.

As defined by the ACCME definition of commercial entity.

Financial Relationship Disclosure



Learning Objectives

At the conclusion of this educational activity, participants should be able to • Describe the progressive nature of chronic kidney disease (CKD)• Summarize recommended guidelines for routine screening for

CKD in patients with cardiorenal‐metabolic disease• Discuss indirect and direct approaches for managing CKD

Burden of CKD in the U.S.

Diabetes as a Driver of CKD

Progressive Nature of CKD

Importance of Screening and Monitoring

Current Approaches to Management

Overview



Burden of Chronic Kidney Disease in the U.S.

Burden of CKD in the U.S.

*Prevalence of CKD in U.S. adults using NHANES 2013‐2016 data. CKD may be overestimated as persistence of albuminuria or creatinine was not accounted for based on KDIGO recommenda ons; †Based on 2017 data.

CKD = chronic kidney disease, KDIGO = Kidney Disease Improving Global Outcomes, NHANES = National Health and Nutrition Examination Survey1. Center for Disease Control. National chronic kidney disease fact sheet, 2019. https://www.cdc.gov/kidneydisease/pdf/2019_National‐Chronic‐Kidney‐Disease‐Fact‐Sheet.pdf. 2. United States Renal Data System. 2018 Annual data report. Volume 1: CKD in the United States; 3. United States Renal Data System. 2019 Annual data report: executive summary.

Approximately 1 in 7 adults are estimated to have CKD1*

In 2016, all‐cause mortality rate for CKD was about

103 per 1,000 patient‐years in Medicare patients2

CKD expenditure represents 25% of overall spending for

Medicare patients3,†

$72 billion



Increases in Prevalence of CKD Risk Factors Anticipated to Increase Burden of ESRD

ESRD Incidence and Prevalence per Million Population2

ESRD In

cidence per Million

ESRD Prevalence per Million

500

1000

1500

2000

2500

3000

3500

1980 1990 2000 2010 2020 203000

200

400

600

800

1000

Simulated Incidence

ProjectedPrevalence

SimulatedPrevalence

ProjectedIncidence

Hypertension

Diabetes Family History

ASCVD

Obesity

Race and Ethnicity

Age

CKD Risk Factors1

ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; ESRD = end‐stage renal disease1. Kazancioğlu R. Kidney Intl Suppl. 2013;3:368‐71; 2. McCullough KP et al. J Am Soc Nephrol. 2019;30:127‐35.

CKD Significantly Shortens Life Span

Reference†

Early CKD‡

Early DKD|

Diabetes§

30 35 40 45 50 55 60 65 70

Age (years)

Life Exp

ectan

cy (years)

10

20

30

40

50

60

70

30 35 40 45 50 55 60 65 70

Age (years)

Life Exp

ectan

cy (years)

10

20

30

40

50

60

70Men Women

Overall life expectancy was shortened by 6 years with early CKD and by 16 years with comorbid T2D

Early CKD: 5.7 years shorter* vs. reference†

Early DKD: 14.8 years shorter* vs. reference†Early CKD: 6.7 years shorter* vs. reference†

Early DKD: 16.9 years shorter* vs. reference†

*At 30 years of age; †Reference group consisted of participants with neither diabetes nor CKD; ‡Early CKD was defined as CKD stage 1‐3 without diabetes; §Diabetes was defined as diabetes without CKD; |Early DKD was defined as diabetes with early CKD stages 1‐3.CKD = chronic kidney disease; DKD = diabetic kidney disease; T2D = type 2 diabetes Wen CP et al. Kidney Int. 2017; 92:388‐96.



Progressive Nature of Chronic Kidney Disease

Progressive Decline in Renal Function in CKD

90%+89‐60%

29‐15% <15%

Normal or high

Mildly decreased

Mildly to moderately decreased

Moderately to severely decreased

Kidney failure

Stage 1GFR ≥90

Stage 2GFR 60‐89

Stage 3aGFR 45‐59

Stage 3bGFR 30‐44

Stage 4GFR 15‐29

Stage 5GFR <15

Progression of CKDKidney Fu

nction (GFR

mL/min/1.73 m

2) Early Stage Late Stage

Severely decreased

• Asymptomatic in early stages• Advanced CKD symptoms can include

o Fatigueo Poor appetiteo Nausea/vomitingo Metallic tasteo Prurituso Peripheral edemao Palloro Altered mental status

Common Symptoms2

59‐45%44‐30%

CKD = chronic kidney disease; GFR = glomerular filtration rate1. Kidney Disease Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012. Kidney Int Suppl. 2013;3:1‐150; 2. Chen T, et al. JAMA. 2019;322(13):1294‐304.



Progression of CKD Increases the Risk for Adverse Outcomes

Event rate per 100 person‐yr



eGFR (mL/min/1.73 m2)

0≥60 45‐59 30‐44 15‐29 <15

5

10

15 14.14

11.36

4.76

1.080.76


0≥60 45‐59 30‐44 15‐29 <15

50

100

150 144.61

86.75

45.26

17.2213.54


0≥60 45‐59 30‐44 15‐29 <15

10

30

40 36.60

21.80

11.29

3.652.11

20

Age‐Standardized Rate of Death from any Cause*

Age‐Standardized Rate of Cardiovascular Events*,†

Age‐Standardized Rate of Hospitalization*

*n = 1,120,295†Cardiovascular event was defined as hospitalization for coronary heart disease, heart failure, ischemic stroke, and peripheral arterial disease CKD = chronic kidney disease; eGFR = estimated glomerular filtration rateGo A et al. N Engl J Med. 2004;351:1296‐305.

CV Death Is More Likely than Progression to ESRD in Patients with CKD

3.8 3.55.4

3.0 2.6

4.80.50.3

1.8

0

2

4

6

8

10

12

14ESRDCV mortalityNon‐CV mortality

< 60 n = 1268

45–59n = 985

< 45n = 283

Leading causes of death in CKD1:• CV events• non‐CV causes (e.g. cancer, infection)

eGFR and ACR are strong predictors of CV mortality

Cardiovascular mortality3

(n=24,777; 15 studies; 1879 cases)

Full model Base C statistic 0.773

eGFR ‐0.0079 (‐0.0123 to ‐0.0036)

ACR ‐0.0141 (‐0.0193 to ‐0.0088)

eGFR and ACR ‐0.0227 (‐0.0296 to ‐0.0158)

Diabetes ‐0.0025 (‐0.0066 to 0.0016)

Systolic blood pressure ‐0.0064 (‐0.0097 to ‐0.0031)

Total cholesterol ‐0.0005 (‐0.0023 to 0.0013)

HDL cholesterol ‐0.0035 (‐0.0060 to ‐0.0010)

Total and HDL cholesterol ‐0.0040 (‐0.0069 to ‐0.0012)

Smoking ‐0.0058 (‐0.0101 to ‐0.0014)

‐0.04 ‐0.02 0.020

ACR = albumin‐to‐creatinine ratio; CKD = chronic kidney disease; CV = cardiovascular; eGFR = estimated glomerular filtration rate; ESRD = end‐stage renal disease; MDRD = modified diet in renal disease1. Thompson S et al. J Am Soc Nephrol. 2015;26:2504‐11; 2. Dalrymple L et al. J Gen Intern Med. 2011;26:379‐85; 3. Matsushita K et al. Lancet Diabetes Endocrinol. 2015;3:514‐25.

Rate per 100 person‐years


ESRD, CV and non‐CV mortality2



Complications Associated with Renal Dysfunction

Sodium & Water Balance1,2

PotassiumBalance3

Elimination of Nitrogenous Wastes1,4

ErythropoietinProduction5

Acid‐BaseBalance1

Activation ofVitamin D5

PhosphateElimination5

Hypertension Hyperkalemia Anemia Hypocalcemia

HyperparathyroidismVolume overload

Heartfailure

Uremia Metabolic acidosis

Bone disorders

1. Bello AK et al. Kidney Int Suppl (2011). 2017;7(2):122‐29; 2. Miller WL. Cic Heart Fail. 2016;9(8):e002922; 3. Viera AJ et al. Am Fam Physician. 2015;92:487‐95;4. Weiner D et al. Clin J Am Soc Nephrol. 2015;10:1444‐58; 5. Thomas R et al. Prim Care. 2008;25:329‐44.

Which of the following is a symptom of uremia? Select all that apply.

a. Altered mental statusb. Fatiguec. Nausea/vomiting or poor appetited. Peripheral edemae. Fever



Diabetes as a Driver of Chronic Kidney Disease

Diabetes Is the Leading Cause of CKD

Diabetes

53.8%

Hypertension

13.2%

Glomerulonephritis

18.3%

Other

14.7%

CKD = chronic kidney diseaseXie Y et al. Kidney Int. 2018;94:567‐81.

Age‐standardized U.S. prevalence of CKD by cause in 2016



In Patients with T2D, Early Stages of CKD Are Most Prevalent

9.1 9.4

11.2

5.5

2.4

0.7

0

2

4

6

8

10

12

≥90 60-89 45-59 30-44 15-29 <15Pro

po

rtio

n o

f p

atie

nts

(%

)

eGFR (mL/min/1.73 m2)* †

Prevalence of CKD in patients with T2DNHANES, 2007–2012

Disease severity

*In addition, UACR ≥30 mg/g; †In addition, UACR ≥30 mg/g.CKD = chronic kidney disease; CI = confidence interval; eGFR = estimated glomerular filtration rate; NHANES = National Health and Nutrition Examination Survey; T2D = type 2 diabetes; UACR = urine albumin‐to‐creatinine ratioWu B et al. BMJ Open Diabetes Res Care. 2016;4(1):e000154.

Most Patients with T2D Do Not Yet Have Significantly Reduced Renal Function or Proteinuria

eGFR

10.2%

UACR

18.7%

Both eGFR and UACR

8.5%

None

62.6%

*CKD defined as UACR ≥30 mg/g or eGFR <60 mL/min/1.73 m2

CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; NHANES = National Health and Nutrition Examination Survey; UACR = urine albumin‐to‐creatinine ratioUnited States Renal Data System. 2018 Annual data report. Volume 1: CKD in the United States.

Distribution of markers of CKD* in NHANES participants with diabetes2013–2016



Long‐term Progression of Kidney Disease in Patients with T2D

United Kingdom Prospective Diabetes Study (UKPDS)1

5,102 patients with T2D*15 years after diagnosis2

Developed albuminuria§

Developed eGFR < 60 mL/min/1.73 m2

(CKD stage 3–5)

Albuminuria

Normoalbuminuria Microalbuminuria† Macroalbuminuria‡

Progressed from normo‐ to micro‐ albuminuria per year 2%

2.8%Progressed from micro‐ to macro‐ albuminuria per year

28%

A substantial proportion of patients with T2D will develop albuminuria and renal impairment

*The UKPDS enrolled patients with newly diagnosed T2D; †Defined as a urinary albumin concentration 50–299 mg/L; ‡Defined as a urinary albumin concentration ≥ 300 mg/L; §Defined as urinary albumin concentration ≥ 50 mg/L.CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; T2D = type 2 diabetes1. Adler A et al. Kidney Int. 2003;63:225‐32; 2. Retnakaran R et al. Diabetes. 2006;55:1832‐9.

38%

Progression of CKD in Diabetes

Preclinical Incipient diabetic nephropathy Overt diabetic nephropathy ESRD

Proteinuria

MicroalbuminuriaHypertension

Proteinuria, nephrotic syndrome, GFRGFR

GFR

Functional

Years

0

50

100

150

Glomerular filtration rate

(GFR

) (mL/min)

Urinary protein excretion

(mg/24

hr)

5000

1000

200

20

5 10 15 20 25

Mild Moderate Severe

CV risk

CKD = chronic kidney disease; CV = cardiovascular; ESRD = end‐stage renal disease; GFR = glomerular filtration rateWilliams ME. Med Clin North Am. 2013;97:75‐89.



Diabetes Is the Leading Cause of ESRD

Diabetes47%

Hypertension29%

Glomerulonephritis7%

Cystic kidney

3%

Other/unknown14%

37

50

33

4750 50

0

10

20

30

40

50

60

70

80

90

100RRI‐CKD StudyDialysis PatientsGeneral Population

c

Quality of Life Score

2

Physical Component Scale‡ Mental Component Scale‡

In U.S. Medicare patients, cost of ESRD in 2016 was $35.4 billion, accounting for 7.2% of overall Medicare spend3

*Data from the International Dialysis Outcomes and Practice Patterns Study (n=2,855); †Data from the Medical Outcomes Study Short Form‐36 manual (n=2,474); ‡Physical and mental component scales consist of physical functioning, physical role, physical pain, general health, vitality, social functioning, emotional role, and mental health. ESRD = end‐stage renal disease; RRI‐CKD = Renal Research Institute‐Chronic Kidney Disease; RRT = renal replacement therapy1. United States Renal Data System. 2019 Annual data report: executive summary; 2. Perlman RL et al. Am J Kidney Dis. 2005;45:658‐66; 3. United States Renal Data System. 2018 Annual data report. Volume 1: CKD in the United States.

Primary cause of ESRD1

U.S. population, 2017†

*

Declining Renal Function Predicts CV Mortality in Patients with CKD, A Pattern that Is Worse in Patients with Comorbid T2D

Diabetes Non‐diabetes

eGFR (mL/min per 1.73 m2)

8

1.5

2

4

1

015 30 45 60 75 90 105 120

Adjusted hazard ratio

CKD = chronic kidney disease; CV = cardiovascular; DKD = diabetic kidney disease; eGFR = estimated glomerular filtration rate; UACR = urine albumin‐to‐creatinine ratioFox C et al. Lancet. 2012;380(9854):1662‐74.

Cardiovascular mortality according to UACR in participants with and without diabetes

Cardiovascular mortality according to eGFRin participants with and without diabetes 8

1.5

2

4

1

02.5 5 10 30 300 1000

Adjusted hazard ratio

UACR (mg/g)



ESRD Risk Appears Stable Despite Improvements in Other Diabetes Complications

Trends in Age‐Standardized Rates of Diabetes‐Related Complications Among U.S.

Adults Diagnosed with Diabetes, 1990–2010

Events per 10,000 Adult Patients

with Diabetes

01990 1995 2000 2005 2010

24

25

50

75

100

125

150

End Stage Renal Disease

Amputation

Stroke

Acute MyocardialInfarction

Death from Hyperglycemic Crisis

Rates of myocardial infarction, stroke, and leg amputation numerators are from the National Hospital Discharge Survey; rates of end‐stage renal disease numerators are from the US Renal Data System; and rates of death from hyperglycemic crisis numerators are from the National Vital Statistics System. Denominators are from the National Health Interview Survey.Note: Circle size is proportional to the absolute number of cases. ESRD = end stage renal diseaseGregg EW et al. N Engl J Med. 2014;370:1514‐23.

Importance of Screening and Monitoring



Assessment of Kidney Function and Damage

• Albuminuria ‒ AER ≥ 30 mg/24 hr‒ UACR ≥ 30 mg/g [≥ 3 mg/mmol]

• Urine sediment abnormalities• Electrolyte and other abnormalities due to tubular disorders• Abnormalities detected by histology• Structural abnormalities detected by imaging• History of kidney transplantation

Kidney damage

Kidney function

• Decreased eGFR‒ Calculate from the serum creatinine concentration‒ eGFR <60 mL/min/1.73 m2 (Stage 3a–5)

Diagnosis of CKD requires two abnormal measurements at least 3 months apart

AER = albumin excretion rate; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; UACR = urine albumin‐to‐creatinine ratioKidney Disease Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012. Kidney Int Suppl. 2013;3:1‐150.

Categories of Kidney Function and DamageGFR category GFR (mL/min/1.73 m2) Kidney function

G1* ≥90 Normal or high

G2* 60–89 Mildly decreased†

G3a 45–59 Mildly to moderately decreased

G3b 30–44 Moderately to severely decreased

G4 15–29 Severely decreased

G5 <15 Kidney failure

Albuminuria category AER (mg/24 hr) ACR‡ (mg/mmol) ACR‡ (mg/g) Albumin in urine

A1 <30 <3 <30 Normal to mildly increased

A2 30–300 3–30 30–300 Moderately increased†

A3 >300 >30 >300 Severely increased§

CKD is classified based on cause, GFR category, and albuminuria category

eGFR

Albuminuria

*Does not fulfill the criteria for CKD in the absence of evidence of kidney damage; †Relative to young adult level; ‡Approximate equivalent;§Including nephrotic syndrome (albumin excretion usually > 2200 mg/24 hr [UACR > 2220 mg/g; > 220 mg/mmol]).ACR = albumin‐to‐creatinine ratio; AER = albumin excretion rate; CKD = chronic kidney disease; GFR = glomerular filtration rateKidney Disease Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012. Kidney Int Suppl. 2013;3:1‐150.



Which of the following patients are at risk for progression and should be referred to nephrologist? Select all that apply.

a. 75yo with eGFR 29 mL/min/1.72m2 in 2019 & 27 mL/min/1.72m2

in 2020

b. 56yo with diabetes, A1C 7.2%, eGFR above 60 mL/min/1.72m2, and UACR 486 mg/g

c. 63yo with eGFR 55 mL/min/1.72m2 at initial visit, 3 months later with eGFR 56 mL/min/1.72m2 and UACR below 30 mg/g

eGFR = estimated glomerular filtration rateUACR = urine albumin creatinine ratio

Monitoring of CKD Should Intensify as Renal Function Declines

KDIGO recommends referral to a nephrologist for advanced CKD

Recommended frequency of monitoring

(number of times per year)by GFR and albuminuria

category

CKD = chronic kidney disease; GFR = glomerular filtration rate; KDIGO = Kidney Disease: Improving Global Outcomes; UACR = urine albumin‐to‐creatinine ratioKidney Disease Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012. Kidney Int Suppl. 2013;3:1‐150.

Green = low risk (if no other markers of kidney disease, no CKD)

Yellow = moderately increased risk

Orange = high risk

Red = very high risk



Diagnosis of CKD in T2D Patients Is Deficient

Primary care setting1

9,307 patients with T2D15‐month review period

52.9%were not testedfor urine ACR

15.2%were not tested

for eGFR

Screening for CKD using GFR and UACR testing should be carried out annually in patients with T2D2

CKD Diagnosis Among Patients withT2D and Renal Impairment1

n = 5,036

No CKD45.9%

88%

Undiagnosed CKD

88%

Diagnosed CKD

12%

ACR = albumin‐to‐creatinine ratio; CKD = chronic kidney disease; DKD = diabetic kidney disease; eGFR = estimated glomerular filtration rate; T2D = type 2 diabetes 1. Szczech LA et al. PLoS One. 2014;9(11):e110535; 2. American Diabetes Association. Diabetes Care. 2020;43(suppl 1):S1‐S212.

Guidelines Recommend Routine Screening for CKD in Patients with Cardiorenal‐metabolic Disease

• At least once yearly, assess urinary albumin (spot urinary ACR) and eGFRin patients with:– T1D with duration of ≥5 years– T2D

American Diabetes Association3

• Test for CKD using eGFR creatinine and ACR in people with:‒ Diabetes‒ Hypertension‒ Acute kidney injury‒ CVD (ischemic heart disease, chronic HF,

peripheral or cerebral vascular disease)‒ Structural renal tract disease, recurrent

renal calculi, or prostatic hypertrophy‒ Multisystem disease with possible kidney

involvement (e.g., systemic lupus erythematosus)

‒ Family history of ESRD or hereditary kidney disease

‒ Opportunistic detection of hematuria

NICE2

• Regular testing of high‐risk groups (including those with diabetes, hypertension, and CVD) can give an early indication of kidney damage

• Public health policies should include screening of these high‐risk populations

KDIGO1

ACR = albumin‐to‐creatinine ratio; CKD = chronic kidney disease; CKD‐EPI = Chronic Kidney Disease Epidemiology Collaboration; CVD = cardiovascular disease; eGFR = estimated glomerular filtration rate; ESRD = end‐stage renal disease; HF = heart failure; KDIGO = Kidney Disease Improving Global Outcomes; NICE = UK National Institute for Health and Care Excellence; T1/2D = Type 1/2 diabetes1. Kidney Disease Improving Global Outcomes CKD Work Group. Kidney Int Suppl 2013;3:1‐150; 2. UK National Institute for Health and Care Excellence. NICE clinical guideline CG182, 2014. Chronic kidney disease in adults: assessment and management; 3. American Diabetes Association. Diabetes Care. 2020;43(suppl 1):S1‐S212.



Current Approaches to Management

Effective Treatment of CKD Includes Both Direct and Indirect Approaches

Hyperglycemia Hypertension Hypervolemia2 Reducing albuminuria

Slowing down eGFR decline

Indirect1 Direct1

Target risk factors* Target renal dysfunction

*This is not an exhaustive list of treatable risk factors.CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate1. Kidney Disease Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012. Kidney Int Suppl. 2013;3:1‐150; 2. Bello AK et al. Kidney Int Suppl. 2017;7:122‐9.



ADA Approach to Selection of Glycemic Target

A1C = glycated hemoglobin; ADA = American Diabetes Association.American Diabetes Association. Standards of Medical Care in Diabetes 2020. Diabetes Care. 2020;43(supplement 1):S1‐S212.

Risks potentially associated with hypoglycemia and other drug adverse events

Disease duration

Life expectancy

Important comorbidities

Established vascular complications

Patient preference

Resources, support system

A1C7%

morestringent

lessstringent

low high

newly diagnosed long‐standing

long short

absent severe

absent severefew / mild

highly motivated, excellent self‐care capacities Preference for less burdensome therapy

readily available limited

few / mild

2020 ADA Standards of Medical Care Antihyperglycemic Medication in Type 2 Diabetes: Overall Approach

*Label indication of reducing CVD eventsADA = American Diabetes Association; ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; CVD = cardiovascular disease; eGFR = estimated glomerular filtration rate; HF = heart failure. Adapted from the American Diabetes Association. Standards of Medical Care in Diabetes 2020. Diabetes Care. 2020;43(Supplement 1):S1‐S212.

Recommendations include a treatment approach to T2D that begins with an assessment of ASCVD, HF, and CKD status

First‐Line Therapy is Metformin and Comprehensive Lifestyle (including weight management and physical activity)

NO

If A1C Above Individualized Target, Proceed as Below

YES

Indicators of High‐Risk or Established ASCVD, CKD, or HF

Compelling Need To Minimize Weight Gain or Promote Weight

Loss

Cost is a Major Issue

Compelling NeedTo Minimize Hypoglycemia

Prioritize agents with low risk for hypoglycemia

Prioritize agents that reduce weight or avoid weight gain

Prioritize low‐cost alternatives

ASCVD Predominates

GLP‐1 RA with proven CVD benefit*

ORSGLT‐2i

with proven CVD benefit* if eGFR adequate

Heart Failure or CKD Predominates

SGLT‐2iwith evidence of reducing HF and/or CKD progression in CVOTs if eGFR

adequate OR

GLP‐1 RA with proven CVD benefit* if eGFR is less than adequate (if SGLT‐2i not tolerated)

Choose an agent with indication to reduce CVD events

Choose an agent with proven HF or CKD benefit for appropriate patients

Consider Independently of Baseline A1C or Individualized A1C Target



Evolution of the Definition of Hypertension

Adapted from Chang AR et al. Clin J Am Soc Nephrol. 2019;14:161-9.

1970 1980 1990 2000 2010 2020

JNC‐IDiastolic≥ 105

JNC‐II≥ 160/90

JNC‐V≥ 140/90

VA Cooperative Studies I, II1967‐1970

MRFIT 1982

SHEP 1991

MDRD 1994

HOT 1998

AASK2002

REIN‐22005

ACCORDADVANCE2010

SPRINT2015

2017 ACC/AHA≥ 130/80

Review of Hypertension Treatment

Angiotensinogen

Angiotensin I

Angiotensin II

Renin Secretion: Macula densa signalRenal artery pressure/blood flowSympathetic stimulation

Adrenal cortex

Kidney Peripheral Nervous System

Vascular Smooth Muscle

Heart

Aldosterone synthesis

Sodium/Water Reabsorption

Total Peripheral Resistance

Cardiac Output

Vasoconstriction

Blood Pressure

Blood Volume

Sympatheticdischarge

Contractility⑦direct renin inhibitor

① ACE inhibitors “‐pril”

② ARB “‐sartan”

③ β‐blockers “‐olol”

④ calcium channel blockers

⑤ diuretics

⑥ aldosterone antagonists

①

②

③④④

⑤⑤

⑦

⑥

Adapted from MacLaughlin EJ, Saseen JJ. Hypertension. In: DiPiro JT et al. Pharmacotherapy: A Pathophysiologic Approach, 11e; 2020.



Which of the following medication classes has NOT been associated with reduction in albuminuria?

a. Angiotensin‐converting enzyme inhibitors b. Mineralocorticoid/aldosterone antagonists c. Alpha blockersd. Angiotensin receptor blockers e. Sodium‐glucose cotransporter 2 inhibitors

Potential Impact of Early Intervention to Prevent Progression of Albuminuria

Follow‐up (6.2 years)*

eGFR

(mL/min per 1.73 m

2)

0

30

60

90

eGFR 10

No Albuminuria Normal aging

Early Intervention(expected)

Late Intervention(demonstrated)

With Albuminuria

*Data acquired from the Prevention of Renal and Vascular Endstage Disease (PREVEND) study, a Dutch population prospective cohort study with sequential follow‐up over a period of 6.2 years.eGFR = estimated glomerular filtration rateGansevoort R et al. J Am Soc Nephrol. 2009;20:465‐8.



Optimal Risk Factor Management Does Not Eliminate Risk of Diabetic Nephropathy*

24

39

46

10

2025

0

10

20

30

40

50

60

3.8 7.8 13.3Proportion of patients with nephropathy (%

)

Follow‐up (years)

Conventional treatmentIntensive treatment

Residual risk

Intensive treatment involved behavior modification and

therapies targeting hyperglycemia, hypertension,

dyslipidemia, and microalbuminuria2

RR: 0.44 (95% CI: 0.25–0.77)p = 0.004

*Diabetic nephropathy was defined as a urinary albumin excretion of more than 300 mg/24 hr in two of three consecutive sterile urine specimens.2CI = confidence interval; RR = relative risk1. Fioretto P et al. Nat Rev Endocrinol. 2010;6:19‐25; 2. Gaede P et al. Lancet. 1999;353(9153):617‐22.

Residual nephropathy risk in patients randomized to multifactorial intensive medical therapy1

Targets for Therapeutic Intervention in CKD

ProteinuriaIntraglomerular hypertension

Hypoxia Volume excess

Tubulointerstitialinjury

Anemia•Metabolic acidosis

Electrolyte imbalance

•Volume status

•Bone disorders

Reduce Kidney Damage1‐3 Address CKD Complications4

1. Phan O et al. Eur Cardiol. 2014;9: 115‐9; 2. Nangaku M. J Am Soc Nephrol. 2006;17:17‐25; 3. Khan Y et al. PLoS One. 2016;11:e0159335; 4. Chen T et al. JAMA. 2019;322:1294‐304.



Addressing Glomerular Hypertension in Managing the Risk of Progressive Kidney Damage in CKD

Efferent arteriole vasodilation

Clinical Implications

• Decreased glomerular pressure• Reduction in albuminuria• Less eGFR decline

Afferent arteriole vasoconstriction

CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate Delanaye P et al. Expert Opin Pharmacother. 2019;20:277‐94.

Summary



CV = cardiovascular; DKD = diabetic kidney disease; eGFR = estimated glomerular filtration rate; T2D = type 2 diabetes1. Wu B et al. BMJ Open Diabetes Res Care. 2016;4(1):e000154; 2. Szczech LA et al. PLoS One 2014;9(11):e110535; 3. Go AS et al. N Engl J Med. 2004;351:1296–305; 4. United States Renal Data System. 2019 Annual data report: executive summary; 5. Kidney Disease Improving Global Outcomes CKD Work Group. Kidney Int Suppl 2013;3:1‐150; 6. UK National Institute for Health and Care Excellence. NICE clinical guideline CG182, 2014. Chronic kidney disease in adults: assessment and management; 7. American Diabetes Association. Diabetes Care. 2020;43(suppl 1):S1‐S212; 8. Fox CS et al. Lancet. 2012;380(9854):1662‐73; 9. Dalrymple L et al. J Gen Intern Med. 2011;26:379‐85; 10. Jansson FJ et al. Diabetologia. 2018;61:1203‐11;11. Ragot S et al. Diabetes Care. 2016;39:1259–66.

The Burden of CKD is Significant Despite Current Approaches to Diagnosis and Treatment

KDIGO recommends routine CKD monitoring with increasing frequency as renal function declines5

Engage patients in risk factor reduction and use multifactorial interventions to tailor treatment regimens to the individual

In patients with T2D, earlier stages (1‐3) of CKD are more common than late stages1

Roughly 10% of patients with CKD and T2D receive a diagnosis2

Progressive deteriorations in renal function increase the risk of adverse outcomes, such as risk of hospitalizations, CV events, mortality, and healthcare costs3,4

Several guidelines recommend to regularly screen patients at increased risk5,6,7

Intervene early Preserve renal function Protect against CV risk, morbidity, and mortality

Lower eGFR and higher albuminuria are independently associated with increased adverse CV outcomes and premature death, which is worse in patients with diabetes8

CV mortality is more likely than progression to ESRD,9 however, protecting against renal decline decreases CV risk10,11


relationship of type 2 diabetes and chronic kidney disease: … · 2020. 9. 22. · 29‐15%

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