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KDIGO 2020 Comprehensive diabetes and CKD management Patients with diabetes and chronic kidney disease CKD should be treated with a comprehensive strategy to reduce risks of kidney dise

Kiểm soát Rối loạn mỡ máu trên bệnh nhân bệnh thận mạn do đái tháo đường

ThS BS Lê Hoài Nam Đai Học Y Dược Tp.HCM

Global Burden of Diabetes

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KDIGO Diabetes Guideline Webinar Looking at the Latest Evidence

Why Is CKD Strongly Associated With

Cardiovascular Morbidity and Mortality?

Ca, calcium; HDL, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein

cholesterol; Lp(a), lipoprotein (a); LPL, lipoprotein lipase; LV, left ventricle;

PO4, phosphate; PTH, parathyroid hormone; RAS, renin angiotensin system;

SNS, sympathetic nervous system; TG, triglycerides

Reprinted from Journal of the American College of Cardiology, 41, McCullough PA, Why Is Chronic Kidney Disease the “Spoiler” for

Cardiovascular Outcomes?, 725–728, Copyright (2003), with permission from Elsevier

Chronic Volume Overload/Diminished Response to Natriuretic

Peptides

Anemia Erythropoietin Deficiency Adverse LV Remodeling Abnormal Structural Proteins/Protein Turnover

“Advanced Glycation End-Products”

SNS Hyperactivation

Platelet Dysfunction

Dyslipidemia LPL/↓HDL/↑TG/↑Lp(a)

RAS Hyperactivation

Dyslipidemia in diabetic nephropathy

Role of dyslipidemia in diabetic nephropathy Dyslipidemia promotes the development of diabetic nephropathy Abnormal lipoprotein metabolism

is accelerated in diabetic nephropathy that causes further renal injury, leading to ESRD as well as cardiovascular (CV) events

Natural course of CKD

(eGFR 60–89, proteinuria) n=1741

Stage 3 (eGFR 30–59) N=11 278

Stage 4 (eGFR 15–29) N=777

Association of eGFR with All-Cause and CV Mortality in

General Population Cohorts: a Collaborative Meta-analysis

Chronic Kidney Disease Prognosis Consortium

Reprinted from The Lancet, 375, Matsushita K, et al, Association of estimated glomerular filtration rate and albuminuria with all-cause

and cardiovascular mortality: a collaborative meta-analysis of general population cohorts, 2073–2081,

Copyright (2010), with permission from Elsevier

KDIGO 2020

Comprehensive diabetes and CKD management

Patients with diabetes and chronic kidney disease (CKD) should be treated with a comprehensive

strategy to reduce risks of kidney disease progression and cardiovascular disease

KDIGO 2020

KDIGO 2013

ASCVD prevention guideline recommendations:

Statins in patients with CKD

ADA5 Diabetic patients aged ≥40 years

No specific recommendation in CKD

Moderate- to high-intensity statin

AHA/ASA6 Primary stroke prevention (general

‡Higher doses can be considered in selected patients

KDIGO, Kidney Disease Improving Global Outcomes;

NICE, National Institute for Health and Care Excellence (UK)

1 Stone NJ, et al J Am Coll Cardiol 2014;63:2889–2934;

2 Fifth Joint Task Force on CVD Prevention Eur Heart J 2012;33:1635–1701;

3 NICE Lipid modification July 2014 http://www.nice.org.uk/Guidance/CG181;

4 Joint British Societies Heart 2014;100:ii1–ii167 doi:10.1136/heartjnl-2014-305693;

5 American Diabetes Association Diabetes Care 2015;38(Suppl 1):S1−S94;

6 Meschia JF et al Stroke 2014;45:3754−3832;

7 Kernan WL et al Stroke 2014;45:2160–2136;

8 KDIGO Kidney Int Suppl 2013;3:271–279

CARDS: Effect of atorvastatin on major CV events

in patients with diabetes

*Primary endpoint (acute coronary heart disease event, coronary

revascularization, or stroke)

1 Colhoun HM, et al Lancet 2004;364:685–696;

2 Hitman GA, et al Diabet Med 2007;24:1313–1321;

3 Lipitor Highlights of US Prescribing Information, 2015 Reprinted from The Lancet, 364, Colhoun HM, et al, Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial, 685–696, Copyright (2004), with permission from Elsevier

Stroke

48%

RRR

HR=0.52 95% CI 0.31–0.89 (p=0.016)2

ARR=1.3%

NNT 77 over 4 years

Fatal/ nonfatal MI

42%

RRR

HR=0.58 95% CI 0.39–0.86 (p=0.007)3

ARR=1.9% NNT 53 over 4 years

Major CV events*

37%

RRR

HR=0.63 95% CI 0.48–0.83 (p=0.001)1

ARR=3.2%

NNT 31 over 4 years

CARDS: Effect of atorvastatin on CV events in

patients with diabetes with and without CKD

*Primary endpoint

CI, confidence interval; CKD, chronic kidney disease; CV,

eGFR <60 mL/min/1.73m2 0.04 eGFR ≥60 mL/min/1.73m2 0.3

eGFR <60 mL/min/1.73m2 0.6 eGFR ≥60 mL/min/1.73m2 0.05

CARDS subgroup analysis: Patients with CKD (n=970) vs without CKD (n=1868) at baseline

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Atorvastatin 10 mg LDL target: 100 mg/dL (≈2.6 mmol/L)

Atorvastatin 80 mg LDL target: 75 mg/dL (≈1.9 mmol/L)

PRIMARY EFFICACY OUTCOME MEASURE

• Time to occurrence of a major CV event

– CHD death – Nonfatal, non-procedure-related MI – Resuscitated cardiac arrest

– Fatal or nonfatal stroke

1–8 Weeks 8 Weeks Median follow-up = 4.9 years

TNT: Effect of high- vs moderate-intensity atorvastatinon

major CV events in patients with CHD

*Primary endpoint: Death from CHD, nonfatal

non–procedure-related myocardial infarction, resuscitation after cardiac arrest, or

fatal or nonfatal stroke

From New England Journal of Medicine, LaRosa JC et al, Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease, 352, 1425–1435

Copyright © (2005) Massachusetts Medical Society Reprinted with

permission from Massachusetts Medical Society

Atorvastatin 10 mg (n=5006) Mean LDL-C during study 101 mg/dL (≈2.6 mmol/L) Atorvastatin 80 mg (n=4995) Mean LDL-C during study 77 mg/dL (≈2.0 mmol/L)

NNT 45 over 4.9 years

26%

RRR

HR=0.74 95% CI 0.49–0.94 (p=0.01) ARR=0.9% NNT 111 over 4.9 years

TNT: Changes in LDL-C in patients with and without CKD* at

baseline

*eGFR <60 mL/min/1.73 m2

†8 weeks’ open-label treatment with atorvastatin 10 mg Shepherd J et al J Am Coll Cardiol 2008;51:1448–1454

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TNT: Time to first major CV event—

CHD patients with and without CKD

*eGFR <60 mL/min/1.73 m2

NNT, number needed to treat to prevent one

major cardiovascular event over 5 years

Reprinted from J Am Coll Cardiol, 51, Shepherd J et al, Intensive Lipid Lowering WithAtorvastatin in Patients With Coronary Heart Disease and Chronic Kidney Disease, 1448–1454

Copyright (2008), with permission from Elsevier

15%

RRR

HR = 0.85 (95% CI:

Atorvastatin 80 mg (n=3225): End-of-Tx LDL = 80 mg/dL (≈2.1 mmol/L)

TNT: Effect of high- vs moderate-intensity atorvastatin on

major CV events in patients with CHD, diabetes and CKD

CKD defined as eGFR <60 mL/min/1.73m2

*Primary endpoint: Death from CHD, nonfatal

non–procedure-related myocardial infarction, resuscitation after cardiac arrest, or

fatal or nonfatal stroke

Reprinted from Mayo Clin Proc, 83, Shepherd J et al Intensive Lipid Lowering With Atorvastatin in Patients With Coronary Artery Disease, Diabetes, and Chronic Kidney Disease, 870–879

Copyright (2008), with permission from Elsevier

NNT 14 over 4.8 years

Major CV events*

Percent change from baseline eGFR in TNT patients

by CKD status

Mean changes from baseline with atorvastatin 10 mg and 80 mg at

the final visit (LOCF) were +6.6% and +9.9% in CKD patients

(P<0.0001), and +5.2% and +7.6% in patients with normal eGFR

(P<0.0001).

Republished with permission of American Society of Nephrology, from

Effect of Intensive Lipid Lowering with Atorvastatin onRenal Function in Patients with Coronary Heart Disease: The Treating

to New Targets (TNT) Study, Shepherd J et al, 2, 2007; permission conveyed through Copyright Clearance Center, Inc

-2

0 2 4 6 8 10

Patients with normal eGFR

Atorvastatin 80 mg Atorvastatin 10 mg

3040 6387

2955 6207

2806 5980

2681 5779

2264 5030

TNT: Adverse events in patients with and without

CKD*

Patients with CKD Patients with normal eGFR

Atorvastatin 10 mg (n=1,505)

Atorvastatin 80 mg (n=1,602)

Atorvastatin 10 mg (n=3,324)

Atorvastatin 80 mg (n=3,225)

Treatment-related adverse events 78 (5.2) 140 (8.7) 191 (5.7) 241 (7.5) Discontinuations attributable to

treatment-related adverse events 29 (1.9) 68 (4.2) 82 (2.5) 121 (3.8) Hematuria 51 (3.4) 58 (3.6) 124 (3.7) 121 (3.8)

Albuminuria 25 (1.7) 28 (1.7) 47 (1.4) 53 (1.6) Persistent elevations in alanine

†Two measurements ≥3 times the upper limit of normal, obtained 4 to 10 days apart;

‡2 measurements ≥10 times the upper limit of normal, obtained 4 to 10 days apart

Reprinted from J Am Coll Cardiol, 51, Shepherd J et al, Intensive Lipid Lowering With Atorvastatin in Patients With Coronary Heart Disease and Chronic Kidney Disease, 1448–1454 Copyright (2008), with permission from Elsevier

Change in eGFR in stroke/TIA patients (SPARCL)

SPARCL:

• Secondary prevention study

• Randomized 4700 patients with prior stroke or TIA to atorvastatin 80 mg/day or placebo.1

Slide shows change in eGFR in patients randomized to atorvastatin or placebo.2

†estimated from graph

1 Amarenco P et al N Engl J Med 2006;355:549–559;

2 Amarenco P et al Stroke 2014;45:2974–2982

Research question: Does atorvastatin improve

kidney function?

 Higher doses reduce CV events further

 Atorvastatin preserves or improves renal function during follow-up

 This effect is dose-dependent

1 Colhoun HM, et al Am J Kidney Dis 2009;54:810–819

2 Shepherd J et al J Am Coll Cardiol 2008;51:1448–1454;

3 Shepherd J et al Clin J Am Soc Nephrol 2007;2:1131–1139

>2 serum creatinine measurements available

atorvastatin 10 mg, atorvastatin 80 mg

Vogt L, et al J Am Heart Assoc 201;8:e010827 DOI:

10.1161/JAHA.118.010827.

Trials in the database

Vogt L, et al J Am Heart Assoc 2019;8:e010827 DOI:

10.1161/JAHA.118.010827.

Trials in the database

patients

Clinical condition Treatment arms Serum creatinine available

ASCOT 10,305 Hypertension without CHD Atorva 10 mg vs

placebo

Baseline/month 6/ year 1/ year 2/year 3/year 4

CARDS 2,838 Type II diabetes mellitus Atorva 10 mg vs

SPARCL 4,731 Stroke or transient ischemic attack Atorva 80 mg vs

placebo

Baseline/year 1/year 2/ year 3/year 4/year 5/etc

TNT 10,001 CHD and LDL-C <130 mg/dL Atorva 80 mg vs

10 mg

Baseline/year 1/year 2/ year 3/year 4/year 5/etc

SAGE$ 893 Elderly (65-85 yrs) with

myocardial ischemia

Atorva 80 mg vs prava 40 mg

Baseline/month 3/

year 1

*Excluded trials;

$atorvastatin 80 arm only; 30,527 subjects left for analysis

Vogt L, et al J Am Heart Assoc 2019;8:e010827 DOI:

10.1161/JAHA.118.010827.

Baseline Characteristics (Mean [SD]) of Pooled Treatment Arms

CKD (eGFR <60 mL/[min.17.73 m 2 )

29.8 / 29.8 / 35.6)

Vogt L, et al J Am Heart Assoc 2019;8:e010827 DOI:

10.1161/JAHA.118.010827.

1/serum creatinine versus time in the placebo,

atorvastatin 10 mg and atorvastatin 80 mg groups

Vogt L, et al J Am Heart Assoc 2019;8:e010827 DOI:

10.1161/JAHA.118.010827.

Comparisons of slope between groups

#p<0.0009

Placebo N=10,057

Atorvastatin 10 mg N=12,763

Slope within TNT only

Study*slope interactions for each pooling: p<0.0005

Vogt L, et al J Am Heart Assoc 2019;8:e010827 DOI:

10.1161/JAHA.118.010827.

Effect of kidney function slope on cardiovascular (CV)

outcomes and all-cause mortality (adjusted analysis)

Vogt L, et al J Am Heart Assoc 2019;8:e010827 DOI:

10.1161/JAHA.118.010827.

◼ In this aggregate analysis of 6 large RCTs with >30,000 patients at

risk or with CV disease, atorvastatin improves kidney function

over time

manner

with reduced CV events and all-cause mortality

Vogt L, et al J Am Heart Assoc 2019;8:e010827 DOI:

10.1161/JAHA.118.010827.

Do statins offer renal protection in patients with

CKD and diabetes?

CV protection and renal protection with statins in CKD or dialysis patients

two statins

parameters (although no direct comparison was prespecified)

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de Zeeuw D, et al Lancet Diabetes Endocrinol 2015;3:181–190;

http://dx.doi.org/10.1016/S2213-8587(14)70246-3

PLANET I and II investigated the effects of atorvastatin and rosuvastatin

on renal function in patients with CKD with and without diabetes

*Intention-to-treat (ITT) populations

1.Urinary protein / creatinine ratio 500–5,000 mg/g;

2.Fasting LDL-C ≥90 mg/dL (2.33 mmol/L);

ACEi, angiotensin converting enzyme inhibitor;

ARB, angiotensin receptor blocker

de Zeeuw D, et al Lancet Diabetes Endocrinol 2015;3:181–190;

▪ ACEis or ARBs for ≥3

months prior to screening

Patient population 52 weeks follow-up

baseline to Week 52 or last on-treatment observation carried forward (Week 52 LOCF)

Rosuvastatin 10 mg/day

Atorvastatin 80 mg/day PLANET I and II were multicenter, randomized, double-blind studies

0.94

0.99 0.96

PLANET I and II: Effect of atorvastatin or rosuvastatin on

urinary protein/creatinine ratio

aPost-hoc analysis

*p<0.05 vs baseline; **p<0.01 vs baseline; ***p<0.001 vs baseline

U , urinary protein/creatinine ratio

de Zeeuw D, et al Lancet Diabetes Endocrinol 2015;3:181–190;

vs baseline (%)

-37 -47 -44

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*p<0.05 vs baseline; **p<0.01 vs baseline; ***p<0.001 vs baseline

eGFR, estimated glomerular filtration rate; LOCF, last observation

PLANET I: Reported adverse events

Any adverse event 69 (59.5) 79 (64.2) 63 (57.3)

Any serious adverse event* 18 (15.5) 20 (16.3) 21 (19.1)

Any renal adverse event 9 (7.8) 12 (9.8) 5 (4.5)

Serum creatinine doubling

or acute renal failure 0 9 (7.3) 1 (0.9)

Reprinted from The Lancet, 3, de Zeeuw D, et al, Renal eff ects of atorvastatin and rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I):

a randomised clinical trial, 181–190 Copyright (2015), with permission from Elsevier

Statistical analysis of adverse events was not presented One serious AE (2 episodes of cardiac failure in rosuvastatin 10 mg group) was considered related to study drug

No episodes of acute renal failure were considered related to study drug

41

◼ In diabetic and non-diabetic patients with proteinuria:

atorvastatin 80 mg reduced proteinuria

in eGFR; atorvastatin 80 mg showed no change in eGFR

concentrations to a greater extent than did high-dose

atorvastatin, atorvastatin seems to have more renoprotective effects in the studied CKD population

de Zeeuw D, et al Lancet Diabetes Endocrinol 2015;3:181–190;

http://dx.doi.org/10.1016/S2213-8587(14)70246-3

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Prescribing information for statins in CKD

Atorvastatin <2% renal excretion 1

Rosuvastatin Severe renal impairment: starting dose 5 mg, not to exceed

Simvastatin Severe renal impairment: use with caution 4

Simvastatin/

ezetimibe

Fluvastatin Mild to moderate renal impairment: dosage adjustment not

Pravastatin Moderate or severe renal impairment: starting dose 10 mg 7

Lovastatin Creatinine clearance <30 mL/min: dose >20 mg with caution 8

1 Harper CR, Jacobson TA J Am Coll Cardiol 2008;51:2375–2384;

2 Lipitor Highlights of US Prescribing Information, 2013; 3 Crestor (Rosuvastatin calcium) Prescribing Information AstraZeneca, December 2012;

4 Zocor (simvastatin calcium) Prescribing Information Merck Sharp & Dohme Ltd, October 2012;

5 Vytorin (ezetimibe/simvastatin) Tablets Prescribing Information Merck/Schering-Plough Pharmaceuticals February 2013;

6 Lescol (fluvastatin sodium) Summary of Product Characteristics Novartis, November 2013;

7 Lipostat (pravastatin sodium) Summary of Product Characteristics Bristol-Myers Squibb, April 2013;

8 Mevacor (lovastatin) Prescribing Information Merck, February 2014

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