pin papdi xvii dyslipidemia surabaya, 4-6 oktober2019 ... suastika... · dyslipidemia in ckd:...

Dyslipidemia Management in

Diabetes and CKD

Ketut SuastikaDivision of Endocrinology and Metabolism

Department of Internal Medicine, Faculty of Medicine, Udayana University-SanglahHospital, Denpasar

PIN Papdi XVII

Surabaya, 4-6 Oktober2019

Disclosures

I have received honorarium asspeaker/consultant, support forresearch/attendance at educationalmeetings from: Novo Nordisk, Sanofi,Astrazeneca, Boeringer Ingelheim, MSD,Merck, Servier, Novartis, Takeda, Otsuka,Pfizer, Dexa Medica, Kalbe

Lipid Metabolism:

Miller M et al. Circulation 2011; 123: 2292-2333

Apo A-I indicates apo- Apo A-V indicates apolipoprotein A-V; CMR, chylomicron remnant; FFAs, free fatty acids; HTGL, hepatic triglyceride lipase; IDL, intermediate-density lipopro-tein; LDL, low-density lipoprotein; LDL-R, low-density lipoprotein receptor; LPL, lipoprotein lipase; LRP, LDL receptor– related protein; VLDL, very low-density lipoprotein; and VLDL-R, very low-density lipoprotein receptor.

HDL metabolism and reverse cholesterol transport

HDL may exert its cardioprotective effect by promoting cholesterol catabolism in two ways:• HDL (acting as a reverse cholesterol transporter) travels to the liver, where it is recognized by the Cla-1/SR-B I receptor, ingested,

and catabolized;• HDL transfers CEs to TG-rich particles via cholesterol ester transfer protein (CETP) to form chylomicron remnants and LDL, which

are then transported to tissues and catabolized.

Metabolic consequences of insulin resistance

Miller M et al. Circulation 2011; 123: 2292-2333

Apo A-I indicates apolipoprotein A-I; Apo B-100, apolipoprotein B-100; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; DGAT, diacyl- glycerol acyltransferase; FFA, free fatty acid; HDL, high-density lipoprotein; HTGL, hepatic triglyceride lipase; LDL, low-density lipoprotein; TG, triglyceride; and VLDL, very low-density lipoprotein.

Dyslipidemia in CKD: Pathogenesis

LDL-C sdLDL TG HDL-C Lp(a)

Predialysis CKD OR

Nephrotic syndrome OR OR OR

Hemodialysis OR

Peritoneal dialysis

Renal transplantation a

aMainly in individuals with high-molecular-weight apolipoprotein(a) phenotypes.

Lipid in CKD Stages 1-4

TG: -Reduced catabolism• LPL activity: down-regulation enzyme

gene; increased Apo C-III• Secondary hyperparathyroidism

-Overproduction: insulin resistanceHDL-C: -Reduced Apo AI and AII

-Diminished activity LCATLp(a): -Low-molecular-weight apo (a) isoform

Lipid in Nephrotic Syndrome

-Increased hepatic production and secretion ofApo B-containing lipoprotein (VLDL, LDL)

-Reduced serum albumin-Reduced catabolism – downregulation endothelian

LPL and hepatic lipase gene -Acquired LDL-receptor deficiency

Lipid in Hemo- and Peritoneal Dialysis

-Increased catabolic rate Apo AI-Related to mebrane (high- or low-flux),

bicarbonate, , heparin, phosphate binder selevamer HCl

Lipid in Kidney Graft Recipients

-Deterioration of Apo B-containing lipoprotein (VLDL, LDL)

-Immunosupressive therapy: azathioprine decreases Lp(a), cyclosporine increases LDL-C and TG and reduces HDL-C

Tsimihodimos V et al. Am J Nephrol 2008; 28: 958-973; Tsimihodimos V et al. The Open Cardiovasc Med J 2011; 5: 41-48

73.8

53.951.2

31.3

20.4

26.2

83.6

60.5 59.7

32.5 32.5

20.7

79

85.280

34.9

46.742.2

0

10

20

30

40

50

60

70

80

90

LDL-C Non-HDL-C ApoB HDL-C TG sdLDL

NGT IFG DM

LDL-C ( 100 mg/dl), Non-HDL-C (130 mg/dl), ApoB (90 mg/dl), HDL-C (men <40 mg/dl, women <50 mg/dl), TG (150 mg/dl), sdLDL (LDL-C/apoB <1.2).

Ketut Suastika1, I Made Siswadi Semadi1, I Made Pande Dwipayana1, Made Ratna Saraswati1, Wira Gotera1, AnakAgung Gde Budhiarta1 , Kinuyo Matsumoto2 , Naemi Kajiwara2, Hiroshi Taniguchi3

1Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Udayana University/SanglahHospital, Denpasar, Bali, Indonesia; 2Graduate School of Life Science, Kobe Women’s University, Kobe, Japan; 3Department of Diabetology, Graduate School of Health Sciences, Kobe University, Kobe, Japan

International Journal of General Medicine 2019;12: 313–321

Major ASCVD Risk FactorAACE 2017 Guideline

Jellinger P et al., Endocr Pract 2017; 23: 479-497

Major Risk Factors

• Advancing age• Total serum

cholesterol• Non-HDL-C• LDL-C• Low HDL-C• DM• HTN• Stage 3 or 4 CKD• Cigarette smoking• Family history of

ASCVD

Nontraditional Risk factors

• Lipoproteinemia (a)

• Clotting factors• Inflammation

markers (hsCRP, Lp-PLA2)

• Homocysteine levels

• Apo E4 isoform• Uric acid• TG-rich

remnants

Additional Risk factors

• Obesity, abdominal obesity

• Family history of hyperlipidemia

• Small, dense LDL-C

• Apo-B• LDL particle

concentration• Fasting/postprand

ial hypertriglyceridemia

• PCOS• Dyslipidemia triad

ASCVD Risk categoriesAACE 2017 guideline


a Major independent risk factors are high LDL-C, polycystic ovary syndrome, cigarette smoking, hypertension (blood pressure ≥140/90 mm Hg or on hypertensive medication), low HDL-C (<40 mg/dL), family history of coronary artery disease (in male, first-degree relative younger than 55 years; in female, first-degree relative younger than 65 years), chronic renal disease (CKD) stage 3/4, evidence of coronary artery calcification and age (men ≥45; women ≥55 years). Subtract 1 risk factor if the person has high HDL-C. b Framingham risk scoring is applied to determine 10-year risk.

Risk category Risk factorsa/10-year riskb

Extreme risk

• Progressive ASCVD, including unstable angina that persists after achieving an LDL-C <70 mg/dL

• Established clinical ASCVD with DM, stage 3 or 4 CKD, and/or HeFH

• History of premature ASCVD (<55 male, <65 female)

Very high risk

• Established or recent hospitalization for ACS; coronary, carotid, or peripheral vascular disease,10-y risk >20%

• DM or stage 3 or 4 CKD with 1 or more risk factor(s)• HeFH

High risk • >2 risk factors and a 10-y risk of 10%-20%• DM or stage 3 or 4 CKD with no other risk factors

Moderate risk

• <2 risk factors and 10-y risk of <10%

Low risk • No risk factors

ASCVD Risk Categories and LDL-C Treatment Goals (AACE 2017 guideline)

Risk CategoryTreatment Goals

LDL-C (mg/dL)

Extreme risk <55

Very high risk <70

High risk <100

Moderate risk <100

Low risk <130


Cardiovascular risk is greatest when both T2DM and CKD are present

AMI CVA/TIA PVD Death

Inci

den

ce p

er 1

00

pat

ien

t-ye

ars

X 2.2

X 1.7

X 2.1

X 2.5

AMI = acute myocardial infarction; CXVA/TIA = cerebrovascular accident/transient ischemic attack;PVD = peripheral vascular disease

T2DM + / CKD +T2DM + / CKD -

0

10

20

30

Foley RN, et al. J Am Soc Nephrol 2005; 16: 489-495

Management of Dyslipidemia in DM and CKD

Nonpharmacologic Dyslipidemia Treatment


Role of the apolipoprotein B-containing lipoproteins in atherosclerotic plaque initiation, progression, rupture and regression

Nordestgaard BG, et al. Nature Rev Cardiol 2018; 15: 261-272

Indications for Statin Pharmacotherapy

Clinical Atherosclero

sisAAA DM CKD LDL-C > 5.0

mmol/L (190 mg/dL)

• MI, ACS, stable angina, CAD

• Stroke TIA, documented carotid disease

• PAD, claudication, and/or ABI <0.9

• Abdominal aorta >3.0 cm; or

• Previous aneurysmasurgery

• >40 y; or• >15 y

duration and age >30 y; or

• Microvascu-lar complications

• >3 moduration; and

• ACR >3.0 mg/mmol; or

• eGFR <60 mL/min/1.73 m2

• LDL-C >5.0 mmol/L; or

• Documented FH

• Excluded secondary causes

Anderson TJ et al. Can J Cardiol 2016; 32: 1263-1282

2018 AHA/ACC/AACVPR/AAPA/ ABC/ACPM/ADA/AGS/APhA/ ASPC/NLA/PCNA Guideline on

the Management of Blood Cholesterol

1. In all individuals, emphasize a heart-healthy lifestyle across the life course

2. In patients with clinical ASCVD, reduce low-density lipoprotein cholesterol (LDL-C) with high-intensity statin therapy or maximally tolerated statin therapy

3. In very high-risk ASCVD, use a LDL-C threshold of 70 mg/dL (1.8 mmol/L) to consider addition of non-statins to statin therapy. Very high-risk includes a history of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions

4. In patients with severe primary hypercholesterolemia (LDL-C level > 190 mg/dL [> 4.9 mmol/L]), without calculating 10-year ASCVD risk, begin high-intensity statin therapy

Top 10 Take-home Messages To Reduce Risk Of Atherosclerotic Cardiovascular Disease Through

Cholesterol Management

Grundy SM et al. JACC 2019; 73:3168–209



5. In patients 40 to 75 years of age with diabetes mellitus and LDL-C > 70 mg/dL (> 1.8 mmol/L), start moderate-intensity statin therapy without calculating 10-year ASCVD risk

6. In adults 40 to 75 years of age evaluated for primary ASCVD prevention, have a clinician–patient risk discussion before starting statin therapy

7. In adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels > 70 mg/dL (> 1.8 mmol/L), at a 10-year ASCVD risk of > 7.5%, start a moderate-intensity statin if a discussion of treatment options favors statin therapy






8. In adults 40 to 75 years of age without diabetes mellitus and 10-year risk of 7.5% to 19.9% (intermediate risk), risk-enhancing factors favorinitiation of statin therapy (see No. 7)

9. In adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels > 70 mg/dL to 189 mg/dL (> 1.8–4.9 mmol/L), at a 10-year ASCVD risk of > 7.5% to 19.9%, if a decision about statin therapy is uncertain, consider measuring CAC.

10.Assess adherence and percentage response to LDL-C– lowering medications and lifestyle changes with repeat lipid measurement 4 to 12 weeks after statin initiation or dose adjustment, repeated every 3 to 12 months as needed




Recommendations for statin and combination treatment in adults with

diabetes (ADA, 2019)

Age ASCVD or 10-year ASCVD risk >20%

Recommended statin intensity^ and combination treatment*

< 40 years NoYes

None†

High• In patients with ASCVD, if LDL

cholesterol >70 mg/dL despite maximally tolerated statin dose, consider adding additional LDL-lowering therapy (such as ezetimibe or PCSK9 inhibitor)#

> 40 years No Yes

Moderate‡

High• In patients with ASCVD, if LDL

cholesterol >70 mg/dL despite maximally tolerated statin dose, consider adding additional LDL-lowering therapy (such as ezetimibe or PCSK9 inhibitor)

ASCVD, atherosclerotic cardiovascular disease; PCSK9, proprotein convertase subtilisin/kexin type 9. *In addition to lifestyle therapy. ^For patients who do not tolerate the intended intensity of statin, the maximally tolerated statin dose should be used. †Moderate-intensity statin may be considered based on risk-benefit profile and presence of ASCVD risk factors. ASCVD risk factors include LDL cholesterol >100 mg/dL (2.6 mmol/L), high blood pressure, smoking, chronic kidney disease, albuminuria, and family history of premature ASCVD. ‡High-intensity statin may be considered based on risk-benefit profile and presence of ASCVD risk factors. #Adults aged ,40 years with prevalent ASCVD were not well represented in clinical trials of non-statin–based LDL reduction. Before initiating combination lipid-lowering therapy, consider the potential for further ASCVD risk reduction, drug-specific adverse effects, and patient preferences.

ADA. Diabetes Care 2019;42(Suppl. 1):S103–S123 | https://doi.org/10.2337/dc19S010

High-intensity and moderate-intensity statin therapy* (ADA, 2019)

High-intensity statin therapy (lowers LDL cholesterol by > 50%)

Moderate-intensity statin therapy (lowers LDL cholesterol by 30–50%)

Atorvastatin 40–80 mg Rosuvastatin 20–40 mg

Atorvastatin 10–20 mg Rosuvastatin 5–10 mg Simvastatin 20–40 mg Pravastatin 40–80 mg Lovastatin 40 mg Fluvastatin XL 80 mg Pitavastatin 2–4 mg

*Once-daily dosing. XL, extended release.

ADA. Diabetes Care 2019;42(Suppl. 1):S103–S123 | https://doi.org/10.2337/dc19S010

Adjusted relation between LDL-C and HR of myocardial infarction by eGFR as a continuous

variable

KDIGO Cinical Practice Guideline for Lipid Management in Chronic Kidney Disease. Kideney Internat Suppl 2013; 3.

eGFR = 15 ml/min/1.73m2 eGFR = 30 ml/min/1.73m2 eGFR = 45 ml/min/1.73m2

eGFR = 90 ml/min/1.73m2

LDL-C, mmol/lLDL-C, mmol/l LDL-C, mmol/l

LDL-C, mmol/l LDL-C, mmol/l

Haz

ard

rat

io

Haz

ard

rat

io

Haz

ard

rat

io

Haz

ard

rat

io

Haz

ard

rat

io

eGFR = 60 ml/min/1.73m2

1.81 mmol/l = 70 mg/dl2.59 mmol/l = 100 mg/dl

Effects of Pitavastatin on the eGFR in hypercholesterolemic patients with CKD

Sub-analysis of LIVES Study

Of the 19,925 patients enrolled in the aforementioned study, data from 3,119 patients were analyzed to evaluate the effects of pitavastatintreatment for 104 weeks on the eGFR. In this sub-analysis, 958 patients with a baseline eGFR of less than 60 mL/min/1.73 m2 (30.7%) were analyzed Kimura K, et al. J Atheroscler Thromb, 2010; 17:601-609.

Differential effect of statins on diabetic nephropathy in db/db mice

In conclusion, our data suggest that pitavastatin and rosuvastatincan improve diabetic nephropathy through the suppression ofglomerular hypertrophy, independent of lipid- lowering or anti-oxidative effects.

Tamura Y, et al. International Journal Of Molecular Medicine 28: 683-687, 2011

A B

Mea

n g

lom

eru

lar

area

(m

m2)

m Con Pra Pit Ros

100,000

80,000

60,000

40,000

***

Recommended doses (mg/d) of statins in adults with CKD

Statins eGFR G1-G2 eGFR G3a-G5, including patients on dialysis or with a kidney transplant

Lovastatin GP nd

Fluvastatin GP 801

Atorvastatin GP 202

Rosuvastatin GP 103

Simvastatin/Ezetimibe GP 20/104

Pravastatin GP 40

Simvastatin GP 40

Pitavastatin GP 2

All statins may not be available in all countries. Lower doses than those used in major trials of statins in CKD populations may beappropriate in Asian countries. Note that rosuvastatin 40mg daily is not recommended for use in CKD 1-2 nontransplant patients,as it may increase the risk of adverse renal events. Cyclosporin inhibits the metabolism of certain statins resulting in higher bloodlevels. Data based on 1ALERT, 24D, 3AURORA, 4SHARP. Abbreviations: eGFR, estimated glomerular filtration rate; GP, generalpopulation; nd, not done or not studied.GFR: G1 (≥90), G2 (60-89), G3a (45-59), G3b (30-44), G4 (15-29), G5 (<15)

KDIGO Cinical Practice Guideline for Lipid Management in Chronic Kidney Disease. Kideney Internat Suppl 2013; 3.

Statin and New Onset Diabetes

Conclusions: It is imperative that patients on statin therapy be monitored carefully for NODM. However, it can be argued that the risk of statin therapy is offset by the multitude of cardiovascular and kidney-protective effects provided by such an important and highly effective therapeutic agent.

Statin induced new onset diabetes

A meta-analysis including ~40 000 patientswith stable coronary heart disease or recentacute coronary syndrome in five RCTs showedthat high intensity statin therapy increasedthe risk of incident DM by 12%, but alsoreduced the risk of CVD events by 16%, or in

absolute terms, prevented 3.5 CVD eventsfor each additional case of diabetes. In

this analysis, a ‘case of diabetes’ was definedby serum glycated haemoglobin (HbA1c)>6.5, a laboratory finding that has noimmediate impact on the quality of life, andtherefore should not be compared with out-comes such as stroke or death frommyocardial infarction

Mach F., et al. European Heart Journal (2018) 39, 2526–2539

Pitavastatin vs. Atorvastatin: Effect on blood glucose in patients with T2DM and combined (mixed)

dyslipidemia

• Reductions in LDL-C and changes in other lipids were not significantly different in patients treated with pitavastatin 4 mg or atorvastatin 20 or 40 mg

• Mean percent changes in blood glucose from core study baseline to week 12 and to extension study week 44. CI, 95% confidence interval; NS, not significant vs. baseline. *p < 0.05 vs. baseline. †Seven patients up-titrated their dose of atorvastatin from 20 to 40 mg/day at extension study week 0

Extension studyPitavastatin 4 mg/day (n = 143)Atorvastatin 20 or 40 mg/day† (n = 71)

Core studyPitavastatin 4 mg/day (n = 275)Atorvastatin 20 mg/day (n = 137)

Week 12Core study

Week 44Extension study

Mea

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ge f

rom

bas

elin

eIn

blo

od

glu

cose

(%

)

NS

NS

* *

10

8

6

4

2

0

Gumprecht J, et al. . Diabetes, Obesity and Metabolism 13: 1047–1055, 2011

Pitavastatin vs. Atorvastatin vs. Rosuvastatin: Effect on new-onset diabetes mellitus in patients with acute myocardial

infarction

Choi JY, et al. Am J cardiol 2018. DOI: 10.1016/j.amjcard.2018.06.017

P value = 0.001

10.4%

3.0%

8.4%

Rosuvastatin

Atorvastatin

Pitavastatin

0 730365 1095

New

-onset

dia

bete

s m

ellit

us

Cumulative (%)

5

10

15

0

Pitava vs. Rosuva, HR = 3.906Pitava vs. Atorva, HR = 2.615

Days

Factors favouring diabetogenic effects of statins and candidate mechanisms

Mach F., et al. European Heart Journal (2018) 39, 2526–2539

Statins

On-target action HMG CoA reductase

• High dose• Prolonged

exposure• Age

• Risk factor cluster of metabolic syndrome

• Prediabetic state• High FBG and/or

HbA1c levels

Extra-hepatic tissues

Isoprenoid intermediatesIsoprenylation

NLRP3 activation

CoQ10ATP production

GLUT4 translocation

AKT activation

Insulin resistance

Pancreatic beta-cell

LDLR GLUT2Isoprenoid

intermediates

Intracellular

cholesterol

Lipotoxicity

Apoproticcell death

Glucose uptake

Insulin granule

exocytosis

CoQ10ATP

production

Potassium ATP channel

activityCytosolic

calcium levels

Insulin production

Statins

On-target action HMG CoA reductase

• High dose• Prolonged

exposure• Age

• Risk factor cluster of metabolic syndrome

• Prediabetic state• High FBG and/or

HbA1c levels

Extra-hepatic tissues

Isoprenoid intermediatesIsoprenylation

NLRP3 activation

CoQ10ATP production

GLUT4 translocation

AKT activation

Insulin resistance

Pancreatic beta-cell

LDLR GLUT2Isoprenoid

intermediates

Intracellular

cholesterol

Lipotoxicity

Apoproticcell death

Glucose uptake

Insulin granule

exocytosis

CoQ10ATP

production

Potassium ATP channel

activityCytosolic

calcium levels

Insulin production

Bioequivalence study of Vitor® vs. comparator drug (Livalo®)

Putri RSI, et al. Summary Report of Bioequivalence Study Date : 10 April 2019 Pitavastatin 2 mg (Data on file, unpublished)

Mean plasma concentration-time profiles of pitavastatin (N =28) after a single dose oral administration of 2 mg Pitavastatin film-coated tablets produced by PT Dexa Medica (Test drug = Pitavastatin 2 mg) and the Reference (Reference drug = Livalo® 2 mg)

Pla

sma

con

cen

trat

ion

(n

g/m

L)

Time (hour)

120.00

100.00

80.00

60.00

40.00

20.00

0.000 4 128 2016 40 44 4828 32 3624

Livalo 2 mg tablet (R1)

Livalo 2 mg tablet (R2)

2 mg tablet

pin papdi xvii dyslipidemia surabaya, 4-6 oktober2019 ... suastika... · dyslipidemia in ckd:...

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