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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 apo- lipoprotein A-I; Apo B-100, apolipoprotein B-100; CE, cholesteryl ester; CETP, cho- lesteryl 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
Jellinger P et al., Endocr Pract 2017; 23: 479-497
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
Jellinger P et al., Endocr Pract 2017; 23: 479-497
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
Jellinger P et al., Endocr Pract 2017; 23: 479-497
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
2018 AHA/ACC/AACVPR/AAPA/ ABC/ACPM/ADA/AGS/APhA/ ASPC/NLA/PCNA Guideline on
the Management of Blood Cholesterol
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
Top 10 Take-home Messages To Reduce Risk Of Atherosclerotic Cardiovascular Disease Through
Cholesterol Management
Grundy SM et al. JACC 2019; 73:3168–209
2018 AHA/ACC/AACVPR/AAPA/ ABC/ACPM/ADA/AGS/APhA/ ASPC/NLA/PCNA Guideline on
the Management of Blood Cholesterol
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
Top 10 Take-home Messages To Reduce Risk Of Atherosclerotic Cardiovascular Disease Through
Cholesterol Management
Grundy SM et al. JACC 2019; 73:3168–209
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
n c
han
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
Recommended