Updates of New Dyslipidemia Guidelines & Hidden Faces of

Diabetes

The Outline

• Dyslipidemia treatment gap in Indonesia

• New Dyslipidemia guidelines

• Statin intensity concept

• Hidden faces of diabetes

Need for optimization of treatment dyslipidemia to maximize benefit and improve outcome

Eur J Prev Cardiol. 2012 Aug;19(4):781-94.

LDL-C goals across risk categories

Sequence of therapies for LDL-C lowering &other key recommendations

1. High-intensity statin up to highest tolerated dose to reach LDL-C goals (IA)

2. If LDL-C goals not achieved with maximally tolerated statin: add ezetimibe (IB) In diabetes: IIa/C

3. Consider/add PCSK9 inhibitor if:• Primary prevention (non ASCVD), very high risk, without FH, goal not

achieved on max. statin + ezetimibe (IIb/C) same condition with FH (IC)• ASCVD, very high risk, goal not achieved on max. statin + ezetimibe (IA)

4. If statin not tolerated at any dose, even after re-challenge: consider ezetimibe or ezetimibe + PCSK9 inhibitor (IIa/C)

5. Statins first choice for high-risk hypertriglyceridemia (IB)6. High- or very high-risk patients, TG 135−499 mg/dL despite

statin: consider omega-3 PolyUnsaturated Fatty Acids (icosapent ethyl 2 x 2 g/day) in combination with statins (IIa/B)

2019 NICE Lipid guidelines:Statin intensity categories are based on LDL-cholesterol reduction

Reduction in low-density lipoprotein cholesterol

Dose (mg/day) 5 10 20 40 80

Fluvastatin – – 21%1 27% 33%2

Pravastatin – 20% 24% 29% –

Simvastatin – 27% 32% 37% 42%3,4

Atorvastatin – 37% 43% 49% 55%

Rosuvastatin 38% 43% 48% 53% –1 20–30% reduction in LDL-C: low-intensity2 31–40% reduction in LDL-C: medium-intensity 3 >40% reduction in LDL-C: high-intensity 4 Advice from the MHRA: there is an increased risk of myopathy associated with high-dose (80 mg) simvastatin.The 80-mg dose should be considered only in patients with severe hypercholesterolemia and high risk ofcardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits areexpected to outweigh the potential risks. The information used to make the table is from Law MR et al BMJ 2003;326:1423

National Institute for Health and Care Excellencehttps://pathways.nice.org.uk/pathways/cardiovascular-disease-prevention/lipid-modification-therapy-for-preventing-cardiovascular-disease.pdf. Accessed on 30 Mar 2020.

NICE= National Institute for Health and Care Excellence, LDL-C= Low-density lipoprotein cholesterol, MHRA= Medicine and Healthcare products Regulatory Agency

Intensity of lipid-lowering treatment

ESC 2019

ACC/AHA 2018Journal of the American College of Cardiology, 2019. 73(24)

1. High-intensity statin up to highest tolerated dose to reach LDL-C goals (IA)

2. If LDL-C goals not achieved with maximally tolerated statin: add ezetimibe (IB) In diabetes: IIa/C

International Diabetes Federation (IDF). IDF Diabetes Atlas, 9th Edition, 2019 update. Available at: https://www.diabetesatlas.org/upload/resources/material/20200302_133351_IDFATLAS9e-final-web.pdf. Accessed 8 March 2020

High burden of Diabetes:Indonesia rank #7 for most countries with Diabetes

Development and progression of T2DM and related complications*

• On average, patients with diabetes has had their condition for ~15 years. Many use multiple medications • Patients commonly feel frustrated or overwhelmed by daily requirements of disease management • Diabetes can lead to many complications, including Cardiovascular Disease (CVD), nephropathy,

retinopathy & neuropathy, such as painful diabetic neuropathy (PDN)Adapted from Ramlo-Halsted BA Prim Care 1999;26:771-789; Garancini MP, et al. Diabetes Care 1996;19:1279–1282; Grant RW, et al. Diabetes Care 2003;26(5):1408–1412; Polonsky WH. Curr Diabetes Rep 2002;2:153–159; Davies M, et al. Diabetes Care 2006;29(7):1518–1522; ADA. Diabetes Care 2011;34(Suppl1):S11–S61.

Progression of T2DM mellitus

Impaired glucose tolerance Diabetes diagnosis Frank diabetes

4–7 years

Beta-cell function

Fasting plasma glucose

Postprandial glucose

Hepatic glucose productionInsulin resistance

Insulin level

Development of macrovascular complicationsDevelopment of microvascular complications

*Conceptual representation

Association between diabetes and cardiovascular events = Diabetes is CVD equivalent

• *P <0.01, ** P <0.001 versus patients without diabetes• OASIS registry: prospectively collected from patients hospitalized with unstable angina or non-Q-wave MI

CHF, congestive heart failure; MI, myocardial infarction

Diabetes is CVD equivalent, therefore belongs to high risk & very high risk group in the guidelines

Malmberg K et al. Circulation 2000;102:1014–1019

2019 ESC and EASD Guidelines on Diabetes, Pre-diabetes and Cardiovascular Diseases

European Heart Journal (2019) 00, 1-69. doi:10.1093/eurheartj/ehz486

A, B, C goals* for Prevention of CV Diseases in Diabetes

*A*B

*C

In reality, majority of diabetic patients are not at treatment goals (ABC goals)

Chan JCN, et al. Diabetes Care 2008

LDL-C < 2.6 mmol/L = < 100 mg/DL

Lipid-Lowering Therapy Accounted for >70% of CV Risk Reduction in Diabetes

Adapted from Gaede P, Pedersen O. Diabetes. 2004;53 (suppl 3):S39–S47.

0

20

40

60

80

Lipids

Perc

ent o

f Tot

al C

alcu

late

dRi

sk R

educ

tion

in C

VD E

vent

s

HbA1c Blood Pressure

Steno-2 study

Multifactorial therapy in type 2 DM , to achieve :BP <130/80, HbA1c < 6.5%, total cholest < 175 mg/dL

The most of the CV benefit in Diabetes was attributable to the use of lipid-lowering therapy

CARDS: Type 2 diabetes outcomes trial

Colhoun HM, et al. Lancet. 2004;364:685–696CARDS, Collaborative AtoRvastatin Diabetes Study

n=2838

Atorvastatin 10 mg/day

Placebo

§ Type 2 diabetes, no clinically evident CHD

§ ≥1 other CHD risk factor (smoking, HTN, albuminuria, retinopathy)

§ LDL-C ≤160 mg/dL § TG ≤600 mg/dL§ Aged 40–75 years

Patient population

CARDS was a multicenter, randomized, double-blind study

3.9-year median follow-up

§ Primary endpoint: Time to first occurrence of a major CV event, defined as acute CHD events (ie MI including silent MI, unstable angina, acute fatal CHD, resuscitated cardiac arrest), coronary revascularization, or stroke

CARDS: Atorvastatin 10 mg reduced LDL-C by 40% VS Placebo in patients with type II diabetes

LDL-C (mmol/L)Average difference 40%(1.2 mmol/L, p<0.0001)

2 3 41 4.5

Years of Study0

0

1

2

3

4

mm

ol/L

Placebo Atorvastatin

TC (mmol/L)Average difference 26%(1.4 mmol/L, p<0.0001)

0 2 3 41 4.5

Years of Study

0

2

4

6

mm

ol/L

Colhoun H, et al. Lancet 2004;364:685-696

CARDS: Efficacy results in patients with type 2 diabetes

5

10

0

15

Cum

ulat

ive

inci

denc

e (%

)

Placebo (n=1410); final LDL-C=121 mg/dL

Atorvastatin 10 mg (n=1428); final LDL-C=82 mg/dL

0.0 1.0 2.0 3.0 3.9

Stroke

Incidence of major CV events*

37%RRR

95% CI 0.17–0.52

(p=0.001) 1

ARR=3.2%

48%RRR

95% CI 0.31–0.89

(p=0.016) 2

ARR=1.3%

Fatal/non-fatal MI

42%RRR

95% CI 0.39–0.86

(p=0.007) 3

ARR=1.9%

1. Colhoun HM, et al. Lancet. 2004;364(9435):685–696; 2. Hitman GA, et al. Diabet Med. 2007;24(12):1313–1321;

n CARDS: Atorvastatin 10 mg provided a significant reduction in CV events in patients with type 2 diabetes and ≥1 risk factor compared with placebo

Time (years)CARDS was stopped ~2 years early due to significant CV benefits with atorvastatin

Reprinted from The Lancet, 364, Colhoun HM, Betteridge DJ 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, 685–96., Copyright (2004), with permission from Elsevier

CARDS: Safety results in patients with type 2 diabetes

% Atorvastatin 10 mg (n=1428)

Placebo(n=1410)

Withdrawals due to muscle-related AEs 0.5 0.6

Myopathy 0.1 0.1

Myalgia 4.3 5.1

≥1 ALT elevation >3 x ULN 1.2 1.0

≥1 AST elevation >3 x ULN 0.4 0.3

Rhabdomyolysis 0 0

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

Data from the CARDS study of 2,838 patients with type 2 diabetes

ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal

Atorvastatin showed efficacy in diabetic patient subgroups within global studies

1. Sever PS, et al. Diabetes Care 2005;28:1151–11572. Shepherd J, et al. Diabetes Care 2006;29:1220–12263. Ahmed S, et al. Eur Heart J 2006;27:2323–23294. Athyros VG, et al. Angiology 2003;54:679–690

Study Patient population Effects in diabetic patient subgroup

ASCOT-LLA1 Hypertension Atorvastatin 10 mg reduced the risk of major CV events

and procedures by 23% compared with placebo

TNT2 Stable CHD Atorvastatin 80 mg reduced the risk of major CV events by 25% compared with atorvastatin 10 mg

PROVE IT3 ACS Atorvastatin 80 mg reduced the risk of acute cardiac events by 25% over pravastatin 40 mg

GREACE4 CVD Atorvastatin 10–80 mg significantly reduced the risk of major vascular events or death compared with usual care

Atorvastatin: Proven safety profile across the dose range

Adverse events, % Atorvastatin 10 mg (n=7,258)

Atorvastatin 80 mg(n=4,798)

Placebo(n=2,180)

Withdrawals due to treatment-related adverse events 2.4 1.8 1.2

Serious treatment-related nonfatal adverse events 0.2 0.5 4.2

Musculoskeletal 2.3 2.7 1.2

Treatment-related myalgia 1.4 1.5 0.7

Persistent ALT or AST >3 × ULN* 0.1 0.6 0.2

Persistent CPK >10 × ULN* 0 0.06 0

Rhabdomyolysis 0 0 0

Albuminuria 0.1 0.04 0

Hematuria 0.3 0.3 0.1

Data from a pooled analysis involving 14,236 patients from 49 trials

ALT, alanine transaminase; AST, aspartate transaminase; CPK, creatinine phosphokinase; ULN, upper limit of normal

*Based on the number of patients with laboratory measurements

Newman C, et al. Am J Cardiol 2006;97;61–67

Algorithm for treatment of muscle

symptoms during statin treatment

High Prevalence of Micro- and Macroalbuminuria in Asian Type 2 Diabetic Patients: MAP Study

Wu AYT et al. Diabetologia. 2005;48:17-26.

0

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50

60

70

80

90

100

China(n=2130)

Hong Kong(n=437)

Indonesia(n=177)

Korea(n=378)

Malaysia(n=733)

Pakistan(n=99)

Philippines(n=753)

Singapore(n=388)

Taiwan(n=357)

Thailand(n=97)

%

Microalbuminuric Macroalbuminuric MAP, MicroAlbuminuria Prevalence.

Development of Diabetic Nephropathy

CKD, chronic kidney disease; CV, cardiovascular; ESRD, end-stage renal disease; GFR, glomerular filtration rate

1. National Kidney Foundation. Am J Kidney Dis 2012; 60:850–886;2. Pellicano R, et al. Kidney Int 2005:94:S101–S106;

3. http://www.patient.co.uk/health/diabetic-kidney-disease-leaflet4. KDIGO CKD Work Group. Kidney Int 2013; Suppl. 3: 1–150;

5. Thorp ML. Am Fam Physician 2005;72:96–99

Recommendations for lipid management in patients with moderate-to-severe (Kidney Disease Outcomes Quality Initiative stages 3-5) Chronic Kidney Disease

Mach F, et al. Eur Heart Journal 2019, 00,1-78

ESC= European Society of Cardiology, EAS= European Atherosclerosis Society, CKD= Chronic kidney disease, ASCVD= Atherosclerotic cardiovascular disease

Statin renal safety data in Asian patients?

25

Background

Han E, et al. Endocrinol Metab 2017;32:274-280

• Hyperglycemia and dyslipidemia is an important risk factor for renal function loss• When DM and Dyslipidemia co-occur risk of CKD is synergistically increased

How about the effect of (moderate intensity) statin in Diabetic Asian Patients on kidney function in clinical practice?

Methods

12 months

Baseline:• FBG, HbA1C• Lipid profile (TC, LDL-C,

HDL-C, Triglyceride)• eGFR

End of Study:• FBG, HbA1C• Lipid profile (TC, LDL-C,

HDL-C, Triglyceride)• eGFR

Clinical Parameter at baseline:• Age, sex, height, weight• Duration of DM• History of HTN and cardiac

disease• Statin treatment information

eGFR : estimated GFR; FBG : fasting Blood Glucose; TC : Total Cholesterol; DM : Diabetes Mellitus; HTN : Hypertension

Han E, et al. Endocrinol Metab 2017;32:274-280

Primary Endpoint : Change in eGFR

*

**mL/

min

/1.7

3m2

eGFR Change

* p = 0.012** p = 0.01

Atorvastatin Rosuvastatin

eGFR Reduction

*

**

• Among all patients, eGFR was slightly decreased from 79.8 to 77.7 mL/min/1.73m2 (P<0.001)• There was a greater reduction of eGFR in rosuvastatin-treated group compared to

atorvastatin

Han E, et al. Endocrinol Metab 2017;32:274-280

PLANET I Study• Patients aged ≥18 years with type I or II diabetes + proteinuria• 353 patients were assigned to randomized treatment; 325 patients in ITT population

– Inclusion criteria• Moderate proteinuria (urinary protein/creatinine ratio 500–5000 mg/g)• Hypercholesterolemia (fasting LDL-C ≥90 mg/dL (2.33 mmol/L)• ACE inhibitors or ARBs or both ≥3 months prior to screening

• There was no placebo group as it was considered unethical to withhold statin therapy in this patient population1

Week: -8 520 8 14 26 394

Atorvastatin 80 mg (n=102)

Rosuvastatin 40 mg (n=116)

Rosuvastatin 10 mg (n=107)

Lead-inPeriod

20

40

De Zeeuw D et al. Lancet Diabetes Endocrinol 2015;3:181-90

PLANET= Prospective Evaluation of Proteinuria and Renal Function in Diabetic Patients with Progressive Renal Disease, ITT= Intention to treat, ACE= Angiotensin converting enzyme, ARB= Angiotensin Receptor Blocker

PLANET I: Primary end point–changes in

UPCR

UPCR was significantly lower at 52 weeks than at baseline for the atorvastatin 80 mg group (P=0.033).1

Data are mean baseline : on-treatment ratios.Error bars are 95% CIs. LOCF marks 52-week data accounting for all patients in ITT population

1.4

1.2

1.0

0.8

0.6

0

Rosuvastatin 10 mgRosuvastatin 40 mgAtorvastatin 80 mg

0

107116102

14

10311296

26

9710791

39

9610688

52

9510682

LOCF

107116102

Number of patientsRosuvastatin 10 mgRosuvastatin 40 mgAtorvastatin 80 mg

Time (weeks)

UPC

R (B

asel

ine

: on-

trea

tmen

t)

De Zeeuw D et al. Lancet Diabetes Endocrinol 2015;3:181-90

PLANET= Prospective Evaluation of Proteinuria and Renal Function in Diabetic Patients with Progressive Renal Disease, UPCR= Urine protein: creatinine ratio, LOCF= Last Observation Carried Forward

PLANET I: Secondary end point–changes in eGFR

Mean eGFR at 52 weeks was not significantly different from baseline in the atorvastatin 80 mg group (p=0.21)

2

0

–2

–4

–8

–100

107116102

14

10311197

26

9910992

39

9510486

52

9510986

LOCF

107116102

Number of patientsRosuvastatin 10 mgRosuvastatin 40 mgAtorvastatin 80 mg

Time (weeks)

–6

4

10611599

8

10411298

Rosuvastatin 10 mg (p=0.0098) Rosuvastatin 40 mg (p=0.0002)Atorvastatin 80 mg (p=0.21)

Chan

ge in

eG

FR(m

L/m

in p

er 1

.73

m2 )

Data are mean changes from baseline. Error bars are 95% CIs.LOCF marks 52-week data accounting for all patients in ITT population.

De Zeeuw D et al. Lancet Diabetes Endocrinol 2015;3:181-90

PLANET= Prospective Evaluation of Proteinuria and Renal Function in Diabetic Patients with Progressive Renal Disease, eGFR= estimated glomerular filtration rate, LOCF= Last Observation Carried Forward

• Statistical analysis of adverse events was not presented• One serious AE (2 episodes of cardiac failure in rosuvastatin 10 mg group) was considered to be related to study drug• No episodes of acute renal failure were considered to be related to study drug

n (%)Rosuvastatin10 mg (n=116)

Rosuvastatin40 mg (n=123)

Atorvastatin80 mg (n=110)

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)Acute renal failure 0 5 (4.1) 1 (0.9)Serum creatinine doubling 0 6 (4.9) 0Serum creatinine doubling or acute renal failure 0 9 (7.3) 1 (0.9)

Death 4 (3.4) 1 (0.8) 0

PLANET I: Renal AEs

De Zeeuw D et al. Lancet Diabetes Endocrinol 2015;3:181-90

PLANET= Prospective Evaluation of Proteinuria and Renal Function in Diabetic Patients with Progressive Renal Disease, AE= Adverse event

Crystalline vs Amorphous Atorvastatin

Atorvastatin amorphous Atorvastatin crystalline

•Lebih stabil•Tidak mudah terdegradasi•Kadar kemurniannya lebih tinggi (Impurity/senyawa pengotor lebih rendah)

•Tidak stabil•Mudah terdegradasi lebih cepat•Kadar kemurniannya rendah (Impurity/senyawa pengotor lebih tinggi)

US FDA Statement on Polymorphism:Polymorphism can affect

the quality, safety, and efficacy of the drug product

Guidance for Industry ANDAs: Pharmaceutical Solid Polymorphism . FDA 2007.

Total Impurities%

WeeksUSFDA Docket. Letter of Pfizer Inc to Gary Buehler, USFDA, 2005(http://www.fda.gov/ohrms/dockets/dockets/05p0452/05p-0452-cp00001-01-vol1).

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

0 1 2 3 4 8

Crystalline

Amorphous

Comparative Stability of the Crystalline & Amorphous Forms of Atorvastatin Calcium