Dyslipidemia Guideline Update

Relation Between the Proportional Reduction in

MAJOR VASCULAR EVENTS and Mean Absolute LDL-C Reduction in 14
Statin Trials

Cholesterol Treatment Trialist Collaborators, Lancet 2005;366:1267

 Dyslipidemia di Indonesia

3
RISKESDAS 2013
European Journal of Preventive Cardiology, 2011;19(4):781-94
NCEP ATP NCEP ATP NCEP ATP ACC/AHA ESC/EAS ACC/AHA NICE ADA ESC/EAS
I (1988) II (1993) III (2004) (2006) (2011) (2013) (2014) (2015) (2016)

Offer Atorvastatin,
Target LDL (20 – 80 mg) for
<130 mg/dL primary and
secondary
Target LDL Target LDL
prevention
≤100 mg/dL < 100 mg/dL

Offer Moderate –
High Intensity Statin
LDL Level at Which to LDL Level at Which
Initiate Therapeutic to Consider
LDL Goal Lifestyle Changes (TLC) Drug Therapy
Risk Category (mg/dL) (mg/dL) (mg/dL)

CHD or CHD Risk < 100

Equivalents  100 130
(10-year risk >20%) < *70

10-year risk 10–20%: 

2+ Risk Factors 130
(10-year risk 20%) < 130  130
10-year risk <10%: 
160

0–1 Risk Factor < 160  160  190

2016 ESC/EAS Guidelines

European Heart
Journal 2016 –
doi:10.1093/eurhea
rtj/ehv272
SCORE CHART
Secondary Severe
ASCVD Hypercholest
Prevention erolemia

Diabetes
Primary
Mellitus in
Prevention
Adults
Statin Intensity
 Secondary Severe
ASCVD Hyercholest
Prevention erolemia

Diabetes
Primary
Secondary ASCVD Prevention Mellitus in
Adults
Prevention
 Secondary Severe
ASCVD Hyercholest
Prevention erolemia

Secondary ASCVD Prevention Diabetes

Mellitus in
Primary
Prevention
Adults
 Secondary Severe
ASCVD Hyercholest
Prevention erolemia

Secondary ASCVD Prevention Diabetes

Mellitus in
Primary
Prevention
Adults
 Secondary Severe
ASCVD Hyercholest
Prevention erolemia

Secondary ASCVD Prevention Diabetes

Mellitus in
Primary
Prevention
Adults
 Secondary Severe
ASCVD Hyercholest
Prevention erolemia

Diabetes
Primary
Secondary ASCVD Prevention Mellitus in
Adults
Prevention
 Secondary Severe
ASCVD Hyercholest
Prevention erolemia

Diabetes
Primary
Secondary ASCVD Prevention Mellitus in
Adults
Prevention
 Secondary Severe
ASCVD Hyercholest
Prevention erolemia

Diabetes
Primary
Mellitus in
Prevention
Severe Hyercholesterolemia Adults
 Secondary Severe
ASCVD Hyercholest
Prevention erolemia

Diabetes
Primary
Mellitus in
Prevention
Severe Hyercholesterolemia Adults
 Secondary Severe
ASCVD Hyercholest
Prevention erolemia

Diabetes
Primary
Mellitus in
Diabetes Mellitus in Adults Adults
Prevention
 Secondary Severe
ASCVD Hyercholest
Prevention erolemia

Diabetes
Primary
Mellitus in
Diabetes Mellitus in Adults Adults
Prevention
 Secondary Severe
ASCVD Hyercholest
Prevention erolemia

Diabetes
Primary
Mellitus in
Diabetes Mellitus in Adults Adults
Prevention
 Secondary Severe
ASCVD Hyercholest
Prevention erolemia

Diabetes
Primary Prevention Mellitus in
Adults
Primary
Prevention
 Secondary Severe
ASCVD Hyercholest
Prevention erolemia

Diabetes
Primary Prevention Mellitus in
Adults
Primary
Prevention
 Secondary Severe
ASCVD Hyercholest
Prevention erolemia

Diabetes
Primary Prevention Mellitus in
Adults
Primary
Prevention
 Secondary Severe
ASCVD Hyercholest
Prevention erolemia

Diabetes
Primary Prevention Mellitus in
Adults
Primary
Prevention
 Secondary Severe
ASCVD Hyercholest
Prevention erolemia

Diabetes
Primary Prevention Mellitus in
Adults
Primary
Prevention
• The risk of statin-induced muscle injury, including rhabdomyolysis, is <
0.1%
• The risk of serious hepatotoxicity is ~ 0.001%
• The risk of statin induced newly diagnosed DM is ~ 0.2% per year of
treatment, depending on the underlying risk of DM in population
studied
• Statin possibly increase the risk of hemorrhagic stroke; however they
clearly produce greater reduction in the risk of atherothrombotic
stroke and thus total stroke as well as CV events
• There is no convincing evidence for a causal relationship between
statin and cancer, cataracts, cognitive dysfunction, peripheral
neuropathy, erectile dysfunction, or tendonisitis
https://doi.org/10.1161/STR.0000000000000158Stroke. 2018;49:e46–e99
https://doi.org/10.1161/STR.0000000000000158Stroke. 2018;49:e46–e99
www.ascotstudy.org
 Background
CTT : Baseline CV risk and CV outcomes
• Overwhelming evidence
exists that statins prevent
cardiovascular (CV) events
across a wide-range of
baseline CV-risk.
• However, recently, there has
been a significant reduction
in uptake of, and adherence
to, statins, particularly in the
primary care setting

Lancet, 2012
www.ascotstudy.org
 Background
• Observational studies have reported that the use of statins is
associated with up-to 10 to 20% excess risk of AE’s, and with
the majority (up to 40%) of these being muscle-related AE’s.

• In 2009, MHRA (Medicines and Healthcare Products Regulatory

Agency)- based on a few case reports and data from a few
observational studies – issued a safety update, which included
cognitive function impairment, increased sleep disturbance and
erectile dysfunction among the list of reported AE’s with the use
of statins.

• These observational findings differ significantly from the findings

of many randomized controlled clinical trials (RCT’s) on statins.
– For example, in a meta-analysis of 26 blinded RCTS, there
was no significant excess of muscle-related AE’s among
those on statins compared with those on placebo (12.7% in
statin vs. 12.4% in placebo arm).

www.ascotstudy.org
 Rationale
• These differences, in the findings of observational
studies and RCT’s, have a potential harmful effect in
dissuading patients from taking statins, particularly those
who are at high CV risk.
• The database of the Anglo-Scandinavian Cardiac
Outcome Trial (ASCOT) was used to evaluate
differences in the incidence of AEs between
observational studies and RCTs.
• This database allows for a comparison of incidence rates
of AE’s both, during the blinded randomized period of the
study (blinded randomized phase), and subsequent,
open-labelled use of statins (non-blinded and non-
randomized phase).

www.ascotstudy.org
 ASCOT Study Design
19,342 hypertensive patients randomised to
antihypertensive treatment
ASCOT-BPLA
Stopped at 5.5 yrs

Atenolol ± Amlodipine ±
bendrofluazide perindopril

10,305 patients eligible and

randomised in lipid-lowering arm
ASCOT-LLA
TC ≤ 6.5 mmol/L (250 mg/dL)
Stopped at 3.3 yrs

Atorvastatin 10 mg Placebo

Investigator lead trial of hypertensive subjects age 40-79 yrs , no history of CHD, but with 3
additional CV risk factors

www.ascotstudy.org
 Methods-1

• Study population: all randomized patients in the

ASCOT-LLA
• Follow-up: Two phases: blinded randomized phase
(median 3.3 yrs) and non-blinded non-randomized phase
(median 2.2 yrs)
• Outcomes: 4 AEs of interest (AEOI) : Muscle related,
erectile dysfunction, cognitive impairment, and sleep
disturbance.
• Outcome ascertainment:
– We used the database of all reported AEs, which used data collected in
the clinical record file at each study, or extra, visit.
– In this database, >114,000 distinct reported AE’s were categorised
using the Medical Dictionary for Regulatory Activities (MedDRA) into 26
distinct system organ classification groups (SOC), 6791 separate lower
level terms (LLT), and 2856 unique preferred terms (PTs).

www.ascotstudy.org
 Incidence of 4 AEOI among those allocated to
Atorvastatin or Placebo in the blinded randomized phase
Placebo Atorvastatin
Adverse events
Number/rate (n = 5,079) (n = 5,101)

Number of patients 283 298

Muscle related AE*
Rate (per 100 yrs) 2.00 2.03
HR (95%CI) 1.03 (0.88, 1.21)

Number of patients 210 149

Sleep disturbance*
Rate (per 100 yrs) 1.46 1.00
HR (95%CI) 0.69 (0.56, 0.85)**

Number of patients 302 272

Erectile dysfunction*
Rate (per 100 yrs) 2.14 1.86
HR (95%CI) 0.88 (0.75, 1.04)

Number of patients 32 31
Cognitive impairment*
Rate (per 100 yrs) 0.22 0.20
HR (95%CI) 0.94 (0.57, 1.54)
* : those classified either as definite or probable
**: p <0.001
www.ascotstudy.org
 Risk of 4 AEOI among those allocated to Atorvastatin or Placebo in the blinded
randomized phase, grouped according to adjudication certainty

Atorvastatin Placebo

www.ascotstudy.org
 Incidence of AEOI among those using statins (users vs non-users)
in the non-blinded non-randomized (open-labelled) phase
Non-user Statin-user
Patients characteristics Number/rate
(n = 3,490) (n = 6,409)

Number of patients 124 161

Muscle related AE* Rate (per 100 yrs) 1.00 1.26

HR (95%CI) 1.41 (1.10, 1.79)**

Number of patients 82 72

Sleep disturbance* Rate (per 100 yrs) 0.66 0.56

HR (95%CI) 0.87 (0.63, 1.20)

Number of patients 99 88

Erectile dysfunction* Rate (per 100 yrs) 0.80 0.68

HR (95%CI) 0.89 (0.66, 1.20)

Number of patients 36 22
Cognitive impairment*
Rate (per 100 yrs) 0.29 0.17
HR (95%CI) 0.59 (0.34, 1.02)
* : those classified either as definite or probable **: p-value = 0.006
www.ascotstudy.org
 Summary of findings
• During the randomized blinded phase, compared
with those on placebo, those allocated to statin
reported :
– NO significant increase in the risk of muscle-
related AE’s
– NO excess of sleep disturbance and erectile
dysfunction, indeed there was a significant
reduction in sleep disturbance.
– NO significant excess of any other AEs, except
for some excess of renal and urinary
complaints
– The number of patients complaining of muscle
related symptoms was far fewer (3.1%) than
recent reports from observational studies .

www.ascotstudy.org
 Summary of findings -2
• During the non-randomized non-blinded
phase, (open label), compared with non-users,
statin users reported:
– a significant excess of muscle-related AE’s

– a lower, albeit statistically insignificant,

incidence of sleep disturbance and erectile
dysfunction.

– no significant risk of other AE’s

www.ascotstudy.org
 Summary of findings -3
• Overall benefits of statins on cardiovascular
events are substantial
• Safety concerns
Little evidence from controlled trials
Observational data likely confounded by
“healthy” participant and prescription bias, knowledge
that patients are taking statins, and widespread
adverse media publicity
"THE NOCEBO EFFECT"

www.ascotstudy.org
CASE STUDIES
 Case Study: Mr. X
46-year-old man returns for a follow-up visit 6 months after he was
diagnosed with type 2 diabetes
• Medical history
– Type 2 diabetes diagnosed 6 months ago; history of hypertension
– Smoker
– Taking metformin; amlodipine + olmesartan
• Physical examination
– BMI: 26 kg/m2
– BP: 132/82 mm Hg
• Laboratory results
– HbA1c: 7.5%
– Fasting plasma glucose: 135 mg/dL
– Serum creatinine: 1.1 mg/dL
– Lipids: TC, 240 mg/dL ; LDL-C, 162 mg/dL ;
TG, 200 mg/dL ; HDL-C 38 mg/dL
 Discussion

• What action would you take to reduce Bpk

Djohan’s
risk of a first CV event (primary prevention)?
– Modification of risk factors?
• What do you think about Bpk Djohan’s lipid
results?
• Would you prescribe a statin for this diabetic
patient to protect against CV events? For
which cholesterol target?
– Which Statin, what dose if using ACC/AHA guideline?
– Which Statin, what dose if using ESC guideline?
 Case Study: Mrs. Y
71-year-old woman with type 2 diabetes controlled by multiple
oral medications is seen for her annual exam

• Medical history
– Type 2 diabetes diagnosed 10 years ago; history of hypertension
– Taking metformin + sitagliptin + a sulfonylurea; amlodipine + olmesartan
• Physical examination
– BMI: 26 kg/m2
– BP: 145/90 mm Hg
• Laboratory results
– HbA1c: 6.9%
– Fasting plasma glucose: 102 mg/dL
– Serum creatinine: 1.4 mg/dL
– eGFR: 37 mL/min/1.73 m2
– Lipids: TC, 251 mg/dL ; LDL-C, 163 mg/dL ;
TG, 272 mg/dL ; HDL-C, 34 mg/dL
 Discussion
• What action would you take to reduce Ibu
Diana
risk of a first CV event (primary prevention)?
– Modification of risk factors?
• Would you prescribe a statin for this diabetic
patient to protect against CV events? For
which cholesterol target?
– Which Statin, what dose if using ACC/AHA guideline?
– Which Statin, what dose if using ESC guideline?
• What do you think about Ibu Diana’s renal
function? How could it affect her risk?
• What interventions might reduce the risk of a
further decrease in renal function?
 Conclusion
• There is a need to control dyslipidemia as one
of important risk factor for CVD
• New 2018 ACC/AHA recommend 4 patient
management group of statins : ASCVD
prevention, severe hypercholesterolemia,
diabetes, and primary prevention
• Statin is safe and tolerable for patient with
dyslipidemia