Dyslipidemia_New GL & Total Vascular Benefit.pptx

Dyslipidemia

1. PP-LIP-IDN-0090-JAN-2021 CV Heart Talk Series Dyslipidemia Management: New Guidelines & Total Vascular Benefit Insert speaker name Insert affiliations

2. Core Principles of Dyslipidemia Management: Guideline, Treatment Targets, Lipid-lowering Therapy

3. FH, familial hypercholesterolemia; HC, hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; RRR, relative risk reduction. Packard CJ. Trends Cardiovasc Med 2018;28:348-354. Age and the impact of LDL-C on atherosclerosis Greater RRR per mmol/l reduction Plaque resolution Fatty streaks LDL chol (mmol/l) Lesser RRR Plaque stabilisation Complex plaque Response to initiation of LDL lowering Artery wall LDLc rise with age (men) Integrated LDL exposure Polygenic HC FH Age (years)

4. ESC/EAS 2019 recommendations for risk assessment New recommendations for risk assessment include: ApoB analysis Measurement of Lp (a) at least once in each person’s lifetime Arterial ultrasound or coronary artery calcium score to refine risk estimation in selected moderate-risk or low-risk patients ACS, acute coronary syndrome; ApoB , apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; CV, cardiovascular; CVD, cardiovascular disease; DM, diabetes mellitus; FH, familial hypercholesterolemia; HDL, high-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; Lp (a), lipoprotein(a); T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TGs, triglycerides. Mach, F. et al. Eur Heart J.2020 Jan 1;41(1):111-188 Risk factor screening including the lipid profile should be considered in men >40 years old and in women >50 years of age or postmenopausal SCORE (Systematic Coronary Risk Evaluation) scheme should be used to estimate the 10-year risk of a first fatal CV event, such as a stroke or heart attack, or cardiac sudden death No risk estimation model is needed in patients already at high or very high risk such as those with: documented ASCVD, type 1 or type 2 diabetes, very high levels of individual risk factors, familial hypercholesterolemia, carotid plaque, or chronic kidney disease

5. 2019 ESC/EAS Guidelines: CV risk categories * Documented ASCVD, either clinical or unequivocal on imaging. Documented ASCVD includes previous ACS (MI or unstable angina), stable angina, coronary revascularization, stroke and TIA, and peripheral arterial disease. Unequivocally documented ASCVD on imaging includes those findings that are known to be predictive of clinical events, such as significant plaque on coronary angiography or CT scan (multivessel coronary disease with two major epicardial arteries having >50% stenosis), or on carotid ultrasound. † Diabetes mellitus with target organ damage, or at least three major risk factors, or early onset of type 1 diabetes mellitus of long duration (>20 years). ‡ eGFR <30 mL/min/1.73 m 2 . § A calculated SCORE ≥10% for 10-year risk of fatal CVD; FH with ASCVD or with another major risk factor. ǁ Diabetes mellitus without target organ damage, with diabetes mellitus duration ≥10 years or another additional risk factor. ¶ eGFR 30-59 mL/min/1.73 m 2 . ASCVD, atherosclerotic cardiovascular disease; BP: blood pressure; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; EAS, European Atherosclerosis Society; eGFR , estimated glomerular filtration rate; ESC, European Society of Cardiology; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; SCORE, Systematic Coronary Risk Estimation; TC, total cholesterol. Mach, F. et al. Eur Heart J.2020 Jan 1;41(1):111-188 Documented ASCVD* Diabetes mellitus † Severe CKD ‡ Very high levels of individual risk factors § VERY HIGH-RISK TC >8 mmol/L (>310 mg/dL); LDL-C >4.9 mmol/L (>190 mg/dL); BP ≥180/110 mmHg Diabetes mellitus ǁ Moderate CKD ¶ Young patients (type 1 diabetes mellitus <35 years; type 2 diabetes mellitus <50 years) with disease duration <10 years, without other risk factors Calculated SCORE ≥1% and <5% for 10-year risk of fatal CVD Calculated SCORE <1% for 10-year risk of fatal CVD HIGH-RISK MODERATE-RISK LOW-RISK

6. Grundy SM, et al. Circulation 2019; 139:e1082-e1143. Family history of premature ASCVD Metabolic syndrome Chronic kidney disease History of preeclampsia or premature menopause (age <40 years) Chronic inflammatory disorders ( eg , rheumatoid arthritis, psoriasis or chronic HIV) Apolipoprotein B ≥130 mg/ dL , high-sensitivity C-reactive protein ≥2.0 mg/L, Ankle-brachial index (ABI) <0.9 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 favour initiation of statin therapy   AHA Cholesterol Guidelines 2018 Executive summary: Risk enhancers

7. ESC/EAS 2019 LDL-C: Goals for patients of different risk levels Risk Group New (2019) LDL-C goals Previous (2016) LDL-C goals Very high including T2DM ≥50% LDL reduction and <1.4 mmol/L (<55 mg/dL) ASCVD + another event within 2 years: consider LDL-C goal <1.0 mmol/L (<40 mg/dL) <1.8 mmol/L (<70 mg/dL) or ≥50% ↓ if baseline 1.8–3.5 mmol/L (70–135 mg/dL) High including T2DM ≥50% LDL reduction and <1.8 mmol/L (<70 mg/dL) <2.6 mmol/L (<100 mg/dL) or ≥50% ↓ if baseline 2.6–5.1 mmol/L (100–200 mg/dL) Moderate <2.6 mmol/L (<100 mg/dL) <3.0 mmol/L (<115 mg/dL) Low <3.0 mmol/L (<116 mg/dL) <3.0 mmol/L (<115 mg/dL) ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium;; CV, cardiovascular; CVD, cardiovascular disease; DM, diabetes mellitus; HDL, high-density lipoprotein; LDL-C, low-density lipoproteins cholesterol; Lp (a), lipoprotein(a); PUFAs, polyunsaturated fatty acids; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus. Mach, F. et al. Eur Heart J.2020 Jan 1;41(1):111-188

8. Risk stratification Tailored regimen Personalized approach Patient preferences Grundy SM, et al. Circulation 2019; 139:e1082-e1143. LDL-C, Low density Lipoprotein-Cholesterol; ASCVD, Atherosclerotic Cardiovascular Disease, AHA: American Heart Association AHA Cholesterol Guidelines 2018: Intervention algorithms Age 0–19 y Lifestyle to prevent or reduce ASCVD risk Diagnosis of familial hypercholesterolemia  statin Age 20–39 y Estimate lifetime risk to encourage lifestyle to reduce ASCVD risk Consider statin if family history premature ASCVD and LDL-C ≥160 mg/ dL (≥4.1 mmol/L) Age 40–75 y LDL-C ≥70-<190 mg/ dL (≥1.8-4.9 mmol/L) without diabetes mellitus 10-year ASCVD risk percent begins risk discussion Age >75 y: Clinical assessment, risk discussion Risk discussion: Emphasize lifestyle to reduce risk factors (Class I) <5% “Low risk” 5%-<7.5% “Borderline risk” ≥7.5%-<20% “Intermediate risk” Risk discussion: If risk enhancers present then risk discussion regarding moderate-intensity statin therapy (Class IIb ) Risk discussion: If risk estimate + risk enhancers favor statin, initiate moderate-intensity statin to reduce LDL-C by 30%-49% (Class I) ≥20% “High risk” Risk discussion: Initiate statin to reduce LDL-C ≥50% (Class I) Diabetes mellitus and age 40-75 y: Risk assessment to consider high-intensity statin (Class llia ) Diabetes mellitus and age 40-75 y: Moderate-intensity statin (Class I) LDL-C ≥190 mg/ dL (≥4.9 mmol /L): No risk assessment; High-intensity statin (Class I) Primary prevention: Access ASCVD risk in each age group emphasize adherence to healthy lifestyle

9. Prospective Studies Collaboration Lancet 2007;370;1829-1839. CHD, coronary heart disease; CI, confidence interval Age, cholesterol and CHD risk – Predicted greater relative risk reduction with early intervention A B Hazard ratio (95% Cl) Usual total cholesterol (1 mmol/L) Age at risk (years): 80–89 70–79 60–69 50–59 40–49 Age at risk (years): 70–79 60–69 50–59 40–49 Sex Number of deaths Men Woman Total 2919 2707 5626 Test for heterogeneity: x 2 1 =12.0 (p=0.0005) Men Woman Total 7372 3457 10829 Test for heterogeneity: x 2 1 =4.1 (p=0.04) Men Woman Total 8594 1825 10419 Test for heterogeneity: x 2 1 =0.3 (p=0.6) Men Woman Total 5001 560 5561 Test for heterogeneity: x 2 1 =1.5 (p=0.2) Men Woman Total 1191 118 1309 Test for heterogeneity: x 2 1 =0.0 (p=0.8) Test for trend by age: x 2 1 =415 (p<0.0001) 0.79 (0.74–0.84) 0.92 (0.86–0.97) 0.85 (0.82–0.89) 0.80 (0.77–0.83) 0.86 (0.82–0.90) 0.82 (0.80–0.85) 0.71 (0.69–0.74) 0.73 (0.68–0.78) 0.72 (0.69–0.74) 0.59 (0.57–0.61) 0.55 (0.49–0.61) 0.58 (0.56–0.61) 0.45 (0.41–0.48) 0.43 (0.34–0.55) 0.44 (0.42–0.48) Hazard ratio (95% Cl) for 1 mmol/L Lower usual total cholesterol 80–89

10. Inherited vs pharmacologically based LDL lowering ‘Earlier is better’ Ference BA, et al . J Am Coll Cardiol 2015;65:1552-1561. 2x2 factorial mendelian randomization study: log-linear association between genetically and pharmacologically mediated lower low-density lipoprotein cholesterol and risk of coronary heart disease Proportional risk reduction (SE) log scale Lower LDL-C (mg/dl) Genetic variants LDL lowering from birth LDL lowering trials Average age 62 yrs Combined NPC1L1 & HMGCR LDL-C score HMGCR LDL-C score NPC1L1 LDL-C score NPC1L1 rs217386 PCSK9 rs2479409 HMGCR rs12916 ABCG5/8 rs4299376 PCSK9 rs11206510 LDLR rs2228671 LDLR rs6511720 NPC1L1 LDL-C score HMGCR LDL-C score A to Z GISSI-P PCSK9 46L rs11591147 SEARCH IMPROVE-IT ALLHAT-LLT

11. 1. Rosensen RS. Exp Opin Emerg Drugs 2004;9:269-279. 2. LaRosa JC, et al. N Engl J Med 2005;352:1425-1435. Association of LDL-C with CHD risk in statin trials Event rate (%) LDL-C achieved mg/dL (mmol/L) Rx - Statin therapy PRA – pravastatin ATV - atorvastatin PROVE - IT – ATV TNT – ATV80 HPS – Rx CARE – Rx LIPID – Rx 4S – Rx LIPID – Placebo CARE – Placebo HPS – Placebo TNT – ATV10 PROVE - IT – PRA JUPITER – RSV AFCAPS – Rx AFCAPS – Placebo WOSCOPS – Placebo WOSCOPS – Rx ASCOT – Placebo JUPITER – Placebo ASCOT – Rx 4S – Placebo Secondary Prevention Primary Prevention

12. 2019 ESC/EAS Guidelines: Treatment algorithm for pharmacological LDL-C lowering Total CV assessment Baseline LDL-C levels Risk modifiers imaging (subclinical atherosclerosis) In selected low- and moderate-risk patients Indication for drug therapy Define treatment goal Lifestyle advice/ interventions High potency statin at highest recommended / tolerable dose to reach the goal LDL-C goal reached? Follow-up annually, or more frequently if indicated Add ezetimibe LDL-C goal reached? Follow-up annually, or more frequently if indicated Add PCSK9 inhibitor Secondary prevention (very high-risk) Primary prevention: patient with FH and another major risk factor (very-high risk) Consider adding PCSK9 inhibitor Primary prevention: patients at very-high risk but without FH Y N Y N N Y ASCVD, atherosclerotic cardiovascular disease; BP, blood pressure; CKD, chronic kidney disease; CV, cardiovascular; DM, diabetes mellitus; eGFR , estimated glomerular filtration rate; FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin/ kexin type 9; SCORE, Systematic Coronary Risk Estimation; T1DM, type 1 DM; T2DM, type 2 DM; TC, total cholesterol. Mach, F. et al. Eur Heart J.2020 Jan 1;41(1):111-188

13. 2019 ESC/EAS Guidelines: Sequence of thera pies for LDL-C lowering High-intensity statin to be prescribed up to the highest tolerated dose to reach treatment goals If goals not achieved: add ezetimibe Consider/add PCSK9 inhibitor if: LDL-C goal is not achieved on maximum tolerated statin and ezetimibe in patients with very high risk, without FH, for primary prevention LDL-C goal not achieved on maximum tolerated statin and ezetimibe in patients with very high risk FH* If a statin-based regimen is not tolerated at any dosage (even after re-challenge), ezetimibe should be considered If a statin-based regimen is not tolerated at any dosage (even after re-challenge), a PCSK9 inhibitor added to ezetimibe may also be considered If the goal is not achieved, statin combination with a bile acid sequestrant may be considered *With ASCVD or with another major risk factor. ASCVD, atherosclerotic cardiovascular disease; FH, familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol ; PCSK9, proprotein convertase subtilisin/ kexin type 9. Mach, F. et al. Eur Heart J.2020 Jan 1;41(1):111-188

14. 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 favours statin therapy  Boldface type indicates specific statins and doses that were evaluated in RCTs, and the Cholesterol Treatment Trialists’ 2010 meta-analysis. All these RCTs demonstrated a reduction in major cardiovascular events.  Grundy SM, et al. Circulation 2019;139:e1082-e1143. AHA Cholesterol Guidelines 2018 Executive summary – statin choice High intensity Moderate intensity Low intensity LDL-C lowering ≥50% 30%–49% <30% Statins Atorvastatin (40 mg) 80 mg Rosuvastatin 20 mg (40 mg) Atorvastatin 10 mg (20 mg) Rosuvastatin (5 mg) 10 mg Simvastatin 20–40 mg Simvastatin 10 mg … Pravastatin 40 mg (80 mg) Lovastatin 40 mg (80 mg) Fluvastatin XL 80 mg Fluvastatin 40 mg BID Pitavastatin 1–4mg Pravastatin 10–20 mg Lovastatin 20 mg Fluvastatin 20–40 mg High-, Moderate-, and Low-intensity Statin Therapy*

15. SPARCL: Assessing effect of atorvastatin on vascular events by territory BACKGROUND In the SPARCL trial : Atorvastatin reduced the first occurrence of stroke and the first occurrence of a composite of vascular events relative to placebo in patients with recent stroke/TIA and no known CHD SPARCL, Stroke Prevention by Aggressive Reduction in Cholesterol Levels. CHD, coronary heart disease; TIA, transient ischemic attack. Szarek M, et al. J Am Coll Cardiol 2020;75:2110-2118. The current post hoc analysis of SPARCL data aimed to determine the extent to which atorvastatin may have reduced vascular events

16. Atorvastatin reduced first and total vascular events Szarek M, et al. J Am Coll Cardiol 2020;75:2110-2118. 390 fewer total vascular events with atorvastatin (1,218 events for placebo, 828 events for atorvastatin) Reductions by atorvastatin were evident in each territory Number of vascular events First event Second event Third event Fourth and subsequent events Atorvastatin Placebo Atorvastatin Placebo Atorvastatin Placebo Atorvastatin Placebo -164 events -102 events -55 events -69 events Cerebrovascular Coronary Peripheral

17. Atorvastatin reduced first and total vascular events Atorvastatin reduced: First vascular events by 27% (p<0.001) Total vascular events by 32% (p<0.001) Total vascular events by 10% during the first year (p=0.19) and by 40% after the first year (p<0.001) Szarek M, et al. J Am Coll Cardiol 2020;75:2110-2118. Expected vascular events per 100 participants Years since randomization Placebo total vascular Atorvastatin total vascular Placebo first vascular Atorvastatin first vascular Total vascular: HR (95% Cl) 0.68 (0.60–0.77), p<0.001 First vascular: HR (95% Cl) 0.73 (0.66–0.82), p<0.001 Cumulative incidence functions for first and total vascular events No. at risk Placebo Atorvastatin 2,366 2,365 2,301 2,287 2,255 2,229 2,192 2,176 2,139 2,123 1,009 1,028 159 140

18. Atorvastatin reduced events in all vascular territories Szarek M, et al. J Am Coll Cardiol 2020;75:2110-2118. Over 6 years, 20 vascular events/100 participants were avoided with atorvastatin treatment Total events [Events per 100 participants]* Atorvastatin (n=2,365) Placebo (n=2,366) HR (95% CI) p-value Total vascular Total cerebrovascular Total coronary Total peripheral 828 [42.3] 571 [28.2] 203 [10.8] 54 [2.8] 1,218 [62.7] 748 [37.1] 373 [20.1] 97 [4.8] 0.68 (0.60–0.77) 0.76 (0.66–0.88) 0.54 (0.42–0.70) 0.56 (0.35–0.89) <0.001 <0.001 <0.001 0.014 * 6 years after randomization Atorvastatin better Placebo better

19. SPARCL Post-hoc analysis Conclusions After a recent stroke or TIA: the total number of vascular events prevented with atorvastatin was more than twice the number of first events prevented with significant reductions in total cerebrovascular, total coronary and total peripheral events Reduction in total events may be considered another comprehensive metric reflecting the clinical benefit and efficiency of atorvastatin treatment in reducing disease burden after stroke or TIA SPARCL, Stroke Prevention by Aggressive Reduction in Cholesterol Levels; TIA, transient ischemic attack. Szarek M, et al. J Am Coll Cardiol 2020;75:2110-2118.

20. BACKGROUND SPARCL : 16% RRR with 5-year treatment with atorvastatin 80 mg/day vs placebo in patients with stroke and no known CHD Based on SPARCL, the 2014 AHA/ASA and 2010 ESO guidelines recommended statin therapy to lower lipid levels after TIA/ischemic stroke The TST trial evaluated the benefit of targeting an LDL-C <70 mg/ dL to reduce the risk of CV events in 2,860 patients with ischemic stroke with atherosclerotic stenosis of cerebral vasculature, in French and Korean populations The present analysis evaluates the French cohort of the TST trial (5.3 years follow-up) TST (French cohort): Evaluating benefit of targeting lower LDL-C levels SPARCL, Stroke Prevention by Aggressive Reduction in Cholesterol Levels; TST, Treating Stroke to Target. AHA/ASA, American Heart Association/American Stroke Association; CV, cardiovascular; ESO, European Stroke Organization; LDL-C, low-density lipoprotein cholesterol. Amarenco P, et al. Stroke 2020;51:1231-1239.

21. Rate of primary endpoint was lower in patients with LDL-C goal <70 mg/ dL Amarenco P, et al. Stroke 2020;51:1231-1239. Primary endpoint: composite of ischemic stroke; MI; new symptoms requiring urgent coronary or carotid revascularization; and vascular death Event rate, % Strategy <70 mg/dL 100±10 mg/dL 1073 1075 915 889 807 800 691 702 590 586 487 475 392 353 253 238 106 104 Time, year

22. Targeting lower LDL-C significantly reduced the primary endpoint Amarenco P, et al. Stroke 2020;51:1231-1239. HR 0.74 (95% Cl 0.57–0.95); p=0.019 Absolute risk reduction = 3.3% NNT = 30 Primary endpoint: composite of ischemic stroke; MI; new symptoms requiring urgent coronary or carotid revascularization; and vascular death Patients (%) Primary endpoint <70 mg/dL 100±10 mg/dL 9.6 12.9

23. Targeting lower LDL-C significantly reduced vascular events Amarenco P, et al. Stroke 2020;51:1231-1239. Patients (%) Cerebral infarction/urgent carotid or cerebral artery revascularization All strokes (Cerebral infarction or intracranial hemorrhage) Primary endpoint or intracranial hemorrhage <70 mg/dL (N=1073) 100±10 mg/dL (N=1075) p=0.046 HR (95% CI) 0.73 (0.54–0.99) p=0.023 HR (95% CI) 0.72 (0.54–0.96) p=0.021 HR (95% CI) 0.75 (0.58–0.96) 6.7 9.1 7.5 10.4 10.3 13.6 Selected secondary outcomes

24. TST (French cohort): Conclusion After an ischemic stroke of documented atherosclerotic origin: Targeting an LDL-C of <70 mg/dL during 5.3 years prevented 1 subsequent major vascular event in 4 without increasing the risk of intracranial hemorrhage (NNT 30) Amarenco P, et al. Stroke 2020;51:1231-1239.

25. 2019 ESC/EAS Guidelines: Treatment of dyslipidemia in patients with prior ischemic stroke Mach, F. et al. Eur Heart J.2020 Jan 1;41(1):111-188 Lipid-lowering therapy for prevention of ASCVD events in patients with prior ischaemic stroke Patients with a history of ischaemic stroke or TIA are at very-high risk of ASCVD, particularly recurrent ischaemic stroke, so it is recommended that they receive intensive LDL-C-lowering therapy. Class Level I A EAS, European Atherosclerosis Society; ESC, European Society of Cardiology; ASCVD, atherosclerotic cardiovascular disease; LDL-C, low-density lipoprotein cholesterol; TIA, transient ischemic attack.

26. Statin-specific Issues in Dyslipidemia Management

27. 2018 AHA/ACC Guidelines: Statin-associated side effects The guideline “prefers statin-associated side effects because the large majority of patients are able to tolerate statin rechallenge with an alternative statin or alternative regimen, such as reduced dose or in combination with non-statins” Statin-associated side effects Frequency Predisposing factors Myalgia (CK Normal) RCTs: 1-5% Observational studies/ clinical setting: 5-10% Age, female sex, low BMI, high-risk medications*, comorbidities # , Asian ancestry, excess alcohol, high levels of physical activity, and trauma Myositis/myopathy (CK > ULN) with symptoms or objective weakness Rare - Rhabdomyolysis Rare - Statin-associated autoimmune myopathy Rare - New-onset DM Depends on population; more frequent if DM risk factors are present DM risk factors: BMI ≥30, FBG ≥100 mg/dL; metabolic syndrome, HbA 1c ≥6% Transaminase elevation 3 x ULN Infrequent - Hepatic failure Rare - *High-risk medications: CYP3A4 inhibitors, OATP1B1 inhibitors. # Comorbidities: HIV, renal, liver, thyroid, preexisting myopathy. BMI, body mass index; CK, creatine kinases; DM, diabetes mellitus; FBG, fasting blood glucose; HbA 1c , hemoglobin A1C; RCTs, randomized controlled trials; ULN, upper limit of normal. Grundy SM, et al. J Am Coll Cardiol 2018:25709.

28. Myalgia occurred at a low and similar incidence in patients receiving atorvastatin 10 mg and atorvastatin 80 mg Newman C, et al. Am J Cardiol 2006;97:61-67. % Atv 10 mg (n=7,258) All cause Treatment-associated Atv 80 mg (n=4,798) Pbo (n=2,180) A retrospective analysis of pooled data from 49 clinical trials of atorvastatin in 14,236 patients treated for an average period of 2 weeks to 52 months Incidence of myalgia with atorvastatin ( Atv ) 10 and 80 mg compared with placebo ( Pbo ) 2.9 1.4 2.7 1.5 1.2 0.7

29. Statin therapy in Asian diabetic patients: E ffects on renal function GFR, glomerular filtration rate; LDL-C, low-density lipoprotein cholesterol. Han E, et al. Endocrinol Metab . 2017;32:274-280. In both statin treatment groups, patients showed improved serum lipid levels and significantly reduced eGFRs Conclusions: Moderate-intensity dose of atorvastatin was associated with fewer detrimental effects on renal function than rosuvastatin Objective: To investigate and compare the statins affecting renal function in Asian patients with diabetes eGFR, ml/min/1.73m 2 LDL-C, mg/dL Atorvastatin Rosuvastatin Atorvastatin Rosuvastatin p=0.001 p=0.012 p<0.001 p<0.001 Baseline 1 year Baseline 1 year Change in kidney function after statin use Change in lipid level after statin use

30. LIPITOR Abbreviated Product Information DESCRIPTION: Atorvastatin tablets for oral administration contain 10, 20, 40, 80 mg atorvastatin. INDICATIONS AND USAGE: Atorvastatin is indicated as an adjunct to diet for the reduction of elevated total-C, LDL-C, apo B, and TG in patients with primary hypercholesterolemia, combined (mixed) hyperlipidemia, and heterozygous and homozygous familial hypercholesterolemia when response to diet and other non pharmacological measures are inadequate. Prevention of cardiovascular complications in patients with hypertension (40 years or older) and dyslipidemia with at least 3 risk factors for future cardiovascular events, such as LVH, ECG abnormalities, NIDDM, peripheral vascular disease, post history of cerebrovascular events including transient ischemic attack (TIA) ≥3 months previously, microalbuminuria/proteinuria, smoking (regular smoker within the last year of 20 cigarettes or cigars/week), TC/HDL – C ratio ≥6, and history of coronary artery disease event in a first degree relative before age 55 (males) or 60 (women), atorvastatin is indicated to: Reduce the risk of fatal CHD and non-fatal MI, Reduce the risk of stroke, Reduce the risk of revascularization procedures and angina pectoris. Pediatric Patients (10-17 years of age), Atorvastatin is indicated as an adjunct to diet to reduce total-C, LDL-C and apo-B levels in boys and postmenarchal girls, 10 to 17 years of age, with heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: LDL-C remains ≥190 mg/dL or LDL-C remains ≥160 mg/dL and: There is a positive family history of premature CVD or Two or more other CVD risk factors are present in the pediatric patient. CONTRAINDICATIONS: Hypersensitivity to any component of this medication, active liver disease or unexplained persistent elevations of serum transaminases exceeding three times the upper limit of normal (ULN), or who are pregnant, breast-feeding, or of childbearing potential who are not using adequate contraceptive measures. SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE: Hepatic Effects: As with other lipid-lowering agents of the same class, moderate (>3 x ULN) elevations of serum transaminases have been reported following therapy with atorvastatin. Skeletal Muscle Effect – Myalgia, has been reported in atorvastatin- treated patients. The risk of myopathy is increased with concurrent administration of drugs that increase the systemic concentration of atorvastatin. Hemorrhagic stroke: Patients with hemorrhagic stroke on entry appeared to be at increased risk for recurrent hemorrhagic stroke. INTERACTION WITH OTHER MEDICAMENTS AND OTHER FORMS OF INTERACTION: The risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of cyclosporine, fibric acid derivatives, lipid-modifying doses of niacin or CYP 3A4 inhibitors ( e.g Erythromycin and azole antifungals). UNDESIRABLE EFFECT: The most frequent (more than 1%) adverse effects associated with atorvastatin therapy, in patients participating in controlled clinical studies were dyspepsia, abdominal pain, headache, nausea, myalgia, asthenia, constipation, flatulence, arthralgia, diarrhea, and insomnia. POSOLOGY AND METHOD OF ADMINISTRATION: The usual starting dose is 10 mg once a day. The dosage range is 10 to 80 mg once daily. Doses may be given any time of the day with or without food. Starting and maintenance dosage should be individualized according to baseline LDL-C levels, the goal of therapy, and patient response. After initiation and/or upon titration of atorvastatin, lipid levels should be analyzed within 2 to 4 weeks, and dosage adjusted accordingly. Primary Hypercholesterolemia and Combined (Mixed) Hyperlipidemia - The majority of patient are controlled with 10 mg atorvastatin once daily. A therapeutic response is evident within 2 weeks, and the maximum response is usually achieved within 4 weeks. The response is maintained during chronic therapy. Homozygous familial Hypercholesterolemia -In a compassionate-use study of patient with homozygous familial hypercholesterolemia, most patient responded to 80 mg of atorvastatin. Heterozygous familial hypercholesterolemia in pediatric patients (10-17 years of age) – The recommended starting dose of atorvastatin is 10 mg/day; the maximum recommended dose is 20 mg/day (doses greater than 20 mg have not been studied in this patient population). Doses should be individualized according to the recommended goal of therapy. Adjustment should be made at intervals of 4 weeks or more. Use in Children - Treatment experience in a pediatric population is limited to doses of atorvastatin up to 80 mg/day for one year in 8 patients with homozygous FH. No clinical or biochemical abnormalities were reported in these patients. Use in Combination with Other Medicinal Compounds - In cases where co-administration of atorvastatin with cyclosporine, telaprevir, or the combination tipranavir/ritonavir is necessary, the dose of atorvastatin should not exceed 10 mg. Use of atorvastatin is not recommended in patients taking letermovir co-administered with cyclosporine. Pharmacokinetic drug interactions that result in increased systemic concentration of atorvastatin have also been noted with other human immunodeficiency virus (HIV) protease inhibitors (lopinavir/ritonavir, saquinavir/ritonavir, darunavir/ritonavir, fosamprenavir , fosamprenavir /ritonavir and nelfinavir), hepatitis C (HCV) protease inhibitors (boceprevir, elbasvir/grazoprevir, simeprevir ), clarithromycin, itraconazole, and letermovir . Caution should be used when co-prescribing atorvastatin, and appropriate clinical assessment is recommended to ensure that the lowest dose of atorvastatin necessary is employed. PRESENTATIONS: Lipitor 10 mg: Box of 3 blisters of 10 tablets; Box of 9 blisters of 10 tablets Reg. No. DKI 9790700217 A1. Lipitor 20 mg: Box of 3 blisters of 10 tablets; Box of 9 blisters of 10 tablets Reg. No. DKI 9790700217 B1, Lipitor 40 mg: Box of 3 blisters of 10 tablets; Box of 9 blisters of 10 tablets Reg. No. DKI 9790700217 C1, Lipitor 80 mg: Box of 3 blister of 10 tablets; Box of 9 blister of 10 tablets Reg No. DKI1790700217D1. STORAGE: Store below 30°C. HARUS DENGAN RESEP DOKTER / On Medical Prescription Only. Reference: Latest BPOM Approved Lipitor Local Product Document 2021 Full product information can be requested to: PT Pfizer Indonesia World Trade Center 3, 28 th Floor Jl. Jend . Sudirman Kav . 29-31 Jakarta 12920