LDL. HDL and CVD. D P Mikhailidis BSc MSc MD FCPP FRSPH FFPM FRCP FRCPath

Transcription

1 LDL. HDL and CVD D P Mikhailidis BSc MSc MD FCPP FRSPH FFPM FRCP FRCPath Dept. of Clinical Biochemistry Royal Free campus University College London (UCL)

2 DECLARATION OF INTEREST Attended conferences and gave talks sponsored by MSD, AstraZeneca and Libytec

3 DECLARATION OF INTEREST Lead for Guidelines on the Management of Carotid Artery Stenosis (Eur Soc Vasc Surg) Chair European Expert Panel on Small Dense Low Density Lipoprotein Co-chair Expert Panel on Post-Prandial Lipaemia

4 DECLARATION OF INTEREST Editor-in-Chief of: Curr Med Res Opin Expert Opin Pharmacother Angiology Curr Vasc Pharmacol Open Cardiovasc Med J Expert Rev Cardiovasc Ther Clinical Lipidology Journal of Drug Assessment

5 What are the LDL-C levels in neonates? What are the LDL-C levels in hunter-gatherers (e.g. living in the Amazon)? What are the LDL-C levels in people with proprotein convertase subtilisin/kexin 9 (PCSK9) loss of function mutations? Martin SS, Blumenthal RS, Miller M. LDL cholesterol: the lower the better. Med Clin North Am 2012; 96: 13-26

6 What are the LDL-C levels in neonates? mg/dl ( mmol/l) What are the LDL-C levels in hunter gatherers (e.g. living in the Amazon)? Similar to above What are the LDL-C levels in people with proprotein convertase subtilisin/kexin 9 (PCSK9) loss of function mutations? Similar to above but 1 case down to 15 mg/dl and is healthy.

7 Low Density Lipoprotein (LDL) What are the new LDL-C targets?

8 GUIDELINE LDL TARGETS USA(2001) 2.6mmol/l (100mg/dl) UK(2004) 2.0mmol/l (80 mg/dl) USA(2004) 1.8mmol/l (70mg/dl) (optional) very high risk patients UK JBS2(2005) 2.0mmol/l (80 mg/dl) (total cholesterol 4.0 mmol/l; 160 mg/dl) European(2007) 2.5mmol/l (96mg/dl) Canada(2009) 2.0mmol/l (80 mg/dl) ESC/EAS(2011) 1.8mmol/l (70mg/dl)

9 American College of Cardiology/American Heart Association 2018 Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella- Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018 Nov 8. pii: S (18)39034-X. doi: /j.jacc [Epub ahead of print] PubMed PMID: and, J Am Coll Cardiol 2018 Nov 3. pii: S (18) doi: /j.jacc [Epub ahead of print] PubMed PMID:

10 Statin treatment groups: (1) Clinical ASCVD (2) Diabetes mellitus with LDL-C 70 mg/dl (3) y of age with LDL-C mg/dl and 10-y ASCVD risk 7.5% (4) Severe hypercholesterolemia (LDL-C 190 mg/dl) ASCVD on maximal statin therapy: Ezetimibe for clinical ASCVD and LDL-C 70 mg/dl (Class IIb; Level of Evidence C); ezetimibe and PCSK9 inhibitor as add-on therapy for very high-risk ASCVD and LDL-C 70 mg/dl (Class IIa) Pooled Cohort Equations: Low risk (<5%), borderline risk (5% - < 7.5%), intermediate risk (7.5% < 20%), and high risk ( 20%) (Class I; Level of Evidence B-NR)

11 2016 Joint European Society of Cardiology (ESC) Guidelines LDL-C 1.8 mmol/l (70 mg/dl) appears to be a reasonable goal for prevention of recurrent CV events and in very-high-risk subjects. LDL-C reduction of 50% is also recommended if the baseline LDL-C level is mmol/l ( mg/dl). Non-HDL-C target values may be an alternate target if non-fasting samples are obtained, and goals should be <2.6, <3.3 and <3.8 mmol/l (<100, <130 and <145 mg/dl) with very high, high and low to moderate CV risk, respectively. Piepoli MF et al. Euro Heart J 2016; 37:

12 2016 Joint European Society of Cardiology (ESC) Guidelines No differences in the relative risk reduction between men and women and between younger and older age or between those with and without DM. Specifically mentions the higher risk for South Asians (CHD and type 2 DM) Piepoli MF et al. Euro Heart J 2016; 37:

13 2016 Joint European Society of Cardiology (ESC) Guidelines Statins: main drugs (even for combined hyperlipidaemia) Ezetimibe: not for monotherapy unless statins not tolerated Resins: not for monotherapy unless statins not tolerated. Poorly tolerated and raise triglycerides. Cost. Fibrates and niacin: primarily for triglyceride lowering and increasing HDL-C. Limited evidence regarding CV events; niacin no longer available in many countries. Fish oils (ω-3 fatty acids): 2-4 g/day for triglyceride lowering. Limited evidence regarding CV events. Recent REDUCE-IT trial more positive but AF/atrial flutter is increased. PCSK9 inhibitors: Limited evidence regarding CV events (evidence now available for evolocumab). Cost. Apheresis: not mentioned!

14 2016 Joint European Society of Cardiology (ESC) Guidelines Knowledge gaps: Triglyceride or HDL-C values as targets for therapy? Can Lp(a) lowering against background statin therapy reduce the risk of CVD? How to increase adoption of non-hdl-c and non-fasting samples in clinical practice. Whether functional foods and food supplements with a lipid-lowering effect can safely reduce the risk of CVD.

15 Goal for Extreme Risk = 55 mg/dl (1.4. mmol/l) Jellinger PS, et al. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY GUIDELINES FOR MANAGEMENT OF DYSLIPIDEMIA AND PREVENTION OF CARDIOVASCULAR DISEASE. Endocr Pract 2017; 23(Suppl 2): 1 87 Extreme risk = Progressive ASCVD including unstable angina after achieving an LDL-C <70 mg/dl Established clinical cardiovascular disease in patients with DM, CKD 3/4, or HeFH Premature ASCVD (<55 male, <65 female)

16 Lower target of LDL-C <55 mg/dl (1.4 mmol/l) can be considered in ACS patients with DM. Li YH, Ueng KC, Jeng JS, Charng MJ, Lin TH, Chien KL, Wang CY, Chao TH, Liu PY, Su CH, Chien SC, Liou CW, Tang SC, Lee CC, Yu TY, Chen JW, Wu CC, Yeh HI; Writing Group of 2017 Taiwan Lipid Guidelines for High Risk Patients Taiwan lipid guidelines for high risk patients. J Formosa Med Assoc 2017; 116:

17 TNT: Baseline and final LDL cholesterol levels (mmol/l) LDL-C Atorvastatin 10 mg (n = 5006) Atorvastatin 80 mg (n = 4995) Baseline LDL-C 2.5 (96 mg/dl) 2.5 (96 mg/dl) Final LDL-C 2.6 (100 mg/dl) 2.0 (77 mg/dl)

18 TNT: Primary efficacy outcomes Outcome Atorvastatin 10 mg (n = 5006) Atorvastatin 80 mg (n =4995) Hazard ratio (95% CI) p Total major cardiovascular events (%) Death from CHD (%) ( ) ( ) Nonfatal MI (%) ( ) Fatal or nonfatal stroke (%) ( ) < LaRosa JC et al. N Engl J Med2005; 352:

19 IDEAL study Simvastatin 20 (n = 4449)* vs atorvastatin 80 mg (n = 4439). Previous MI; 4.8 years follow-up. No difference in primary end point. However, there were significant differences in secondary endpoints favouring more aggressive treatment. Myalgia 51 vs 97 P < Diarrhoea 9 vs 38 P < Abdominal pain 10 vs 37 P < Nausea 6 vs 32 P< AST 2 vs 18 >3X ULN P < ALT 5 vs 43 >3X ULN P < Adverse event leading to permanent discontinuation 186 vs 426 P < *23% were on simvastatin 40 mg and 13% had atorvastatin 40 mg Pedersen TR et al. JAMA 2005; 294:

20 IMProved Reduction of Outcomes: Vytorin Efficacy International Trial A Multicenter, Double-Blind, Randomized Study to Establish the Clinical Benefit and Safety of Vytorin (Ezetimibe/Simvastatin Tablet) vs Simvastatin Monotherapy in High-Risk Subjects Presenting With Acute Coronary Syndrome

21 Study Design Patients stabilized post ACS 10 days: LDL-C * mg/dl (or ** mg/dl if prior lipid-lowering Rx) *3.2 mm **2.6 mm n = 18,144 Standard Medical & Interventional Therapy Simvastatin 40 mg Uptitrated to Simva 80 mg if LDL-C > 79 (adapted per FDA label 2011) Ezetimibe / Simvastatin 10 / 40 mg Follow-up Visit Day 30, every 4 months 90% power to detect ~9% difference Duration:Minimum 2 ½-year follow-up (at least 5250events) Primary Endpoint:CV death, MI, hospital admission for UA, coronary revascularization ( 30 days after randomization), or stroke Cannon CP AHJ 2008; 156: ; Califf RM NEJM 2009; 361: 712-7; Blazing MA AHJ 2014; 168:

22 LDL-C and Lipid Changes Median Time averaged: 1.80 vs 1.39 mmol/l 70 vs54 mg/dl

23 Primary Endpoint ITT Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization ( 30 days), or stroke HR CI (0.887, 0.988) p = Simva 34.7% 2742 events NNT = 50 EZ/Simva 32.7% 2572 events 7-year event rates

24 CV Death, Non-fatal MI, or Non-fatal Stroke HR 0.90 CI (0.84, 0.97) P = NNT = 56 Simva 22.2% 1704 events EZ/Simva 20.4% 1544 events 7-year event rates

25 IMPROVE-IT added to CTT: Ezetimibevs. Statin Benefit IMPROVE-IT CTT Collaboration: Lancet 2005; 366: Lancet 2010;376:

26 Conclusions First trial demonstrating incremental clinical benefit when adding a non-statin agent (ezetimibe) to statin therapy: YES: Non-statin lowering LDL-C with ezetimibe reduces cardiovascular events YES: Even Lower is Even Better (mean LDL-C 1.40 vs1.81 mmol/l at 1 year; 55 vs70 mg/dl) YES: Confirms ezetimibe safety

27 COMBINATION THERAPY META-ANALYSIS 11 RCTs: 109,244 patients Overall, the incidences of major adverse cardiovascular events (MACEs) were 9.70% in the statin combination groups and 9.92% in the statin monotherapy groups No significant difference observed in the risk of MACEs either in subgroup analysis (CETP inhibitor: RR 1.07, 95% CI , p = 0.37; niacin: RR 1.03, 95% CI , p = 0.79; n-3 fatty acid: RR 0.98, 95% CI , p = 0.70; fenofibrate: RR 0.93, 95% CI , p = 0.38), with the exception of the statin/ezetimibe combination subgroup (RR 0.92, 95% CI , p = 0.004) Adding lipid-modifying agent to statin significantly increased liver injury risk Adding ezetimibe to statin did not alter side effect profile Ip CK, et al. Int J Cardiol 2015; 191:

28 Meta-Analysis: Ezetimibe Added to a Statin n = 5, 039 LDL fall = 23.6% p< HDL increase = 1.7% p< TG fall = 10.7% p< Mikhailidis DP et al. Curr Med Res Opin 2007; 23:

29 IMPROVE-IT LDL-C difference = 69.9 vs 53.2 mg/dl i.e mg/dl or 23.9% Our meta-analysis = 23.6%

30 A Naturally Randomized IMPROVE-IT Trial Ference, BA et al. J Am Coll Cardiol 2015; 65: Brian A Ference, MD, MPhil, MSc, FACC Division of Translational Research and Clinical Epidemiology (TRaCE) Division of Cardiovascular Medicine Wayne State University School of Medicine

31 2x2 Factorial Mendelian Randomization Group LDL-C Effect Size (mg/dl) OR CHD (95%CI) Both NPC1L1 & HMGCR LDL-C Scores above median ( ) p = 2.4x10-4 HMGCR LDL-C Score above median ( ) p = 3.3x10-3 NPC1L1 LDL-C Score above median ( ) p = 2.6x Ference, BA et al. J Am Coll Cardiol 2015; 65:

32 IMPROVE-IT Concepts: 1] Even lower is even better 2] A lower LDL-C for even longer is even better

33 FOURIER Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk MS Sabatine, RP Giugliano, AC Keech, N Honarpour, SM Wasserman, PS Sever, and TR Pedersen, for the FOURIER Steering Committee & Investigators American College of Cardiology 66 th Annual Scientific Session Late-Breaking Clinical Trial March 17, 2017 An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

34 Trial Design 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD) Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe) LDL-C 70 mg/dl or non-hdl-c 100 mg/dl Evolocumab SC 140 mg Q2W or 420 mg QM RANDOMIZED DOUBLE BLIND Placebo SC Q2W or QM Follow-up Q 12 weeks An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Sabatine MS et al. Am Heart J 2016;173:94-101

35 Follow-up Randomized 27,564 patients Evolocumab (N=13,784) Placebo (N=13,780) Follow-up median 26 months (IQR 22-30) 2907 patients experienced primary endpoint 1829 experienced key secondary endpoint Premature perm. drug discontinuation 5.6%/yr 5.8%/yr Withdrew consent 0.29%/yr 0.35%/yr Lost to follow-up 5 patients 13 patients Ascertainment for primary endpoint was complete for 99.5% of potential patient-years of follow up An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

36 Baseline Characteristics Characteristic Value Age, years,mean (SD) 63 (9) Male sex (%) 75 Type of cardiovascular disease (%) Myocardial infarction 81 Stroke (non-hemorrhagic) 19 Symptomatic PAD 13 Cardiovascular risk factor (%) Hypertension 80 Diabetes mellitus 37 Current cigarette use 28 Median time from most recent event ~3 yrs An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Pooled data; no differences between treatment arms

37 Lipid Lowering Therapy & Lipid Levels at Baseline Characteristic Statin use (%)* Value High-intensity 69 Moderate-intensity 30 Ezetimibeuse (%) 5 Median lipid measures (IQR) mg/dl LDL-C 92 (80-109) Total cholesterol 168 ( ) HDL-C 44(37-53) Triglycerides 133( ) *Per protocol, patients were to be on atorva 20 mg/d or equivalent. 1% were on low intensity or intensity data were missing. Statin intensity defined per ACC/AHA 2013 Cholesterol Guidelines. An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Pooled data; no differences between treatment arms

38 LDL Cholesterol Placebo LDL Cholesterol (mg/dl) % mean reduction (95%CI 58-60), P< Absolute reduction: 56 mg/dl (95%CI 55-57) Evolocumab (median 30 mg/dl, IQR mg/dl) Weeks An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

39 Primary Endpoint CV Death, MI, Stroke, Hosp for UA, or Cor Revasc 16% 14% 12% 10% 8% 6% 4% 2% Hazard ratio % (95% CI, ) P< Placebo 12.6% Evolocumab 0% An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Months from Randomization

40 Types of CV Outcomes Endpoint Evolocumab (n = 13,784) 3-yr Kaplan-Meier rate Placebo (n = 13,780) HR (95% CI) CV death, MI, or stroke ( ) Cardiovascular death ( ) Death due to acute MI ( ) Death due to stroke ( ) Other CV death ( ) MI ( ) Stroke ( ) An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

41 Types of CV Outcomes Endpoint Evolocumab (n = 13,784) 3-yr Kaplan-Meier rate Placebo (n = 13,780) HR (95% CI) CVD, MI, stroke, UA, or revasc ( ) CV death, MI, or stroke ( ) Cardiovascular death ( ) MI ( ) Stroke ( ) Hosp for unstableangina ( ) Coronary revasc ( ) Urgent ( ) Elective ( ) Death from any cause ( ) An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

42 Comparison to Cholesterol Treatment Trialists Collaboration Hazard Ratio (95% CI) per 1 mmol/l reduction in LDL-C Major Coronary Events 0.78 ( ) 0.80 ( ) Stroke Coronary revascularization Urgent Elective 0.77 ( ) 0.77 ( ) 0.75 ( ) 0.73 ( ) 0.84 ( ) CTTC Meta-analysis Year 2 FOURIER Year 2 Major Vascular Events 0.77 ( ) 0.83 ( ) Lipid-lowering therapy better Lipid-lowering therapy worse 2.0 An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School CTTC data: Lancet2010; 376:

43 Summary LDL-C by 59% Consistent throughout duration of trial Median achieved LDL-C of 30 mg/dl (IQR mg/dl) CV outcomes in patients already on statin therapy 15% broad primary endpoint; 20% CV death, MI, or stroke Consistent benefit, incl. in those on high-intensity statin, low LDL-C 25% reduction in CV death, MI, or stroke after 1 st year Long-term benefits consistent w/ statins per mmol/l LDL-C Safe and well-tolerated Similar rates of AEs, incl DM & neurocog events w/ EvoMab & pbo Rates of EvoMab discontinuation low and no greater than pbo No neutralizing antibodies developed An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

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62 Event Rates vs LDL Cholesterol during Statin Therapy in Secondary-Prevention Studies LaRosa JC et al. N Engl J Med2005; 352:

63 Landmark Statin Trials: LDL-C vs Events 10 Percentage with CHD event AFCAPS-S ASCOT-S WOSCOPS-S ASCOT-P AFCAPS-P WOSCOPS-P Primary prevention Pravastatin Lovastatin Atorvastatin (90) 2.8 (110) 3.4 (130) 3.9 (150) 4.4 (170) 4.9 (190) LDL-C, mmol/l (mg/dl) 5.4 (210) S = statin treated; P = placebo treated Modified from Kastelein JJP. Atherosclerosis 1999; 143(suppl 1): S17 - S21

64 Low Density Lipoprotein (LDL) Small dense LDL (sdldl) Difficult to prove causality on trial based evidence but experimental evidence is strong. How to measure sdldl? Clinical sign: high TG levels: > 150 mg/dl (1.7 mmol/l). Also, low HDL-C levels Mikhailidis DP, Elisaf M, Rizzo M, Berneis K, Griffin B, Zambon A, Athyros V, de Graaf J, März W, Parhofer KG, Rini GB, Spinas GA, Tomkin GH, Tselepis AD, Wierzbicki AS, Winkler K, Florentin M, Liberopoulos E. European panel on low density lipoprotein (LDL) subclasses: a statement on the pathophysiology, atherogenicity and clinical significance of LDL subclasses: executive summary. Curr Vasc Pharmacol 2011; 9: (open access) Mikhailidis DP, Elisaf M, Rizzo M, Berneis K, Griffin B, Zambon A, Athyros V, de Graaf J, März W, Parhofer KG, Rini GB, Spinas GA, Tomkin GH, Tselepis AD, Wierzbicki AS, Winkler K, Florentin M, Liberopoulos E. European panel on low density lipoprotein (LDL) subclasses: a statement on the pathophysiology, atherogenicity and clinical significance of LDL subclasses. Curr Vasc Pharmacol 2011; 9:

65 Low Density Lipoprotein (LDL) Friedewald formula LDL-C = Total cholesterol HDL TG/5 (mg/dl) 1] Fasting 2] TG levels > 400 mg/dl (4.5 mmol/l)

66 High Density Lipoprotein (HDL) The key is Quantity and Quality Harmful (torcetrapib) or neutral trials (evacetrapib and dalcetrapib) with CETP inhibitors. REVEAL was positive but anacetrapib will not be developed further; why? Remember: epidemiology/genetics vs an individual case. HDL Milano: low levels but long life High HDL-C may be harmful. How to tell? HDL-like infusions for ACS?

67 Jafri H, Alsheikh-Ali AA, Karas RH. Meta-analysis: statin therapy does not alter the association between low levels of high-density lipoprotein cholesterol and increased cardiovascular risk. Ann Intern Med ; 153: RCTs: person-years of follow-up; MIs Adjustment for on-treatment LDL-C levels, age, hypertension, diabetes, and tobacco use. In Poisson meta-regressions, every 0.26 mmol/l (10 mg/dl) decrease in HDL-C was associated with 7.1 (95% CI ) and 8.3 ( ) more MIs per 1000 person-years in statin-treated patients and control participants, respectively.

68 High Density Lipoprotein (HDL) Otocka-Kmiecik A, Mikhailidis DP, Nicholls SJ, Davidson M, Rysz J, Banach M. Dysfunctional HDL: a novel important diagnostic and therapeutic target in cardiovascular disease? Prog Lipid Res 2012; 51: Katsiki N, Athyros VG, Karagiannis A, Mikhailidis DP. High-density lipoprotein, vascular risk, cancer and infection: a case of quantity and quality? Curr Med Chem 2014; 21: Madsen CM, Varbo A, Tybjærg-Hansen A, Frikke-Schmidt R, Nordestgaard BG. U-shaped relationship of HDL and risk of infectious disease: two prospective population-based cohort studies. Eur Heart J 2017 Dec 8. doi: /eurheartj/ehx665. [Epub ahead of print] PubMed PMID: Vitali C, Khetarpal SA, Rader DJ. HDL Cholesterol Metabolism and the Risk of CHD: New Insights from Human Genetics. Curr Cardiol Rep 2017; 19: 132

69 RISK FACTOR ANALYSIS IN SPARCL Optimal control: LDL-C <70 mg/dl, HDL-C >50 mg/dl, TG <150 mg/dl and SBP/DBP <120/80 mmhg. Risk of stroke decreased as control increased (HR [95% CI] 0.98 [0.76 to 1.27], 0.78 [0.61 to 0.99], 0.62 [0.46 to 0.84], and 0.35 [0.13 to 0.96]) for those achieving control of 1, 2, 3, or 4 factors as compared with none, respectively. Amarenco P et al. Stroke 2009; 40:

70 STATINS AND OPERATIVE CARDIAC MORTALITY Decreased operative mortality associated with general and vascular surgery Benefit evident even after short-term use of statins Paraskevas KI, Liapis CD, Hamilton G, Mikhailidis DP. Eur J Vasc Endovasc Surg 2006;32: Paraskevas KI, Veith FJ, Liapis CD, Mikhailidis DP. Curr Vasc Pharmacol 2013;11:112-20

71 STATINS AND OPERATIVE CARDIAC MORTALITY Pre-interventional use of statins has a protective effect against peri-interventional stroke, MI, or death in patients with internal carotid artery stenosis treated with stent-angioplasty (n = 344) Reiff T, et al. Eur J Vasc Endovasc Surg 2014; 48: Pre-interventional use of statins not only reduce CV events and mortality but may also have an important effect on the anatomic durability of CEA. Avgerinos ED, et al. Curr Vasc Pharmacol 2015; 13:

72 NEW ONSET DIABETES (NOD) How long did it take to identify this adverse effect of statins? Do not look at general percentages there are high risk populations. However, it seems that there is benefit overall. Important to discuss weight gain etc with patients. Ezetimibe? PCSK-9 inhibitors?

73 EZETIMIBE AND DIABETES Giugliano RP, et al.benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With vs. Without Diabetes: Results from IMPROVE-IT.Circulation2017; in press. Baseline LDL-C was significantly lower in diabetic s vs non-diabetics; 89 vs 97 mg/dl (2.3 vs 2.5 mmol/l) (p<0.001). Diabetic post ACS patients, using E+S achieved a 5.5% absolute risk reduction; HR 0.85 ( ); In the non-dm patients the absolute event rates were reduced by 0.7%; HR 0.98 ( ). Perhaps the favourable effects of ezetimibe on glucose metabolism, including reductions in fasting plasma glucose, insulin levels, and insulin resistance, may have contributed to the enhanced benefit observed in diabetic patients (stated by the authors).

74 Clearly, Lower is better for LDL-C Lower for longer is better for LDL-C The question is how much lower and for whom?