Dislipidemie: come districarsi tra nuove linee guida e nota AIFA

Dislipidemie: come districarsi tra nuove linee guida e nota AIFA

Marco Giorgio Baroni

Dipartimento di Medicina Clinica, Sanità Pubblica, Scienze della Vita e dell’Ambiente (MeSVA)

Università dell’Aquila

Il Prof Marco Giorgio Baroni dichiara di aver ricevuto negli ultimi due anni compensi o finanziamenti dalle seguenti Aziende

Farmaceutiche e/o Diagnostiche:

- Novo Nordisk - Sanofi

- Abbott - MSD

- Mundipharma - Astra Zeneca

Dichiara altresì il proprio impegno ad astenersi, nell’ambito dell’evento, dal nominare, in

qualsivoglia modo o forma, aziende farmaceutiche e/o denominazione commerciale e di

non fare pubblicità di qualsiasi tipo relativamente a specifici prodotti di interesse sanitario

(farmaci, strumenti, dispositivi medico-chirurgici, ecc.).

• Diabete, LDL-C e rischio CV: burden of disease

• Nuove linee guida, nuovi target (e nuovi problemi?)

• Le (tante) soluzioni terapeutiche

Dislipidemie: come districarsi tra nuove linee guida

e nota AIFA

Cumulative incidence curves for first presentation of 12 cardiovascular

diseases in patients aged ≥40 years, by diabetes status (1.9 million people cohort)

Shah AD et al. Lancet Diabetes Endocrinol 2015; 3:105-13.

Coronary heart disease (n = 280)

Position in model Variable P value

1 ^st LDL-C <0.0001

2 ^nd HDL-C 0.0001

3 ^rd Hemoglobin A _1c 0.0022

4 ^th Systolic blood pressure 0.0065

5 ^th Smoking 0.056

Turner RC et al. BMJ 1998; 316:823–828.

Stepwise Selection of Risk Factors in 2,693 White Patients With NIDDM

United Kingdom Prospective Diabetes Study (UKPDS)

• Prospective studies, randomized trials, and Mendelian randomization studies have all shown that raised LDL-C is a cause of ASCVD ^1–3

• The cumulative arterial burden of LDL-C drives the development and progression of ASCVD ²

• Patients who achieve very low LDL-C levels have a lower risk of major CV events than those who achieve

moderately low levels ^{4 Ri sk}

o f m ajo r CV e ven ts (a djus ted ha za rd ra tio )

LDL-C Levels (mg/dL)

ASCVD, atherosclerotic cardiovascular disease; CHD, coronary heart disease; CVD, cardiovascular disease 1. ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J. 2020; 41(1): 111-188.

2. Borén J et al. Eur Heart J. 2020; 0: 1-28.

3. Ference BA et al. Eur Heart J. 2017; 38(32): 2459–2472.

4. Boekholdt et al. JACC 2014;64: 485–494.

Increased LDL-C Levels are a Proven and Direct Cause of CV Events

-1.0 mM LDL: diabete vs no diabete

Cholesterol Treatment Trialists’

(CTT) Collaboration- Lancet 2008

LDL -40 mg/dl = -20%

(-0.5% / mg)

-1.0 mM LDL: sia in prev primaria che secondaria

-20%

Cholesterol Treatment Trialists’

(CTT) Collaboration- Lancet

2008

-1.0 mM LDL: a prescindere dalle comorbidità

Cholesterol Treatment Trialists’

(CTT) Collaboration- Lancet 2008

-20%

IMPROVE-IT: On-Treatment LDL Predicts Clinical Event Rates

Risk reduction

-1 mg/dl = - 0.5%

-50 mg/dl = -25% !!!!

Simva ^† EZ/Simva ^†

Male 34.9 33.3

Female 34.0 31.0

Age < 65 years 30.8 29.9

Age ≥ 65 years 39.9 36.4

No diabetes 30.8 30.2

Diabetes 45.5 40.0

Prior LLT 43.4 40.7

No prior LLT 30.0 28.6

LDL-C > 95 ^mg/dl 31.2 29.6

LDL-C ≤ 95 ^mg/dl 38.4 36.0

Improve-IT

Major Pre-specified Subgroups

Ezetimibe/Simva

Better Simva

Better

0.7 1.0 1.3 ^† 7- year

event rates

*

*p-interaction = 0.023, otherwise > 0.05

• Diabete, LDL-C e rischio CV: burden of disease

• Nuove linee guida, nuovi target (e nuovi problemi?)

• Le (tante) soluzioni terapeutiche

Dislipidemie: come districarsi tra nuove linee guida

e nota AIFA

Sintesi sulla rimborsabilità delle statine (e ezetimibe) in base al livello

di rischio CV secondo la nuova nota 13 Nota AIFA 4-5-2020

Sintesi sulla rimborsabilità delle statine (e ezetimibe) in

base al livello di rischio CV secondo la nuova nota 13

Sintesi sulla rimborsabilità delle statine (e ezetimibe) in base al livello

di rischio CV secondo la nuova nota 13 Nota AIFA 4-5-2020

SCORE chart: 10-year risk of fatal cardiovascular disease (CVD)

ESC Guidelines 2011

• Sono considerati per definizione a rischio alto (e il loro target terapeutico è pertanto un valore di colesterolo LDL <100)

• coloro che presentano un risk score ≥5% e < 10% per CVD fatale a 10 anni,

• i pazienti con dislipidemie familiari, quelli con ipertensione severa,

• ⁱ pazienti diabetici senza fattori di rischio CV e senza danno d'organo

• i pazienti con IRC moderata (FG 30-59 ml/min/1.73m2).

• Sono invece considerati a rischio molto alto (e pertanto con target terapeutico di colesterolo LDL <70),

• i soggetti con uno score ≥10%,

• i pazienti con malattia coronarica, stroke ischemico, arteriopatie periferiche, pregresso infarto, bypass aorto-coronarico,

• i pazienti diabetici con uno o più fattori di rischio CV e/o markers di danno d'organo (come la microalbuminuria)

• i pazienti con IRC grave (FG 15-29 ml/min/1.73m2).

CATEGORIE DI RISCHIO

Nota 13 AIFA 4-5-2020

ESC/EAS Guidelines Eur Heart J. 2020; 41: 111-188.

Low

Moderate

High

Very-High

(116mg/dL)

Treatment goal for

LDL-C

1.8mmol/L (70mg/dL)

1.4mmol/L (55mg/dL)

& ≥50%

reduction from baseline

Low Moderate High Very-High CV Risk

•SCORE<1%

•SCORE ≥1% and <5%

•Young patients (T1DM <35 years; T2DM <50 years) with DM duration <10 years without other risk factors

•SCORE ≥5% and <10%

•Markedly elevated single risk factors, in particular TC >8 mmol/L (310 mg/dL) or LDL-C >4.9 mmol/L (190 mg/dL) or BP ≥180/110 mmHg

•FH without other major risk factors

•Moderate CKD (eGFR 30–59 mL/min)

•DM w/o target organ damage, with DMduration ≥10 years or other additional risk factor

•ASCVD (clinical/imaging)

•SCORE ≥10%

•FH with ASCVD or with another major risk factor

•Severe CKD (eGFR <30 mL/min)

•DM & target organ damage: ≥3 major risk factors; or early onset of T1DM of long duration (>20 years)

• The updated ESC/EAS Guidelines recommend an LDL-C reduction of ≥50% and LDL-C goals of <70 (1.8 mmol/L) and <55 mg/dL (1.4 mmol/L) in high- and very high-risk patients, respectively

• These goals are more stringent than previously because the greater the absolute LDL-C reduction, the greater the CV risk reduction

The 2019 ESC/EAS Guidelines Recommend to Intensively Lower LDL-C to Reduce

Cardiovascular Risk, Particularly in Uncontrolled Patients

Life years lost in relation to age at onset of type 1 diabetes

Rawshani et al. Lancet 2018

Adjusted hazard ratios for all outcomes, according to age at type 1 diabetes diagnosis

Rawshani et al. Lancet 2018

10-year CVD risk prediction according to Steno type 1 Risk Engine (ST1RE) in a cohort of adults aged < 35 or ≥ 35 years in whom the CVD risk was classified according to 2019 ESC criteria (n = 532)

Tecce et al. Cardiovasc Diabetol (2020) 19:166

ESC/EAS Guidelines Eur Heart J. 2020; 41: 111-188.

Low

Moderate

High

Very-High

(116mg/dL)

Treatment goal for

LDL-C

1.8mmol/L (70mg/dL)

1.4mmol/L (55mg/dL)

& ≥50%

reduction from baseline

Low Moderate High Very-High CV Risk

•SCORE<1%

•SCORE ≥1% and <5%

•Young patients (T1DM <35 years; T2DM <50 years) with DM duration <10 years without other risk factors

•SCORE ≥5% and <10%

•Markedly elevated single risk factors, in particular TC >8 mmol/L (310 mg/dL) or LDL-C >4.9 mmol/L (190 mg/dL) or BP ≥180/110 mmHg

•FH without other major risk factors

•Moderate CKD (eGFR 30–59 mL/min)

•DM w/o target organ damage, with DMduration ≥10 years or other additional risk factor

•ASCVD (clinical/imaging)

•SCORE ≥10%

•FH with ASCVD or with another major risk factor

•Severe CKD (eGFR <30 mL/min)

•DM & target organ damage: ≥3 major risk factors; or early onset of T1DM of long duration (>20 years)

• The updated ESC/EAS Guidelines recommend an LDL-C reduction of ≥50% and LDL-C goals of <70 (1.8 mmol/L) and <55 mg/dL (1.4 mmol/L) in high- and very high-risk patients, respectively

• These goals are more stringent than previously because the greater the absolute LDL-C reduction, the greater the CV risk reduction

The 2019 ESC/EAS Guidelines Recommend to Intensively Lower LDL-C to Reduce

Cardiovascular Risk, Particularly in Uncontrolled Patients

• Analysis of the hospital arm of the EUROASPIRE V survey of risk factors and management in coronary heart disease patients with/without diabetes

• Carried out in 27 European countries, 2016–17

• Coronary patients followed up n=7,824

• 84.3% of patients were receiving LLT

– 49.9% were receiving high intensity LLT

– 34.1% were receiving low/moderate intensity LLT

• Overall, 71.0% of coronary patients across Europe were not at LDL-C goal <1.8 mmol/L (<70 mg/dL)

Conclusions

• The majority of patients with CAD did not reach LDL-C goals recommended by the 2016 ESC/EAS guidelines

• The 2019 ESC/EAS guidelines recommend even lower LDL-C goals, so, in reality, the unmet need will be greater

Belgium 66.8%

Italy 62.5%

Portugal 68.8%

Spain 51.3%

Poland 67.3%

Germany 74.1%

de Backer G et al. Atherosclerosis. 2019;285:135–146.

UK 54.5%

EUROASPIRE, European Action on Secondary and Primary Prevention by Intervention to Reduce Events

Unmet Need: Very High Risk Patients with LDL-C ≥70 mg/dL Across EUROPE

Maggioni AP et al. Int J Cardiol 2017; 246:62–67.

Prescription rate and continuity of treatment with statins is suboptimal in DM patients with recent CV events

• The rate of use of statins

with/without ezetimibe in the

diabetics cohort was 68.5, 59.3 and 53.1% during the first, the second and the third year of follow-up, respectively.

• In the subgroup of diabetics, at least one readmission over the first year of follow-up occurred in 59.6% of

patients. The total number of re- hospitalizations of diabetics was

6118. Of them, 56.9% was due to CV

causes

Ipolipemizzanti «real life»

ANNALI AMD 2018

80,5% 77,1%

0 20 40 60 80 100

Overall Statins plus…

Proportion (%) of patients who did not achieve LDL-C goal (≥70 mg/dL [1.8 mmol/L])

Retrospective cohort study of 42,000 ASCVD patients on moderate- to high-dose statins²

Figure adapted from Fox KM et al. Clin Res Cardiol 2018; 107: 380–388.

Additional LLTs are Needed to Complement Current Therapies to Help

Uncontrolled Patients Achieve Their Goals

CV Outcomes Trials with PCSK-9 Inhibitors

Other Lipid Parameters The FOURIER Study: Diabetes Subgroup

Sabatine MS et al. Lancet Diabetes Endocrinol. 2017;5:941-950

(85mg/dL)

(27mg/dL)

LDL cholesterol

Primary Endpoint Secondary Endpoints

Sabatine MS et al. Lancet Diabetes Endocrinol. 2017;5:941-950

The FOURIER Study: Diabetes Subgroup

Median percent change from baseline presented below eachbar Intention-to-treat analysis

HDL-C Triglyceride

0 40 80 120 160 200

M edi an ( Q 1, Q 3) , m g/dL

Diabetes Prediabetes

Normoglycemia

Alirocumab

-64% -64% -65%

LDL-C Non-HDL-C

+1% +1% 0%

-54% -54% -54%

0% 0%

+1%

+8% +8% +7% +3% +3% +3%

-14% -15% -16%

0% +1% -2%

Placebo

Alirocumab

Placebo

Alirocumab Placebo

Alirocumab

Placebo

RayKKetal.Lancet Diabetes Endocrinol. 2019;7:618-628

Lipids at 16 Weeks After Randomization In the ODYSSEY OUTCOMES

Median (Q1, Q3) follow-up: 2.8 (2.3, 3.4)years

Relative riskreduction P

=0.98

Absolute riskreduction P

=0.0019

1.0 Alirocumab

n/N (%)

903/9462 (9.5) Overall

Diabetes Prediabetes

Placebo

n/N (%) HR (95% CI)

0.84 (0.74, 0.97) 0.86 (0.74, 1.00) 0.85 (0.70, 1.03) Subgroup

1052/9462 (11.1) 0.85 (0.78, 0.93)

380/2693 (14.1) 452/2751 (16.4) 331/4130 (8.0) 380/4116 (9.2) Normoglycemia 192/2639 (7.3) 220/2595 (8.5)

0.75 0.85

Alirocumab Better

Treatment × baseline glucometabolic status:

MACE Incidence

A

1.6%

1.2%

1.2

2.3%

Placebo Better

0%

ARR (95% CI)

1.6% (0.7%, 2.4%)

2.3% (0.4%, 4.2%) 1.2% (0%, 2.4%) 1.2% (-0.3%, 2.7%)

3.2% 1.6%

Alirocumab Better

Placebo Better

RayKKetal.Lancet Diabetes Endocrinol. 2019;7:618-628

Relative and Absolute Risk Reduction with Alirocumab

By Glucometabolic Status

G.U 6-3-2017

Paziente prevenzione secondaria LDL≥100,

età≤80aa, no ipercolest. secondaria, no GFR<30ml/min, no insuff.epatica

HeF (Dutch Lipid Score>8) e CAD o CVD o AOP o DMC

Ipercolesterolemia non familiare o

Dislipidemia mista e CAD o CVD o AOP o DMC

HeF o Ipercolesterolemia non familiare o Dislipidemia mista e CAD o CVD o AOP o DMC

e intolleranza alle statine

1. Almeno 6 mesi di terapia con statina alta intensità* max dose tollerata + EZETIMIBE;

2. Trattamento con Anti-PCSK9

1. Almeno 6 mesi di terapia con EZETIMIBE; la

prescrizione

2. Trattamento con Anti-PCSK9

*atorvastatina/rosuvastatina

2. Paziente con storia di ipercolesterolemia, in prevenzione secondaria,

in trattamento con statina ad alta intensità alla massima dose tollerata ma senza ezetimibe e con LDL-c ≥100mg/dl:

 Aggiungere ezetimibe e poi fare nuovo profilo lipidico (1°). Se LDL-c ancora≥100……

 Fare 2° profilo lipidico….

 Fare 3° profilo lipidico e P.T. entro 30gg.

6 mesi alirocumab o

evolocumab

Nota 13 vs Linee Guida

• nota 13 AIFA è vincolante ai fini giuridici ed amministrativi e deve tener conto di compatibilità economiche specifiche della realtà italiana (cosa decisamente secondaria invece per linee guida internazionali)

• Target LDL e livelli di rischio CV

• Utilizzo carte di rischio SCORE (Carte CUORE?)

• Uso di Rosuvastatina: perché nei pazienti ad alto rischio sia compresa

tra i trattamenti di seconda scelta, mentre per i pazienti a rischio molto

alto sia tra i farmaci di prima scelta, ma solo nei pazienti in cui ci sia

stata evidenza di effetti collaterali severi nei primi 6 mesi di terapia con

altre statine (devo aspettare 6 mesi?)

• LDL-C va ridotto aggressivamente nel paziente con DM (solide evidenze da RCTs, studi osservazionali, registri amministrativi…)

• Molte opzioni/alternative terapeutiche, tutte efficaci e sicure

• Ostacoli:

• Inerzia terapeutica

• Non aderenza e/o persistenza in terapia

• Difficile accesso ad alcune cure

Dislipidemie: come districarsi tra nuove linee guida e

nota AIFA

Terapia ipolipemizzante e diabete

• Dagli studi con statine è chiaramente emerso un aumento significativo del 11-12% del rischio di sviluppare diabete mellito

• OR 1·12, 95% CI 1·06-1·18 in tutti i trials;

• OR 1·11, 95% CI 1·03-1·20 in trials controllati con placebo o standard care

• OR 1·12, 95% CI 1·04-1·22 in trials di confronto tra dose intensiva e moderata) (Swerdlow DI et al Lancet 2015).

• Tre studi di randomizzazione mendeliana hanno tutti dimostrato che i pazienti portatori di varianti genetiche in PCSK9 con perdita di funzione hanno livelli di LDL inferiori, ma più elevati di glicemia, con un rischio maggiore di sviluppare T2D

(Lotta LA JAMA 2016, Schmidt AF Lancet Diabetes Endocrinol 2017,

Ference BA N Engl J Med 2016 ^).

Meccanismi di induzione dell’iperglicemia delle terapie ipolipemizzanti

• Il meccanismo ipotizzato identifica nell’accumulo di colesterolo via LDL-R nelle beta-cellule l’elemento determinante.

• Qualsiasi intervento farmacologico o genetico che aumenti l’espressione dell’LDL-R nelle beta- cellule si associa quindi con un accumulo di colesterolo, con alterazioni nella secrezione

insulinica e nel controllo glicemico

• PCSK9: topi knock-out di PCSK9 presentano ridotta secrezione di insulina e intolleranza al glucosio (Mbikay M FEBS 2010).

• La perdita sistemica di PCSK9, promuovendo l'up-regolazione di LDLR nelle beta-cellule, determina un conseguente accumulo di colesterolo, disfunzione cellulare e ridotta

secrezione insulinica.

DA Dalt et al.- European Heart

Journal, Volume 40, Issue 4, 02

July 2018, Pages 357–368

Post-randomization A1c, Fasting Glucose, and New- onset Diabetes by Baseline Glucometabolic Status

Ray KK et al. Lancet Diab Endocr, July 1, 2019

New onset diabetes among patients without diabetes at baseline: Fourier trial

Sabatine MS et al Lancet Diab Endocr 2017

Da Dalt L et al. European Heart Journal (2019) 40, 357–368

Effects of PCSK9 loss-of function vs. blockade of circulating, liver-

derived proprotein convertase subtilisin/kexin type 9