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Caso clinico

Ilaria MalandruccoUOC Endocrinologia e Diabetologia

Ospedale Fatebenefratelli Isola Tiberina RomaDiapositiva preparata da ILARIA MALANDRUCCO e ceduta alla Società Italiana di Diabetologia.

Per ricevere la versione originale si prega di scrivere a [email protected]

La dr.ssa Ilaria Malandrucco dichiara di aver ricevuto negli ultimi due anni compensio finanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche: Roche.

Dichiara altresì il proprio impegno ad astenersi, nell’ambito dell’evento, dalnominare, in qualsivoglia modo o forma, aziende farmaceutiche e/o denominazionecommerciale e di non fare pubblicità di qualsiasi tipo relativamente a specificiprodotti di interesse sanitario (farmaci, strumenti, dispositivi medico-chirurgici, ecc.).

Diapositiva preparata da ILARIA MALANDRUCCO e ceduta alla Società Italiana di Diabetologia.


al paziente con diabeteal

La nostra attenzione è rivolta



Giancarlo paziente di 68 aa ex operaio in pensione affetto:

• DM 2 noto dall’età di 46 anni trattato con farmaci assunti per os per i primi10 anni dalla diagnosi e successivamente in terapia insulinica basal bolus(MDI) associata alla metformina dal 2007 e in terapia con microinfusore (emetformina) dal 2009

• ipertensione arteriosa nota dall’età di 46 anni (diagnosticata in concomitanzadella diagnosi di diabete)

• dislipidemia nota da 10 anni

• aterosclerosi carotidea con stenosi bilaterale del 40%

• retinopatia diabetica non proliferante

• polineuropatia sensitivo motoria simmetrica distale

• obesità (scarsa aderenza alla terapia medica nutrizionale)

ANAMNESI



ANAMNESIA. Familiare: nonno affetto da diabete tipo 2

padre deceduto a 70 anni per ictus

fratello IMA all’età di 58 aa

A. Fisiologica: pensionato

ex fumatore, ha fumato 20sigarette al giorno per 30 annifino a 12 anni fa

pratica regolare attività dicammino



• metformina 850mg 1cp colazione, 1cp pranzo, 1 cp cena

• insulina aspart 41,4 UI/24h in infusione continua secondo lo schema:

TERAPIA T-3

FASCIA ORARIA Infusione UI/h00:00 - 06:00 2,00 06:00 - 10:00 1,80 10:00 - 12:00 1,20 12:00 - 15:00 1,90 15:00 - 21:00 2,00 21:00 - 24:00 2,10

COLAZIONE PRANZO CENA

1:5.0 1:5.8 1:5.3

• Boli ai pasti secondo i rapporti I:CHO: (̴ 52UI/die)

• Sensibilità insulinica 1:30 mg/dl



TERAPIA

o telmisartan 80mg 1 cp die

o nebivololo 5 mg 1 cp die

o atorvastatina 20 mg 1 cp die

o acido acetilsalicilico 100 mg 1 cp die



• Peso: 98 Kg

• Altezza: 1,75 mt

• BMI: 32,0 kg/m2

• PA: 130/75mmHg

• FC: 68 bpm

PARAMETRI T-3



ESAMI EMATOCHIMICIPARAMETRO T-3 T-0 T-3

Glicemia 210 mg/dl 180 mg/dl 160 mg/dl

HbA1c 9,3% 78 mmol/mol 9,6% 81 mmol/mol 8,1% 65 mmol/mol

GFR 80 ml/min 87 ml/min 80 ml/min

creatinina 1,0 mg/dl 0,9 mg/dl 1,0 mg/dl

colesterolo totale 165 mg/dl 170 mg/dl 160 mg/dl

HDL 50 mg/dl 48 mg/dl 50 mg/dl

LDL 67 mg/dl 78 mg/dl 78 mg/dl

trigliceridi 240 mg/dl 220 mg/dl 160 mg/dl

microalbuminuria 92 mg/gr 87 mg/gr 56 mg/grDiapositiva preparata da ILARIA MALANDRUCCO e ceduta alla Società Italiana di Diabetologia.


ESAMI STRUMENTALI

ECG: ritmo sinusale, FC 64 bpm, anomalie aspecifiche dellaripolarizzazione ventricolare

ECOCARDIOGRAMMA COLOR DOPPLER: ipertrofiaventricolare sinistra di grado lieve FE=60%

TEST ERGOMETRICO: negativo per ischemia inducibile dallosforzo



MONITORAGGIO GLICEMICO CONTINUO

Andamento glicemico estremamente variabile

Ipoglicemie



Il nostro paziente…giovane con lunga durata di malattia con scompenso glicemico

Presenta comorbilità:

o obesità

o ipertensione

o dislipidemia

Presenta complicanze:

o microalbuminuria e lieveriduzione GFR

o stenosi carotidea

o retinopatia diabetica nonproliferante

o polineuropatia sensitivomotoria



Criticità…

Profilo glicemico estremamente variabile (iperglicemie-ipoglicemie e ipercorrezioni)

Diabete scompensato

Stile di vita, pessima aderenza alla dieta

Si propone più volte di interrompere la terapia conmicroinfusore (grande resistenza da parte del paziente)

Si attua un rinforzo educazionale sullo stile divita e si aumenta la terapia insulinica





TERAPIA T-0



1:4.8 1:5.5 1:5.0





9,39,6

8,17,4 7,5

66,5

77,5

88,5

99,510

10,511

11,512

T -3 T 0 T +3 T +6 T +12

HbA1c%

HbA1c%

HbA1c



9,3 9,6

8,17,4 7,5

6

7

8

9

10

11

12

T -3 T 0 T +3 T +6 T +12

41 4939 41 43

57

65

48 50 50

T -3 T 0 T +3 T +6 T +12

Insulina basale Insulina bolo

HbA

1c %

Insu

lina

UI/

die

HbA1c e UI insulina die



98 98

9093 92

80

90

100

110

T -3 T 0 T +3 T +6 T +12

Peso

KgPeso




• insulina aspart in infusione continua con microinfusore

si modifica la TERAPIA

• dapagliflozin 10mg 1cp colazione





TERAPIA T+3



1:5.5 1:6.5 1:6.0





9,39,6

8,17,4 7,5

66,5

77,5

88,5

99,510

10,511

11,512

T -3 T 0 T +3 T +6 T +12

HbA1c%

HbA1c%

HbA1c



9,3 9,6

8,17,4 7,5

6

7

8

9

10

11

12

T -3 T 0 T +3 T +6 T +12

41 4939 41 43

57

65

48 50 50

T -3 T 0 T +3 T +6 T +12


HbA

1c %

Insu

lina

UI/

die




98 98

9093 92

80

90

100

110

T -3 T 0 T +3 T +6 T +12

Peso

KgPeso



9,39,6

8,17,4 7,5

66,5

77,5

88,5

99,510

10,511

11,512

T -3 T 0 T +3 T +6 T +12

HbA1c%

HbA1c%

HbA1c



9,3 9,6

8,17,4 7,5

6

7

8

9

10

11

12

T -3 T 0 T +3 T +6 T +12

41 4939 41 43

57

65

48 50 50

T -3 T 0 T +3 T +6 T +12


HbA

1c %

Insu

lina

UI/

die

1,16UI/kg/die

0,97UI/kg/die




MONITORAGGIO GLICEMICO CONTINUO

Andamento glicemico migliorato

Assenza di ipoglicemie



98 98

9093 92

80

90

100

110

T -3 T 0 T +3 T +6 T +12

Peso

KgPeso



Nauck. Drug Design, Development and Therapy 2014:8 1335–1380

Effetto degli SGLT-2-i sul PESO



9092

7871 69

2030405060708090

100110120130140150

T -3 T 0 T +3 T +6 T +12

Microalbuminuria mg/gr

GFR ml/minT-3 T 0 T+3 T+6 T+12

80 87 80 85 85

Microalbuminuriam

g/gr



240220

160 175 170

100

150

200

250

300

T -3 T 0 T +3 T +6 T +12

Trigliceridi (mg/dl)

6778 78 78

70

50

70

90

110

130

T -3 T 0 T +3 T +6 T +12

LDL-colesterolo (mg/dl)

50 48 50 52 50

30

40

50

60

70

T -3 T 0 T +3 T +6 T +12

HDL-colesterolo (mg/dl)

Profilo Lipidico

165 170160 165 159

150

170

190

210

230

250

T -3 T 0 T +3 T +6 T +12

Colesterolo tot (mg/dl)



PAS/PAD mmHg

T-3 T 0 T+3 T+6 T+12

130/80 120/75 125/75 130/80 120/75

Pressione Arteriosa



Nauck. Drug Design, Development and Therapy 2014:8 1335–1380

Effetto degli SGLT-2-i sulla PA



Acido Urico

Uricemia mg/dl

T-3 T 0 T+3 T+6 T+12

5,5 5,7 6,0 5,6 6,1



Quali considerazioni possiamo fare?



Risultati ottenuti

«misurabili sul nostro paziente»

Miglioramento del compenso glicemico

• Riduzione dell’HbA1c

• Miglioramento del profilo glicemico

• Riduzione delle iperglicemie

• Riduzione delle ipoglicemie

• Riduzione delle UI di insulina

Riduzione del peso

Riduzione della microalbuminuria



Risultati non «misurabili sul singolo paziente»



Myocardial damage leading to LV dysfunction and HF is an early and often undetected complication of T2D1,2

*Western European cohort.HF, heart failure; HFpEF, HF with preserved ejection fraction; HFrEF, HF with reduced ejection fraction; LV, left ventricular; LVD, LV dysfunction; T2D, type 2 diabetes.1. Faden G, et al. Diabetes Res Clin Pract. 2013;101:309-316. 2. Boonman-de Winter LJ, et al. Diabetologia. 2012;55:2154-2162.

Undiagnosed HF was detected in 28% of patients* with diabetes (n=581) during cardiac

screening2

16%

27%

25%

32%

Systolic LVDn=106

Systolic anddiastolic LVD

n=95

Normal LVfunction

n=124

Diastolic LVDn=61

Patients had no evidence of inducible ischaemia

68% of patients with T2D had evidence ofLV dysfunction 5 years after T2D diagnosis1

HF is an early and forgotten complication of T2D patients1,2

72%Heart

failure (HFrEF)

Heart failure

(HFpEF)

No heart failure

23%

5%



Diabetes increases the riskof CV events and death, in both HFrEF and HFpEF

MacDonald MR et al. Eur Heart J. 2008;29:1377-1385.

CV death or hospitalization due to HF(Cumulative incidence, %)

Follow-up(years)

0

60

40

20

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Diabetes (low EF)

Diabetes (preserved EF)

No diabetes (low EF)

No diabetes (preserved EF)

All-cause mortality(Cumulative incidence, %)

Follow-up(years)

0

60

40

20

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Diabetes (low EF)

Diabetes (preserved EF)

No diabetes (low EF)

No diabetes (preserved EF)



Risultati non «misurabili sul singolo paziente»



In this low CV risk population, dapagliflozin patients had a significant reduction of hHF/CV death and fewer MACE events compared to placebo

N at risk is the number of subjects at risk at the beginning of the period. 2-sided p-value is displayed; HR, CI, and p-value are from cox proportional hazard model.CV, cardiovascular; Dapa, dapagliflozin; hHF, hospitalization for heart failure; MACE, major adverse cardiac eventWiviott SD et al. Online ahead of print. N Engl J Med. 2018

Months from Randomization

Patie

nts

with

eve

nt (%

)

6

0 6 12 18 24 30 36 42 48 54 60

8582 8517 8415 8322 8224 8110 7970 7497 5445 16268578 8485 8387 8259 8127 8003 7880 7367 5362 1573

N at riskDP

4

2

0

Placebo (496 Events)

DAPA 10 mg (417 Events)

hHF/CVD

HR 95% CI P value

0.83 (0.73, 0.95) 0.005

8582 8466 8303 8166 8017 7873 7708 7237 5225 15488578 8433 8281 8129 7969 7805 7649 7137 5158 1501

N at riskDP

Months from Randomization

Patie

nts

with

eve

nt (%

)

10.0

0 6 12 18 24 30 36 42 48 54 60

7.5

5.0

2.5

0.0

Placebo (803 Events)

DAPA 10 mg (756 Events)

MACE

HR 95% CI P value

0.93 (0.84, 1.03) 0.172



Overall populationOverall population

CV, cardiovascular; eCVD, established CV disease; HF, heart failure; hHF, hospitalized heart failure; SGLT-2i, SGLT co-transporter 2 inhibitor; T2D, type 2 diabetesWiviott SD et al. Online ahead of print. N Engl J Med. 2018

0.78 (0.63, 0.97)

Hazard ratio (95% CI)

Favors Dapagliflozin

Favors Placebo

0.64 (0.46, 0.88)

0 0,5 1 1,5

Established CV Disease (eCVD)

Multiple Risk Factors (No eCVD)

0 0,5 1 1,5

0.73 (0.55, 0.96)

Hazard ratio (95% CI)

Favors Dapagliflozin

Favors Placebo

Prior HF*

0.73 (0.58, 0.92)No prior HF

*10% of patients in DECLARE had prior HF

hHF hHF

CV risk

0.73 (0.61, 0.88) 0.73 (0.61, 0.88)

HF history

Dapagliflozin prevents hHF consistently across a broad range of T2D patients regardless of history of eCVD or HF



Il piano di cura personalizzato per il nostro paziente prevede azioni che portano adei risultati, alcuni sono «misurabili» sul singolo paziente, altri «non misurabili»sul singolo paziente

CONCLUSIONE

Il cuore del paziente è al centro del piano di cura personalizzato

La centralità del paziente è il cuore del piano di cura personalizzato



Grazie per l’attenzione



Definition of Heart Failure Classifications:DECLARE HF Subgroup Analysis

EF = ejection fraction; HF = heart failure; HFrEF = heart failure with reduced EF; rEF = reduced EF.Kato ET et al. Online ahead of print. Circulation. 2019. Accessed March 18, 2019.

• Documented EF <45% or severe/moderate left ventricular systolic dysfunction

HFrEF

• HF without known reduced EF– History of HF and EF ≥45%– History of HF

and no documented EF

• No history of HF– EF ≥45%– No documented EF

No HFrEF

88.4%

3.9%

7.7%

HFrEF

No HFrEF

DECLARE Patient Population

HFrEF (n=671)HF without known rEF (n=1,316)No known HF (n=15,173)



INTERNAL MEDICAL USE ONLY

In high CV risk T2D patients with prior MI, dapagliflozin reduced MACE by 16% with a 4-year NNT of 39

Primary Outcome – MACE

Prior MI - PBO

Prior MI - DAPA

Patients with prior MIHR (95% CI) = 0.84 (0.72 to 0.99)Patients without prior MIHR (95% CI) = 1.00 (0.88 to 1.13)Absolute risk reduction (pts with events)2.6% (prior MI) vs. 0% (no prior MI)

20%

15%

10%

5%

0%360 720 1080 1440

Days

No Prior MI - PBONo Prior MI - DAPA

DAPA has a clear beneficial MACE outcome in high

CV risk T2D patients with prior

MI’s

Cum

ulat

ive

Inci

denc

e

Prior MI was a prespecified subgroup of interest in DECLARE TIMI-58.CV = cardiovascular; DAPA = dapagliflozin; HR = hazard ratio; MACE = major adverse cardiovascular events; MI = myocardial infarction; NNT = number needed to treat; PBO = placebo; T2D = type 2 diabetes.Furtado RHM et al. Online ahead of print. Circulation. 2019.



INTERNAL MEDICAL USE ONLY

This benefit of dapagliflozin in reducing MACE was greatest in the first 24 months of a prior MI

CV = cardiovascular; DAPA = dapagliflozin; HR = hazard ratio; MACE = major adverse CV event; MI = myocardial infarction; PBO = placebo.Furtado RHM et al. Online ahead of print. Circulation. 2019.

HR (95 % CI)

Overall 0.84 (0.72 to 0.99)

≤ 12 months 0.66 (0.42 to 1.03)

12 to 24 months 0.42 (0.25 to 0.71)

24 to 36 months 0.83 (0.50 to 1.40)

>36 months 1.01 (0.82 to 1.23)

MACE – stratified by time from last MI

0,25 0,50 1,00 2,00 4,00DAPA Better PBO Better

“exclusion of patients with

prior MI within the first 8

weeks after index-event

does not allow for

understanding of the effects of

SGLT2i in patients with MI during the

acute” Diapositiva preparata da ILARIA MALANDRUCCO e ceduta alla Società Italiana di Diabetologia.


Primary Endpoint: Composite of MACE and the Individual Components

aTwo-sided p-value is shown for the primary efficacy outcome of MACE; p-value for noninferiority was p<0.001.DAPA, dapagliflozin; MACE, major adverse cardiovascular events. Wiviott SD et al. Online ahead of print. New Engl J Med. 2018.

Number of events

DAPA 10 mg(N=8582)

Placebo(N=8578) HR (95%CI) p-valuea

1.21.11.00.90.80.7

MACE

Cardiovascular death

Ischemic stroke

756 803 0.93 (0.84,1.03) 0.17

245 249

0.98 (0.82,1.17)

235 231 1.01 (0.84,1.21)

393 441 0.89 (0.77,1.01)Myocardial infarction

Favors DAPA

Favors Placebo



The CV benefits of dapagliflozin appear early in T2D patients with HFrEFa

aDefined as EF <45% or severe/moderate LV systolic dysfunction, with or without history of HF. CV = cardiovascular; DAPA = dapagliflozin; EF =ejection fraction; HFrEF = heart failure with reduced ejection fraction; hHF = hospitalization for heart failure; HR = hazard ratio; LV = left ventricular; NNT = number needed to treat; PBO = placebo; T2D = type 2 diabetes; yrs = years.Kato ET et al. Online ahead of print. Circulation. 2019.

Cum

ulat

ive

Inci

denc

e R

ate

(%)

Patie

nts

with

HFr

EFa

DAPA PBO

30

25

20

15

10

5

0

0 180 360 540 720 900 1080 1260 1440

NNT (4yrs) = 11 20

15

10

5

0

0 180 360 540 720 900 1080 1260 1440

NNT (4yrs) = 16 20

0

15

10

5

0 180 360 540 720 900 1080 1260 1440

NNT (4yrs) = 19

0 180 360 540 720 900 1080 1260 1440

30

25

20

15

10

5

0

NNT (4yrs) = 18

hHF/CV death hHF CV death All-cause mortality

HR 95% CI0.62 (0.45,

0.86)

HR 95% CI0.64 (0.43,

0.95)

HR 95% CI0.55 (0.34,

0.90)

HR 95% CI0.59 (0.40,

0.88)

Days DaysDays Days



Dapagliflozin Reduces Albuminuria in Patients with Diabetes and Hypertension on Top of ACEi/ARB Therapy

• Dapagliflozin reduces albuminuria in T2DM patients with hypertension receiving ACE inhibitors or an ARB –without increasing the frequency of renal adverse events

Data taken from NCT01137474 and NCT01195662ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; DAPA, dapagliflozin; PBO, placebo; UACR, urine albumin:creatinine ratioLambers Heerspink HJ, et al. Diabetes Obes Metab 2016;18:590–597

Change in UACR in an analysis of data pooled from two placebo-controlled trials

185165

182160

172154

163153

158PBO + ACEi/ARBDAPA + ACEi/ARB

Chan

ge (9

5% C

I)fr

om b

asel

ine

in U

ACR

(%)

Week

0

–10

–20

–30

–40

–50

–600 2 4 6 8 10 12

Placebo + ACEi/ARB

DAPA + ACEi/ARB

Treatment

Patients, nFollow-up(week 13)

14

144

-33.2%



HbA1c SBP

Effects of Dapagliflozin on Albuminuria Appear to be Independent of HbA1c and Systolic Blood Pressure Effects

CI, confidence interval; HbA1c, glycated hemoglobin; SBP, systolic blood pressure; UACR, urine albumin:creatinine ratioLambers Heerspink HJ, et al. Diabetes Obes Metab 2016;18:590–597

Responders

Non-responders

–30.0

–58.5

n 75 7895% CI

–66.2, –48.9

–42.9, –14.2

UAC

R a

djus

ted

mea

n ch

ange

fro

m b

asel

ine

(%)

0

–10

–20

–30

–40

–50

–60

–70

n

UAC

R a

djus

ted

mea

n ch

ange

fro

m b

asel

ine

(%)

95% CI

–47.4

70–57.9, –

34.3

–44.5

83–54.7, –

32.0

0

–10

–20

–30

–40

–50

–60

–70



Dapagliflozin Reduces Albuminuria in CKD Stage 3

• This post-hoc analysis included 166 patients with CKD stage 3 and increased albuminuria (≥3.4 mg/mmol)

CI, confidence interval; CKD, chronic kidney disease; DAPA, dapagliflozin; PBO, placebo; UACR, urine albumin-to-creatinine ratioFioretto P, et al. Diabetologia 2016;59:2036–2039

–80

–40

0

40

80

120

0 4 52 104

Adju

sted

chan

ge (9

5% C

I)in

UAC

R (%

)

Weeks

PlaceboDapagliflozin 5 mgDapagliflozin 10 mg

PatientsPBO 56 49 31 25DAPA 5 mg 53 50 39 20DAPA 10 mg 56 52 40 29

−26.4%

−43.9%

31.0%



presentazione di powerpoint - sid italia...1,0 mg/dl 0,9 mg/dl 1,0 mg/dl colesterolo totale 165...

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