Gli algoritmi terapeutici e le novità

nella terapia di combinazione

per il diabete di tipo 2

Dipartimento di Medicina dei Sistemi Università di Roma, Tor Vergata

Simona Frontoni

Il sottoscritto Simona Frontoni

ai sensi dell’art. 76 comma 4 dell’Accordo Stato-Regioni del 2 febbraio 2017 e

in accordo con il Codice Etico della SIMI

dichiara

per l’evento in oggetto l’esistenza negli ultimi due anni di rapporti di natura

finanziaria e lavorativa con le seguenti imprese commerciali operanti in ambito

sanitario

Sanofi- Aventis, Novo Nordisk, Eli-Lilly, Takeda, Sigma-Tau, Astrazeneca,

Boheringer

GLICEMIA

SU e glinidi acarbosio bromocriptina

gliptine

pramlintide

metformina TZDs incretine

gliflozine

ag. GLP-1 R cervello

rene

intestino

pancreas

endocrino

cervello

adipociti

muscolo fegato

digestione cellule beta

asse entero-insulare

meccanismo di azione dei farmaci

Network meta-analysis of pairwise comparisons of randomized controlled trials evaluating the use of anti-

hyperglycemic agents in addition to metformin vs. placebo

mean change from baseline in A1C

Liu S-C et al. Diabetes Obes and Metab 14: 810–820, 2012 Fujita Y et al. J Diabetes Investing 5: 265-275, 2014

Network meta-analysis of pairwise comparisons of randomized controlled trials evaluating the use of anti-

hyperglycemic agents in addition to metformin vs. placebo

mean change from baseline in body weight

Liu S-C et al. Diabetes Obes and Metab 14: 810–820, 2012 Fujita Y et al. J Diabetes Investing 5: 265-275, 2014

Katout M al. Am J Hypertens 27: 130-139 , 2014

Meta-analysis of change in systolic blood pressure, in RCTs after at least 12 weeks of treatment

with GLP-1 RA

Baker WL et al. J Am Soc Hypertens 8: 262–275, 2014

Effects of sodium-glucose co-transporter 2 inhibitors on systolic blood pressure: Meta-analysis

Network meta-analysis of pairwise comparisons of randomized controlled trials evaluating the use of anti-

hyperglycemic agents in addition to metformin vs. placebo

At least one event of overall hypoglycemia

Liu S-C et al. Diabetes Obes and Metab 14: 810–820, 2012 Fujita Y et al. J Diabetes Investing 5: 265-275, 2014

Ongoing and recently completed cardiovascular outcomes trials within diabetes enrolling >130,000 patients

2013 2014 2015 2016 2017 2018 2019 2020

SGLT2i

GLP-1

DPP-4

Source: ClinicalTrials.gov (30 June 2015). ‘Completion date’ is the estimated completion date for the primary outcomes measure. *Also known as C-SCADE-8.

TECOS (Sitagliptin, DPP-4i)

n=14,671; follow-up ~3 yrs Q1 2015 - RESULTS

CARMELINA (Linagliptin, DPP-4i)

n= 8,300; duration ~4 yrs completion Q1 2018

CAROLINA (Linagliptin, DPP-4i vs SU) n= 6,000; duration ~8 yrs

completion Q3 2018

SAVOR TIMI-53 (Saxagliptin, DPP-4i)

n=16,492; follow-up ~2 yrs Q2 2013 - RESULTS

EXAMINE (Alogliptin, DPP-4i)

n=5,380; follow-up ~1.5 yrs Q3 2013 - RESULTS

ALECARDIO (Aleglitazar, PPAR-αγ)

n=7,226; follow-up 2.0 yrs Termin. Q3 2013 RESULTS

LEADER (Liraglutide, GLP-1)

n=9,340; duration 3.5-5 yrs completion Q4 2015

ELIXA (Lixisenatide, GLP-1)

n=6,068; follow-up ~2 yrs Q1 2015 –RESULTS

EMPA-REG OUTCOME* (Empagliflozin, SGLT2i)

n=7,097; duration up to 5yrs Q2 2015 –RESULTS

SUSTAIN 6 (Semaglutide, GLP-1)

n=3,297; duration ~2.8 yrs completion Q1 2016

EXSCEL (Exenatide QW, QW GLP-1)

n=14,000; duration ~7.5 yrs completion Q1 2018

OMNEON (Omarigliptin, QW DPP-4i) n=4,000; duration ~3 yrs

completion Q4 2017

CANVAS (Canagliflozin, SGLT2i)

n=4,407; duration 4+yrs completion Q2 2017

CANVAS-R (Canagliflozin, SGLT2i)

n=5,865; duration ~3 yrs completion Q1 2017

DEVOTE (Insulin degludec, basal insulin)

n=7,637; duration up to 5yrs completion H2 2016

FREEDOM-CVO (ITCA 650, GLP-1 in DUROS)

n=4,000; duration ~2 yrs completion Q3 2018

CREDENCE (cardio-renal) (Canagliflozin, SGLT2i)

n= 3,700; duration ~5.5 yrs completion Q1 2019

REWIND (Dulaglutide, QW GLP-1)

n=9,622; duration ~6.5yrs completion Q2 2019

DECLARE-TIMI-58 (Dapagliflozin, SGLT2i)

n=17,150; duration~6 yrs completion Q2 2019

NCT01986881 (Ertugliflozin, SGLT2i)

n=3,900; duration~6.3 yrs completion Q2 2021

HARMONY OUTCOMES (Albiglutide, GLP-1)

n=9,400; duration ~4yrs completion by Q2 2019

Completed with results Ongoing

STANDARD ITALIANI 2016

Diabetes duration

Age/Life expectancy

Frailty

Occupation

Overweight/Obese

Dyslipidemia

Hypertension

Inflammation

LADA

MODY

CHD/CVD

Heart failure

NAFLD

CKD

Dementia

Osteoporosis

Psoriasis

Baseline HbA1c

Fasting hyperglycemia

Postprandial hyperglycemia

Glucose variability

Durability

Risk of hypoglycemia

Ramadan

Clinical features which may influence response to anti-hyperglycemic therapy in type 2 diabetes

triple therapy from diagnosis

time (months)

HbA1c (%)

Abdul-Ghani MA et al.: DOM 17:268, 2015

conventional:

1. titrated metformin

2. add-on and titrate glipizide

3. add-on and titrate glargine

triple:

since diagnosis

start metformin

+ pioglitazone

+ exenatide bid

gliflozin vs. gliptin as add on to metformin or combined

% of patients with HbA1c < 7.0% at W 24

0%

10%

20%

30%

40%

50%

saxagliptin dapagliflozin saxa + dapa

18%

22%

41%

Rosenstock J, et al. Diabetes Care 2015;38:376–383

gliflozins vs. gliptins pros

non insulin-mediated

no hypoglycemia

all settings

weight loss

reduce blood pressure

prevent heart failure

CV protection (one)

cons

genital infections

possible (rare) eDKA

stimulate glucagon

no with CKD (safe)

pros

stimulate insulin

no hypoglycemia

proved CV safety (some)

weight neutral

inhibit glucagon

efficacious in CKD

easy to handle

cons

non responders

No CV protection

efficacy of GLP-1 RA +insulin LixiLan-L: iGlarLixi vs. glargine

Aroda VR, et al. Diabetes Care 2016, 39(9):1579-86

Gough SC, et al. DOM 17:965, 2015

efficacy of GLP-1 RA +insulin DUAL I: Ideg and/or Lira

efficacy of GLP-1 RA + SGLT-2i HbA1c

Frias JP, et al. Lancet D&E 4(12):1004-1016

efficacy of GLP-1 RA + SGLT-2i weight

Frias JP, et al. Lancet D&E 4(12):1004-1016

how to choose the combination

age

BMI

gender

disease duration

occupation

driving

social/ center support

patient preference

ethnicity

renal function

blood pressure

CV disease

liver function

pancreatitis

osteoporosis

cognitive function

frailty

cancer

Patient characteristics Patient co-morbities

HealthCare System

Avogaro A et al. Cardiovasc Diabetol 15:111, 2016

1To be used with caution because of the risk of hypoglycemia;2consider dose reduction (except for linagliptin) and monitor eGFR frequently; 3preferred in the presence of marked insulin resistance; 4initiation of therapy currently not recommended. aUKPDS; bPROACTIVE trial; cSAVOR; dTECOS, eEXAMINE; fLEADER trial; gEMPA-REG Outcome trial; hORIGIN trial;kADVANCE; jELIXA; mDIGAMI 1

A treatment algorithm based on cardiac and renal co-morbidities and CVOTs

Diabetes duration

Age/Life expectancy

Frailty

Occupation

Overweight/Obese

Dyslipidemia

Hypertension

Inflammation

Clinical features which may influence response to anti-hyperglycemic therapy in type 2 diabetes

Baseline HbA1c

Fasting hyperglycemia

Postprandial hyperglycemia

Glucose variability

Durability

Risk of hypoglycemia

Ramadan

Clinical features which may influence response to anti-hyperglycemic therapy in type 2 diabetes

CHD/CVD

Heart failure

NAFLD

CKD

Dementia

Osteoporosis

Psoriasis

Clinical features which may influence response to anti-hyperglycemic therapy in type 2 diabetes

Cardiovascular Outcomes trials for diabetes

Proactive 16% secondary outcome (all-cause mortality, MI,

stroke)

HR 0.84 (0.72-0.98)

P= 0.027

Leader 13% primary outcome (CV death, non fatal MI,

non fatal stroke)

HR 0.87 (0.78-0.97)

P= 0.001 for

superiority

EMPA-REG 14% primary outcome (CV death, non fatal MI, non

fatal stroke)

HR 0.86 (0.74-0.99)

P= 0.0382 for

superiority

SUSTAIN 6 26% primary outcome (CV death, non fatal MI,

non fatal stroke)

HR 0.74 (0.58-0.95)

P<0.001 for

superiority

Pugliese G et at. Nutr Metab Cardiovasc Dis 24: 815-822, 2014

Prevalence of albuminuria and eGFR categoried and CKD stages (with stratification of subjects with Stages 3-5

CKD by albuminuria) in the RIACE cohort