sliding door pazienti al bivio: oltre la terapia orale · presentazione di powerpoint author:...

Frittitta LuciaUniversità di Catania

SLIDING DOORPazienti al bivio: oltre la terapia orale

Glucose-lowering medication in type 2 diabetes: overall approach.

American Diabetes Association Dia Care 2019;42:S90-S102

Pharmacologic approches to Glycemic treatment

▪ In most patients who need the greater glucoselowering effect of an injectable medication, GLP1-R-aare preferred to insulin. B


Pharmacologic approches to Glycemic treatment

▪ Intensification of treatment for patients with T2Dnot meeting treatment goals should not bedelayed. B


Domanda 1

Nel vostro ambulatorio quanti pazienti sono trattati con un GLP-1-Ra:

A. < 5%

B. 5-10%

C. 10-15 %

D. > 20%

Domanda 2

Nella vostra pratica clinica, quando ritenete opportuno iniziare il trattamento con GLP-1 in pazienti in prevenzione primaria:

A. Se i valori di HbA1c sono > di 8.0 %

B. Se il paziente è sovrappeso/obeso

C. Preferisco ritardare il più possibile la terapia iniettiva

D. Se il paziente presenta variabilità glicemica


GLP-1 RA

Insulina

Variabilità glicemia e rischio cardio-vascolare

Visit-to-Visit Glycemic Variability and Risks of Cardiovascular Events and All-CauseMortality: The ALLHAT Study

Diabetes Care 2019 Mar; 42(3): 486-493

Glycemic Variability Is a Powerful Independent Predictive Factor of Midterm MajorAdverse Cardiac Events in Patients With Diabetes With Acute Coronary Syndrome

Diabetes Care 2019 Apr; 42(4): 674-681

Prognostic impact of visit-to-visit glycemic variability on the risks of major adversecardiovascular outcomes and hypoglycemia in patients with different glycemic controland type 2 diabetes

Endocrine 13 March 2019, https://doi.org/10.1007/s12020-019-01893-1

Sun B, Endocrine 13 March 2019, https://doi.org/10.1007/s12020-019-01893-1

Glycemic variability was associated with the risk of MACE (HR 2.21) and hypoglycemia(HR 1.36) in total patients and subgroups of different glycemic control.

Variabilità glicemia e rischio cardio-vascolare

Nei pazienti DMT2 trattati con metformina, Exenatideonce-weekly riduce la variabilità glicemica

▪ RCT of metformin- treated adults with T2D to once-weekly exenatide 2.0 mg or placebo.

▪ Continuous glucose monitoring (CGM) was performed at baseline and weeks 4 and 10.

Frias JP, Diab Ob Metab, 2017, 19: 40-48

Frias JP, Diab Ob Metab, 2017, 19: 40-48

Domanda 3

Quali ritenete siano le principali barriere all’inizio della terapia con GLP-1-R-A:

1. Paura del paziente a iniziare una terapia iniettiva

2. Poco tempo a disposizione da parte del medico

3. Minore compliance del paziente alla terapia iniettiva

4. Timore degli effetti collaterali

American Diabetes Association Diab Care 2019;42:S90-S102

1In most patientswho need the greater glucoselowering effect of an injectablemedication, GLP1-R-a are preferredto insulin. B

DURATION-3: Disegno dello Studio

Diamant M, et al. Lancet. 2010; 375: 2234-43

Criteri di inclusione

• HbA1c ≥7.1% e ≤11.0%

• BMI ≥25 e ≤45 kg/m2

• Peso corporeo stabile ≥3 mesi

• Dose stabile di Met≥1500 mg per ≥8 sett

Sett -2 0 26 ~156

Screen

2.0 mg Exenatide QW + Met o Met + SU

Insulina Glargine QDa + Met o Met + SU

Estensione

Estensione

Randomizzazione

Criteri di Esclusione

• 3+ episodi di ipoglicemia maggiore negliultimi 6 mesi

• Trattamento con specifici farmaci negli ultimi3 mesi

Diamant M, et al. Lancet Diabetes Endocrinol 2014; 2(6): 464-73

DURATION-3: Exenatide QW vs. insulin glargine for T2D 3-year results


HbA1c BG

BW

DURATION-3


• Miglior controllo glicemico con EQWnonostante la titolazione dell’insulina

• Maggiore % di pazienti con HbA1c ≤7% nei 3anni con ExeQW

• Titolazione della dose di insulina glargine da10 UI a 40 UI

• EQW sicura e ben tollerata nei 3 anni conincidenza di nausea e vomito che si riduce neltempo

• Minor rischio di ipoglicemie nei pazientitrattati con ExeQW

• Superiore miglioramento di diversi dominidella QoL correlata al peso

Predictive factors associated with three years of response to HbA1c goals with exenatide QW or insulinglargine: Post-hoc analysis of the DURATION-3 study

• Responders (61%) were defined as patients who achieved a HbA1c <7.0% at Week 26;

• Sustained responders (48%) were those who maintained the treatment target goal for ≥80% of time untile week 156

Guerci B, Diabetes Obes Metab. 2019;21:1049–1053.

Three predictors of sustained response: (a) exenatide QW vs IG treatment (b) lower HbA1c at Week 26 (c) lower fasting serum glucose at Week 26

American Diabetes Association Diab Care 2019;42:S90-S102

1

2

Potential Clinical Benefits of Adding a GLP-1 RA to Basal Insulin

Basal insulin GLP-1 RA+

Potential for:

FPG reductions

Reduced PPG excursions

Less weight gain

Reduced risk of

hypoglycemia

Improvement in CV risk

factors

Additional HbA1c

reductions

DURATION-7: Exenatide QW Add-on to Basal Insulin

Secondary endpoints

measured at Week 28b

• Change in body weight

• Change in 2-hour PPG

• Proportion of patients

achieving HbA1c <7.0%

• Change in mean daily insulin glargine dose

• Proportion of patients achieving composite of HbA1c <7%,

no weight gain, and no major hypoglycemia

• Change in SBP

Primary endpoint • Change from baseline in HbA1c at 28 weeks

Key inclusion criteria:

≥18 years; T2D;

HbA1c of 7.5–12.0% and

FPG <280mg/dL on IG ≥20

U/day

± metformin ≥1500 mg/day

OR ± metformin

≥1500 mg/day + SU

1:1

Ra

nd

om

iza

tion

HbA

1c 7

-0–

10

.5%

PBO + up-titrated IG ± MET

EQW + up-titrated IG ± MET

Primary endpointScreeninga

IG titration

SU

stopped

INITIATE algorithm: Titrate IG to FPG 72–99 mg/dL (4.0–5.5 mmol/L)

Follow-up

(10 weeks)0 28–8S 12

Week

Rescue: prandial insulin

Diabetes Obes Metab. 2018;20:1602–1614.

DURATION-7: Exenatide QW Add-on to Basal Insulin


DURATION-7:Summary

• Compared with placebo + IG, EQW + IG resulted in reductions in HbA1c, FPG, body weight, and 2-hour PPG, and more patients reached an HbA1c <7% at Week 28

• EQW + IG was well tolerated

– No new or unexpected safety findings

– Hypoglycemia was similar in both treatment arms

– No major hypoglycemia

• EQW is an effective and well-tolerated option for patients with T2D inadequately controlled with basal insulin


GLP1 RA and SGLT-2 Inhibitors Address a Broad Range of Pathophysiologic Defects Associated With T2D

GLP-1RA

SGLT-2-i

↓ Blood Glucose

↓ Blood

Pressure

↓ Body Weight

↓ Appetite↑ Glucose-

dependent insulin

secretion

Slows gastric

emptying

↓ Systolic Blood

Pressure

↓ Vascular

stiffness

↑ Urinary

glucose

excretion

↓

Inflammation

Naturesis

↑ Heart rate

↓ Blood pressure

↑ LV function

↓ Infarct size

De Fronzo RA, Diabetes Obes Metab. 2018

COMBINATION THERAPY WITH GLP-1 RA AND SGLT2i GLP1-RA GLP1-RA+SGLT2iSGLT2i

DURATION-8

Secondary Endpoints• Change in body weight• Change in FPG• Change in 2-hour PPG

• Proportion of patients achieving HbA1c <7%• Proportion of patients achieving weight loss ≥5%• Change in SBP

Exploratory Endpoints • Change in HbA1c by baseline HbA1c†

• Change in weight by baseline HbA1c†

• Change from baseline in fasting lipids

Screening

1040

N=695*Key Inclusion Criteria:≥18 y; T2D; HbA1c 8-12%; stable dose MET ≥2 mo

1:1

:1R

and

om

izat

ion

DAPA 10 mg + PBO (n=233)

EQW 2 mg + DAPA 10 mg (n=231)

MET ≥1500 mg/day

EQW 2 mg + PBO (n=230)

28

Double-blind treatment period

-1

PBO Lead-in period Extension periods

52

Primary Endpoint • Change in HbA1c from baseline to Week 28

Frías JP et al. Lancet Diabetes Endocrinol. 2016;4:1004-1016; 2. Jabbour SA, Diabetes Care 2018, 41:2136-46 ; Jabbour S et al. Presented at: ADA Congress; June 22-26, 2018;

Frías JP et al. Lancet Diabetes Endocrinol. 2016;4:1004-1016; 2. Jabbour SA, Diabetes Care 2018, 41:2136-46 ; Jabbour S et al. Presented at: ADA Congress; June 22-26, 2018;

DURATION-8 At 104 weeks, differences were maintained3

Safety and Tolerability Over 104 Weeks

Jabbour S et al. Presented at: ADA Congress; June 22-26, 2018; Orlando, FL. Poster 104-LB.

Adverse Event, n (%)EQW+DAPA

(n=231)

EQW+PBO

(n=230)

DAPA+PBO

(n=233)

Any AE 165 (71.4) 161 (70.0) 156 (67.0)

Death 3 (1.3) 1 (0.4) 2 (0.9)

Any serious AE (including death) 17 (7.4) 17 (7.8) 18 (7.7)

Any AE leading to treatment discontinuation 16 (6.9) 14 (6.1) 12 (5.2)

Gastrointestinal AEs 48 (20.8) 55 (23.9) 38 (16.3)

AEs occurring in ≥5% of patients in any group

Injection-site nodule 20 (8.7) 14 (6.1) 13 (5.6)

Nausea 13 (5.6) 26 (11.3) 10 (4.3)

Vomiting 8 (3.5) 12 (5.2) 7 (3.0)

Urinary tract infection 19 (8.2) 15 (6.5) 16 (6.9)

Diarrhea 13 (5.6) 17 (7.4) 11 (4.7)

Upper respiratory tract infection 15 (6.5) 17 (7.4) 22 (9.4)

Headache 16 (6.9) 12 (5.2) 12 (5.2)

Nasopharyngitis 15 (6.5) 8 (3.5) 12 (5.2)

Adverse Events of Special Interest Over 104 Weeks1

* Occurred in the 28-week study period.

† Major hypoglycemia was defined as loss of consciousness, seizure, or coma resolving after glucagon or glucose administration or any event that required third-party assistance to resolve because of

severe impairment in consciousness or behavior with a glucose level <3 mmol/L (<54 mg/dL).

‡ Minor hypoglycemia was defined as any non-major event with symptoms consistent with hypoglycemia and a glucose concentration <3 mmol/L (<54 mg/dL).

§ Other hypoglycemia was defined as event not meeting the criteria for a major or minor event.

1. Jabbour S et al. Presented at: ADA Congress; June 22-26, 2018; Orlando, Florida ; 2. Frías JP et al. Published correction for Lancet Diabetes Endocrinol. 2016;4:1004-1016.

Adverse Event, n (%)EQW+DAPA

(n=231)

EQW+PBO

(n=230)

DAPA+PBO

(n=233)

Potentially volume depletion-related 3 (1.3) 1 (0.4) 5 (2.1)

Pancreatitis-related 3 (1.3) 1 (0.4) 0

Acute renal failure-related 0 2 (0.9) 3 (1.3)

Any genital infection 12 (5.2) 5 (2.2) 18 (7.7)

Diabetic ketoacidosis2* 0 1 (<1.0) 0

Hypoglycemia

Major† 0 0 0

Minor‡ 4 (1.7) 0 1 (0.4)

Other§ 16 (6.9) 8 (3.5) 8 (3.4)

Take home massage

La terapia con GLP-1RA:➢ È indicata nel paziente con DT2 con pregresso evento CV ➢ Deve essere considerata nel paziente con DT2 in prevenzione primaria in aggiunta

alla metformina

Exenatide OW ha dimostrato miglior controllo glicemico, riduzione del peso e delle ipoglicemie rispetto a glargine e tale effetto si mantiene nel tempo (3 anni)

L’associazione Exenatide OW + Glargine è efficace e ben tollerata ed indicata nei pazienti che richiedono una intensificazione della terapia

L’associazione Exenatide OW + Dapagliflozin è efficace e migliora il controllo glicemico, del peso corporeo e della PAS a lungo termine (3 anni)

Grazie per l’attenzione

sliding door pazienti al bivio: oltre la terapia orale · presentazione di powerpoint author:...

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