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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
American Diabetes Association Dia Care 2019;42:S90-S102
Pharmacologic approches to Glycemic treatment
▪ Intensification of treatment for patients with T2Dnot meeting treatment goals should not bedelayed. B
American Diabetes Association Dia Care 2019;42:S90-S102
American Diabetes Association Dia Care 2019;42:S90-S102
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
American Diabetes Association Dia Care 2019;42:S90-S102
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
Diamant M, et al. Lancet Diabetes Endocrinol 2014; 2(6): 464-73
HbA1c BG
BW
DURATION-3
Diamant M, et al. Lancet Diabetes Endocrinol 2014; 2(6): 464-73
• 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
Diabetes Obes Metab. 2018;20:1602–1614.
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
Diabetes Obes Metab. 2018;20:1602–1614.
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