“Few can foresee whither their road
will lead them, till they come to its end.”
J.R.R Tolkien, The two towers
SGLT2 Reduced glucose
reabsorption
Increased urinary
excretion of excess
glucose
(~70 g/day,
corresponding to 280
kcal/day*)
Proximal tubule
Glucose
filtration
*Increases urinary volume by only ~1 additional void/day (~375 mL/day) in a 12-week study of healthy subjects and patients with Type 2 diabetes.4
SGLT2
Glucose
Dapagliflozin
Dapagliflozin
1. Wright EM. Renal Na+-glucose cotransporters. Am J Physiol Renal Physiol 2001;280:F10–18;
2. Lee YJ, et al. Regulatory mechanisms of Na+/glucose cotransporters in renal proximal tubule cells. Kidney Int Suppl 2007;106:S27–35;
3. Hummel CS, et al. Glucose transport by human renal Na+/d-glucose cotransporters SGLT1 and SGLT2. Am J Physiol Cell Physiol 2011;300:C14–21;
4. www.swissmedicinfo.ch
SGLT2 ridotto riassorbimento tubulare
di glucosio inibendo SGLT2
aumento della
glicosuria a
~70 g/giorno
(280 kcal/giorno)
tubulo prossimale
filtrazione
di glucosio
Il meccanismo d’azione delle gliflozine
SGLT2
glucosio
gliflozina
SGLT2 and GLUT2 mechanism of transport
Interstitial space
Adapted from Wright EM, et al. Surprising versatility of Na+-glucose cotransporters: SLC5. Physiology 2004;19:370–376;
Basolateral membrane Tubular lumen
Na+
SGLT2 GLUT2
Glucose
Tight
junction
Na+
Lateral intercellular space
K+ Na+/K+
pump
Na+
K+
Glucose
Glucose
Gli inibitori del trasportatore sodio-glucosio tipo 2 (SGLT2-inibitori, “gliflozine”)
canagliflozina Invokana®, 100 e 300 mg
canagliflozina con
metformina Vokanamet®
dapagliflozina Forxiga®, 5 e 10 mg
empagliflozina Jardiance®, 10 mg
In fase di sviluppo:
luseogliflozina
ipragliflozina
tofogliflozina
Dapagliflozina aggiunta all’insulina:
cambiamento della HbA1c in 104 settimane1
Week 104 adjusted mean change,
(95% CI)
−0.43 (−0.58, −0.28)
−0.64 (−0.78, −0.50)
−0.78 (−0.92, −0.65)
−0.82 (−0.96, −0.68)
At 24 weeks, dapagliflozin was associated with HbA1c reductions of –0.96% versus –0.39% with
placebo (p<0.001)2
1. Wilding et al. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med 2012;156:405-415
2. Wilding et al. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes Metab. 2014 Feb;16(2):124-36
0.35%
difference
p=0.0007
Dapagliflozin vs Sulfonilurea aggiunta aMET:
cambiamento del peso in 208 settimane1
*Data are adjusted mean change from baseline ±95% CI derived from a longitudinal repeated-measures mixed model.
At 52 weeks, dapagliflozin was associated with weight loss of –3.2 kg versus weight gain of +1.4 kg with glipizide (p<0.0001)2
1. Del Prato S, et al. Durability of Dapagliflozin vs. Glipizide as Add-On Therapies in T2DM Inadequately Controlled on Metformin: 4-Year Data. ADA 2013; poster 62-LB.
2. Nauck MA et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-
week, double-blind, active-controlled noninferiority trial. Diabetes Care. 2011 Sep;34(9):2015-22
Gli inibitori del SGLT-2 (“gliflozine”) permettono, in sintesi
- un calo di HbA1c di 0.6-2%
- un riduzione della glicemia a digiuno di circa 1-2 mmol/L e
- postprandiale di 2-3 mmol/L
- un calo ponderale di 2-4 kg
- un calo di PA sistolica di 3-4mmHg
Gli inibitori del SGLT-2 (“gliflozine”), in sintesi
impiegabili in combinazione con praticamente tutti gli altri
antidiabetici, insulina inclusa
non sono efficaci nell’insufficienza renale, lo sono per contro in
caso di epatopatia
causano un aumento del rischio di infezioni genitali micotiche
possono essere problematici a causa della poliuria e
dell’ipotensione ortostatica in soggetti predisposti
Tre
nd
s i
n A
ge-S
tan
dard
ize
d R
ate
s o
f D
iab
ete
s-R
ela
ted
Co
mp
lic
ati
on
s a
mo
ng
U.S
. A
du
lts
, 1
99
0–2010.
Gregg EW et al. N Engl J Med 2014;370:1514-1523
Levemir 24-0-0-0
Galvumet
Diamicron
Tresiba 24-0-0-0
Galvumet
Diamicron
HbA1c:
9.3%
HbA1c:
7.5%
ZeLu1936
Tresiba ® (insulina degludec)
100u = 8.60CHF
Tresiba 200® (insulina degludec) 100u = 10.20CHF
Lantus® (insulina glargina) 100u = 6.30CHF
Tresiba ® vs Lantus® 50u/giorno : +840.-/anno
Combinazione con
- Aspart (Novorapid®) = Ryzodeg® (30% Aspart)
- Liraglutide (Victoza®) = Xultophy ® (0.6mg/16u)
Insulina degludec
“Indicazioni”
- Ipoglicemie frequenti
- Diabete “instabile”
- Lenta in 2 iniezioni/giorno
Tresiba ® (insulina degludec)
Cosa ci hanno insegnato ACCORD, ADVANCE, e VADT ?
ACCORD ADVANCE VADT
Participant Characteristics
n 10,251 11,140 1,791
Mean age, y 62 66 60
Duration of diabetes, y 10 8 11.5
Sex, % male/female 39/61 42/58 97/3
History of CVD, % 35 32 40
BMI, kg/m2 32 28 31
Median baseline A1C, % 8.1 7.2 9.4
On insulin at baseline, % 35 1.5 52
BMI = body mass index.
Skyler JS et al. J Am Coll Cardiol. 2009;53:298-304.
49
Cosa ci hanno insegnato ACCORD, ADVANCE, e VADT ?
ACCORD ADVANCE VADT
Protocol Characteristics
A1C goals, % (I vs S)a
<6.0 vs 7.0-7.9 6.5 vs based on local guidelines
<6.0 (action if >6.5) vs planned separation of 1.5
Protocol for glycemic control (I vs S)a
Multiple drugs in both arms
Multiple drugs added to gliclazide vs multiple drugs with no gliclazide
Multiple drugs in both arms
Management of other risk factors
Embedded blood pressure and lipid trials
Embedded blood pressure trial
Protocol for intensive treatment in both arms
aMedication rates for ACCORD are for any use during the study.
I = intensive glycemic control; S = standard glycemic control.
Skyler JS et al. J Am Coll Cardiol. 2009;53:298-304.
50 CI = confidence interval; HR = hazard ratio. Skyler JS et al. J Am Coll Cardiol. 2009;53:298-304.
ACCORD ADVANCE VADT
Outcomes
Definition of primary outcome
Nonfatal MI, nonfatal stroke, CVD death
Microvascular plus macrovascular (nonfatal MI, nonfatal stroke, CVD
death) outcomes
Nonfatal MI, nonfatal stroke, CVD death, hospitalization for
heart failure, revascularization
HR for primary outcome (95% CI)
0.90 (0.78-1.04)ns nonfatal AMI 0.76 microvasc. 0.79
0.9 (0.82-0.98); macrovascular 0.94 (0.84-1.06) p=0.01
microvasc. 0.86
0.88 (0.74-1.05)ns microvasc.
HR for mortality findings (95% CI)
1.22 (1.01-1.46) 1.41 vs 1.14%
CV death 1.35
0.93 (0.83-1.06) 1.07 (0.81-1.42)
Cosa ci hanno insegnato ACCORD, ADVANCE, e VADT ?
51
ACCORD ADVANCE VADT
Weight changes, kg
Intensive glycemic control arm +3.5 –0.1 +7.8
Standard glycemic control arm +0.4 –1.0 +3.4
Severe hypoglycemia (participants with one or more episodes during study), %
Intensive glycemic control arm 16.2 2.7 21.2
Standard glycemic control arm 5.1 1.5 9.9
Cosa ci hanno insegnato ACCORD, ADVANCE, e VADT ?
Skyler JS et al. J Am Coll Cardiol. 2009;53:298-304.
Quali pazienti hanno beneficiato?
subgroups analysis:
< 65 Y AC
non antecedenti macrovascolari AC
durata del diabete < 12 Y V
HbA1c di partenza < 8% AC
classe molecole (esempi) specialità registrate (esempi)
biguanidi metformina Glucophage®, Metfin® sulfanilurea glibenclamide
glimepiride
gliclazide
Daonil® Amaryl® Diamicron®
glinidi repaglinide
nateglinide
Novonorm® Starlix®
glitazoni pioglitazone Actos® gliptine
(inibitori della DPP-4)
sitagliptina
vildagliptina
Januvia® Galvus®
analoghi del GLP-1
(iniettabili s.c.)
exenatide
liraglutide
Byetta®, Bydureon® Victoza®
Glicosidasi-inibitori acarbosi Glucobay® gliflozine
(inibitori del SGLT2)
canagliflozina
Dapagliflozina
Invokana®
Forxiga®
2015: Classi di antidiabetici
classe molecole (esempi) specialità registrate (esempi)
biguanidi metformina Glucophage®, Metfin® sulfanilurea glibenclamide
glimepiride
gliclazide
Daonil® Amaryl® Diamicron®
glinidi repaglinide
nateglinide
Novonorm® Starlix®
glitazoni pioglitazone Actos® gliptine
(inibitori della DPP-4)
sitagliptina
vildagliptina
Januvia® Galvus®
analoghi del GLP-1
(iniettabili s.c.) exenatide
liraglutide
Byetta®, Bydureon® Victoza®
Glicosidasi-inibitori acarbosi Glucobay® gliflozine
(inibitori del SGLT2)
canagliflozina
Dapagliflozina
Invokana®
Forxiga®
2015: Classi di antidiabetici
Copyright ©2009 The Endocrine Society
Abu-Hamdah, R. et al.
J Clin Endocrinol Metab
2009;94:1843-1852
Effetti del GLP-1 sui tessuti periferici
* * *
*
* *
*p<0.05, DM2 vs. NGT , pasto iniziato a T0 e terminato dopo 10-15 minutes.
Toft-Nielsen M-B et al J Clin Endocrinol Metab 2001;86:3717–3723.
GLP-1 ridotto nel DM2
NGT (n=33)
DM 2 (n=54)
0
5
10
15
20
0 60 120 180 240
Tempo (min.)
GL
P-1
(p
mo
l/L
) d
op
o p
asto
sta
nd
ard
*
Liraglutide, 52 sett. s.c.
6.5
9.0
8.5
8.0
7.5
7.0
0 Weeks
HbA
1c (
%)
LEAD-3, previous diet and exercise-treated patients
Liraglutide 1.2 mg monotherapy Liraglutide 1.8 mg monotherapy
Glimepiride 8 mg
4 8 12 16 20 24 28 32 36 40 44 48 52
Chan
ge
in H
bA
1c (%
)*
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
-1.6
-1.6
-1.2
-0.9
Garber et al. Lancet 2009;373:473–81 (LEAD-3). Data are mean (SD)
No diet and exercise regimen was provided.
N = 283; Mean (± SE); P<0.05.
Henry R, et al. Diabetes. 2006; 55:A116.
Placebo-Controlled/Open-Label Extension (Combined):
Exenatide Continued to Reduce Weight
Baseline Weight
Time (week)
0 10 20 30 40 50 60 70 80 90 100 110 -7
-6
-5
-4
-3
-2
-1
0
1
100 kg
-4.7 ± 0.3 kg
D W
eigh
t (k
g)
Placebo-Controlled Open-Label Extensions
Janumet
Glimeryl
Glucophage
Glimeryl
+Victoza + dietista
8/2014
HbA1c:11.9%
106kg GugRob1947
11/2014
HbA1c: 7.1%
102kg
Studio ROSSO
• 3.268 pazienti con DM2
• Seguiti in studi medici (s. retrospettivo)
• Parametri:
A. infarti + ictus + amputazione + cecità +dialisi
B. mortalità
• Follow-up : 6,5 (± 1.6) anni
• 1.543 pazienti (47%): almeno 1anno SMBG
Der positive Effekt einer SMBG auf Morbidität und Mortalität blieb eindeutig nachweisbar, auch
wenn Patienten mit einer Insulintherapie nicht in die Analyse eingeschlossen wurden.
Grafico-3 ore
BG Reading Time
Graph Type
BG Reading
Bolus Indicators
Hour Mark
Lower BG Limit
Upper BG Limit
time