DPP4GLP1SGLT2
Inwooncursus : Hormonopolis 16 april 2014 Dr. Ann Verhaegen ZNA Jan Palfijn UZA
Casus 1 – Marie 54 jarige psychiatrisch verpleegkundige met wisselende werkuren (ook nachtshifts) Antecedenten: Enkele niet relevante kleine chirurgische ingrepen Type 2 diabetes sinds 3 jaar – geen gekende verwikkelingen Arteriele hypertensie Dyslipidemie
Huidige medicatie metformin 2x 850 mg/d Ramipril 10 mg simvastatine 40 mg
Levenswijze: rookt niet drinkt in weekend enkele glazen wijn probeert sinds haar diagnose 3 x per week te sporten onder begeleiding van dietiste sinds diagnose 8 kg vermagerd
Casus 1 – Marie 54 jarige psychiatrisch verpleegkundige met wisselende werkuren (ook nachtshifts) K.O.: G 73 kg, L 165 cm, BMI 27 kg/m² buikomtrek 93 cm Bloeddruk 128/78, P 72/min
lab: HbA1c progressief lichtjes toenemend begin vorig jaar 6,6 % (59 mmol/mol) naar nu 7,8 % (62 mmol/mol)
creatinine 0,78 mg/dl e GFR > 60 ml/min
lipiden: totaal cholesterol 151 mg/dl HDL cholesterol 60 mg/dl Triglyceriden 173 mg/dl LDL cholesterol 56 mg/dl
Voldoende of toch behandeling aanpassen?
Wat is volgende stap in de behandeling?
Depiction of the elements of decision making used to determine appropriate efforts to achieve glycemic targets.
Inzucchi S E et al. Diab Care 2012;35:1364-1379
4
5
Incretines algemene inleiding – fysiopathologie van natief GLP-1 medicatie actief op incretinesysteem DPP-4 inhibitoren GLP-1 agonisten
The incretin effect increases -cell response to oral vs IV glucose The incretin effect is demonstrated by increased C-peptide levels after oral glucose load 2.0
Oral glucose IV glucose
* C-peptide (mmol/L)
Venous plasma glucose (mmol/L†)
10.0
7.5
5.0
2.5
0
1.5
*
*
* Incretin effect
* 1.0
*
*
0.5
0.0 01 02
60
120
180
01 02
Time (min)
60
120
Time (min)
Responses to an oral glucose load of 50 g and IV glucose infusion measured in 8 healthy control subjects. Mean ± SE; n=6; *P≤0.05; 01 and 02 = -10 and -5 min, respectively, before glucose infusion. †To convert mmol/L of glucose to mg/dL, multiply by 18.
Nauck MA. J Clin Endocrinol Metab. 1986;63:492-8.
180
De effecten van GLP-1 zijn glucose-afhankelijk bij diabetes type 2 patiënten Placebo GLP-1
1
2
3
PBO GLP-1
PBO GLP-1 300
*
*
*
* * *
0,90
0 -30 0
60
120
180
Tijd (min)
240
20
200
*
100
* * *
* * 0 -30 0
60
120
180
* * 240
Glucagon (pmol/L)
Glucose (g/l)
*
Insuline (pmol/L)
2,70
1,80
PBO GLP-1
10
0 -300
Tijd (min)
*
60
* * *
120
Tijd (min)
Een gerandomiseerde, cross-over; placebo gecontroleerde trial bij patiënten met Diabetes type 2 (n=10) ; gemiddelde ±SEM ; *p <0,05. (16) Nauck MA, et al. Diabetologia. 1993;36:741-744. Reproduced with the permission of Springer-Verlag © 1993.
180
240
Physiological actions of GLP 1
Baggio & Drucker. Gastroenterology 2007; 132: 2131-2157
Release and action of Glucagon Like Peptide-1 (GLP-1)
Mixed Meal
Half-life of GLP-1 Is <2 minutes
DPP-4
Intestinal GLP-1 Release GLP-1 (7-36) Active
Rapid Inactivation (>80% of pool)
GLP-1(9-36) Inactive Mentlein et al. in Eur J Biochem. 214(3):829-35, 1993 Eng J, et al. J Biol Chem 1992; 267:7402-7405
Resistant to DPP-4 inactivation Incretine-analogen - Exenatide (Byetta) - Liraglutide ( Victoza) - Lixisenatide ( Lyxumia) - exenatide LAR ( Bydureon)
Block DPP-4 enzyme activity DPP-4 inhibitore - Vildagliptin (Galvus) - Sitagliptin(Januvia) - Saxagliptin (Onglyza) - Linagliptine ( Trajenta)
10
producten actief via incretinesysteem
GLP-1 analogen (incretine mimetica of analogen) Exenatide (Byetta ®) Liraglutide (Victoza ®) Exenatide LAR Lixisenatide ( Lyxumia ®) DPP-4 inhibitoren Sitagliptin (Januvia ®) Saxagliptin (Onglyza ®) Vildagliptin (Galvus ®) Linagliptin ( Trajenta ®)
Sitagliptin – doeltreffendheid Add-on to metformin Reductions in HbA1c comparable to glipizide when added to metformin Glipizide 5 mg/day + metformin (n=584)
Sitagliptin 100 mg q.d. + metformin (n=588)
Mean HbA1C (%)
8.4 7.6 7.2 6.8 6.4 6.0 0
6
12
18
24
30
38
Week
Adapted from: Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205.
46
52
Saxagliptin is non-inferior to SU in lowering HbA1c as an add-on to metformin at 52 weeks1 Adjusted mean change in HbA1c from baseline (PP analysis set)
HbA1c (%) ± SE
0.0
Mean Baseline HbA1c: 7.5%
-0.25
-
-0.50
-
-0.75
-0.74
-1.00
-
MET + SAXA (n=293)
7.5%
-0.80 MET + GPZ (n=293)
Absolute difference between groups: 0.06% 95% CI -0.05 to 0.16 MET+SAXA was considered non-inferior to MET+GPZ if upper confidence limit of difference in adjusted HbA1c change from baseline to week 52 was <0.35%; PP: per protocol; GPZ: glipizide; PBO: placebo; MET: metformin; SAXA: saxagliptin. 1. Göke B, et al. Int J Clin Pract. 2010;64(12):1619-31.
13
Doeltreffendheid Therapeutisch effect van verschillende DPP-4-remmers in monotherapie zoals vermeld in samenvatting van producteigenschappen. Voor placebo gecorrigeerde, gemiddelde verandering van het HbA1c na 18 / 24 weken behandeling t.o.v. beginwaarde**. Linagliptin1
Gemiddelde daling van de HbA1c*
Doserin g Baselin e HbA1c
Saxagliptin2
Sitagliptin3
Vildagliptin4
5 mg QD
5 mg QD
5 mg QD
5 mg QD
100 mg QD
100 mg QD
50 mg QD
50 mg QD
8,1%
8,0%
7,9%
8,0%
8,0%
8,0%
8,6%
8,4%
-0,4% -0,5% -0,6%
-0,6%
-0,6% -0,7%
-0,7% -0,8%
n=
147
272
69
103
193
229
90
79
pvalue*
< 0,0001
< 0,0001
< 0,0059
< 0,0001
< 0,0001
< 0,0001
< 0,05
< 0,05
*Gemiddelde daling HbA1c vesus placebo **Geen rechtstreekse vergelijkende studie tussen de verschillende moleculen. 1. Samenvatting van de producteigenschappen Trajenta®, 2. Samenvatting van de producteigenschappen Onglyza®, 3. Sam envatting van de producteigenschappen Januvia®, 4. Samenvatting van producteigenschappen Galvus® .
Difference in weight change was significant between saxagliptin vs SU as add-on to metformin Adjusted mean change in body weight from baseline to Week 52 (safety analysis set) 1.5
-
1.1
Body weight (kg) ± SE
p<0.0001 1.0
-
0.5
-
0 -0.5
-
-1.0
-
-1.5
-
-1.1
MET + SAXA (n=428)
MET + GPZ (n=430)
GPZ: glipizide; MET: metformin; SAXA: saxagliptin.
1. Göke B, et al. Int J Clin Pract. 2010;64(12):1619-31.
15
Significantly fewer patients experience hypoglycaemia with saxagliptin vs SU as add-on to metformin Proportion of patients with ≥1 hypoglycaemic episode at Week 52 (safety analysis set) 50
-
Patients (%) ± CI
p<0.0001 40
-
30
-
20
-
10
-
0
36.3%
3.0%
MET + SAXA (n=428)
MET + GPZ (n=430)
Severe hypoglycaemic events or events requiring medical assistance 0 with saxagliptin vs 11 for glipizide CI: confidence interval; GPZ: glipizide; MET: metformin; SAXA: saxagliptin.
1. Göke B, et al. Int J Clin Pract. 2010;64(12):1619-31.
16
Characteristics of DPP-4 Inhibitors in Clinical Development
Chemistry Sitagliptin Januvia®
Metabolism
Elimination route
β-amino acid-based
Not appreciably metabolised
Renal (~80% unchanged
Vildagliptin Galvus®
Cyanopyrrolidine
Hepatically hydrolysed to inactive metabolite (P450 enzyme
Renal (22% as parent,
Saxagliptin Onglyza®
Cyanopyrrolidine
Hepatically metabolised to active metabolite (via P450 3A4/5)
Renal (12-29% as parent,
Linagliptin Trajenta®
Xanthine-based
Not appreciably metabolised
Biliary (unchanged as parent); <6% via kidney
independent)
as parent)
55% as metabolite)
21-52% as metabolite)
17
Sulfonylurea vs DPP-4 voordelen Sulfonylurea Bewezen effect op microvasculaire verwikkelingen Beperkte nevenwerkingen Lang bekend Effect zowel op nuchtere als PP glycemie Keuze ifv nierfunctie / leverfunctie/ werkingsduur Goedkoop
DPP-4 inhibitoren Gewichtsneutraal Laag risico hypoglycemie Eenvoudig in dosering Weinig nevenwerkingen CV neutraal Kunnen gebruikt worden bij nierinsufficientie ( mits dosisaanpassing)
Sulfonylurea vs DPP-4 nadelen Sulfonylurea
DPP-4 inhibitoren
Hypo’s
geen lange termijn gegevens
Gewichtstoename
Geen studies op microvasculaire eindpunten
Niet consistente gegevens op macrovasculaire verwikkelingen Betacel onder druk CI bij ernstig nier en leverfalen
Duur
Casus 2: Francois -79 jaar Alleenstaande man, echtgenote 3 jaar geleden overleden Sindsdien gezondheid/dieet wel wat verwaarloosd
Antecedenten: unieke nier na een trauma als kind waarbij nefrectomie CVA 5 jaar geleden, volledige recuperatie prostaatcarcinoom waarvoor radicale prostatectomie en hormonale therapie 10 jaar geleden myocardinfarct jarenlange arteriele hypertensie chronische nierinsufficientie hypercholesterolemie
Casus 2: Francois 79 jaar HZG: opname omwille van een pneumonie K.O.: na recuperatie van de acute fase ivm pneumonie , vitale man G 81 kg, L 174 cm, BMI 26 kg/m² bloeddruk 140/78
lab: glycemie 280 mg/dl bij opname tijdens opname steeds > target
HbA1c 8,1% creatinine 2,64 mg/dl, e GFR 23 ml/min •
Behandeltarget? Welke eerste stap?
Depiction of the elements of decision making used to determine appropriate efforts to achieve glycemic targets.
Inzucchi S E et al. Dia Care 2012;35:1364-1379
22
Starttherapie Type 2 diabetes: steeds Metformin Voordelen
Geen hypo’s in monotherapie Gewichtsneutraal Bewezen effect op reductie van micro en macrovasculaire verwikkelingen ( UKPDS) “betacelsparend” – tragere nood insulinetherapie vs SU ( ADOPT) Verminderde insulinenood bij combinatie met insuline Verminderd kankerrisico bij obese Type 2 diabetes (? )
nadelen
GI nevenwerkingen ( traag optitreren) Geen gebruik bij nierinsufficientie ( GFR < 30 ml/min)- dosis reductie bij mildere nierinsufficientie hartinsufficientie en andere oorzaken van acidose of ischemie ( lactaatacidose)
Vit B 12 en foliumzuurdeficientie
DPP-4 inhibitoren - aanpassing nierfunctie eGFR (ml/min)
>90
60-89
30-59
15-29
<15
Normaal
Lichte NI
Matige NI
Ernstige NI
End stage
Sitagliptine Januvia®
100 mg
100 mg
50 mg
25 mg
25 mg
Vildagliptine Galvus ®
2 x 50 mg
2 x 50 mg
1 x 50 mg
1 x 50 mg
1 x 50 mg
Saxagliptine Onglyza®
5 mg
5 mg
2,5 mg
2,5 mg + opvolging
CI
Linagliptine Trajenta®
5 mg
5 mg
5 mg
5 mg
5 mg
Terugbetaling DPP-4 (04/2014) Januvia
Onglyza:
Galvus
Trajenta
1 x 50 mg/d (50 ml/min)
X (<30 ml/min)
x
x
Monotherapie
50 mg (30-50 ml ) 25 mg (<30 ml )
Bitherapie met Metformin
x
Bitherapie met SU
x
X
x
x
x
+ metformin en gliptine ( indien GFR < 50 ml/min)
neen
x
Bitherapie met TZD Tritherapie met Metformin + SU
Tritherapie met TZD Insuline
Niet vermeld
Niet vermeld
Opm. combinatiepreparaten: Janumet, Komboglyze, Jentadueto: enkel in monotherapie terugbetaaald, nooit met insuline Eucreas: combinatie therapie met SU en gliptine
Casus 3: Paul, 68 jaar Antecedenten: Myocardinfarct in 2002 CABG in 2008 Hypertensie Hartfalen op basis van ischemische CMP en hypertensie waarvoor 2 x opname in 2011 en 2012 Chronische VKF Hypercholesterolemie Perifeer vaatlijden Diabetes sinds 2004
Medicatie Novonorm 3 x 2 mg, metformin 2 x 850 Burinex 1 mg, Kredex 25, Aprovel 300, Hydralazine, Moxonidine 0,4 Atorvastatine 40 Eliquis
Casus 3: Paul, 68 jaar K.O.: G 81 kg, L 176 cm RR 128/78
Lab: Creatinine 1,1 mg/dl HbA1c 8,1 %
Welke verdere stappen in de behandeling Triple therapie door toevoegen van een DPP-4 aan Novonorm en metformin? Toevoegen van een GLP-1 agonist Toevoegen of omschakelen naar insuline? Wat weten we van CV veiligheid?
DPP-4 inhibitoren CV events – meta analyse Grafische compilatie van CV-veiligheidsdata tijdens onafhankelijke klinische studies met DPP-4inhibitoren DPP-4-remmer beter 0,15
Linagliptine1
0,34
Sitagliptine2
Vergelijkingsproduct beter
0,74
0,41
0,68
1,12
0,62 0,84
Vildagliptine3
1,14
Saxagliptine4
0,23
1/8
1/4
0,42
1/2
0,80
1
2
4
Primair eindpunt
Commentaar
5.239
CV-sterfte, MI, CVA, ziekenhuisopname wegens angina
Vooraf gespecificeerde / onafhankelijke evaluatie
10.246
Med DRA-termen voor MACE
Geen formele evaluatie
10.988
Acuut coronair syndroom, TIA, CVA, CV-sterfte
Vooraf gespecificeerde / onafhankelijke evaluatie
4.607
MI, CVA, CV-sterfte
Vooraf gespecificeerde / onafhankelijke evaluatie
8
Risicoratio voor macrovasculaire events
* CV-sterfte, niet-fataal MI, niet-fataal CVA, ziekenhuisopname wegens instabiele angina pectoris. Aangepast naar 1.Johansen et al. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a prespecified, prospective and adjudicated meta-analysis of a phase 3 programme. Cardiovasc Diabetol. 2012 Jan 10;11:3; 2. Sitagliptine WilliamsHerman et al. 2010, BMC Endocrine disorders; 3. Vildagliptine; Schweizer et al. 2010, DOM; 4. Saxagliptine: Frederich et al. 2010, Postgraduate Medicines.
SAVOR-TIMI & EXAMINE Saxagliptin SAVOR
Alogliptin EXAMINE
1.00 (.89-1.12)
0.96 (UL 1.16)
CV Death
1.03 (.87-1.22)
0.79 (.60-1.04)
MI
0.95 (.80-1.12)
1.08 (.88-1.03)
Stroke
1.11 (.88-1.39)
0.91 (.55-1.50)
1.11 (.96-1.27)
.88 (.71-1.09)
Saxa/PBO - %
Alo/Pbo - %
3.5/2.8*
Reported as NS
14.2/12.5*
6.7/6.5
2.1/1.7*
0.7/0.6
Pancreatitis
n
n
Any
24/21
NR
Acute
22/16
12/8
Chronic
2/6
5/4
5/12
0/0
Primary MACE
Total Mortality
Heart Failure Admissions Hypoglycemia Mild Severe
Pancreatic Cancer *<0.05
producten actief via incretinesysteem
GLP-1 mimetica: Mimetica Exenatide (Byetta ®) -BID Exenatide LAR(Bydureon®) - OW
Analogen Liraglutide (Victoza ®) -OD Lixisenatide ( Lyxumia ®) - OD
DPP-4 inhibitoren Sitagliptin (Januvia ®) Saxagliptin (Onglyza ®) Vildagliptin (Galvus ®) Linagliptin ( Trajenta ®)
BYDUREON
At steady state, there are minimal peak-to-trough fluctuations in exenatide concentration Exenatide once-weekly injection
Establishing steady-state exenatide levels
Mean plasma level of exenatide
450 Steady state is maintained with subsequent weekly doses
Plasma exenatide (pg/mL)
400
350
300
Steady state achieved for continuous glycaemic control
250
200
150
100
50
N=15
0 0
1
2
3
4
5
6
7
8
9
Microsphere diffusion over time (weeks)
Kim D, et al. Diabetes Care 2007;30:1487–93.
10
11
12
13
14
BYDUREON – DURATION TRIALS EFFECT OP HBA1C DURATION-2 Exenatide once weekly vs:
Exenatide QW
−0.9%
−1.0
8.4
Insulin glargine#5 n=448 26 weeks
8.5
8.4
8.3
−0.9% −1.2% −1.3%§
−1.5 −1.5%
−1.5%*
−2.0
8.3
Insulin glargine
8.5
Liraglutide 1.8 mg¶4 n=911 26 weeks
Exenatide QW
8.3
DURATION-3
Liraglutide
8.3
DURATION-6
Exenatide QW
8.5
Exenatide BID
8.5
Exenatide BID
8.6
Exenatide QW
LS mean change in HbA1c (%)
Exenatide BID¶3 n=252 24 weeks
Pioglitazone
−0.5
Sitagliptin (100 mg QD) or Exenatide BID¶2 pioglitazone (45 mg QD)1 n=491 n=295 26 weeks 30 weeks
Exenatide QW
0
DURATION-5
Sitagliptin
Baseline (%)
DURATION-1
−1.6%‡
−1.5%
−1.3% −1.5%||
−1.9%†
Data from 24–30 Weeks. *P<0.05 vs both; †P<0.01; ‡P<0.0001; §P=0.02; ||P=0.017; ¶ITT population; #Modified ITT population. LS, least squares
1. Bergenstal RM, et al. Lancet 2010;376:431–9; 2. Drucker DJ, et al. Lancet. 2008;372:1240–50; 3. Blevins T, et al. J Clin Endocrin Metab 2011;96:1301–10; 4. Buse JB, et al. Lancet 2013;381:117–24; 5. Diamant M, et al. Lancet 2010;375:2234–43.
Bydureon - DURATION trials: Effect op gewicht Exenatide once weekly vs:
Baseline (kg)
DURATION-2
DURATION-1
Sitagliptin (100 mg QD) or pioglitazone (45 mg QD)1
Exenatide BID#2
89
87
88
102
102
DURATION-5 Exenatide BID#3 97
94
DURATION-6 Liraglutide 1.8 mg#4 91
91
DURATION-3 Insulin glargine#5 91
91
−2.3
(n=123)
(n=129)
(n=160)
−3.7 (n=148)
−3.6 (n=147)
+1.4
(n=222)
−2.6*
−2.7* (n=461)
Exenatide QW
−5
−1.4
Liraglutide
−4
(n=166)
Exenatide QW
−2.3*
−0.8
Exenatide BID
−3
(n=165)
Exenatide BID
−2
−1
Exenatide QW
0
Sitagliptin
1
Pioglitazone
2
Insulin glargine
+2.8
3
Exenatide QW
LS mean change in body weight (kg)
4
−3.6
(n=233)
(n=450)
Data from 24–30 Weeks. *P<0.05 vs each comparator; #ITT population. LS, least squares
1. Bergenstal RM, et al. Lancet 2010;376:431–9; 2. Drucker DJ, et al. Lancet 2008;372:1240–50; 3. Blevins T, et al. J Clin Endocrin Metab 2011;96:1301–10; 4. Buse JB, et al. Lancet 2013;381:117–24; 5. Diamant M, et al. Lancet 2010;375:2234–43.
DURATION-1: 3 jaar gegevens
Exenatide once weekly2 mg (n = 96)1,2
Body Weight (kg)
20
27%
7%
59%
7%
0
-20
-40 -6
-4
-2 0 A1C (%)
2
4
LS Mean ± SE weight loss at 3 years (completer population) was -2.3 ± 0.6kg Exenatide QW 3-year completer population (n = 96) LS, least squares
Macconell L, et al. Diabetes Metab Syndr Obes 2013;6:31–41. Epub 2013 Jan 21.
When used to treat type 2 diabetes liraglutide consistently reduces SBP Met combination LEAD-2
0
Met + SU Met ± SU combination combination LEAD-5 LEAD-6
–2.8
–3.6
*
*
–2.6
–2.8
–1.1
–2.5
–4.0
*
–2.0
*
Exenatide
–3
–2.3
–0.9
Glargine
–2.1
0.5
Placebo
–2
–5
Met + TZD combination LEAD-4
Rosiglitazone
–0.7
Glimepiride
–1
–4
SU combination LEAD-1
0.4
Glimepiride
Change in SBP (mmHg)
1
Monotherapy LEAD-3
–5.5
–6 –6.6
–7 Liraglutide 1.2 mg
Liraglutide 1.8 mg
*p<0.05; **p<0.001; ***p<0.0001 vs. baseline Colagiuri et al. Diabetes 2008;57(Suppl. 1):A16 (LEAD-1-5); Buse et al. Lancet 2009;374:39–47 (LEAD-6).
**
***
37
Consistent minor increase in heart rate without any clear dose-response relationship in patients with type 2 diabetes
*Significant difference compared to active comparator ** Significant difference compared to placebo in each trial NN2211 – Regulatory Submission Data
Liraglutide improves lipid profiles in patients with type 2 diabetes
Change from baseline (mmol/L)
LEAD-6
p<0.05
BID, twice daily; OD, once daily Buse et al. Lancet 2009. Jul 4;374:39-47.
Native GLP-1 improves left ventricular function in highrisk cardiac patients
Data are mean±SEM Post IV GLP-1 = post 72-h intravenous (IV) GLP-1 infusion ASE, American Society of Echocardiography Nikolaidis et al. Circulation 2004;109:962–5
Not all GLP-1 RAs are the same Prandial GLP-1
non-prandial GLP-1
Lyxumia/Byetta
Victoza
Mechanism of action in the fasting state
Enhance insulin secretion
+/Neutral
++
Suppress glucagon secretion
+/Neutral
++
Mechanism of action in the postprandial state
Enhance insulin secretion
+++
++
Suppress glucagon secretion
+++
++
Slow gastric emptying
+++
+
Reduce food intake
++
++
+
+++
+++
++
+
+
Clinical effects
Reduce FPG
Reduce PPG increment
Reduce body weight
(a)
Adapted from Fineman et al. 2012, Diabetes, Obesity and Metabolism 14: 675–688.
Classification of GLP-1 RAs Based on Regimen Twice daily (BID)
Starting dose Maintenance dose
Additional instructions
Once daily (QD)
Exenatide
Lixisenatide
Liraglutide
5 mcg BID X 1 month
10 mcg QD X 14 days
0.6 mg QD X 7 days
10 mcg BID
20 mcg QD
1.2 mg QD
Given within 1 hr before the morning and evening meal (or 2 main meals of the day, ~6 hours or more apart). Should not be given after a meal
Given 1 hr prior to first or evening meal
May be increased to max 1.8 mg QD given unrelated to meals at any time of day
Once weekly (QW) Exenatide LAR
2 mg QW
Administer same day each week; given anytime of day, with or without meals. If dosing day is changed, must be at least 24 hours after prior schedule’s dosing time
SmPCs for exenatide, liraglutide, lixisenatide, exenatide LAR; Rosenstock JC et al. Diabetes Care. 2009; 32:1880-1886.
42
Insuline vs GLP-1 agonistenvoordelen Insuline
Lang bekend Zeer goed effect op nuchtere en postprandiale glycemie en op HbA1c ( > 1%)
Dosistitratie mogelijk EB reductie microvasculaire verwikkelingen
GLP -1
Goed effect op nuchtere, postprandiale glycemie en HbA1c (1-1,5 %) Eenvoudige toediening: minder educatie, geen dosititratie Weinig hypo’s Mogelijk betacelsparend
Verlagen triglyceriden
Mogelijk cardioprotectief
Verlagen inflammatoire parameters
Beperkte zelfcontrole
Gebruik bij nierinsufficientie, leverfalen, cordecompensatie,…
gewichtsreductie
Insuline vs GLP-1 agonisten: nadelen Insuline
Hypo risico
GLP-1
Geen lange termijn effecten
gewichtstoename
Geen lange termijn veiligheid
Soms moeizame educatie
Geen aangetoonde effecten op harde end points
Medewerking patiënt vereist
Duur Geen gebruik bij nierinsufficientie
Alleen bij nog aanwezige endogene insuline-activiteit
Casus 3: Paul, 68 jaar - vervolg Medicatie Novonorm 3x 2 mg, metformin 2 x 850, Victoza 1,2 mg Burinex 1 mg, Kredex 25, Aprovel 300, Hydralazine, Moxonidine 0,4 Atorvastatine 40 Eliquis
Initieel goede respons op associatie van Victoza Laatste 6 maand toch terug oplopen van het HbA1c HbA1c 6,8 in okt 2012 tot nu in december 2013 8,1 % Dagkurve Gemiddeld nuchter 180 mg/dl, middag 140 mg/dl, voor avondmaal 110 mg/dl en voor slapen 120 mg/dl
Welke behandelingsopties??
46
Rationale for combination of basal insulin plus a GLP-1 agonist Basal Insulin Analogs
GLP-1 Receptor Agonists
Simple to initiate
Simple to use
Control nocturnal and FPG
Control PPG and some FPG
Less hypoglycemia risk vs NPH
No Increase in hypoglycemia
Weight Gain ~1-3 kg
Weight Loss ~1-3 kg
Complementary and Potentially Synergistic Effects
Effect of Twice-Daily Exenatide in Combination with Insulin Glargine on HbA1C
HbA1C (%)
9 8
8.53
p < 0.001* 7.49
7
8.35
p < 0.001*
6.7
6 5 Glargine + placebo
Glargine + exenatide
Patients achieving targets (%)
p = 0.001† p < 0.001†
80 60
60 40
p < 0.001†
49
35
20
12
0
HbA1C <7.0%
HbA1C <6.5%
*Versus baseline, †between treatment groups Buse JB, et al. Ann Intern Med 2011;154:103-12.
Combinatie Glargine/Exenatide Change in HbA1c from baseline Exenatide first then glargine
% Change in A1C from baseline
0. 0 0. 20. 40. 60. 81. 01. 2
6 months
Glargine first then exenatide
12 months
18 months
Treatment groups Combined
24 months
ap < 0.0001 vs baseline, bp ≤ 0.0008 vs baseline
Significant decreases in HbA1c were seen at 6 months and maintained, irrespective of therapy order Levin P. Endocr Pract 2011 [Epub ahead of print]
GetGoal-L: Study Design Objective: to evaluate the efficacy & safety of lixisenatide 20 µg QD vs. placebo as additional therapy in patients with T2DM inadequately controlled on basal insulin ± metformin. 1 wk
20 µg 15 µg
1 wk Key Inclusion Criteria:
10 µg
Type 2 DM HbA1c ≥7.0%– ≤10.0% Basal insulin ≥30 U/day
R
Diet & lifestyle counselling every 3 months from D 1
(n=496)
10 µg
1 wk
15 µg
1 wk
20 µg
Screening Run-in
W-3
Basal insulin ± metformin + Lixisenatide (n=329)
W-1
Basal insulin ± metformin + Placebo + (n=167)
Main double-blind period
W0
Variable extension ≥52 weeks W24
Primary endpoint Riddle et al., Diabetes Care Publish Ahead of Print, published online April 29, 2013
3 d F/U
W52 End of treatment
FU Visit
50
GetGoal-L : HbA1c at Week 24 Placebo (n=158)
Lixisenatide (n=304)
8.4 8.2
-0.38%*
8.0
7.8
-0.74%*
7.6
7.4 Baseline 4
8
12 16 Week
*LS mean change in HbA1c at Week 24, LOCF data mITT population (LOCF), on treatment value available
20
24
LS mean change in HbA1c (%)
Mean HbA1c (%) ±SE
8.6
0 -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8 -0.9 -1.0
-0.38
-0.74
LS mean difference [95%CI] vs placebo= -0.36% [-0.550, -0.174]; p=0.0002
Riddle et al., Diabetes Care Publish Ahead of Print, published online April 29, 2013
51
GetGoal-L: HbA1c Target reached at Week 24
% of patients
30
20
Lixisenatide (n=304) Placebo (n=158)
p<0.000 1
28.3%
p=0.000 3
14.5%
12.0% 10
3.8% 0
HbA1c ≤6.5% mITT population (LOCF), on treatment value available
HbA1c <7.0%
52 Riddle et al., Diabetes Care Publish Ahead of Print, published online April 29, 2013
GetGoal-L: Body Weight Changes at Week 24 Lixisenatide (n=311)
92 91 90 89
-0.5 kg*
88
87 86
-1.8 kg*
85 84 83
Baseline 4
8
12
16
20
LS mean change in body weight (kg)
Mean change in body weight (kg) ± SE
Placebo (n=161)
0 -0.2 -0.4 -0.6 -0.8 -1.0 -1.2 -1.4 -1.6 -1.8 -2.0
-0.5
-1.8
24
Week *LS mean change in body weight at Week 24, LOCF data mITT population (LOCF), on treatment value available
LS mean difference [95%CI] vs placebo= -1.28 kg [-1.803, -0.747]; p<0.0001
Riddle et al., Diabetes Care Publish Ahead of Print, published online April 29, 2013
53
GetGoal-L: Change in Basal Insulin Dose at Week 24
LS mean change in basal insulin dose (U)
0
Placebo (n=165)
Lixisenatide (n=325)
-1 -2
-1.93
-3 LS mean difference [95%CI] vs placebo= -3.69 U [-6.568, -0.815]; p=0.0120
-4 -5 -6
-5.62
mITT population (LOCF), on treatment value available
p=0.01 20 Riddle et al., Diabetes Care Publish Ahead of Print, published online April 29, 2013
54
Terugbetalingsvoorwaarden voor GLP-1 agonisten ( 04-2014) Byetta
Victoza
Lyxumia
Bydureon
Eerste aanvraag HbA1c > 7,5% , min 3 maand basis therapie Metformin + sulfonylurea
x
Metformin + pioglitazone
x
x
x
x
Basale insuline +/perorale
x
Verhogen dosis Als HbA1c > 7,5 na 6 maand Verlenging na 1 jaar als < 7 % of verschil tov voor behandeling ≥ 1 % x
x
x
x
Summary of Key Benefits and Risks of Medications Metformin
DPP-4 Inhibitor
GLP-1 Agonist
Sulfonylurea
Glinide
TZD
Insulin
Benefits PPG - lowering
Mild
Moderate
Moderate to Marked
Moderate
Moderate
Mild
Moderate to Marked
FPG - lowering
Moderate
Mild
Mild
Moderate
Mild
Moderate
Moderate to Marked
Mild
Neutral
Mild
Neutral
Neutral
Moderate
Neutral
Nonalcoholic fatty liver disease (NAFLD)
Risks Hypoglycemia
Neutral
Neutral
Neutral
Moderate
Mild
Neutral
Moderate to Severe
GI Symptoms
Moderate
Neutral
Moderate
Neutral
Neutral
Neutral
Neutral
Risk of use with renal insufficiency
Severe
Reduce Dosage
Moderate
Moderate
Neutral
Mild
Moderate
Contraindicated if liver failure or predisposition to lactic acidosis
Severe
Neutral
Neutral
Moderate
Moderate
Moderate
Neutral
Contraindicted in CHF
???
Neutral
Neutral
Neutral
Mild/ Moderate
Neutral
Heart failure/Edema
Contraindicted in class 1, 4 CHF Weight Gain
Benefit
Neutral
Benefit
Mild
Mild
Moderate
Mild to Moderate
Fractures
Neutral
Neutral
Neutral
Neutral
Neutral
Moderate
Neutral
Drug-Drug Interactions
Neutral
Neutral
Neutral
Moderate
Moderate
Neutral
Neutral
SGLT-2 INHIBITOREN
Targeting the Kidney
Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559.
Changes from Baseline in A1C in Phase 3 Dapagliflozin Studies Placebo
Dapa 2.5mg
Dapa 5mg
Dapa 10mg
Wilding JPH, et al. Abstract 78-OR. ADA 2010; Strojek K, et al. Abstract 870. EASD 2010; Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224; Bailey CJ, et al. Lancet. 2010;375(9733):2223-2233.
Canagliflozin SGLT2 Inhibition for Type 2 Diabetes: Metformin + Canagliflozin Dose-Ranging Study Mean Baseline Weight (kg)
85.5 87.5 87.7 87.7 87.8 86.3 87
* *
* *
*
* Rosenstock J, et al. Abstract 77-OR. ADA 2010.
* *P˂.001 vs. placebo calculated using LS means
Dapagliflozin Add-on to Metformin: 2 Year Extension Study Δ from BL (SE)
Placebo
DAPA 2.5mg
DAPA 5mg
DAPA 10mg
A1c, %
0.2 (0.11)
-0.48 (-.1)
-0.58 (0.1)
-0.78 (0.09)
FPG, mg/dl
-10.4 (3.6)
-19.3 (3.2)
-26.5 (2.8)
-24.5 (2.7)
Body weight, kg
-0.7 (0.5)
-2.2 (0.5)
-3.4 (0.4)
-2.8 (0.4)
3.6
5.1
5.2
% Pts with ≥ 1 5.8 hypoglycemic event •
Events suggestive of urinary tract infection – Dapagliflozin 2.5 mg: 8.0%, 5 mg: 8.8%, 10 mg: 13.3% – Placebo: 8.0%
• Events suggestive of urinary tract infection – Dapagliflozin 2.5 mg: 11.7%, 5 mg: 14.6%, 10 mg: 12.6% – Placebo: 5.1%
•
Events primarily mild or moderate in intensity and responded to standard treatment
Bailey CJ et al. Abstract 988-P. ADA 2011.
Safety SGLT2: Malignancies Bladder cancer incidence rate: 0.16% patients (n=5,478) treated with dapagliflozin vs 0.03% patients (n3,156) in placebo group (p = 0.15)
Breast cancer incidence rate: 0.4% patients (n=2,223) treated with dapagliflozin vs 0.09% patients (n=1,053) in placebo group (p = 0.27)
Jones D. Nat Rev Drug Discov. 2011;10(9):645-646.
Dapagliflozin: Effect on BP and Lipids
Systolic Blood Pressure (mmHg) – Placebo: -0.2 – Dapa 2.5mg: -2.1 – Dapa 5mg: -4.3 – Dapa 10mg: -5.1
HDL (% change) Placebo: +0.4 Dapa 2.5mg: +1.8 Dapa 5mg: +3.3 Dapa 10mg: +4.4
Diastolic Blood Pressure (mmHg) – Placebo: -0.1 – Dapa 2.5mg: -1.8 – Dapa 5mg: -2.5 – Dapa 10mg: -1.8
Triglycerides (% change) Placebo: +2.1 Dapa 2.5mg: -2.4 Dapa 5mg: -6.2 Dapa 10mg: -6.2
Bailey CJ, et al. Lancet. 2010.
SGLT2 Inhibitie Mogelijke voordelen Onafhankelijk van insuline Gewichtsverlies (75g urine glucose = 300kcal/dag) Laag hypoglycemie risico bloeddrukdaling
Mogelijke nadelen Polyurie electrolytenstoornissen urineweginfecties Genitale ( schimmel) infecties Blaas CA
