Post EASD: Blodsukkersenkende medikamenter – hvilke er trygge å bruke i dag?
Trond Jenssen MD, PhD
Oslo Universitetssykehus
UIT – Norges Arktiske Universitet
Interessekonflikter
• Har mottatt foredragshonorar fra Eli Lilly, Boehringer
Ingelheim, NovoNordisk, MSD, Sanofi, Shire.
• Mottar lønn fra Oslo Universitetssykehus
• Passes på av HELFO iht til reguleringer fra Statens
legemiddelverk
• Mottar lønn fra Diabetesforbundet
«De gode gamle»
• Sulfonylurea
• Metformin
• Insulin
• Glitazoner
(Actos)
Targets of hypoglycemic agents
Liver
Kidney
Metformin
Insulin
SGLT2 inhibitors
Insulin
Pancreas
Skeletal muscle
Sulfonylureas
Glinides
DPP4 inhibitors
GLP-1 analogues
Glitazones
Insulin
2013
2014
EXAMINE
Alogliptin
2015
2016
2017
2018
2020
CARMELINA
Linagliptin
TECOS
Saxagliptin
CAROLINA
Interim
Linagliptin
SAVOR-TIMI
Saxagliptin
ELIXA
Lixisenatid
2019
Canagliflozin
2nd interim
EMPAREG
Empagliflozine
Omparigliptin
Merck
EXCEL
Exenatide
SUSTAIN
Semaglutide
LEADER
Liraglutide
CAROLINA
Linagliptin
Canagliflozin
FDA/PMR
REWIND
Dulaglutide
CANVAS
Canagliflozin
NCT01455896
ITCA650
Intarcia
DECLARE
Dapagliflozin
TAK-875
Takeda
FDA requirements
Safety studies
Upper
95%
CI for
CV events
<1.3
1.3-1.8
Approvable Approvable with
safety studies
Insulin
degludec
NovoNordisk
>1.8
Not approvable
2013
2014
EXAMINE
Alogliptin
2015
2016
2017
CAROLINA
Interim
Linagliptin
SAVOR-TIMI
Saxagliptin
Canagliflozin
2nd interim
EMPAREG
Empagliflozine
SUSTAIN
Semaglutide
LEADER
Liraglutide
2013: SAVOR-TIMI
2013: EXAMINE
2015: TECOS
2015: ELIXA
2019
2020
CARMELINA
Linagliptin
TECOS
Saxagliptin
ELIXA
Lixisenatid
2018
HR 1.0 [0.89-1.12]
HR 0.96 [UL ≤1.16]
HR 0.98 [0,88-1.09]
HR 1.02 [0.89-1,17]
FDA requirements, status June 2015
Omparigliptin
Merck
EXCEL
Exenatide
CAROLINA
Linagliptin
Canagliflozin
FDA/PMR
REWIND
Dulaglutide
CANVAS
Canagliflozin
NCT01455896
ITCA650
Intarcia
DECLARE
Dapagliflozin
TAK-875
Takeda
Insulin
degludec
NovoNordisk
TECOS: Glycated Hemoglobin Level.
Green JB et al. N Engl J Med 2015;373:232-242
Kaplan–Meier Curves for Primary and Secondary Outcomes (Intention-to-Treat Population).
Green JB et al. N Engl J Med 2015;373:232-242
2013
2014
EXAMINE
Alogliptin
2015
2016
2017
2019
2020
CARMELINA
Linagliptin
TECOS
Saxagliptin
CAROLINA
Interim
Linagliptin
SAVOR-TIMI
Saxagliptin
ELIXA
Lixisenatid
2018
Canagliflozin
2nd interim
EMPAREG
Empagliflozine
SUSTAIN
Semaglutide
LEADER
Liraglutide
Omparigliptin
Merck
EXCEL
Exenatide
CAROLINA
Linagliptin
Canagliflozin
FDA/PMR
?
REWIND
Dulaglutide
CANVAS
Canagliflozin
NCT01455896
ITCA650
Intarcia
DECLARE
Dapagliflozin
TAK-875
Takeda
Insulin
degludec
NovoNordisk
2013
2014
EXAMINE
Alogliptin
2015
2016
2017
2019
2020
CARMELINA
Linagliptin
TECOS
Saxagliptin
CAROLINA
Interim
Linagliptin
SAVOR-TIMI
Saxagliptin
ELIXA
Lixisenatid
2018
Canagliflozin
2nd interim
EMPAREG
Empagliflozine
SUSTAIN
Semaglutide
LEADER
Liraglutide
Omparigliptin
Merck
EXCEL
Exenatide
CAROLINA
Linagliptin
Canagliflozin
FDA/PMR
Sulfonylurea
REWIND
Dulaglutide
CANVAS
Canagliflozin
NCT01455896
ITCA650
Intarcia
DECLARE
Dapagliflozin
TAK-875
Takeda
Insulin
degludec
NovoNordisk
2013
2014
EXAMINE
Alogliptin
2015
2016
2017
2019
2020
CARMELINA
Linagliptin
TECOS
Saxagliptin
CAROLINA
Interim
Linagliptin
SAVOR-TIMI
Saxagliptin
ELIXA
Lixisenatid
2018
Canagliflozin
2nd interim
EMPAREG
Empagliflozine
SUSTAIN
Semaglutide
LEADER
Liragluide
Omparigliptin
Merck
EXCEL
Exenatide
CAROLINA
Linagliptin
Canagliflozin
FDA/PMR
Sulfonylurea
REWIND
Dulaglutide
CANVAS
Canagliflozin
NCT01455896
ITCA650
Intarcia
DECLARE
Dapagliflozin
TAK-875
Takeda
Insulin
degludec
NovoNordisk
Le médaille d’or
Metformin
•Mekanisme uavhengig av beta-cellen
•Gir ikke hypoglykemi i monoterapi
•UKPDS 34 (Lancet 1998;352:854-65)
– Overvektige personer med T2DM
– n=342 vs. 951 personer med SU/ insulin
– Sekundæranalyse: CV
– ACEi eller statiner var ikke brukt
PLoS Medicine 2012;9: e1001204
Total
mortality
Gir ikke hypoglykemi
eller vektøkning.
Døgnpris 1-3 NOK
CV
mortality
Boussageon R, et al. PLoS Medicine 2012;9: e1001204
Diabetes Care 2008;31:1672-8
Rao et al., Diabetes Care 2008;31:1672-8
EASD 2015
•
•
•
•
Nunes AP, et al. USA. Interim results on the relationship between mildmoderate and severe hyperglycaemia and cardiovascular disease in a cohort of
sulfonylurea users (n=82.321)
Baxter CA, et al. Canada. Increased risk of cardiovascular-related events
associated with sulfonylureas compared toother antihyperglycemic drugs: a
Bayesian meta-analysis of survival data (91 RCTs with 36.573 patients, 26
observational studies with 1.553.856 patients)
Eriksson JW, et al. Sweden. Second-line treatment with sulfonylurea compared
to DPP4 inhibitors is associated with risk of cardiovascular disease, all cause
mortality and severe hypoglycaemia (n=68.351)
Berg B, et al. Germany. Treatment characteristics and outcomes associated
with sulphonylurea versus metformin therapy in incident type 2 diabetes
mellitus patients, results of the German CREST study (n=35.661)
Roumie L, et al. Ann Intern Med 2012; 157: 601-10
”How might sulfonylureas increase adverse CV outcomes?.......
Regardless of mechanisms, this scientific question demands
a definite answer. In the asbsence of an industry-sponsored
study, public health authorities should conduct such a clinical
trial. With more than two thirds of diabetic patients dying of
CV causes and millions of patients currently receiving
sulfonylureas, this question must be resolved with high-quality
evidence. Continued darkness is not an acceptable option.”
Nissen SE, Ann Intern Med 2012; 157: 671-2
Bare konger, redaktører og folk
med bendelorm har rett til å bruke
det redaksjonelle vi *
Mark Twain (1874-1891)
*…og kanskje Helsedirektoratet (?)
Levevaner
Metformin
SU
DPP4i
GLP-1
Glitazoner SGLT2i
Insulin
Trond Jenssen 24.09.2015
Adverse Clinical Outcomes among Patients with Severe Hypoglycemia
Zoungas S et al. N Engl J Med 2010;363:1410-1418
Å leve med type 2-diabetes
n=2725
Andel påvirket av hypoglykemi i daglige aktiviteter (%)
38
17
27
12
27
9
56
25
40
22
49
27
52
26
50
26
26
11
Sjøholm Å, et al. 2012
46 studier, n=532.432
Hypoglykemi hos 51%
(6% alvorlig hypoglykemi)
20 pr. pasientår med insulin
2 pr. pasientår med tabletter
The Risk of Severe Hypoglycaemia: Post-hoc
Epidemiological Analysis of the ACCORD Study
C
D
B
C
P<0.0001
A
P=0.01
P<0.03
P=0.03
P<0.0001
P<0.0001
P<0.0001
Diabetes duration
BMI
Serum creatinine
(years)
(kg/m2)
(mol/l)
*History of peripheral neuropathy (yes vs. no); **per 1 year increase
Miller ME et al . BMJ 2010;340: b5444
Hvilke medikamenter er «sikre»?
Levevaner
Metformin
SU*
DPP4i
GLP-1 Pioglitazon SGLT2i
Insulin
Trond Jenssen 24.09.2015
*Avvent resultater fra Carolina-studien