Post EASD: Blodsukkersenkende medikamenter hvilke er trygge å bruke i dag? Trond Jenssen MD, PhD Oslo Universitetssykehus UIT Norges Arktiske

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1 Post EASD: Blodsukkersenkende medikamenter hvilke er trygge å bruke i dag? Trond Jenssen MD, PhD Oslo Universitetssykehus UIT Norges Arktiske Universitet

2 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

3 «De gode gamle» Sulfonylurea Metformin Insulin Glitazoner (Actos)

4 Targets of hypoglycemic agents Liver Kidney Metformin Insulin SGLT2 inhibitors Insulin Pancreas Skeletal muscle Sulfonylureas Glinides DPP4 inhibitors GLP-1 analogues Glitazones Insulin

5 EXAMINE Alogliptin TECOS Saxagliptin CARMELINA Linagliptin SAVOR-TIMI Saxagliptin CAROLINA Interim Linagliptin Omparigliptin Merck CAROLINA Linagliptin ELIXA Lixisenatid Canagliflozin 2nd interim EXCEL Exenatide Canagliflozin FDA/PMR REWIND Dulaglutide EMPAREG Empagliflozine SUSTAIN Semaglutide CANVAS Canagliflozin Upper 95% CI for CV events FDA requirements Safety studies < >1.8 Approvable Approvable with safety studies LEADER Liraglutide Not approvable NCT ITCA650 Intarcia TAK-875 Takeda DECLARE Dapagliflozin Insulin degludec NovoNordisk

6 EXAMINE Alogliptin TECOS Saxagliptin CARMELINA Linagliptin SAVOR-TIMI Saxagliptin CAROLINA Interim Linagliptin Omparigliptin Merck CAROLINA Linagliptin ELIXA Lixisenatid Canagliflozin 2nd interim EXCEL Exenatide Canagliflozin FDA/PMR REWIND Dulaglutide EMPAREG Empagliflozine SUSTAIN Semaglutide CANVAS Canagliflozin LEADER Liraglutide 2013: SAVOR-TIMI HR 1.0 [ ] 2013: EXAMINE HR 0.96 [UL 1.16] 2015: TECOS HR 0.98 [0, ] 2015: ELIXA HR 1.02 [0.89-1,17] NCT ITCA650 Intarcia TAK-875 Takeda DECLARE Dapagliflozin Insulin degludec NovoNordisk FDA requirements, status June 2015

7 Green JB et al. N Engl J Med 2015;373: TECOS: Glycated Hemoglobin Level.

8 Kaplan Meier Curves for Primary and Secondary Outcomes (Intention-to-Treat Population). Green JB et al. N Engl J Med 2015;373:

9 EXAMINE Alogliptin TECOS Saxagliptin CARMELINA Linagliptin SAVOR-TIMI Saxagliptin CAROLINA Interim Linagliptin Omparigliptin Merck CAROLINA Linagliptin ELIXA Lixisenatid Canagliflozin 2nd interim EXCEL Exenatide Canagliflozin FDA/PMR REWIND Dulaglutide EMPAREG Empagliflozine SUSTAIN Semaglutide? CANVAS Canagliflozin LEADER Liraglutide NCT ITCA650 Intarcia TAK-875 Takeda DECLARE Dapagliflozin Insulin degludec NovoNordisk

10 EXAMINE Alogliptin TECOS Saxagliptin CARMELINA Linagliptin SAVOR-TIMI Saxagliptin CAROLINA Interim Linagliptin Omparigliptin Merck CAROLINA Linagliptin ELIXA Lixisenatid Canagliflozin 2nd interim EXCEL Exenatide Canagliflozin FDA/PMR REWIND Dulaglutide EMPAREG Empagliflozine SUSTAIN Semaglutide Sulfonylurea CANVAS Canagliflozin LEADER Liraglutide NCT ITCA650 Intarcia TAK-875 Takeda DECLARE Dapagliflozin Insulin degludec NovoNordisk

11 EXAMINE Alogliptin TECOS Saxagliptin CARMELINA Linagliptin SAVOR-TIMI Saxagliptin CAROLINA Interim Linagliptin Omparigliptin Merck CAROLINA Linagliptin ELIXA Lixisenatid Canagliflozin 2nd interim EXCEL Exenatide Canagliflozin FDA/PMR REWIND Dulaglutide EMPAREG Empagliflozine SUSTAIN Semaglutide Sulfonylurea CANVAS Canagliflozin LEADER Liragluide NCT ITCA650 Intarcia TAK-875 Takeda DECLARE Dapagliflozin Insulin degludec NovoNordisk

12 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

13 PLoS Medicine 2012;9: e

14 Total mortality Gir ikke hypoglykemi eller vektøkning. Døgnpris 1-3 NOK CV mortality Boussageon R, et al. PLoS Medicine 2012;9: e

15 Diabetes Care 2008;31:1672-8

16 Rao et al., Diabetes Care 2008;31:1672-8

17 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 patients, 26 observational studies with 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)

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19 Roumie L, et al. Ann Intern Med 2012; 157:

20 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

21 Bare konger, redaktører og folk med bendelorm har rett til å bruke det redaksjonelle vi * Mark Twain ( ) * og kanskje Helsedirektoratet (?)

22 Levevaner Metformin SU DPP4i GLP-1 Glitazoner SGLT2i Insulin Trond Jenssen

23 Adverse Clinical Outcomes among Patients with Severe Hypoglycemia Zoungas S et al. N Engl J Med 2010;363:

24 Å leve med type 2-diabetes n=2725 Andel påvirket av hypoglykemi i daglige aktiviteter (%) Sjøholm Å, et al. 2012

25 46 studier, n= Hypoglykemi hos 51% (6% alvorlig hypoglykemi) 20 pr. pasientår med insulin 2 pr. pasientår med tabletter

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28 The Risk of Severe Hypoglycaemia: Post-hoc Epidemiological Analysis of the ACCORD Study C D B C P< A P=0.01 P=0.03 P<0.03 P< P< P< Diabetes duration (years) BMI (kg/m 2 ) Serum creatinine ( mol/l) *History of peripheral neuropathy (yes vs. no); **per 1 year increase Miller ME et al. BMJ 2010;340: b5444

29 Hvilke medikamenter er «sikre»? Levevaner Metformin SU* DPP4i GLP-1 Pioglitazon SGLT2i Insulin Trond Jenssen *Avvent resultater fra Carolina-studien

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