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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
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