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

Metformin Insulin

Sulfonylureas Glinides DPP4 inhibitors GLP-1 analogues

SGLT2 inhibitors Insulin

Glitazones Insulin

Liver Kidney

Pancreas Skeletal muscle

2013 2014 2015 2016 2017 2018 2019 2020

DECLARE

Dapagliflozin

NCT01455896

ITCA650

Intarcia

CANVAS

Canagliflozin

REWIND

Dulaglutide

Canagliflozin

FDA/PMR

TAK-875

Takeda

Insulin

degludec

NovoNordisk

EXAMINE

Alogliptin

SAVOR-TIMI

Saxagliptin

TECOS

Saxagliptin

ELIXA

Lixisenatid

EMPAREG

Empagliflozine

Canagliflozin

2nd interim

EXCEL

Exenatide

CARMELINA

Linagliptin

CAROLINA

Interim

Linagliptin

CAROLINA

Linagliptin

Omparigliptin

Merck

SUSTAIN

Semaglutide

FDA requirements

Safety studies Upper

95%

CI for

CV events

<1.3 >1.8 1.3-1.8

Approvable Not approvable Approvable with

safety studies

LEADER

Liraglutide

2013 2014 2015 2016 2017 2018 2019 2020

DECLARE

Dapagliflozin

NCT01455896

ITCA650

Intarcia

CANVAS

Canagliflozin

REWIND

Dulaglutide

Canagliflozin

FDA/PMR

TAK-875

Takeda

Insulin

degludec

NovoNordisk

EXAMINE

Alogliptin

SAVOR-TIMI

Saxagliptin

TECOS

Saxagliptin

ELIXA

Lixisenatid

EMPAREG

Empagliflozine

Canagliflozin

2nd interim

EXCEL

Exenatide

CARMELINA

Linagliptin

CAROLINA

Interim

Linagliptin

CAROLINA

Linagliptin

Omparigliptin

Merck

SUSTAIN

Semaglutide

2013: SAVOR-TIMI HR 1.0 [0.89-1.12]

2013: EXAMINE HR 0.96 [UL ≤1.16]

2015: TECOS HR 0.98 [0,88-1.09]

2015: ELIXA HR 1.02 [0.89-1,17]

FDA requirements, status June 2015

LEADER

Liraglutide

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 2015 2016 2017 2018 2019 2020

DECLARE

Dapagliflozin

NCT01455896

ITCA650

Intarcia

CANVAS

Canagliflozin ?

REWIND

Dulaglutide

Canagliflozin

FDA/PMR

TAK-875

Takeda

Insulin

degludec

NovoNordisk

EXAMINE

Alogliptin

SAVOR-TIMI

Saxagliptin

TECOS

Saxagliptin

ELIXA

Lixisenatid

EMPAREG

Empagliflozine

Canagliflozin

2nd interim

EXCEL

Exenatide

CARMELINA

Linagliptin

CAROLINA

Interim

Linagliptin

CAROLINA

Linagliptin

Omparigliptin

Merck

SUSTAIN

Semaglutide

LEADER

Liraglutide

2013 2014 2015 2016 2017 2018 2019 2020

DECLARE

Dapagliflozin

NCT01455896

ITCA650

Intarcia

CANVAS

Canagliflozin Sulfonylurea

REWIND

Dulaglutide

Canagliflozin

FDA/PMR

TAK-875

Takeda

Insulin

degludec

NovoNordisk

EXAMINE

Alogliptin

SAVOR-TIMI

Saxagliptin

TECOS

Saxagliptin

ELIXA

Lixisenatid

EMPAREG

Empagliflozine

Canagliflozin

2nd interim

EXCEL

Exenatide

CARMELINA

Linagliptin

CAROLINA

Interim

Linagliptin

CAROLINA

Linagliptin

Omparigliptin

Merck

SUSTAIN

Semaglutide

LEADER

Liraglutide

2013 2014 2015 2016 2017 2018 2019 2020

DECLARE

Dapagliflozin

NCT01455896

ITCA650

Intarcia

CANVAS

Canagliflozin Sulfonylurea

REWIND

Dulaglutide

Canagliflozin

FDA/PMR

TAK-875

Takeda

Insulin

degludec

NovoNordisk

EXAMINE

Alogliptin

SAVOR-TIMI

Saxagliptin

TECOS

Saxagliptin

ELIXA

Lixisenatid

EMPAREG

Empagliflozine

Canagliflozin

2nd interim

EXCEL

Exenatide

CARMELINA

Linagliptin

CAROLINA

Interim

Linagliptin

CAROLINA

Linagliptin

Omparigliptin

Merck

SUSTAIN

Semaglutide

LEADER

Liragluide

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

Boussageon R, et al. PLoS Medicine 2012;9: e1001204

Gir ikke hypoglykemi

eller vektøkning.

Døgnpris 1-3 NOK

Total

mortality

CV

mortality

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 mild-

moderate 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

Nissen SE, Ann Intern Med 2012; 157: 671-2

”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.”

Bare konger, redaktører og folk

med bendelorm har rett til å bruke

det redaksjonelle vi *

Mark Twain (1874-1891)

*…og kanskje Helsedirektoratet (?)

Levevaner

SU DPP4i

Metformin

GLP-1 Glitazoner Insulin SGLT2i

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 (%)

Sjøholm Å, et al. 2012

17 12 9 25 22 27 26 26 11

38 27 27 56 40 49 52 50 26

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

Diabetes duration (years)

BMI (kg/m2)

Serum creatinine (mol/l)

*History of peripheral neuropathy (yes vs. no); **per 1 year increase

P=0.03

P=0.01

P<0.0001

P<0.0001

P<0.0001

P<0.03

P<0.0001

Miller ME et al . BMJ 2010;340: b5444

A B C C D

Levevaner

SU* DPP4i

Metformin

GLP-1 Pioglitazon Insulin SGLT2i

Trond Jenssen 24.09.2015

Hvilke medikamenter er «sikre»?

*Avvent resultater fra Carolina-studien