GLP-1r-agonisten en nieuwe insulines

Cees J. Tack, internist

How do we modify CV risk in T2DM?

Lifestyle modification

Glycaemic control

Platelet inhibition

Blood pressure control

Management of dyslipidaemia

Multifactorial Approach

Meta-analysis: Modest reduction in major cardiovascular events with glycaemia

CI, confidence interval; HbA1c, glycosylated haemoglobin Turnbull et al. Diabetologia 2009;52:2288–2298

• *Difference between more intensive and less intensive groups

• CI, confidence interval; HbA1c, glycosylated haemoglobin

• Turnbull FM et al. Diabetologia 2009;52:2288–2298 Trials

Annual event rate, %

ΔHbA1c

(%) Favours more

intensive

Favours less intensive

More intensive

Less intensive

Major cardiac events1

ACCORD1 2.11 2.29 –1.01

ADVANCE2 2.15 2.28 –0.72

UKPDS3 1.30 1.60 –0.66

VADT4 2.68 2.98 –1.16

Overall number of events, n

1194 1176 –0.88

Hazard ratio (95% CI)

0.5 1.0 2.0

• verlaagt nuchtere glucose 30-50% • verlaagt het HbA1c met 15% • verlaagt systolische bloeddruk met 10 mmHg • verlaagt diastolische bloeddruk met 20 mmHg • gunstige werking op lipiden:

30% daling triglyceriden 10% daling totaal cholesterol 15% daling LDL-cholesterol 8% stijging HDL-cholesterol

Een ideaal anti-diabetes geneesmiddel

Dit geneesmiddel bestaat al!

10 kg afvallen

Jung, BMB 1997

Moraal

• Gewichtsvermindering is een buitengewoon effectieve behandeling van type 2 diabetes en metabool syndroom

MAAR • Huidige dieetinterventies amper effectief • Veel (medicamenteuze) behandelingen

leiden tot verdere toename van gewicht

• Aanvullende therapie vaak nodig

Long-term Trends in Antidiabetes Drug Usage in the U.S.: Real-world Evidence in Patients Newly Diagnosed With Type 2 Diabetes. Montvida O, Shaw J, Atherton JJ, Stringer F, Paul SK. Diabetes Care. 2018 Jan;41(1):69-78.

USA: Initiatie met orale middelen

TZD repa GLP-1ra

OPTIONS

Failing on metformin monotherapy

SU SGLT-2i DPP-4i AG-i

Addition of

insulin

SU=Sulphonylurea derivative DPP-4i=Dipeptidyl peptidase iinhibitro Repa=repagline (meglitinide) GLP-1ra=Glucagon-like Protein receptor agonist AG-i=aminoglucosidase inhibor SGLT-2i=sodium glucose transporter -2 inhibitor TZD=thiazolidine-diones

Diabetes Care 2013; 36: 2254-61.

Diabetes Care 2013; 36:

2254-61.

Direct comparison of SU and DPP-4i

Rosenstock et al. Poster 1103, scientific session of

ADA, San Diego 2011

.

Design of CAROLINA

Montvida O, ea. Diabetes Care. 2018 Jan;41(1):69-78.

USA: behandeling met tweede orale middel

Het

incretine effect

Nauck MA ea. JCEM 1986; 63:492

Nauck MA ea. JCEM 1986; 63:492

Incretine effect

Het incretine effect

Holst JJ. Trends Moll Med 2008;14:161-168.

• Versterkte insulinesecretie wanneer glucose (KH) oraal worden genomen

• Verantwoordelijk voor maximaal 70% van de postprandiale insulinesecretie

• Bijdrage Glucagon-like peptide-1 (GLP-1) ~ glucose-dependent insulinotropic polypeptide (GIP)

• Onduidelijk: - is er daadwerkelijk een defect bij DM2? - Werking – via hormonen zelf of neuronaal - Extra-pancreatische effecten

Incretine effect

Kim W, Egan JM. Pharmacol Rev 2008;60:470-512

After release incretins are rapidly inactivated

Kim W, Egan JM. Pharmacol Rev 2008;60:470-512

Degradation of incretins can be decreased by inhibition of the DPP-4 enzyme

Effecten van GLP-1

Een nieuwe trend:

Cardiovasculaire veiligheid

CV, cardiovascular; HbA1c, glycosylated haemoglobin

Cardiovascular outcomes trials Efficacy vs safety; superiority vs non-inferiority

Efficacy trials Aim: Demonstrate CV benefit

Lower CV risk vs placebo/active comparator

Initiation of treatment vs comparator

Difference between treatment arms e.g. biomarkers such as HbA1c or lipids

Significant reduction in CV outcomes vs active comparator

No treatment adjustment

Safety trials Aim: Demonstrate CV safety

No unacceptable increase in CV risk vs placebo as part of standard care

Initiation of treatment vs placebo

Small/no difference in biomarkers e.g. HbA1c observed between treatment arms

Maintain similar HbA1c

in treatment arms

Non-inferiority vs placebo

Treatment adjustment

(standard of care)

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022

Recent and ongoing CVOTs

SAVOR-TIMI 53 (saxagliptin)

EXAMINE (Alogliptin)

TECOS (Sitagliptin)

CARMELINA (Linagliptin)

CAROLINA (Linagliptin)

FREEDOM CVO (ITCA Q 6 months)

ELIXA (Lixisenatide)

LEADER (Liraglutide)

SUSTAIN 6 (Semaglutide)

EXSCEL (Exenatide QW)

REWIND (Dulaglutide QW)

EMPA-REG OUTCOME (Empagliflozin)

CANVAS-R (Canagliflozin)

CANVAS (Canagliflozin)

DECLARE-TIMI 58 (Dapagliflozin)

CREDENCE (Canagliflozin)

VERTIS CV (Ertugliflozin)

Class of drug of interest being evaluated:

DPP-4i

GLP-1RA

SGLT-2i

Basal insulin

HARMONY outcomes (Albiglutide QW)

DEVOTE (Degludec)

ACS, acute coronary syndrome; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction; T2DM, type 2 diabetes; UA, unstable angina 1. Sciria et al. N Engl J Med 2013;369(14):1317–1326; 2. White et al. N Engl J Med 2013;369(14):1327–1335; 3. Green et al. N Engl J Med 2015;16;373(3):232-242

Alogliptin (6.25, 12.5 or 25 mg/day) + standard of care

T2DM; HbA1c 6.5–11.0%; ACS within 15–90 days (n=5,380)

Placebo + standard of care

Saxagliptin (2.5 or 5 mg/day) + standard of care

Placebo + standard of care

T2DM; HbA1c 6.5–12.0%; ≥40 years + CVD; ≥55 (men) or ≥60 (women) years + CV risk factors (n=16,492)

T2DM; HbA1c 6.5–8.0%; ≥50 years; CVD history (n=14,671)

Sitagliptin (100 or 50 mg/day) + standard of care

Placebo + standard of care

SAVOR-TIMI-531 EXAMINE2

TECOS3

EXAMINE2

CV-related death, non-fatal MI, non-fatal stroke, or unstable angina

requiring hospitalisation

CV death, non-fatal MI or non-fatal ischaemic stroke

CV death, non-fatal MI or non-fatal ischaemic stroke

DPP-4 inhibitors

• Gliptins – beste papieren sitagliptin

• Redelijk effectief in glucoseverlaging, geen hypo

• “gewichtsneutraal” , weinig bijwerkingen; “makkelijke” middelen, ook bij nierinsufficiëntie

• Oraal; combi met andere klassen, alternatief voor SU

• Durable?

• Long term safety aangetoond – no harm / no benefit

• pancreatitis geen issue meer – hartfalen bij saxa?

• Binnenkort uit patent – komt als optie in nieuwe NHG standaard

DPP-4 remmers

Albiglutide

His Gly Thr Thr Ser Phe Glu Gly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln

Lys

Phe Glu Ile Ala Trp Leu Gly Val Gly Arg Lys His Gly Thr Thr Ser Phe Glu Gly

Asp

Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Phe Glu Ile Ala Trp Leu

Asp

Val

Gly Arg

Lys

ALBUMIN

97% amino acid homology to human GLP-1

Dulaglutide

90% amino acid homology to human GLP-1

His Gly Thr Thr Ser Phe Glu Gly Asp Val

Ser

Ser Tyr Leu Glu Glu Ala Ala Gln Lys

Phe

Glu

Ile Ala Trp Leu Gly Val Gly Gly Lys

Linker peptide

Modified IgG4 Fc domain

Phe Ile Ala Trp Leu Gly Val Gly Gly Lys

Glu

Ser Tyr Leu Glu Glu Ala Ala Gln Lys

Ser His Gly Thr Thr Ser Phe Glu Gly Asp Val

97% amino acid homology to human GLP-1

Liraglutide

His Ala Thr Thr Ser Phe Glu Gly Asp Val

Ser

Ser Tyr Leu Glu Gly Ala Ala Gln Lys

Phe

Glu

Ile Ala Trp Leu Gly Val Gly Arg

Glu

Arg

C-16 Fatty acid

Exenatide

His Gly Thr Thr Ser Phe Glu Gly Asp

Leu

Ser

Lys Gln Met Glu Glu Ala Val Glu Arg

Phe

Leu

Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser

~ 50% amino acid homology to human GLP-1

Lixisenatide

His Gly Thr Thr Ser Phe Glu Gly Asp

Leu

Ser

Lys Gln Met Glu Glu Ala Val Glu Arg

Ile Glu Trp Leu Pro Lys Gly Gly Asp Ser Ser Gly Ala Pro Pro Pro Ser Lys

Lys

Lys

Lys Lys Lys

Phe

Leu

~ 50% amino acid homology to human GLP-1

FREEDOM-CVO

ELIXA

LEADER REWIND

HARMONY Outcomes

GLP-1RAs

Semaglutide

94% amino acid homology to human GLP-1

C-18 Fatty di-acid chain

spacer

His Aib Thr Thr Ser Phe Glu Gly Asp Val

Ser

Ser Tyr Leu Glu Gly Ala Ala Gln Lys

Phe

Glu

Ile Ala Trp Leu Gly Val Gly Arg Arg

SUSTAIN 6

CV benefit CV non-inferiority Not yet reported

EXSCEL

CVOTs for exendin-based GLP-1RAs

FREEDOM-CVO: Placebo-controlled cardiovascular outcomes study examining the

safety of ITCA 650 vs placebo

Lixisenatide in acute coronary syndrome, a long-term cardiovascular end point trial of

lixisenatide vs placebo

A trial to evaluate cardiovascular outcomes after treatment with exenatide ER* vs placebo

“FREEDOM-CVO … meets its primary and secondary

endpoints by demonstrating FDA required non-inferiority for pre-

approval CV safety”

CV death, non-fatal MI, or non-fatal stroke or

hospitalisation for unstable angina

CV death, non-fatal MI, or non-fatal stroke or

hospitalisation for unstable angina

HR: 1.02

(95% CI: 0.89 ; 1.17)

HR: 0.91

(95% CI: 0.83 ; 1.00)

p<0.001 for non-inferiority

p=0.06 for superiority

0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4

0

5

1 0

1 5

2 0

CVOTs for human GLP-1RAs

Semaglutide

Placebo

Pati

en

ts w

ith

ev

en

t (%

)

HR: 0.74

(95% CI: 0.58 ; 0.95)

p<0.001 for non-inferiority

p=0.02 for superiority

Pati

en

ts w

ith

ev

en

t (%

)

LEADER

Time to first occurrence of CV death, non-fatal MI, or non-fatal

stroke

Placebo

Liraglutide

HR: 0.87 (95% CI: 0.78 ; 0.97) p<0.001 for non-inferiority p=0.01 for superiority

Time from randomisation (months)

SUSTAIN 6

Time to first occurrence of CV death, non-fatal MI, or non-fatal

stroke

LEADER is a post-approval CVOT with 1302 primary events

SUSTAIN 6 is a pre-approval CVOT with 254 primary events

Time from randomisation (months)

GLP-1 analogen • Effectieve glucoseverlaging, geen hypo • gewichtsverlies • GI bijwerkingen • Outcome trials: CV benefit voor liraglutide (1

dd) en semaglutide (1pw), neutraal voor exenatide, lixisenatide, volgt voor dulaglutide

• Combinatie met insuline goed mogelijk • Durability? • Duur – restricties in vergoeding

En nu de praktijk - wat te kiezen?

Plaatsbepaling • NHG wordt herzien:

- 1e keus na metformine blijft gliclazide - DPP4-remmers prominenter - GLP-1ra’s liberaler - SGLT-2i: restrictief

• Leidraad tweede lijn in de maak - Combinaties met insuline: GLP-1ra, SGLT-2i

• GLP-1ra zeker overwegen indien vergoed, vóór insuline, in combinatie met (basaal) insuline (evt. fixed dose) – liraglutide / semaglutide lijken meest effectief

NIEUWE INSULINES

Nieuwe insulines • Lang(er)werkende insuline-analogen:

- Glargine 300 U/ml - Insuline degludec (100 en 200 U/ml) - Biosimilar glargine – Lilly / MSD / Biogen

(Abasaglar, Lusduna, Semglee) - PEG-Lispro

• Kort(er)werkende insuline-analogen: - Fast-acting insulin aspart - (Ultra-Rapid BioChaperone® Lispro)

Mathieu C, ea. Nat Rev

Endocrinol. 2017; 13:385-399.

Mathieu C, ea. Nat Rev

Endocrinol. 2017; 13:385-399.

Werkingsprofiel basale insulines

Plaatsbepaling • Glargine 300U/mL:

- Voordeel bij hoge dosis – minder volume - Verschillen met glargine 100 U/mL minimaal

• Degludec: - Meest stabiele profiel, langst werkzaam - Voordeel: minder (nachtelijke) hypo’s,

injectiemoment “komt niet zo nauw” - Nadeel: dosisaanpassing per dag minder

makkelijk • Vergoeding momenteel geen probleem –

NB: biosimilar glargine

NIEUWE KORTWERKENDE

INSULINES

Bespreking

•Faster acting Insulin Aspart lijkt iets betere

postprandiale controle te geven bij type 1

•Pompstudies volgen – in theorie ideale

pompinsuline, praktijk lijkt wat tegen te vallen

•Type 2 waarschijnlijk geen voordeel

• In het ziekenhuis: mogelijk voordeel. Kan ook

intraveneus gegeven worden.

•Plaats nu nog niet duidelijk – genoeg voordelen

om alles om te zetten?