GLP-1r-agonisten en nieuwe insulines. Cees J. Tack, internist

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1 GLP-1r-agonisten en nieuwe insulines Cees J. Tack, internist

2 How do we modify CV risk in T2DM? Glycaemic control Lifestyle modification Multifactorial Approach Platelet inhibition Management of dyslipidaemia Blood pressure control

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4 Meta-analysis: Modest reduction in major cardiovascular events with glycaemia *Difference between more intensive and less intensive groups CI, confidence interval; HbA1c, glycosylated haemoglobin Trials Annual event rate, % More intensive Less intensive ΔHbA 1c (%) Turnbull FM et al. Diabetologia 2009;52: Favours more intensive Favours less intensive Major cardiac events 1 ACCORD ADVANCE UKPDS VADT Overall number of events, n Hazard ratio (95% CI) CI, confidence interval; HbA 1c, glycosylated haemoglobin Turnbull et al. Diabetologia 2009;52:

5 Een ideaal anti-diabetes geneesmiddel 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

6 Dit geneesmiddel bestaat al! 10 kg afvallen Jung, BMB 1997

7 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

8 USA: Initiatie met orale middelen 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 Jan;41(1):69-78.

9 OPTIONS Failing on metformin monotherapy Addition of SU repa AG-i TZD DPP-4i GLP-1ra SGLT-2i insulin SU=Sulphonylurea derivative Repa=repagline (meglitinide) AG-i=aminoglucosidase inhibor TZD=thiazolidine-diones DPP-4i=Dipeptidyl peptidase iinhibitro GLP-1ra=Glucagon-like Protein receptor agonist SGLT-2i=sodium glucose transporter -2 inhibitor

10 Diabetes Care 2013; 36:

11 Diabetes Care 2013; 36:

12 Direct comparison of SU and DPP-4i

13 Design of CAROLINA Rosenstock et al. Poster 1103, scientific session of ADA, San Diego 2011.

14 USA: behandeling met tweede orale middel Montvida O, ea. Diabetes Care Jan;41(1):69-78.

15 Het incretine effect

16 Nauck MA ea. JCEM 1986; 63:492

17 Nauck MA ea. JCEM 1986; 63:492 Incretine effect

18 Het incretine effect Holst JJ. Trends Moll Med 2008;14:

19 Incretine effect Versterkte insulinesecretie wanneer glucose (KH) oraal worden genomen Verantwoordelijk voor maximaal 70% van de postprandiale insulinesecretie Bijdrage Glucagon-like peptide-1 (GLP-1) ~ glucosedependent insulinotropic polypeptide (GIP) Onduidelijk: - is er daadwerkelijk een defect bij DM2? - Werking via hormonen zelf of neuronaal - Extra-pancreatische effecten

20 After release incretins are rapidly inactivated Kim W, Egan JM. Pharmacol Rev 2008;60:

21 Degradation of incretins can be decreased by inhibition of the DPP-4 enzyme Kim W, Egan JM. Pharmacol Rev 2008;60:

22 Effecten van GLP-1

23 Een nieuwe trend: Cardiovasculaire veiligheid

24 Cardiovascular outcomes trials Efficacy vs safety; superiority vs non-inferiority Efficacy trials Aim: Demonstrate CV benefit Initiation of treatment vs comparator Safety trials Aim: Demonstrate CV safety Initiation of treatment vs placebo No treatment adjustment Maintain similar HbA 1c in treatment arms Treatment adjustment (standard of care) Difference between treatment arms e.g. biomarkers such as HbA 1c or lipids Small/no difference in biomarkers e.g. HbA 1c observed between treatment arms Significant reduction in CV outcomes vs active comparator Lower CV risk vs placebo/active comparator Non-inferiority vs placebo No unacceptable increase in CV risk vs placebo as part of standard care CV, cardiovascular; HbA 1c, glycosylated haemoglobin

25 Recent and ongoing CVOTs SAVOR-TIMI 53 (saxagliptin) Class of drug of interest being evaluated: EXAMINE (Alogliptin) ELIXA (Lixisenatide) TECOS (Sitagliptin) EMPA-REG OUTCOME (Empagliflozin) LEADER (Liraglutide) FREEDOM CVO (ITCA Q 6 months) DPP-4i GLP-1RA SGLT-2i Basal insulin SUSTAIN 6 (Semaglutide) CANVAS-R (Canagliflozin) CARMELINA (Linagliptin) EXSCEL (Exenatide QW) CANVAS (Canagliflozin) CAROLINA (Linagliptin) DEVOTE (Degludec) REWIND (Dulaglutide QW) DECLARE-TIMI 58 (Dapagliflozin) CREDENCE (Canagliflozin) VERTIS CV (Ertugliflozin) HARMONY outcomes (Albiglutide QW)

26 SAVOR-TIMI-53 1 EXAMINE 2 CV death, non-fatal MI or non-fatal ischaemic stroke CV death, non-fatal MI or non-fatal ischaemic stroke T2DM; HbA 1c %; 40 years + CVD; 55 (men) or 60 (women) years + CV risk factors (n=16,492) Saxagliptin (2.5 or 5 mg/day) + standard of care Placebo + standard of care T2DM; HbA 1c %; ACS within days (n=5,380) Alogliptin (6.25, 12.5 or 25 mg/day) + standard of care Placebo + standard of care TECOS 3 T2DM; HbA 1c %; 50 years; CVD history (n=14,671) CV-related death, non-fatal MI, non-fatal stroke, or unstable angina requiring hospitalisation Sitagliptin (100 or 50 mg/day) + standard of care Placebo + standard of care DPP-4 inhibitors 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): ; 2. White et al. N Engl J Med 2013;369(14): ; 3. Green et al. N Engl J Med 2015;16;373(3):

27 DPP-4 remmers 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

28 Exenatide His Gly Glu Gly Thr Phe Thr Ser Asp Leu Phe GLP-1RAs EXSCEL Leu Ser Lys Arg Val Ala Glu Glu Glu Met Gln FREEDOM- CVO Ile Glu Trp Leu Lys Asp Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser ~ 50% amino acid homology to human GLP-1 C-16 Fatty acid Liraglutide His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Glu Lys Ala Ala Gln Gly Glu Leu Tyr Ser LEADER Glu Phe Ile Ala Trp Leu Val Arg Gly Arg Gly 97% amino acid homology to human GLP-1 Dulaglutide His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Lys Ala Ala Gln Glu Glu Leu Tyr Ser Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly REWIND Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Glu Lys Ala Ala Gln Glu Glu Leu Tyr Ser Ser His Gly Glu Gly Thr Phe Thr Ser Asp Val Linker peptide 90% amino acid homology to human GLP-1 Modified IgG4 Fc domain Lixisenatide Semaglutide Albiglutide His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Arg Val Ala Glu Glu Glu Met Gln Leu Phe ELIXA Ile Glu Trp Leu Lys Asp Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Lys Lys ~ 50% amino acid homology to human GLP-1 C-18 Fatty di-acid chain Lys Lys Lys Lys spacer His Aib Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Ala Gly Glu Leu Tyr Lys Ala Gln Glu SUSTAIN 6 Phe Ile Ala Trp Leu Val Arg Gly Arg Gly 94% amino acid homology to human GLP-1 CV benefit CV non-inferiority Not yet reported His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Ser Thr Phe Thr Gly Glu Gly His Gly Arg Gly Lys Val Leu Trp Ala Ile Phe Glu Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu ALBUMIN HARMONY Outcomes Val Lys Gly Asp Arg 97% amino acid homology to human GLP-1

29 CVOTs for exendin-based GLP-1RAs Lixisenatide in acute coronary syndrome, a long-term cardiovascular end point trial of lixisenatide vs placebo FREEDOM-CVO: Placebo-controlled cardiovascular outcomes study examining the safety of ITCA 650 vs placebo A trial to evaluate cardiovascular outcomes after treatment with exenatide ER* vs placebo CV death, non-fatal MI, or non-fatal stroke or hospitalisation for unstable angina HR: 1.02 (95% CI: 0.89 ; 1.17) CV death, non-fatal MI, or non-fatal stroke or hospitalisation for unstable angina HR: 0.91 (95% CI: 0.83 ; 1.00) p<0.001 for non-inferiority p=0.06 for superiority FREEDOM-CVO meets its primary and secondary endpoints by demonstrating FDA required non-inferiority for preapproval CV safety

30 Patients with event (%) Patients with event (%) CVOTs for human GLP-1RAs LEADER SUSTAIN 6 Time to first occurrence of CV death, non-fatal MI, or non-fatal stroke Time to first occurrence of CV death, non-fatal MI, or non-fatal stroke HR: 0.87 (95% CI: 0.78 ; 0.97) p<0.001 for non-inferiority p=0.01 for superiority Placebo HR: 0.74 (95% CI: 0.58 ; 0.95) p<0.001 for non-inferiority p=0.02 for superiority 1 0 Liraglutide Placebo 5 Semaglutide Time from randomisation (months) Time from randomisation (months) LEADER is a post-approval CVOT with 1302 primary events SUSTAIN 6 is a pre-approval CVOT with 254 primary events

31 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

32 En nu de praktijk - wat te kiezen?

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37 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

38 NIEUWE INSULINES

39 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)

40 Mathieu C, ea. Nat Rev Endocrinol. 2017; 13:

41 Werkingsprofiel basale insulines Mathieu C, ea. Nat Rev Endocrinol. 2017; 13:

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45 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

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47 NIEUWE KORTWERKENDE INSULINES

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53 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?

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