Diabetes and cardiovascular outcome trials. Cees J. Tack, internist

Transcription

1 Diabetes and cardiovascular outcome trials Cees J. Tack, internist

2 Take home messages (2013) Glucoseverlaging: beperkt effect op CV outcomes tijd nodig DPP-4 remmers: veilig, maar niet superieur Onverwachte bijwerking: hartfalen - Mechanisme volledig onduidelijk - Consequentie: wellicht terughoudend zijn bij patienten met hartfalen GLP-1 analogen andere klasse outcomestudies onderweg

3 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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5 Accord trial Patients from North America: > Age 62 years - Diabetes duration ~ 10 years - BMI 32.2 kg/m 2 - HbA 1c 8.1% Comparing - Intensive glucose control: HbA1c<6.% - Standard treatment: HbA1c %

6 Glucose control in ACCORD Treatments in intensive control group Insulin 77% TZD 92% SU 78% Metformin 95% N Engl J Med 2008;358:

7 Glucose control in ACCORD Number of events: Intensive 352 Standard 371 OR 0.90, P=0.16 N Engl J Med 2008;358:

8 Glucose control in ACCORD Number of events: Intensive 257 Standard 203 OR 1.22, P=0.04 N Engl J Med 2008;358:

9 Glucoseverlagende geneesmiddelen

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11 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

12 Effecten van GLP-1

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14 Een nieuwe trend: Cardiovasculaire veiligheid

15 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

16 CVOTs in diabetes EMPA-REG OUTCOME (Empagliflozin, SGLT-2i) n=7000; duration up to 5 years Q RESULTS CANVAS-R (Canagliflozin, SGLT-2i) n=5826; duration ~3 years Q RESULTS DECLARE-TIMI-58 (Dapagliflozin, SGLT-2i) n=17,276; duration ~6 years Completion Q CREDENCE (cardio-renal) (Canagliflozin, SGLT-2i) n=4464; duration ~5.5 years Completion Q ALECARDIO (Aleglitazar, PPAR-αγ ) n=7226; follow-up 2 years Termin. Q RESULTS SUSTAIN 6 (Semaglutide, GLP-1RA) n=3297; duration ~2.8 years Q RESULTS CANVAS (Canagliflozin, SGLT-2i) n=4418; duration 4+ years Q RESULTS PIONEER-6 (Semaglutide, QW GLP-1RA) n=3176; duration ~1.5 years Completion Q EXAMINE (Alogliptin, DPP4i) n=5380; follow-up ~1.5 years Q RESULTS ELIXA (Lixisenatide, GLP-1RA) n=6068; follow-up ~2 years Q RESULTS FREEDOM (ITCA 650, GLP-1RA in DUROS) n=4000; duration ~2 years Q COMPLETED REWIND (Dulaglutide, QW GLP-1RA) n=9622; duration ~6.5 years Completion Q VERTIS CV (Ertugliflozin, SGLT-2i) n=8000; duration ~6.3 years Completion Q SAVOR TIMI-53 (Saxagliptin, DPP-4i) n=16,492; follow-up ~2 years Q RESULTS LEADER (Liraglutide, GLP-1RA) n=9340; duration years Q RESULTS EXSCEL (Exenatide ER, QW GLP-1RA) n=14,752; follow-up ~3 years Q RESULTS HARMONY OUTCOMES (Albiglutide, QW GLP-1RA) n~9400; duration ~4 years Completion Q TECOS (Sitagliptin, DPP-4i) n=14,671; duration ~3 years Q RESULTS DEVOTE (Insulin degludec, insulin) n=7637; duration ~2 years Q RESULTS CARMELINA (Linagliptin, DPP-4i) n=8300*; duration ~4 years Completion Q CAROLINA (Linagliptin, DPP-4i vs SU) n=6072; duration ~8 years Completion Q PPAR-αγ DPP-4i GLP-1RA SGLT-2i Insulin

17 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):

18 Carmelina (linagliptin)

19 DPP-4 remmers Gliptins. Redelijk effectief in glucoseverlaging, geen hypo gewichtsneutraal, weinig bijwerkingen; makkelijke middelen, ook bij nierinsufficiëntie Oraal; combi met andere klassen, alternatief voor SU Long term safety aangetoond geen benefit pancreatitis geen issue meer hartfalen bij saxa? Binnenkort uit patent Inmiddels in NHG standaard

20 Exenatide HisGlyGluGlyThrPheThrSerAsp Leu Ser ArgValAlaGluGluGluMetGln Lys Leu Phe GLP-1RAs EXSCEL FREEDOM-CVO Ile GluTrpLeuLysAspGlyGlyProSerSerGlyAlaProProProSer ~ 50% amino acid homology to human GLP-1 Lixisenatide C-16 Fatty acid Liraglutide His Ala Glu Gly Thr PheThr Ser Asp Val Ser Glu Lys Ala Ala Gln GlyLEADER Glu Leu Tyr Ser Glu Phe Ile Ala Trp Leu Val ArgGly Arg Gly 97% amino acid homology to human GLP-1 Semaglutide Dulaglutide His Gly Glu Gly ThrPheThrSerAspVal Ser Lys Ala Ala GlnGluGluLeuTyrSer Glu Phe Ile Ala TrpLeu Val Lys Gly Gly Gly REWIND Phe Ile Ala TrpLeu Val Lys Gly Gly Gly Glu Lys Ala Ala Gln Glu GluLeuTyr Ser Ser His Gly Glu Gly ThrPheThrSerAspVal 90% amino acid homology to human GLP-1 Albiglutide Linker peptide Modified IgG4 Fc domain His GlyGluGlyThrPheThrSerAsp Leu Ser Arg Val Ala Glu Glu GluMetGln Lys Leu Phe ELIXA Ile GluTrpLeuLysAspGlyGlyProSerSerGlyAlaProProProSerLys Lys ~ 50% amino acid homology to human GLP-1 C-18 Fatty di-acid chain Lys Lys Lys Lys His Aib GluGly ThrPheThrSerAsp Val Ser Ser spacer Lys Ala Ala GlnGly GluLeuTyr SUSTAIN 6 Glu Phe Ile Ala TrpLeu Val Arg GlyArg Gly 94% amino acid homology to human GLP-1 CV benefit CV non-inferiority Not yet reported HisGlyGluGlyThrPheThrSerAspValSerSerTyrLeuGlu GlyGlnAla Ala Lys SerThrPheThrGlyGluGlyHis GlyArgGlyLysVal LeuTrpAla IlePheGlu Asp HARMONY ValSerSerTyrLeuGluGly Gln Ala Ala Lys GluPhe Ile Ala TrpLeu ALBUMIN Outcomes Val Lys Gly Asp Arg 97% amino acid homology to human GLP-1

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28 - Accumulated occurrence of 137 major adverse cardiovascular events, median follow-up f 16 months - Primary endpoint: MACE composite outcome showed a hazard ratio of 0.79 in favour of oral semaglutide compared with placebo (not statistically significant). - The MACE results were driven by a statistically significant reduction in cardiovascular death of 51% (HR 0.49, p=0.03). - Statistically significant reduction in all-cause mortality of 49%

29 Patients with event (%) EMPA-REG OUTCOME Study design and inclusion criteria EMPA 25 mg once daily Placebo EMPA 10 mg once daily Placebo once daily Time to first occurrence of CV death, non-fatal MI, or non-fatal stroke HR: % CI: p=0.04 for superiority Screening Placebo run-in Randomisation (1:1:1) Treatment period Median duration: 2.6 years Median observation time: 3.1 years N=7028 T2DM with established CV disease Age: 18 years; 20 years in Japan; 65 years in India Drug-naïve and HbA 1c 7.0 to 9.0% or stable background antidiabetes therapy* and HbA 1c 7.0 to 10.0% BMI 45.0 kg/m 2 and egfr 30 ml/min/1.73m 2 Primary endpoint Three-point MACE time to first occurrence of: CV death, non-fatal MI, or non-fatal stroke End of treatment Followup +30 days Patients at risk Month Empagliflozin Placebo Empagliflo Placebo

30 Patients with an event (%) No. of patients CANVAS Program: Primary outcome Death from CV causes, non-fatal MI or non-fatal stroke HR: % CI: ( ) p<0.001 for non-inferiority T2DM; HbA 1c %; p=0.02 for superiority 30 years + CVD*; 55 (men) or 50 years + high risk of CVD (n=4,330) Canagliflozin (100 or 300 mg/day) + standard of care Placebo + standard of care Weeks since randomisation Placebo Canagliflozin Placebo Canagliflozin HR and 95% CI were estimated with the use of Cox regression models with stratification according to trial and history of CV disease for all canagliflozin groups combined versus placebo. Analyses are based upon the full integrated data set comprising all participants who underwent randomisation CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction; T2DM, type 2 diabetes mellitus Neal B et al. N Engl J Med 2017;377:

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36 Heerspink H et al. Circulation 2016;134: SGLT-2 inhibitors: Decrease in glomerular hyperfiltration

37 Heerspink H et al. Circulation 2016;134: SGLT-2 inhibitors: Decrease in glomerular hyperfiltration

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39 Stappenplan bloedglucoseverlagende middelen NHG-Standaard Diabetes Mellitus type 2, juni

40 EASD/ADA position statement

41 EASD/ADA position statement

42 Samenvatting Nu twee klassen glucoseverlagende geneesmiddelen met reductie CV eindpunten bij DM 2 met CVD: GLP-1ra sema- > lira- > albi/dulaglutide SGLT-2i empa-, dapa- en canagliflozin Werkingsmechanisme lijkt verschillend: GLP-1ra rechtstreeks effect GLP-1 hoe? SGLT-2i diuretisch effect Vragen: extrapolatie DM2 zonder CVD Positionering - NNT cost/benefit Safety