ADA EASD 2017 Jarl Hellman, Överläkare
INNEHÅLL EXSCEL (GLP-1 Agonist nummer 4) TOSCA-IT (Pioglitazon vs SU) CANVAS (SGLT2 nummer 2) SAMMANFATTNING (ACE) (DEVOTE) (FOURIER) (TANDEM) (JDOIT3) (Insulin 338)
Rury Holman, UK EXSCEL Primary Results Presentation EASD Lisbon, Portugal Thursday 14 th September, 2017 Exena2de, Bydureon
EXSCEL: Study Design ~14,000 Patients EXENATIDE ONCE WEEKLY PLACEBO ONCE WEEKLY Safety Follow-up (70-days) Randomisation (double blind) 1w 2m 6m 1y Visits every 6 months End of Treatment Minimum 1360 primary events Aim is for glycaemic equipoise Key Inclusion Criteria T2DM, HbA1c 6.5-10% (inclusive) Anti-DM drug naïve, oral agents and/or insulin 18 years old Any level of CV risk ~70% with prior CV event Prior coronary, cerebrovascular or peripheral vascular event or stenosis Key Exclusion Criteria T1DM 2 episodes of severe hypoglycaemia within 12 months Current or prior GLP1-RA egfr <30mL/min/1.73m 2 Prior pancreatitis Personal or familial history of MEN-2 Baseline calcitonin >40ng/L
Recruitment North America n=3708 (25%) 190 sites Europe n=6788 (46%) 329 sites Latin America n=2727 (18%) 64 sites Asia Pacific n=1529 (10%) 104 sites Total Randomised = 14752 Mentz RJ, et al. Am Heart J, 2017; 187: 1-9
Baseline characteristics 14.752 patienter under 3.2 år Ålder: 62 år (38% kvinnor) Hba1c: 64 mmol/mol (8%) Diabetes: 12 år BMI:32 73% CV sjukdom (16% hjärtsvikt) LEADER:3,8 år 9340 patienter Ålder 64 år Diabetes 13 år HbA1c 8.7% (72 mmol/mol) 81 % CV sjukdom 14% hjärtsvikt Liraglutide (Victoza) SUSTAIN 6:2år 3297 patienter Ålder: 64 år Diabetes 14 år HbA1c: 8.7% (72 mmol/mol) 83% CV sjukdom 23% hjärtsvikt Semaglutide (ej godk ännu) ELIXA (4P-MACE):2år 6066 patienter Ålder: 60 Diabetes: 9 år HbA1c:7.7% (61 mmol/mol) 100% CV sjukdom (AKS 180 dygn) 22% Hjärtsvikt Lixisenatide (Lyxumia)
Baseline Antihyperglycaemic Medication Usage 90 80 5618 5677 70 Proportion (%) 60 50 40 2697 2704 3397 3439 30 20 1118 1085 10 0 292 287 49 28 Metformin Sulfonylureas Thiazolidinediones DPP-4i SGLT-2i* Insulin Exenatide Placebo Includes medications taken alone or in combination. Percentages presented are for available data. * Information regarding SGLT-2 inhibitor usage was added to the ecrf on 9th May, 2013. Percentages presented are for ITT population.
Participant Follow-Up Study Duration Median (IQR), years Premature Study Medication Discontinuation* n (%) Study Treatment Duration Median (IQR), years Proportion of Time on Study Medication Mean (SD), % Exenatide n=7356 Placebo n=7396 3.3 (2.3, 4.4) 3.2 (2.2, 4.3) 3164 (43.0) 3343 (45.2) 2.4 (1.4, 3.8) 2.3 (1.2, 3.6) 76.0 (35.3) 75.0 (35.1) * Site-reported premature permanent discontinuation of study medication
Between Group HbA1c Differences Over Time -5,8 mmol/mol (0,53%) LEADER: HbA1c -0.4% SUSTAIN 6: -0.7%/-1.0% ELIXA: -0.3% Overall least squares mean difference was estimated from the model including only patients with baseline and at least one post-baseline measure
Between Group Body Weight Differences Over Time Vikt: -1,27kg LEADER: -2.3kg SUSTAIN 6: -2.9/4.3kg ELIXA: -0.7kg Overall least squares mean difference was estimated from the model including only patients with baseline and at least one post-baseline measure
Primary Composite Cardiovascular Outcome Intention-to-Treat Analysis for Non-inferiority & Superiority HR (95% CI) 0.91 (0.83, 1.00) P value (non-inferiority) <.001 P value (superiority) 0.061 3P MACE: Kardiovaskulär död, stroke eller hjär2nfarkt
Primary Composite Cardiovascular Outcome Intention-to-Treat Analysis Exenatide N=7356 Placebo N=7396 Hazard Ratio 95% CI P value MACE 839 (11.4%) 3.7 per 100 pt-yrs 905 (12.2%) 4.0 per 100 pt-yrs 0.91 0.83, 1.00 <.001 (non-inferiority) 0.061 (superiority) CV-death 229 (3.1%) 258 (3.5%) 0.88 0.73, 1.05 Non-fatal MI 455 (6.2%) 470 (6.4%) 0.95 0.84, 1.09 0.628 (homogeneity among components) Non-fatal stroke 155 (2.1%) 177 (2.4%) 0.86 0.70, 1.07 0 0,5 1 1,5 2 Exenatide favoured Placebo favoured
Forest Plot of Secondary Endpoints (Intention-to-Treat Analysis) Exenatide N=7356 Placebo N=7396 Hazard Ratio 95% CI P value All-cause mortality 507 (6.9%) 584 (7.9%) 0.86 0.77, 0.97 0.016 CV-death 340 (4.6%) 383 (5.2%) 0.88 0.76, 1.02 0.096 Fatal or non-fatal MI 483 (6.6%) 493 (6.7%) 0.97 0.85, 1.10 0.622 Fatal or non-fatal stroke 187 (2.5%) 218 (2.9%) 0.85 0.70, 1.03 0.095 Hospitalisation for ACS 602 (8.2%) 570 (7.7%) 1.05 0.94, 1.18 0.402 Hospitalisation for heart failure 219 (3.0%) 231 (3.1%) 0.94 0.78, 1.13 0.485 0 0,5 1 1,5 2 HIERARKISK TESTNING Exenatide favoured Placebo favoured
Sammanfattning EXSCEL Exenatide (Bydureon ) en gång per vecka vs placebo Primär endpoint neutral= kardiovaskulär säkerhet (3år) Superiority dock ej visad, p= 0,061 Stort bortfall (>40%) i båda armar 5 mmol/mol lägre HbA1c och 1,3kg lättare Inga nya signaler biverkningar, ingen ökad retinopati
Stefano Del Prato T2D minst 2år, ålder 50-75 år, MeEormin minst 2g och HbA1c 7-9%, ingen känd hjärtsvikt! xx 16
Italien men.. Mr UKPDS AGAIN xx 17
FAILURE OF TREATMENT: HbA1c >= 8.0% 64 mmol/mol (x2) Rescue insulinbehandling.. xx 18
Baseline characteris-cs 3028 pa2enter under 5 år (bröts för2d) Ålder: 62 år (60% män) Hba1c: 60 mmol/mol (7.7%) Diabetes: 8,5 år BMI:30 ENDAST 11% känd CV sjukdom
55 vs 56 mmol/mol xx 20
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Sammanfa2ning TOSCA-IT Pa2enter (62 år) med mebormin och låg kardiovaskulär sjuklighet (11%) och ed HbA1c på 60 mmol/mol, 5 års data Ingen säker skillnad Kardiovaskulär sjuklighet/död Lägre hyporisk med pioglitazon vs SU Fler med pioglitazon avbröt och ej mer hjärtsvikt (?) Ingen skillnad blåscancer (5 år) xx 26
SGLT2- hämmare Canagliflozin, Invokana DAVID MATTHEWS U.K håller hov
10.142 patienter under 3,5 år INKLUSION: >30 år med CVD eller >50 år minst 2 riskfakt CVD. HbA1c 7-10.5%. GFR>30
Baseline characteristics 10.142 patienter under 3,5 år Ålder: 63 år (64% män) Hba1c: 66 mmol/mol (8.2%) Diabetes: 14 år BMI: 32 2/3 känd CV sjukdom 18% hjärtsvikt EMPA REG -7034 pat 3,1 år Medelålder: 63 år HbA1c 65 mmol/mol (8.1%) Diabetes: 60% >10 år (80%>5år) BMI 31 100% CV sjukdom 10% Hjärtsvikt
-6,3mmol/mol EMPA REG: 0,42% diff HbA1c
EMPA REG: Diff 3,8 mm Hg
EMPA-REG: Diff 2kg
Hierarkisk testning
NNT 43 på 3,5 år EMPA REG: HR 0.86; 95% CI 0.74-0.99; p=0.04; NNT 62 på 3år
EMPA REG: All-cause mortality 5.7% vs. 8.3% (HR 0.68; 95% CI 0.57-0.82; P<0.001; NNT 38
(18% hjärtsvikt vid baseline) EMPA REG: HR 0.65 (95% CI 0.5-0.85), P=0.002 10% hjärtsvikt baseline
EMPA REG: HR 0.61 (CI 0.53-0.70) för ny albuminuri eller progression albuminuri
NNH 225
Sammanfattning CANVAS 3,6 år med canagliflozin vs placebo (3,1 år EMPA REG) Positiva effekter Kardiovaskulärt Låg risk DKA, tolereras väl (70% kvar på läkemedel) Ingen skillnad subgrupper utom betablockad/diuretika Orosmoment amputation? (fraktur?)
SAMMANFATTNING EXSCEL (2-2) GLP-1 agonist EXENATIDE- neutralt utfall (lixisenatide neutralt, liraglutide och semaglutide positiva kardiovaskulära studier) TOSCA-IT Pioglitazon versus SU- neutralt utfall, båda lika säkra kardiovaskulärt.. CANVAS (2-0) Canagliflozin positiv studie likt empagliflozin= klasseffekt (?) Olika biverkningsmönster SGLT2 gällande amputation, skelett?