Tidig intervention vid typ-2 diabetes nya insikter från ADA och EASD 2015 en personlig reflektion

Transkript

1 Tidig intervention vid typ-2 diabetes nya insikter från ADA och EASD 2015 en personlig reflektion Magnus Löndahl överläkare Endokrinologen Skånes Universitetssjukhus

2 En bild fr

3 Hur bör vi använda behandlingsriktlinjer?

4 Hur bör vi använda behandlingsriktlinjer?

5 Hur bör vi använda behandlingsriktlinjer?

6 INSULINER(minst 13 olika läkemedel tillgängliga, imorgon är det fler.) Blod-glukos sänkande läkemedel Totalt ca 20 olika läkemedel, exkl insuliner, tillgängliga idag, imorgon är det fler..

7

8 Studiedesign Nationell studie baserad på läkemedelsregistret, patientregistret och dödsregistret Patienter på metformin som adderas andra linjens behandling SU vs DDP-4 hämmare

9 Patient flöde

10 Vad bör vi använda som andra linjens per orala läkemedel?

11 Mortalitet

12 Resultat

13 Vad behandlar vi?

14 Vad behandlar vi

15

16

17

18 Trippel terapi vs. Konventionell behandling Trippel Metformin, 1g till 2 g Pioglitazon 15 mg till 30mg Exenatide 5ug till 10 ug Konventionell 1. Metformin 2. Om HbA1c> 6.5% (48 mmol/mol) SU in (glipizid) 3. Om HbA1c> 6.5% (48 mmol/mol) Basal insulin (glargine)

19 Design Open label ranomiserad kontrollerad studie 249 nyligen (<2 år) diagnosticerade DM2 Titrering månad 1, därefter kontroll/ 3månad Trippel Konventionell Ålder 47 år 48 år Manligt kön 55% 62% BMI Diabetesduration 5.9 månader 5.1 månader HbA1c (DCCT %)

20 HbA 1c utveckling

21 Måluppfyllelse HbA 1c 48 mmol/mol

22 Måluppfyllelse HbA 1c 2 år HbA 1c mål Trippel Konventionell p 45 mmol/mol 60 % 27 % < mmol/mol 92 % 72 % <0.0001

23 Andra outcomes Vikt Trippel Blodtryck Konventionell 6 månader -1.2 (1.1) kg (0.6) kg 2 år 1.2 (1.1) kg (0.9) kg Skillnad 2 år 5.3 kg, p<0.01 Blodtryck FPG Trippel Konventionell Systolisk BP 2 år -9.2 (4) mmhg -3.6 (3) mmhg P vs baseline <0.05 n.s p trippel vs baseline n.s Trippel Konventionell Start 10.6 (0.3) mmol/l 10.7 (0.3) mmol/l 6 månader 6.6 (0.2) mmol/l 7.2 (0.3) mmol/l 2 år 5.4 (0.2) mmol/l 6.4 (0.3) mmol/l

24 Biverkningar Trippel Konventionell Hypoglykemi (%) Allvarlig hypoglykemi (%) 0 0 Ödem (%) GI biverkningar (%) Död (%) 0 2

25 VINST HbA 1c Hypoglykemier Vikt

26 VAD ÄR DÅ NYTT????

27 EASD års uppföljning Kvarstående gynnsam HbA 1c effekt Kvarstående gynnsam vikteffekt Kvarstående effekt på hypoglykemier Kvarstående betacells funktion!!! Fortsatt färre biverkningar

28 Framtidens startbehandling vid typ 2 diabetes? SGLT-2 hämmare Inkretin Metformin RAS-blockad Statin

29

30 Trial design Placebo (n=2333) Screening (n=11531) Randomised and treated (n=7020) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Study medication was given in addition to standard of care Glucose-lowering therapy was to remain unchanged for first 12 weeks Treatment assignment double masked The trial was to continue until at least 691 patients experienced an adjudicated primary outcome event 30

31 Patient selektion Vuxen med känd typ 2 diabetes diagnos BMI 45 kg/m 2 HbA1c 7 10% DCCT* Etablerad kardiovaskulär sjukdom Genomgången hjärtinfarkt Känd korornosjukdom Stroke Perifer arteriell kärlsjukdom egfr >30 ml/min/1.73m 2 (MDRD) BMI, body mass index; egfr, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease *No glucose-lowering therapy for 12 weeks prior to randomisation or no change in dose for 12 weeks prior to randomisation or, in the case of insulin, unchanged by >10% compared to the dose at randomisation 31

32 Baseline characteristics Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Age, years 63.2 (8.8) 63.0 (8.6) 63.2 (8.6) Male 1680 (72.0) 1653 (70.5) 1683 (71.9) Region Europe 959 (41.1) 966 (41.2) 960 (41.0) North America* 462 (19.8) 466 (19.9) 466 (19.9) Asia 450 (19.3) 447 (19.1) 450 (19.2) Latin America 360 (15.4) 359 (15.3) 362 (15.5) Africa 102 (4.4) 107 (4.6) 104 (4.4) Data are n (%) or mean (SD) in patients treated with 1 dose of study drug *Includes Australia and New Zealand 32

33 Baseline characteristics: type 2 Glucose-lowering medication* Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) HbA1c, % 8.08 (0.84) 8.07 (0.86) 8.06 (0.84) Time since diagnosis of type 2 diabetes, years diabetes (18.1) 406 (17.3) 434 (18.6) >5 to (24.5) 585 (24.9) 590 (25.2) > (57.4) 1354 (57.7) 1318 (56.3) Metformin 1734 (74.3) 1729 (73.7) 1730 (73.9) Sulphonylurea 992 (42.5) 985 (42.0) 1029 (43.9) Thiazolidinedione 101 (4.3) 96 (4.1) 102 (4.4) Insulin 1135 (48.6) 1132 (48.3) 1120 (47.8) Mean daily dose, U** 65 (50.6) 65 (47.9) 66 (48.9) Data are n (%) or mean (SD) in patients treated with 1 dose of study drug *Medication taken alone or in combination **Placebo, n=1135; empagliflozin 10 mg, n=1132; empagliflozin 25 mg, n=

34 Baseline characteristics: CV risk factors Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Body mass index, kg/m (5.2) 30.6 (5.2) 30.6 (5.3) Weight, kg 86.6 (19.1) 85.9 (18.8) 86.5 (19.0) Waist circumference, cm (14.0) (13.7) (13.7) Systolic blood pressure, mmhg (17.2) (16.8) (17.0) Diastolic blood pressure, mmhg 76.8 (10.1) 76.6 (9.8) 76.6 (9.7) Heart rate, bpm* 70.7 (0.2) 71.0 (0.2) 70.5 (0.2) LDL cholesterol, mg/dl 84.9 (35.3) 86.3 (36.7) 85.5 (35.2) HDL cholesterol, mg/dl 44.0 (11.3) 44.7 (12.0) 44.5 (11.8) egfr, ml/min/1.73m 2 (MDRD) 73.8 (21.1) 74.3 (21.8) 74.0 (21.4) 90 ml/min/1.73m (20.9%) 519 (22.1%) 531 (22.7%) 60 to <90 ml/min/1.73m (53.1%) 1221 (52.1%) 1204 (51.4%) <60 ml/min/1.73m (26.0%) 605 (25.8%) 607 (25.9%) Data are n (%) or mean (SD) in patients treated with *Mean 1 dose (SE). of LDL, study low drug density lipoprotein; HDL, high density lipoprotein; egfr, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease 34

35 Adjusted mean (SE) HbA1c (%) HbA1c 9,0.0 8,50.0 8,0.0 7,50.0 Placebo Empagliflozin 10 mg Empagliflozin 25 mg 7,0.0 6,50.0 6, Week Placebo Empagliflozin 10 mg Empagliflozin 25 mg All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat) X-axis: timepoints 35

36 Adjusted mean (SE) weight (kg) Weight 90,0 88,0 86,0 84,0 Placebo Empagliflozin 10 mg Empagliflozin 25 mg 82,0 80, Week Placebo Empagliflozin 10 mg Empagliflozin 25 mg All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat) X-axis: timepoints 36

37 Adjusted mean (SE) waist circumference (cm) Waist circumference 107,0 106,0 105,0 Placebo 104,0 Empagliflozin 10 mg 103,0 Empagliflozin 25 mg 102,0 101, Week Placebo Empagliflozin 10 mg Empagliflozin 25 mg All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat) X-axis: timepoints 37

38 Adjusted mean (SE) systolic blood pressure (mmhg) Systolic blood pressure 145,0 143,0 141,0 139,0 137,0 135,0 133,0 Placebo Empagliflozin 25 mg Empagliflozin 10 mg 131,0 129,0 127,0 125, Week Placebo 2322 Empagliflozin 10 mg 2322 Empagliflozin 25 mg All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat) X-axis: timepoints 38

39 3-point MACE Empagliflozin 10 mg HR 0.85 (95% CI 0.72, 1.01) p= Empagliflozin 25 mg HR 0.86 (95% CI 0.73, 1.02) p= Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio 39

40 CV death Empagliflozin 10 mg HR 0.65 (95% CI 0.50, 0.85) p= Empagliflozin 25 mg HR 0.59 (95% CI 0.45, 0.77) p= Cumulative incidence function. HR, hazard ratio 40

41 CV death, MI and stroke Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 490/ / (0.74, 0.99)* CV death 172/ / (0.49, 0.77) < Non-fatal MI 213/ / (0.70, 1.09) Non-fatal stroke 150/ / (0.92, 1.67) Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction,250.00, ,0.00 2,0.00 Favours empagliflozin Favours placebo 41

42 Hospitalisation for heart failure Empagliflozin 10 mg HR 0.62 (95% CI 0.45, 0.86) p= Empagliflozin 25 mg HR 0.68 (95% CI 0.50, 0.93) p= Cumulative incidence function. HR, hazard ratio 42

43 All-cause mortality Empagliflozin 10 mg HR 0.70 (95% CI 0.56, 0.87) p= Empagliflozin 25 mg HR 0.67 (95% CI 0.54, 0.83) p= HR 0.68 (95% CI 0.57, 0.82) p< Kaplan-Meier estimate. HR, hazard ratio 43

44 All-cause mortality, CV death and non- CV death Patients with event/analysed Empagliflozin Placebo HR 95% CI p-value All-cause mortality 269/ / (0.57, 0.82) < CV death 172/ / (0.49, 0.77) < Non-CV death 97/ / (0.60, 1.16) ,250.00, ,0.00 2,0.00 Favours empagliflozin Favours placebo Cox regression analysis. CV, cardiovascular; HR, hazard ratio 44

45 Number needed to treat (NNT) to prevent one death across landmark trials in patients with high CV risk Simvastatin 1 for 5.4 years Ramipril 2 for 5 years Empagliflozin for 3 years High CV risk 5% diabetes, 26% hypertension Pre-statin era High CV risk 38% diabetes, 46% hypertension Pre-ACEi/ARB era <29% statin T2DM with high CV risk 92% hypertension >80% ACEi/ARB >75% statin S investigator. Lancet 1994; 344: , 2. HOPE investigator N Engl J Med 2000;342:145-53, 45

46 Initial behandling av typ 2 diabetes ad modum mig själv hösten 2015 Livsstilsintervention + metformin Ingen kardiovaskulär sjukdom Känd kardiovaskulär sjukdom Glc Glc GFR <30 SU Inkretin empagliflozin NPH insulin Inkretin