Tidig intervention vid typ-2 diabetes nya insikter från ADA och EASD 2015 en personlig reflektion Magnus Löndahl överläkare Endokrinologen Skånes Universitetssjukhus
En bild fr
Hur bör vi använda behandlingsriktlinjer?
Hur bör vi använda behandlingsriktlinjer?
Hur bör vi använda behandlingsriktlinjer?
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..
Studiedesign Nationell studie baserad på läkemedelsregistret, patientregistret och dödsregistret 2006-2013 Patienter på metformin som adderas andra linjens behandling SU vs DDP-4 hämmare
Patient flöde
Vad bör vi använda som andra linjens per orala läkemedel?
Mortalitet
Resultat
Vad behandlar vi?
Vad behandlar vi
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)
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 36.1 36.6 Diabetesduration 5.9 månader 5.1 månader HbA1c (DCCT %) 8.6 8.6
HbA 1c utveckling
Måluppfyllelse HbA 1c 48 mmol/mol
Måluppfyllelse HbA 1c 2 år HbA 1c mål Trippel Konventionell p 45 mmol/mol 60 % 27 % <0.0001 52 mmol/mol 92 % 72 % <0.0001
Andra outcomes Vikt Trippel Blodtryck Konventionell 6 månader -1.2 (1.1) kg + 0.7 (0.6) kg 2 år 1.2 (1.1) kg + 4.2 (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
Biverkningar Trippel Konventionell Hypoglykemi (%) 15 46 Allvarlig hypoglykemi (%) 0 0 Ödem (%) 5.3 1.3 GI biverkningar (%) 33 21 Död (%) 0 2
VINST HbA 1c Hypoglykemier Vikt
VAD ÄR DÅ NYTT????
EASD 2015 3 års uppföljning Kvarstående gynnsam HbA 1c effekt Kvarstående gynnsam vikteffekt Kvarstående effekt på hypoglykemier Kvarstående betacells funktion!!! Fortsatt färre biverkningar
Framtidens startbehandling vid typ 2 diabetes? SGLT-2 hämmare Inkretin Metformin RAS-blockad Statin
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
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
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
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 5 423 (18.1) 406 (17.3) 434 (18.6) >5 to 10 571 (24.5) 585 (24.9) 590 (25.2) >10 1339 (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=1120 33
Baseline characteristics: CV risk factors Placebo (n=2333) Empagliflozin 10 mg (n=2345) Empagliflozin 25 mg (n=2342) Body mass index, kg/m 2 30.7 (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 105.0 (14.0) 104.7 (13.7) 104.8 (13.7) Systolic blood pressure, mmhg 135.8 (17.2) 134.9 (16.8) 135.6 (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 2 488 (20.9%) 519 (22.1%) 531 (22.7%) 60 to <90 ml/min/1.73m 2 1238 (53.1%) 1221 (52.1%) 1204 (51.4%) <60 ml/min/1.73m 2 607 (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
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 6,0.0 0 12 28 40 52 66 80 94 108 122 136 150 164 178 192 206 Week Placebo Empagliflozin 10 mg Empagliflozin 25 mg 2294 2296 2296 2272 2272 2280 2188 2218 2212 2133 2150 2152 2113 2155 2150 2063 2108 2115 2008 2072 2080 1967 2058 2044 1741 1805 1842 1456 1520 1540 1241 1297 1327 1109 1164 1190 962 1006 1043 705 749 795 420 488 498 151 170 195 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
Adjusted mean (SE) weight (kg) Weight 90,0 88,0 86,0 84,0 Placebo Empagliflozin 10 mg Empagliflozin 25 mg 82,0 80,0 0 12 28 52 108 164 220 Week Placebo Empagliflozin 10 mg Empagliflozin 25 mg 2285 2290 2283 1915 1893 1891 2215 2238 2226 2138 2174 2178 1598 1673 1678 1239 1298 1335 425 483 489 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
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 102,0 101,0 0 12 28 52 108 164 220 Week Placebo Empagliflozin 10 mg Empagliflozin 25 mg 2259 2272 2273 1869 1836 1857 2183 2219 2209 2110 2155 2157 1562 1644 1648 1220 1285 1329 418 475 486 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
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 131,0 129,0 127,0 125,0 0 16 28 40 52 66 80 94 108 122 136 150 164 178 192 206 Week Placebo 2322 Empagliflozin 10 mg 2322 Empagliflozin 25 mg 2323 2235 2250 2247 2203 2235 2221 2161 2193 2197 2133 2174 2169 2073 2125 2129 2024 2095 2102 1974 2072 2066 1771 1853 1878 1492 1556 1571 1274 1327 1351 1126 1189 1212 981 1034 1070 735 790 842 450 518 528 171 199 216 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
3-point MACE Empagliflozin 10 mg HR 0.85 (95% CI 0.72, 1.01) p=0.0668 Empagliflozin 25 mg HR 0.86 (95% CI 0.73, 1.02) p=0.0865 Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio 39
CV death Empagliflozin 10 mg HR 0.65 (95% CI 0.50, 0.85) p=0.0016 Empagliflozin 25 mg HR 0.59 (95% CI 0.45, 0.77) p=0.0001 Cumulative incidence function. HR, hazard ratio 40
CV death, MI and stroke Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382 CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001 Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189 Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638 Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction,250.00,50.00 1,0.00 2,0.00 Favours empagliflozin Favours placebo 41
Hospitalisation for heart failure Empagliflozin 10 mg HR 0.62 (95% CI 0.45, 0.86) p=0.0044 Empagliflozin 25 mg HR 0.68 (95% CI 0.50, 0.93) p=0.0166 Cumulative incidence function. HR, hazard ratio 42
All-cause mortality Empagliflozin 10 mg HR 0.70 (95% CI 0.56, 0.87) p=0.0013 Empagliflozin 25 mg HR 0.67 (95% CI 0.54, 0.83) p=0.0003 HR 0.68 (95% CI 0.57, 0.82) p<0.0001 Kaplan-Meier estimate. HR, hazard ratio 43
All-cause mortality, CV death and non- CV death Patients with event/analysed Empagliflozin Placebo HR 95% CI p-value All-cause mortality 269/4687 194/2333 0.68 (0.57, 0.82) <0.0001 CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001 Non-CV death 97/4687 57/2333 0.84 (0.60, 1.16) 0.2852,250.00,50.00 1,0.00 2,0.00 Favours empagliflozin Favours placebo Cox regression analysis. CV, cardiovascular; HR, hazard ratio 44
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 1994 2000 2015 1. 4S investigator. Lancet 1994; 344: 1383-89, http://www.trialresultscenter.org/study2590-4s.htm; 2. HOPE investigator N Engl J Med 2000;342:145-53, http://www.trialresultscenter.org/study2606-hope.htm 45
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