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?
Blod-glukos sänkande läkemedel
Totalt ca 20 olika läkemedel, exkl insuliner, tillgängliga idag, imorgon är det fler……..
INSULINER
(minst 13 olika läkemedel tillgängliga, 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
HbA1c utveckling
Måluppfyllelse HbA1c ≤ 48 mmol/mol
Måluppfyllelse HbA1c 2 år
HbA1c mål
Trippel
Konventionell
p
45 mmol/mol
60 %
27 %
<0.0001
52 mmol/mol
92 %
72 %
<0.0001
Andra outcomes
Vikt
Trippel
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
Blodtryck
Konventionell
Blodtryck
Systolisk BP 2 år
P vs baseline
5.3 kg, p<0.01
Trippel
Konventionell
-9.2 (4) mmHg
-3.6 (3) mmHg
<0.05
n.s
p trippel vs baseline n.s
FPG
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
HbA1c
Hypoglykemier
Vikt
VAD ÄR DÅ NYTT????
EASD 2015
3 års uppföljning
• Kvarstående gynnsam HbA1c effekt
• Kvarstående gynnsam vikteffekt
• Kvarstående effekt på hypoglykemier
• Kvarstående betacells funktion!!!
• Fortsatt färre biverkningar
Framtidens startbehandling vid typ 2
diabetes?
SGLT-2 hämmare
Inkretin
RAS-blockad
Metformin
Statin
Trial design
Screening
(n=11531)
Randomised and
treated
(n=7020)
Placebo
(n=2333)
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/m2
HbA1c 7–10% DCCT*
Etablerad kardiovaskulär sjukdom
–
–
–
–
Genomgången hjärtinfarkt
Känd korornosjukdom
Stroke
Perifer arteriell kärlsjukdom
– eGFR >30 mL/min/1.73m2 (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)
63.2 (8.8)
63.0 (8.6)
63.2 (8.6)
1680 (72.0)
1653 (70.5)
1683 (71.9)
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)
Age, years
Male
Region
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
diabetes
HbA1c, %
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
8.08 (0.84)
8.07 (0.86)
8.06 (0.84)
Time since diagnosis of type 2 diabetes, years
≤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)
1135 (48.6)
1132 (48.3)
1120 (47.8)
65 (50.6)
65 (47.9)
66 (48.9)
Glucose-lowering medication*
Insulin
Mean daily dose, U**
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/m2
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/1.73m2 (MDRD)
73.8 (21.1)
74.3 (21.8)
74.0 (21.4)
≥90 mL/min/1.73m2
488 (20.9%)
519 (22.1%)
531 (22.7%)
60 to <90 mL/min/1.73m2
1238 (53.1%)
1221 (52.1%)
1204 (51.4%)
<60 mL/min/1.73m2
607 (26.0%)
605 (25.8%)
607 (25.9%)
Data are n (%) or mean (SD) in patients treated with
≥1 dose
study
*Mean
(SE). of
LDL,
low drug
density lipoprotein;
HDL, high density lipoprotein; eGFR,
estimated glomerular filtration rate; MDRD,
Modification of Diet in Renal Disease
34
HbA1c
Adjusted mean (SE) HbA1c (%)
9,0.0
8,50.0
Placebo
8,0.0
Empagliflozin 10 mg
Empagliflozin 25 mg
7,50.0
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
2294 2272
2188 2133 2113 2063
2008 1967
1741
1456
1241
1109
962
705
420
151
Empagliflozin 10 mg
2296 2272
2218 2150 2155 2108
2072 2058
1805
1520
1297
1164
1006
749
488
170
Empagliflozin 25 mg
2296 2280
2212 2152 2150 2115
2080 2044
1842
1540
1327
1190
1043
795
498
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
Weight
Adjusted mean (SE) weight (kg)
90,0
88,0
86,0
Placebo
Empagliflozin 10 mg
84,0
Empagliflozin 25 mg
82,0
80,0
0
12
28
52
108
164
220
Week
Placebo
2285 1915
2215
2138
1598
1239
425
Empagliflozin 10 mg
2290 1893
2238
2174
1673
1298
483
Empagliflozin 25 mg
2283 1891
2226
2178
1678
1335
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
Waist circumference
Adjusted mean (SE) waist circumference (cm)
107,0
106,0
Placebo
105,0
104,0
Empagliflozin 10 mg
103,0
Empagliflozin 25 mg
102,0
101,0
Placebo
0
12
28
52
108
164
220
Week
2183
2110
1562
1220
418
Empagliflozin 10 mg
2259 1869
2272 1836
2219
2155
1644
1285
475
Empagliflozin 25 mg
2273 1857
2209
2157
1648
1329
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
Systolic blood pressure
145,0
Adjusted mean (SE) systolic
blood pressure (mmHg)
143,0
141,0
139,0
137,0
Placebo
135,0
Empagliflozin 25 mg
Empagliflozin 10 mg
133,0
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
2235 2203 2161 2133
2073
2024
1974
1771
1492 1274 1126
981
735
450
171
2250 2235 2193 2174
2125
2095
2072
1853
1556 1327 1189
1034
790
518
199
Empagliflozin 25 mg 2323
2247 2221 2197 2169
2129
2102
2066
1878
1571 1351 1212
1070
842
528
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
3-point MACE
Patients with event/analysed
Empagliflozin
Placebo
HR
(95% CI)
p-value
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
,250.00
,50.00
Favours empagliflozin
Cox regression analysis. MACE, Major
Adverse Cardiovascular Event;
HR, hazard ratio; CV, cardiovascular; MI,
myocardial infarction
1,0.00
2,0.00
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)
HR 0.68
p=0.0003
(95% CI 0.57, 0.82)
p<0.0001
Kaplan-Meier estimate. HR, hazard ratio
43
All-cause mortality, CV death and nonCV 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
Favours empagliflozin
Cox regression analysis. CV, cardiovascular;
HR, hazard ratio
1,0.00
2,0.00
Favours placebo
44
Number needed to treat (NNT) to prevent one death across
landmark trials in patients with high CV risk
Simvastatin1
Ramipril2
Empagliflozin
for 5.4 years
for 5 years
for 3 years
High CV risk
High CV risk
T2DM with high CV risk
5% diabetes, 26% hypertension
38% diabetes, 46% hypertension
92% hypertension
Pre-statin era
1994
Pre-ACEi/ARB era
>80% ACEi/ARB
<29% statin
>75% statin
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
Inkretin
empagliflozin
NPH
insulin
GFR
<30
Inkretin
SU
Känd kardiovaskulär sjukdom
Glc
Glc
