update diabetes therapie - rheumapraxis solothurn...• n engl j med. 2015 373:2117-28 (empa-reg...
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Marc Y Donath
Update Diabetes Therapie
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• N Engl J Med. 2015 373:2117-28
(Empa-Reg outcome study)
• N Engl J Med. 2016 June 13
(LEADER trial)
• N Engl J Med. 2017 June 12
(CANVAS trial)
Recent CV outcome studies in Diabetes
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Cardiomyocytes
Control Glucose
Dyntar et al. Diabetes 50: 2105-13
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Type 2 diabetes=
Protection against Overnutrition
Islet:
Protection
=
Insulin produc.on↓
Fat, liver, muscle:
Protection
=
Insulin sensi.vity ↓
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IL-1β
Metformin
SportSGLT2iBariatric surgery
Insulinsulfonylureas
UCP-1
Anti-IL-1β
GLP-1
Treatment Treatment Treatment Treatment ofofofof Typ 2 DiabetesTyp 2 DiabetesTyp 2 DiabetesTyp 2 Diabetes
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Therapie targets
• Microvascular: HbA1c
• Macrovasular: Multifactorial:
• Nutrient
� Life Style, GLP1a, SGLT2i, Bariatric surgery
• Lipid
� Statin, PCSK9i
• Blood pressure
• Heart failure
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Glycemic targets
• HbA1c < 7.0%
Individualization is key:
• Tighter targets (6.0 - 6.5%)
- younger, healthier
• Looser targets (7.5 - 8.0%)
- older, comorbidities, hypoglycemia prone, etc.
• Avoidance of hypoglycemia
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Treatment of Typ 2 Diabetes
1. Prevention – Life-style intervention
� Sport is the best drug
2. Anti-obesity treatment
�GLP-1, GLP1-Glucagon etc.
3. Glucose lowering without tissue accumulation
� SGLTi, bariatric surgery
4. Damage limitation
�DPP-IVi, Anti-inflammation
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Lifestyle: Future or past?
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Exercise improves
• Well beeing
• Glucose uptake in muscles
• Insulin production (cross-talk muscle-islet)
• Body weight (?)
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Incretins
• DPP-IV inhibitors
• GLP-1 analoga
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• No Hypoglycaemia
• No changes in Body weight
• Safe
But no demonstrated cardiovascular protection
DPPDPPDPPDPP----IV IV IV IV inhibitorsinhibitorsinhibitorsinhibitors
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DPP-IV inhibitors
• Sitagliptin (Januvia und Xelevia bzw. Janumet & Velmetia)
• Vildagliptin (Galvus und Galvumet)
• Saxagliptin (Onglyza und Kombiglyze XR)
• Linagliptin (Trajenta und Jentadueto)
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GLP-1 analoga
Twice-daily
• Exenatide (Byetta)
Daily
• Liraglutide (Victoza) & Liraglutide & Degludec (Xultophy)
• Lixisenatid (Lyxumia) & Lixisenatid & Glargin (Suliqua)
Once-weekly
• Exenatide Once Weekly Sustained-release (Bydureon)
• Dulaglutide (Trulicity)
• Semaglutide (Ozempic)
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SGLT2 Inhibitors
1. Canagliflozin (Invokana)
2. Dapagliflozin (Forxiga)
3. Empagliflozin (Jardiance)
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SGLT2 Inhibitors• HbA1c↓
• Body weight ↓( 80-100 gr. glucose = ~ 300-400 cal/day)
• Blood pressure ↓
• No hypoglyceamia
• All combination possible (incretin limits)
BUT:
• Genital infections
• Ketoacidosis
• New drug (Glucagon secre.on ↑, Osteoporosis ?)
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Therapeutic schema
1. Lifestyle
2. Metformin
3. Individualization :
A. Early case: Gliptin or GLP-1analog (BMI>28)
B. Established cardiovascular disease: SGLT2i or GLP-1analog
C. Uncontrolled diabetes or GFR < 30 : Basal insulin (& GLP-1analog)
D. BMI>35: consider bariatric surgery
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NEJM 356: 1517
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Primary endpoint: Primary endpoint: Primary endpoint: Primary endpoint:
change in HbAchange in HbAchange in HbAchange in HbA1c1c1c1c at 13 weeksat 13 weeksat 13 weeksat 13 weeks
Placebo
Anakinra
4
Week
13
–0.6
–0.3
0.0
0.3
Gly
cate
d
he
mo
glo
bin
(%
)
P=0.004 P=0.03
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–2
–1
0
1
Ch
an
ge
fro
m b
ase
lin
e (
mg
/lit
er)
Placebo
Anakinra
P<0.001
C-Reactive protein Interleukin-6
–3
–4
–5
–6
–2
–1
0
1
Ch
an
ge
fro
m b
ase
lin
e (
mg
/lit
er)
–3
4
Week
13 4
Week
13
P<0.001P=0.002P=0.02
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Stable CAD (post MI)
On Statin, ACE/ARB, BB, ASA
Persistent Elevation
of hsCRP (> 2 mg/L)
Randomized
Canakinumab 150 mg
SC q 3 months
Randomized
Placebo
SC q 3 months
Primary CV Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death
(MACE)
Randomized
Canakinumab 300 mg
SC q 3 months*
Randomized
Canakinumab 50 mg
SC q 3 months
Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)
N = 10,061
39 Countries
April 2011 - June 2017
1490 Primary Events
Ridker ESC 2017
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Canakinumab SC q 3 months
Characteristic Placebo
(N=3347)
50 mg
(N=2170)
150 mg
(N=2284)
300 mg
(N=2263)
Age (years) 61.1 61.1 61.2 61.1
Median body-mass index (IQR) 29.7 29.9 29.8 29.8
Diabetes (%) 39.9 39.4 41.8 39.2
Prediabetes (%) 49 49 49 49
Hypertension (%) 79.1 80.7 79.4 79.5
Renin-angiotensin inhibitors (%) 79.8 79.3 79.8 79.6
Statin (%) 91.1 91.7 90.6 91.1
hsCRP (mg/L) 4.1 4.1 4.2 4.1
CANTOS CANTOS CANTOS CANTOS ---- Baseline Clinical CharacteristicsBaseline Clinical CharacteristicsBaseline Clinical CharacteristicsBaseline Clinical Characteristics
⇒⇒⇒⇒ Population with metabolic syndrome
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0 1 2 3 4 5
F o llo w -u p Y e a rs
0.00
0.05
0.10
0.15
0.20
0.25
Cum
ulat
ive
Inci
denc
e
M A C E
P la c e b o1 5 0 /3 0 0 m g
Placebo SC q 3 months
Canakinumab 150/300 SC q 3 months
CANTOS: Primary Cardiovascular EndpointCANTOS: Primary Cardiovascular EndpointCANTOS: Primary Cardiovascular EndpointCANTOS: Primary Cardiovascular Endpoint
(MACE) (MACE) (MACE) (MACE)
HR 0.85
95%CI 0.76-0.96
P = 0.007
39% reduction in hsCRP
No change in LDLC
15% reduction in MACE
Cu
mu
lati
ve I
nci
de
nce
(%
)
The 150mg group met multiplicity
adjusted thresholds for formal
statistical significance for both the
primary and secondary
cardiovascular endpoints
Ridker PM et al, NEJM 2017 [DOI:10.1056/NEJMoa1707914]
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Canakinumab SC q 3 months
Adverse Event Placebo(N=3347)
50 mg(N=2170)
150 mg(N=2284)
300 mg(N=2263)
P-trend
Any SAE 12.0 11.4 11.7 12.3 0.43
Leukopenia 0.24 0.30 0.37 0.52 0.002
Any infection 2.86 3.03 3.13 3.25 0.12
Fatal infection 0.18 0.31 0.28 0.34 0.09/0.02*
Injection site reaction 0.23 0.27 0.28 0.30 0.49
Any Malignancy 1.88 1.85 1.69 1.72 0.31
Fatal Malignancy 0.64 0.55 0.50 0.31 0.0007
Arthritis 3.32 2.15 2.17 2.47 0.002
Osteoarthritis 1.67 1.21 1.12 1.30 0.04
Gout 0.80 0.43 0.35 0.37 0.0001
ALT > 3x normal 1.4 1.9 1.9 2.0 0.19
Bilirubin > 2x normal 0.8 1.0 0.7 0.7 0.34
CANTOS: Additional Outcomes (per 100 person years of exposure)CANTOS: Additional Outcomes (per 100 person years of exposure)CANTOS: Additional Outcomes (per 100 person years of exposure)CANTOS: Additional Outcomes (per 100 person years of exposure)
* P-value for combined canakinumab doses vs placebo Ridker ESC 2017
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- Low (4%) conversion rate to diabetes
(diabetes prevention program: 25%)
- Over 4 y successful prevention,
then follow up loss & loss of effect
Incident of Diabetes in CANTOS
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Baseline HbA1c 7.1%
(target HbA1c for this patient population : <8)
-During the first months, “pure” anti-Il-1
effect, before drug alteration.
Similar pattern observed in Studies with
similar design using DPP-4 inhibitors:
SAVOR, at 2.9 years:
Placebo 7.9; Saxagliptin 7.7%
TECOS, at 48 Months:
Placebo 7.3; Sitagliptin 7.2%
Magnitude of the effects depends on
baseline HbA1c
HbA1c in CANTOS
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AntiAntiAntiAnti----ILILILIL----1β Treatment in patient with a metabolic 1β Treatment in patient with a metabolic 1β Treatment in patient with a metabolic 1β Treatment in patient with a metabolic
syndrome syndrome syndrome syndrome
• Cardiovascular complica.ons ↓
(never shown for DPP-IV inhibitors)
• Glycaemia ↓
• Gout ↓
• Arthri.s ↓
• Cancer mortality ↓
• Convenient (injection every 3 month)
• Safe: no hypoglycaemia (Cave: severe infections)
• Possible additional effects:– renal protection
– eye protection
– NASH prevention