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MarcDonath
TYP2DIABETES
IL-1β
Metformin
SportSGLT2iBariatric surgery
Insulinsulfonylureas
UCP-1
Anti-IL-1β
GLP-1
Treatmentof Typ2Diabetes
Cardiomyocytes
Control Glucose
Dyntar etal.Diabetes50:2105-13
Therapie targets¨ Microvascular:HbA1c
¨ Macrovasular:Multifactorial:¤ Nutrient
à LifeStyle,GLP1a,SGLT2i,Bariatricsurgery¤ Lipid
à Statin,PCSK9i¤ Bloodpressure
¨ Heartfailure
Glycemictargets
¨ HbA1c<7.0%
Individualizationiskey:¨ Tightertargets(6.0- 6.5%)- younger,healthier¨ Loosertargets(7.5- 8.0%)- older,comorbidities,hypoglycemiaprone,etc.¨ Avoidanceofhypoglycemia
Incretins
¨ DPP-IVinhibitors¨ GLP-1analoga
¨ No Hypoglycaemia¨ No changes inBodyweight¨ SafeButno demonstrated cardiovascular protection
DPP-IVinhibitors
DPP-IVinhibitors
¨ Sitagliptin(JanuviaundXeleviabzw.Janumet&Velmetia)
¨ Vildagliptin(GalvusundGalvumet)
¨ Saxagliptin(OnglyzaundKombiglyzeXR)
¨ Linagliptin(TrajentaundJentadueto)
GLP-1analoga
Twice-daily¨ Exenatide (Byetta)Daily¨ Liraglutide (Victoza)&Liraglutide &Degludec (Xultophy)¨ Lixisenatid (Lyxumia)&Lixisenatid &Glargin (Suliqua)Once-weekly¨ Exenatide OnceWeeklySustained-release (Bydureon)¨ Dulaglutide (Trulicity)¨ Semaglutide (Ozempic)
SGLT2Inhibitors
1. Canagliflozin (Invokana)2. Dapagliflozin (Forxiga)3. Empagliflozin (Jardiance)
SGLT2Inhibitors
¨ HbA1c↓¨ Bodyweight↓(80-100gr.glucose=~300-400cal/day)¨ Bloodpressure↓¨ Nohypoglyceamia¨ Allcombinationpossible(incretinlimits)
BUT:¨ Genitalinfections¨ Ketoacidosis¨ Newdrug(Glucagonsecretion↑,Osteoporosis?)
Therapeuticschema
1. Lifestyle2. Metformin3. Individualization:
A. Earlycase:GliptinorGLP-1analog(BMI>28)B. Establishedcardiovasculardisease:SGLT2iorGLP-1analogC. UncontrolleddiabetesorGFR<30:Basalinsulin(&GLP-1analog)D. BMI>35:considerbariatricsurgery
Limitthedamage
NEJM356:1517
Primaryendpoint:changeinHbA1c at13weeks
PlaceboAnakinra
4
Week
13–0.6
–0.3
0.0
0.3Glycated
hemoglobin(%)
P=0.004 P=0.03
–2
–1
0
1
Changefrom
baseline(m
g/liter)
PlaceboAnakinra
P
StableCAD(postMI)OnStatin,ACE/ARB,BB,ASA
PersistentElevationofhsCRP(> 2mg/L)
RandomizedCanakinumab150mg
SCq3months
RandomizedPlacebo
SCq3months
PrimaryCVEndpoint:NonfatalMI,NonfatalStroke,CardiovascularDeath(MACE)
RandomizedCanakinumab 300mg
SCq3months*
RandomizedCanakinumab50mg
SCq3months
CanakinumabAnti-InflammatoryThrombosisOutcomesStudy(CANTOS)
N=10,06139Countries
April2011- June20171490PrimaryEvents
RidkerESC2017
CanakinumabSCq3months
Characteristic Placebo(N=3347)
50mg(N=2170)
150mg(N=2284)
300mg(N=2263)
Age(years) 61.1 61.1 61.2 61.1Medianbody-massindex(IQR) 29.7 29.9 29.8 29.8Diabetes(%) 39.9 39.4 41.8 39.2Prediabetes(%) 49 49 49 49Hypertension (%) 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 91.1hsCRP (mg/L) 4.1 4.1 4.2 4.1
CANTOS- BaselineClinicalCharacteristics
⇒ Population with metabolic syndrome
0 1 2 3 4 5
Follow-up Years
0.00
0.05
0.10
0.15
0.20
0.25
Cumu
lative
Incid
enceMACE
Placebo150/300mg
PlaceboSCq3monthsCanakinumab150/300SCq3months
CANTOS:PrimaryCardiovascularEndpoint(MACE)
HR0.8595%CI0.76-0.96
P=0.007
39%reductioninhsCRPNochangeinLDLC
15%reductioninMACE
CumulativeIncidence(%)
The150mggroupmetmultiplicityadjustedthresholds forformalstatisticalsignificanceforboththeprimaryandsecondarycardiovascularendpoints
RidkerPMetal,NEJM2017[DOI:10.1056/NEJMoa1707914]
CanakinumabSCq3monthsAdverse Event Placebo
(N=3347)50mg(N=2170)
150mg(N=2284)
300mg(N=2263)
P-trend
AnySAE 12.0 11.4 11.7 12.3 0.43Leukopenia 0.24 0.30 0.37 0.52 0.002Anyinfection 2.86 3.03 3.13 3.25 0.12
Fatalinfection 0.18 0.31 0.28 0.34 0.09/0.02*Injectionsite reaction 0.23 0.27 0.28 0.30 0.49AnyMalignancy 1.88 1.85 1.69 1.72 0.31FatalMalignancy 0.64 0.55 0.50 0.31 0.0007Arthritis 3.32 2.15 2.17 2.47 0.002Osteoarthritis 1.67 1.21 1.12 1.30 0.04Gout 0.80 0.43 0.35 0.37 0.0001ALT >3xnormal 1.4 1.9 1.9 2.0 0.19Bilirubin>2xnormal 0.8 1.0 0.7 0.7 0.34
CANTOS:AdditionalOutcomes(per100personyearsofexposure)
*P-valueforcombined canakinumabdosesvsplacebo RidkerESC2017
- Low(4%)conversionratetodiabetes(diabetespreventionprogram:25%)
- Over4ysuccessfulprevention,thenfollowup loss&lossofeffect
Incident of DiabetesinCANTOS
BaselineHbA1c7.1%(targetHbA1cforthispatientpopulation :
Anti-IL-1βTreatmentinpatientwithametabolicsyndrome• Cardiovascularcomplications↓(nevershownforDPP-IVinhibitors)• Glycaemia↓• Gout↓• Arthritis↓• Cancer mortality↓• Convenient(injectionevery3month)• Safe:nohypoglycaemia (Cave:severeinfections)• Possibleadditionaleffects:
– renalprotection– eyeprotection– NASHprevention
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