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