M arc o G a lloSC Endocrinologia Oncologica DU

AOU Città della Salute e della Scienza di Torino

COES – Centro Oncologico ed Ematologico Subalpino

L’ins ulina e la s ua L’ins ulina e la s ua influenza s ulla c ellula influenza s ulla c ellula

tumora letumora le

S opravvivenza e morta lità per diabete

97 s tudi pros pettic i821.000 pz

♂ ♀

As pettativa di vita per un s og g etto di 50 anni

Con DM, senza precedenti vascolari noti• -6 anni vs soggetto non diabetico• 40% della differenza per mortalità extravascolare• 10% per patologie oncologiche

Senza DM, ma con lunga durata di consuetudine al fumo• -10 anni

DIABETE: fattore di rischio

• entrambe patologie dell’età avanzata• aumento prevalenza DM e aspettativa

di vita• differenze nello stile di vita• fattori di rischio comuni• fattori genetici• minor ricorso ed efficacia degli esami

di screening

diabete + tumori:

epidemiolog iaepidemiolog ia

DIABETE: fattore prognostico s favorevole

• diagnosi in stadio più avanzato• riduzione sopravvivenza complessiva• riduzione sopravvivenza tumore-

specifica• trattamenti meno aggressivi• aumentata tossicità terapie

Cancer and diabetes are diagnosed within the same individual more frequently than would be expected by chance, even after adjusting for age

Giovannucci E et al., Diabetes Care 2010

diabete e ris c hio tumoriris c hio tumori

diabete e ris c hio tumoriris c hio tumori:c ontributo fa ttori g enetic i e ambienta li?

Liu X et al., Int J Cancer 2015

Ana lis i s is tematic a 35 neoplas ieAumento SIR per 24 neoplasieMaggior incremento:- pancreas (2.98)- fegato (2.43)

N ON aumento SIR in fratelli e coniugi

Popolazione s vedes e: 14,4 M abitanti380.196 con T2DMFollow-up 1964-2010

diabete e outc ome onc olog ic ioutc ome onc olog ic iprog nos i a lung o term ine più s favorevole

A critical question is whether the associations between diabetes and risk of certain cancers is largely due to shared risk factors, or

whether diabetes itself, and the specific metabolic derangements typical of diabetes, increase the risk for some

types of cancer

These factors are generally interrelated, making the contribution of each factor difficult to assess

Giovannucci E et al., Diabetes Care 2010

DM & c anc ro: mec c anis mi biolog ic i c omunimec c anis mi biolog ic i c omuni

diabete + tumori:

fis iopatolog iafis iopatolog ia

obes ità

iperg lic emiaiperins uline

mia

a ltri fa ttori

terapie

obes ità

iperg lic emiaiperins uline

mia

a ltri fa ttori

terapie

diabete + tumori:

fis iopatolog iafis iopatolog ia

L’ins ulina e la s ua L’ins ulina e la s ua influenza s ulla c ellula influenza s ulla c ellula tumora letumora le• ins ulina = ormone favorente la proliferazione c on

effetti m itog eni

• evidenze s perimenta li s u anima li e c as e s tudies neg li

uomini

ruolo mediato da IG F- insulina aumenta espressione dei recettori epatici per il GH- effetto sulle IGF-BP

ruolo diretto- iperinsulinemia endogena- terapia insulinica

L’ins ulina e la s ua influenza s ulla c ellula

tumora le

ruolo media to da IG Fruolo media to da IG F

Pollak MN e coll.; Nat Rev Cancer 2004

IG F1 e ris chio IG F1 e ris chio tumora letumora le

Pollak MN e coll.; Nat Rev Cancer 2004

IG F1 e ris chio IG F1 e ris chio tumora letumora le

Pollak MN e coll.; Nat Rev Cancer 2004

IG F1 e ris chio IG F1 e ris chio tumora letumora le

Does a fa s ter metabolis m lead to a s horter life?”Pathways that regulate growth and metabolism also promote aging and genomic instability”

• Yeast: mutations in genes encoding for component of the growth promoting pathway protect against age-dependent genomic instability

• Worms: mutations in the insulin/IGF-1 like signaling pathway increase life span and reduce abnormal cellular proliferation

• Mice with defects in GH and IGF-1 live exceptionally long lives, with delayed appearance of age-dependent mutations, insulin resistance, and cancer

Guevara-Aguirre J et al., Sci Transl Med 2011

• 99 pts with a mutation in the GH-R gene IGF-1 deficiency vs. 1606 not affected family members

• Follow-up 22 years• Abnormally low incidence of DM (0

vs. 5%) and cancer (1 vs. 17%)• Lower insulin concentrations• Much higher insulin sensitivity

(HOMA)• Pts serum prevented oxidative DNA

damage from H2O2 in vitro Guevara-Aguirre J et al., Sci Transl Med 2011

Pos s ibili approc c i terapeutic i

Ab monoc lona li anti-IG F1R in fa s e di s perimentazione

• CP-751 [figitumumab], Pfizer, Fase III• IMC-A12, ImClone, Fase II• AMG-749, Amgen, Fase II• MK-0646, Merck, Fase II• R1507, Roche, Fase II• SCH-717454, Schering-Plough, Fase II • AVE-1642, Sanofi-Aventis, Fase I• BIIB022, Biogen Idec, Fase I

May 22 , 2016

L’ins ulina e la s ua influenza s ulla c ellula

tumora le

ruolo diretto:ruolo diretto: iperins ulinemia endog ena

Joshi S et al.; BioMed Res Int 2015

omologia tra IR e IGF-IR 45-65%

60-85%

rec ettore ins ulinic o e rec ettore ins ulinic o e tumoritumori

Frasca F et al.; Arch Physiol Bioch 2008

Mathieu MC et al; Proc Assoc Am Phys 1997

Frasca F et al.; Arch Physiol Bioch 2008

rec ettore ins ulinic o e rec ettore ins ulinic o e tumoritumori

Metabolic syndrome is associated with increased risk of common cancers; for some cancers, the risk differs betweens sexes, populations, and definitions of metabolic syndrome

s d metabolic a & s d metabolic a & c anc roc anc ro

iperins ulinemia & tumoriiperins ulinemia & tumori

• Ruolo iperinsulinemia e aumento IGF-1• Ruolo iperinsulinemia e riduzione SHBG

(aumento E2 e T)

Wolpin BM et al.; J Clin Oncol 2009

L’ins ulina e la s ua influenza s ulla c ellula

tumora le

ruolo diretto:ruolo diretto: terapia ins ulinic a

“especially in T2DM, the potential harm of glargine must be weighed against rather minor potential therapeutic advantages”

truth or witch-hunt?

24/06/2009

• missing relevant basal informations (risk factors, comorbidities, cancer history, etc.)

• increased risk of cancer observed in pts. using glargine only, not confirmed in those treated with glargine + other insulins

• short duration of follow-up• insulin doses• therapy variations during follow-up• inclusion of probably pre-existing cases of cancer diagnosed shortly after insulin

initiation

qua lity of data for ana lys esqua lity of data for ana lys es

…… s inc e June 2009s inc e June 2009

These papers awakened an unprecedented debate:• large number of studies• Diabetes & Cancer Research Consortium

• consensus document ACS-ADA

Giovannucci E et al., Diabetes Care 2010

modifying the insulin molecule not only changes its metabolic effects, but can also alter its mitogenic and antiapoptotic potency

• Lispro: receptor-binding domain not affected• Aspart: receptor-binding affinity similar to human insulin• Glulisine: binding affinity similar to native human insulin• Glargine: insulin receptor affinity similar to that of human insulin• Detemir: binding affinity reduced (interference of albumin)

X 10 (A s pB 10): primo ana log o rapido s viluppato“But then came the discovery that halted any future clinical

development of insulin X10.”• affinità di legame IR: 200-400% vs insulina umana• affinità di legame IGF-1R: 600% vs insulina umana

X10 is now recommended by EMA as the positive control in insulin analogue mitogenicity studies

X 10 (A s pB 10)

• aspart/lispro do not differ substantially from human insulin, nor from each other

• glargine more potent than human insulin/detemir in activating IR-B and IGF-1R

Growth Horm IGF Res 2010

IR-B IR-A

IGF-1R

• both glargine and detemir show a decreased binding to IR and increased binding to IGF-IR

• prevalent activation of ER K vs AK T pathway

Acta Diabetol 2010

E R K(mainly mitogenic)

AKT(mainly metabolic)

pres c ription bia s :• pts. receiving prescriptions for different therapies might differ for clinical

characteristics, potentially accounting for diversities in cancer incidencedetec tion time bia s :

• exaggerated risk associations due to increased surveillance around the time of diagnosis of diabetes or cancer

time-varying expos ures• refer to real-life variation in prescription of medications with time, and may

result in false risk associations in either positive or inverse directionsc umula tive expos ureadjus tment for a lim ited number of c onfounders

s tatis tic a l mana g ements tatis tic a l mana g ement

Mannucci E. et al. Diabetes Care 2010

• Nested case-control study– cohort of 1340 insulin-treated T2DM pts– follow-up > 6 yy– 112 incident cancer cases vs. 370

matched controls• endpoint: long-term association of

different insulin analogues with cancer incidence

• adjus ted for: comorbidities, exposure to metformin, and doses of each type of insulin

Previous s tudies lim ita tions :

- limited information on comorbidities- short duration of observation- inclusion of probably pre-existing cases of cancer diagnosed shortly after the initiation of insulin - failure to discriminate between basal and prandial human insulin

res ults : higher mean daily dose of glargine in case vs. control subjects (p =.036)

incident cancer associated with a dose of glargine >/= 0.3 IU/kg/day (both sexes)

no association between incident cancer and insulin doses was found for human insulin or other analogues

after adjusting for confounders, lispro was associated with a marginally lower risk of cancer, which was not confirmed after exclusion of cases occurring within the first 12 months of observation

adjusted for comorbidity, exposure to metformin, and doses of other types of insulin

dos ag es s hould a lw ays be c ons idered w hen as s es s ing the pos s ible a s s oc ia tion of ins ulin

and its ana log ues w ith c anc er

Mannucci E. et al. Diabetes Care 2010

Monami M. et al. Diabetes Care 2011

• nested case-control study– cohort of 1340 insulin-treated T2DM pts– follow-up > 6 yy– 112 incident cancer cases vs. 370

matched controls• endpoint: to assess the effect of

metformin on cancer incidence in a consecutive series of insulin-treated patients

• res ults : after adjustment for comorbidity, glargine, and total insulin doses, exposure to metformin, but not SUs, was associated with reduced incidence of cancer

maintain metformin, unless contraindicated,

in all insulin-treated T2DM patients

• large population-based cohort study: 19,337 incident insulin users [878 developed cancer]

• association between glargine, other analogues, and cancer vs human insulin

• cumulative duration of drug use

Diabetologia 2011

• glargine (& other analogues) associated with a lower risk of malignancies in general vs human insulinHR 0.75 (95% CI 0.71, 0.80)

G larg ine:• significantly lower risk of colon cancer• however, increased risk for breast cancer

HR 1.58 (95% CI 1.22, 2.05)• no dose–response relationships identifiedIns ulin ana log ues other than g larg ine:• No increased risk of breast cancer

Diabetologia 2011

la rg e c ohort s tudy (UK General Practice Research Database)

– 15,227 insulin-treated T2DM women > 40yy– follow-up 8 yy– 246 incident breast cancer cases– adjustment for: age, BMI, cancer history, HRT use,

smoking, alcohol, HbA1c, duration of DM and of insulin use, other antidiabetics

– exclusion of 1st year of follow-upres ults :

• glargine not associated with increased risk of breast cancer during first 5yy of use

• the risk tended to increase after 5 yy (3x)• significantly increased risk for women on insulin

therapy before starting glargine

N orthern E uropean Databas e S tudy– 447.821 pz trattati con insulina– follow-up medio: 3,1 anni– non evidenza di aumento significativo del rischio di ca prostata, colon-retto, polmone, pancreas e

mammella con glargine (HR 1.12; 95% CI 0.99-1.27)

(N orthern and S outhern C a lifornia ) K a is er Permanente C ollaboration S tudy– 115.000 pz– mediana d’impiego di glargine: 1,2 anni– nessuna evidenza di aumento del rischio di ca prostata, colon-retto o tutte le neoplasie combinate;

non escludibile modesto incremento rischio ca mammella

M edAs s urant Databas e S tudy– 43.306 pazienti trattati con glargine– durata media di trattamento 1,2 anni– non aumento del rischio di ca mammario (14 casi complessivi…)

"This robust analysis of high-quality data from the United S tates shows that there is no association with an increased risk of cancer in users of

insulin glargine“ [John Buse]

• 12.537 pz (età media 63.5aa) con fattori di rischio CV e:– IFG-IGT– T2DM (durata di malattia ~5,5 anni)

• randomizzati tra: – terapia con glargine (target: FBG </=95mg/dl)– standard care

• outcome coprimari: IM non fatale, ictus non fatale, morte per cause CV (microvascular outcomes, incident diabetes, hypoglycemia, weight, and cancers were also compared between groups)

• mediana di follow-up: 6,2 anni• nessuna differenza significativa in termini di

– outcome cardiovascolari– neoplasie (HR 1.00)

systematic review and meta-analysis of 27 cohort and 15 case-control studies in T1DM/T2DM:– 42 examining risk of any cancer – 27 examining risk of site-specific cancers

• few studies available for most cancer sites • 8 providing estimates by dose or duration

Curr Drug S af. 2013

Insulin vs No Insulin• increased risk for pancreas, liver, kidney, stomach and respiratory

cancer• decreased risk for prostate cancerInsulin vs Non-Insulin Antidiabetics• increased risk for any, pancreatic and CRCGlargine vs Non-Glargine Insulin• increased risk for breast cancer• decreased risk for colon cancer

Curr Drug S af. 2013

• associazione tra esposizione a monoterapia insulinica (dal 2000 in poi) e– mortalità per tutte le cause– MACE– incidenza tumori

• studio retrospettivo su 6584 pz con T2DM• UK Clinical Practice Research Datalink• follow-up medio 3,3 anni (minimo 6 mesi)• dose media: 0.75 U/kg/die

Diabetes Obes Metab. 2014 Nov 14

Diabetes Obes Metab. 2014 Nov 14

1. Evaluate patient’s individual profile in terms of cancer risk

2. Assess cancer screening in our patients as routinely as for diabetes complications

3. Metformin

Lifes tyle chang es c ould prevent Lifes tyle chang es c ould prevent

50% 50% of c ommon c anc ersof c ommon c anc ers

• Smoking cessation • Maintain a healthy BMI (21-23)• Increase physical activity• Eradicate main viruses associated with cancer (HPV,

HBV, HCV)• ASA & screening for colorectal cancer

L’ins ulina e la s ua influenza s ulla c ellula

tumora leM arc o G a llo

SC Endocrinologia Oncologica DUAOU Città della Salute e della Scienza di Torino

COES – Centro Oncologico ed Ematologico Subalpino

Grazie!

G razie!