Terapie antidiabetiche e tumori - Rete Oncologica · Terapie antidiabetiche e tumori Marco Gallo...

Terapie antidiabetiche e tumori

Marco Gallo SCDU Endocrinologia Oncologica AOU Città della Salute e della Scienza di Torino Molinette - COES

Torino, 23 gennaio 2015

In ottemperanza alla normativa ECM ed al principio trasparenza delle fonti di

finanziamento e dei rapporti con soggetti portatori di interessi commerciali in

campo sanitario, dichiaro che negli ultimi due anni non ho avuto rapporti diretti

di finanziamento con soggetti portatori di interessi commerciali in campo

sanitario

Marco Gallo

DICHIARAZIONE CONFLITTO D’INTERESSE DOCENTI

Insulina e analoghi


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

Professor Edwin Gale Editor of Diabetologia

from 2003-2010

M Gallo Torino, 23 gennaio 2015

quality of data for analyses 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

statistical management prescription bias:

– pts. receiving prescriptions for different therapies might differ for clinical characteristics, potentially accounting for diversities in cancer incidence

cumulative exposure

adjustment for a limited number of confounders

methodological limitations


omologia tra IR e IGF-IR 45-65%

60-85%

recettore insulinico e tumori

Frasca F et al.; Arch Physiol Bioch 2008

Mathieu MC et al; Proc Assoc Am Phys 1997

M Gallo Torino, 23 gennaio 2015 Frasca F et al.; Arch Physiol Bioch 2008


recettore insulinico e tumori


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)


X10 (AspB10): primo analogo rapido sviluppato “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


• 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


• metanalisi di 21 RCT sponsorizzati su 8693 pz • confronto vs NPH o glargine OR di sviluppare neoplasie

– significativamente inferiore vs NPH – n.s. inferiore vs glargine

• (mediana di esposizione: 24 settimane)

M Gallo Torino, 23 gennaio 2015 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

adjusted for: comorbidities, exposure to metformin, and doses of each type of insulin

Previous studies limitations: - 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


results: 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

dosages should always be considered when assessing the possible association of insulin

and its analogues with cancer

Mannucci E. et al. Diabetes Care 2010

M Gallo Torino, 23 gennaio 2015 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

results: 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 insulin HR 0.75 (95% CI 0.71, 0.80)

Glargine: • 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 identified Insulin analogues other than glargine: • No increased risk of breast cancer

Diabetologia 2011


large cohort study (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-up results:

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


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)


“However, on the basis of the findings from epidemiological studies and the latest welcome and overdue pharmacokinetic data, the chapter on whether insulin glargine per se is an independent risk factor for cancer should now be closed.”

Owens DR., Diab Care 2012


diabete d’insorgenza recente o pre-diabete o mediana della dose di glargine: 0.31-0.4U/kg o differenza FBG 29mg/dl; HbA1c 0.3%

~27-47% dei pazienti trattati anche con metformina

al baseline o entro la fine dello studio!

elevato drop-off dopo 6,2 anni

elevata contaminazione tra i bracci

breve periodo di esposizione


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 Saf. 2013


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

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

Curr Drug Saf. 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


rate of progression of solid tumour cancers in people with diabetes receiving alternative glucose-lowering therapies

sulfonylurea monotherapy

sulfonylurea plus metformin

insulin-based therapy

no diabetes treatment exposure

metformin monotherapy

• population-based retrospective cohort study on 10,300 users of metformin or sulphonylureas

• follow-up 5.4 years

limits: no information on glycemic control, BMI, or smoking status


studio osservazionale prospettico di coorte olandese (1998-1999) su relazione tra metformina e mortalità tumorale.

1353 pazienti, follow-up medio 9,6aa

l’impiego di metformina (289 pazienti) è risultato associato ad una minore mortalità per cancro nel T2DM

effetto protettivo dose-dipendente

HR 0.43 (95%IC 0.23-0.80)

Landman GW et al. Diabetes Care 2010


studio osservazionale su relazione tra terapie antidiabetiche e mortalità (tumorale e non) in pz con T2DM

3685 pz, follow-up medio 4,5aa

l’impiego di metformina è risultato associato a una minore mortalità per cancro nel T2DM (HR 1.56)

effetto protettivo dose e tempo-dipendente (ogni 5 anni di trattamento associato a riduzione R mortalità tumorale 0,73)

Diab Ob Metab 2011


metformina e neoplasie: studi clinici

limite principale: utilizzo della metformina con T2DM in fase precoce, mentre gli altri farmaci vengono introdotti successivamente, quando vi è già stato un periodo più o meno lungo di inadeguato compenso glicemico

DeCensi A et al, Cancer Prev Res 2010


metanalisi di 6 studi osservazionali (21.000 pz diabetici)


attivazione della via di segnale LKB1-AMPK

o effetti antiproliferativi/antiangiogenici

riduzione dell’espressione di HER-2

effetti sulla fase G0-G1 del ciclo cellulare

riduzione dei livelli di VEGF, PAI-1, TNFα, TPA (angiogenesi, flogosi)

induzione dell’apoptosi (p53)

effetti immunomodulanti sulle cellule CD8+

effetto sulle cellule staminali tumorali

metformina & tumori meccanismi proposti

effetti sull’iperglicemia

o Inibizione della gluconeogenesi

effetti sul peso

aumento della sensibilità insulinica

riduzione dei livelli di vitamina B12?


current evidence suggests that there is a real possibility that metformin may have beneficial effects on breast cancer outcome

metformin is an inexpensive and safe drug effects on pts w/o hyperinsulinemia?

“We believe the science underlying such a trial is

strong, the novelty of the intervention is high, and the potential for benefit is large”


Consensus statement su

prevenzione ca mammario

– stile di vita

– BMI

– attività fisica

– moderato consumo alcol

– farmaci

Cuzick J et al., Lancet 2011

“In view of these promising data, the potential usefulness of this drug for many diseases, and the good side-effect profi le, metformin deserves to be given high priority

for further clinical research.”

Lancet Oncol. 2011

Compared with patients with metformin as first diabetes medication, no increased

risks of cancer of all sites were found in patients with other first diabetes

medication, i.e., either sulfonylurea, insulin, or other medication but metformin.


glitazoni

• reduce insulin resistance and hyperinsulinemia

• promote terminal cell differentiation (adypocites)

• PPARγ effect on oncogenesis pathway: • inhibit tumor growth by inducing cell cycle arrest? • induce apoptosis? • anti-angiogenic mechanism?

• experimental antitumoral effects on: • colon carcinoma cell culture (HT-29) • adenomatous polyposis (mice) • glyoma (in vivo) • lung cancer cell cultures (NSCLC H841, A549, abd PC14) • prostate cancer cell culture (LNCaP) • thyroid cancer cell culture • HCC cell culture • liposarcoma


PPARγ agonists: • Alter cell proliferation rates and differentiation in

uroepithelial tissue • Increased risk of bladder cancer • May be prevented with diet? (acid milieu of urine) • Increased in situ cancer rate:

– greater surveillance? – effect on early stages of development?


Revisione sistematica e metanalisi di RCT e studi osservazionali 2.600.000 pz con T2DM complessivi RR pioglitazone: 1,22 (IC95% 1,07-1,39)

Colmers IN et al., 2012

Torino, 23 gennaio 2015 M Gallo

Incidenza di tumore della vescica nei diabetici in prospettiva

Incidenza per 100.000 pazienti diabetici-anno

Eventi cardiovascolari maggiori 5000

Decessi cardiovascolari 1330

Neoplasie maligne 1308

Tumori colo-rettali 198

Tumori polmonari 159

Tumori della vescica 69

• NNH studio CNAMTS 10.620 K vescica • NNH studio KPNC 7874 K vescica • NNT studio PROactive 144 MACE


pioglitazone & carcinoma della vescica

Diabetologia 2014 Dec 7


pioglitazone & ca vescica: “pearls for practice” • Prima d’iniziare trattamento con pioglitazone, valutare la

presenza di fattori di rischio per ca vescica – età – fumo – esposizione a tossici lavorativi o farmaci (es. ciclofosfamide) – RT pregressa sull’area pelvica

• Escludere pazienti con anamnesi positiva per ca vescica • Indagare qualunque ematuria, prima d’iniziare terapia con

pioglitazone • Prestare attenzione a comparsa di ematuria (da monitorare),

disuria o urgenza minzionale durante il trattamento


Sequence of events in rodents after long-term GLP-1 receptor agonist dosing:

1. GLP-1 receptor agonists bind to and activate GLP-1 receptors on C-cells

2. GLP-1 receptor activation on C-cells induces calcitonin release

3. Continued calcitonin secretion is followed by increased synthesis

4. Persistent stimulation of calcitonin synthesis is followed by C-cell

hyperplasia in rodents

5. Long-term C-cell hyperplasia may lead to C-cell neoplasia in rodents

Knudsen LB Endocrinology 2010

GLP1-RA e ca midollare della tiroide


1. Humans have far fewer C-cells than rodents

2. GLP-1 has effects in rodent, but not human, C-cells

cAMP, cyclic adenosine monophosphate

Species C-cell density

(n/mm thyroid)

Difference to humans

in fold

Human 10±26 –

Monkey 23±10 2

Mouse 216±62 22

Rat 449±222 45

Rodents

Humans

GLP-1 receptor density (n/cell)

1600–13,000 0–105

cAMP generation (liraglutide EC50, pM) 5800 Not

detected

Calcitonin release (liraglutide EC50, pM)

5300 Not detected

RODENTS VS HUMANS DENSITY OF GLP 1 RECEPTORS

Knudsen LB Endocrinology 2010

GLP1-RA e ca midollare della tiroide


CT was measured every 3 months in >5,000 subjects in long-term phase 3 trials and in 500 obese subjects without diabetes in a phase 2 trial (liraglutide up to 3 mg for up to 1 year).

a calcium stimulation test was performed in a sub-population of subjects

CT levels were within the normal range in all treatment groups throughout the treatment period, with no difference between liraglutide and active comparator at any point in time

No significant differences between treatments observed with stimulation test

calcitonin monitoring in humans

Hegedus L et al., J Clin Endocrinol Metab 2011


liraglutide e carcinoma (midollare?) della tiroide


“…based on the clinical safety database from the liraglutide development program and consistent with the nonclinical data, there is no suggestion of a link

between liraglutide exposure and the development of neoplasms in humans”

Liraglutide Analysis of Malignant Neoplasm Adverse Events

sconsigliato monitoraggio CT nei pazienti in terapia con liraglutide

riserve in pazienti con familiarità MEN2 o FMTC

…further long-term data are awaited…


Limits: • unpublished data? • subjects with established thyroid neoplastic and hyperplastic

lesions could have a different response to GLP-1R agonists aberrant GLP-1R expression detected in: 18% of human PTCs 27-50% of MTCs

• different responses in subjects with RET oncogene mutations? • longer duration of exposure?

Butler PC et al. Dia b Care 2013


• FDA AERS database – 2004-2009 – events with sitagliptin or exenatide vs.

rosiglitazone, nateglinide, repaglinide, or glipizide

• aumentato rischio: – pancreatite 6x – ca pancreas 2.7-2.9x – ca tiroide 4x (exenatide)

EASD: “…there is no definitive evidence pointing to an

increase in cancer risk. The only robust way of measuring comparative risk is within RCTs which record adverse events. There is no immediate need for action, and patients should under no circumstances stop taking any medication”


GLP-1 binding with GLP-1R: • induces insulin secretion from β-cells • promotes β-cells proliferation/differentiation • Inhibits β-cells apoptosis promoting effect on pancreas tumorigenesis?


clinical trial program (2 years): – 5478 pts treated with dapaglifozin

• 9 breast cancers • 9 bladder cancers (all males)

– 3156 control: 1 breast + 1 bladder ca. not increased risk in animal studies (doses 100x) breast and bladder cells don't express SGLT-2

relatively high incidence of urinary tract infections role? detection bias?

“…The timing of the cases made it seem unlikely that dapagliflozin caused the cancers, although it may have accelerated them”

dapaglifozin, SGLT2-inhibitors, & cancer

Henry RR, ADA 71st Scientific Sessions 2011


Stumvoll & Nawroth, Diabetologia 2009

“patients are left alone trying to achieve a balance between the risks of unsatisfactory glucose control and media alerts on supposed increased cancer risks with the drugs they use”

“clinicians, on their part, have to venture into a challenging slalom between a healthy skepticism and the always lurking fear to harm, rather than to benefit their patients”

Gallo, Esposito, & Giugliano, Diab Res Clin Pract 2012

bladder cancer

breast cancer

thyroid cancer

CHF

pancreatic cancer

LDL-C

durability

hypos

HbA1c

weight

pioglitazone

glargine insulin

rosiglitazone

exenatide-sitagliptin

liraglutide


Preclinical or laboratory testing procedures are insufficient to confirm or to exclude potential cancer risks in humans

Prospective clinical trials are not feasible and are largely impracticable

Observational studies, due to their methodological limitations, cannot conclusively support a causal relationship

There is currently no definitive evidence that any diabetic medication (included insulin) has a causal, harmful effect on cancer development. Even if such a relationship were to be established, it would need to be weighed against the established benefits of these drugs.

trials…


How’s your attitude?

Torino, 23 gennaio 2015 Science. 2015 Jan 2

Torino, 23 gennaio 2015 M Gallo

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


personalizzazione della terapia

• stile di vita

• acarbose

• metformina

• sulfoniluree

• glinidi

• glitazoni

• GLP-1

• inibitori DPP-IV

• Insulina

• Inibitori SGLT-2

• meccanismo d’azione

• FPG / PPG

• effetti sul peso

• effetti extra-glicemici

• reazioni avverse

• compliance

• efficacia (target?)

• costi

• durability

• età & durata di malattia

• comorbilità

• patologia CDV

• complicanze microvascolari

• rischio ipoglicemie

• autogestione/supporto sociale

• funzionalità d’organo

• condizioni psicologiche

• stato cognitivo

• rischio tumorale

Torino, 23 gennaio 2015 M Gallo Badrick E & Renehan AG; Eur J Cancer 2014

Terapie antidiabetiche e tumori - Rete Oncologica · Terapie antidiabetiche e tumori Marco Gallo...

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