Le plus sûr, c'est de n'être sûr de rien

Voltaire

Analyse des faits

• Quatre articles publiés en juillet dans Diabetologia :

– Hemkens et al.: Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study (Germany)

– Jonasson JM et al: Insulin glargine use and short-term incidence of malignancies – a population-based follow-up study in Sweden

– Brearley S et al. for SDRN Epidemiology Group: Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group

– Currie CJ et al: The influence of glucose-lowering therapies on cancer risk in type 2 diabetes (UK)

La dose quotidienne (totale) d’insuline est plus élevée dans le groupe insulines humaines que dans celui de la glargine (médiane: 37 vs 22U )

FACTS

Cancer risk (in general and breast) in three cohorts*

(1) glargine (monotherapy)

(2) glargine combined to other insulins

(3) no glargine in the insulin scheme

[ * n = 114 841]

Jonassonet al, 2009

(p=0.004)

Analyse des faits

• Currie et al, UK– Bénéfice statistique de la metformine

� du risque de cancer (en général) si administration

avec des sulfamides ou de l’insuline

– Insulinothérapie � du risque de cancers du colon et du pancréas (pas du sein ni prostate)

– Absence d’« effet cancer » des analogues par rapport aux insulines conventionnelles

Kurtzhals et al, 2000

Analyses contradictoires: aucune association glargine/cancers

• Rosenstock et al, 2009glargine vs NPH (n=1017)

• Home et Lagarenne, 2009

glargine vs NPH (20/31 études; n=10880)

• Dejgaard et al, 2009 (n=9000)detemir vs NPH/glargine

Rosenstock et al, 2009

In these randomised controlled diabetes trials, patients treated with insulin detemir had a lower or similar occurrence of a cancer diagnosis comparedwith patients treated with NPH insulin or insulinglargine,respectively

Insulines et cancers :

Données récentes

(et contradictoires)

“To kill an error is as good a service, and sometimes even better than the establishing of a new truth or

fact”

Charles Darwin

Inoue et al, 2006

Rapp et al, Diabetologia 2006

Cancers dans le diabète de type 2

• HépatocarcinomeInoue et al x2El Serag et al x2

• Cancer colorectalLarsson et al 26%Yang et al 42%

• SeinsLarsson et al 20%

• Cancer du pancréasLi et al x2Jamal et al x2

• Cancer des voies biliairesJamal et al x2

Cancers dans le diabète de type 2

• ProstateGong et al 47% (28%)Bonovas et al 10%Kasper et al 16%

D.Simon, 2009

Calle et al ,New Engl J Med, 2003

D.Simon, 2009

Vigneri et al ,2009

Voies de signalisation de l’insuline

Vigneri,2009

Voies de signalisation

Diabète de type 2 et cancers : hypothèse étiopathog énique

Yang, Gastroenterology, 2009

Yang et al, Gastroenterology, 2004

Prolifération

Récepteurs Récepteurs

IGF-1 insuline

Hyperinsulinémie

insulines

[insulinostimulants]Insulinorésistance

analogues

[glargine]

Diabète de type 2

(?)

Conclusions• Il existe une augmentation des cancers en cas

de diabète de type 2.

• L'hyperinsulinémie pourrait être le lien

étiopathogénique.

• Les résultats des études "glargine" ne sont pas

concordants mais constituent un signal incitant

à d'autres enquêtes. A ce stade néanmoins,

aucune modification de traitement n’a été,

logiquement, recommandée.

�� CaseCase--control study of 314127 subjects (UK) including control study of 314127 subjects (UK) including 1187611876 newlynewly--diagnosed diagnosed Type 2 Diabetes patientsType 2 Diabetes patients..

�� 923 were admitted with malignant cancer (1993923 were admitted with malignant cancer (1993--2001)2001)

�� Patients were stratified whether they received Metformin or notPatients were stratified whether they received Metformin or not

�� Receipt of Receipt of MetforminMetformin was associated with a was associated with a reduce risk of cancerreduce risk of cancerwith a greater protective effect with increasing duration of expwith a greater protective effect with increasing duration of exposure osure and the total doses dispensed. Adjusted* and the total doses dispensed. Adjusted* OR for any exposure to OR for any exposure to metformine = 0.77 (0.64metformine = 0.77 (0.64--0.92)0.92)

Evans JMM et al. BMJ 2005; 330: 1304-5 *adjusted for BMI,BP, smoking

DARTS Pilot Observationnel Study

Role of Diabetes Treatment in CancerRole of Diabetes Treatment in CancerSaskatchewan Health databaseSaskatchewan Health database

�� PopulationPopulation--based cohort study based cohort study ~ ~ 1,000,000 subjects1,000,000 subjects

�� The cohort contained The cohort contained 10309 diabetic10309 diabetic patients, of whom 6969 received patients, of whom 6969 received Metformin, and 3340 a SulfonylureaMetformin, and 3340 a Sulfonylurea

�� Compared Compared cancercancer--related mortalityrelated mortality according to use OAD or insulinaccording to use OAD or insulin

�� Cancer mortality over 5.4Cancer mortality over 5.4±±1.9 yrs of follow1.9 yrs of follow--up :up :4.9% in sulfonylurea monotherapy users4.9% in sulfonylurea monotherapy users3.5%3.5% in in metforminmetformin users (users (3.3%3.3% in monotherapy)in monotherapy)5.8% in insulin users (vs. 3.6% without insulin)5.8% in insulin users (vs. 3.6% without insulin)HR for cancer death: SU vs. HR for cancer death: SU vs. MetformineMetformine =1.3 (1.1=1.3 (1.1--1.6) 1.6)

Insulin vs. no insulin = 1.9 (1.5Insulin vs. no insulin = 1.9 (1.5--2.4)2.4)

BowkerBowker SL et al. Diabetes Care 2006; 29: 254SL et al. Diabetes Care 2006; 29: 254--88

Cancer events in ADOPT and RECORD studies(metformine,rosiglitazone and sulfonylureas)

Home et al, Diabetologia ,2010

Conclusions

1. There is a modest increase in cases of malignancies in the presence of diabetes.

2. Hyperinsulinemia could be the link.

3. Concerns about a relationship between glargine and cancer are insufficient to

bring in a verdict and were not confirmed by recent papers. These observations,

however, require further analyses and evaluation.

4. Up to now, scientific organizations (ADA, EASD, SFD) advised patients to

maintain their insulin treatment unchanged.

5. Metformine could have “anticancer” effects, which have to be confirmed.