Diabetes Therapy and Cancerdiabetes.or.kr/new_workshop/201001/file/S6-4_Dong-Jun KIM...Metformin & Cancer GP database study in UK J ClinOncol27:3297-3302, 2009 Humaninsulin group Insulin

Diabetes Therapy and CancerDiabetes Therapy and Cancer

InjeInje University College of Medicine, University College of Medicine, IlsanpaikIlsanpaik Hospital, Hospital, Department of Internal MedicineDepartment of Internal Medicine

DongDong--Jun Kim Jun Kim

�� Diabetes & cancerDiabetes & cancer

�� AntiAnti--diabetic drugs & cancerdiabetic drugs & cancer

-- Insulin Insulin

Contents

-- Insulin Insulin

-- SUSU

-- METMET

-- insulin analogueinsulin analogue

-- other drugsother drugs

Gastroenterology132:2208-2225, 2007


Hazard ratios for all cancer deaths by FPG in Korean men, 1993-2002

JAMA 293:194-202, 2005JAMA 293:194-202, 2005

Causes of deathCauses of death

Pooled analysis of three communityPooled analysis of three community--based cohort studiesbased cohort studies

MultivariateMultivariate--adjusted adjusted Cancer Mortality Cancer Mortality according to according to Baseline Glucose Tolerance StatusBaseline Glucose Tolerance Status

(age, sex, cohort, BMI, SBP, T. Cholesterol, HDL-C, TG, and current smoking)

IFG

Normal

IFG &IGT

HR 2.55 (1.48-4.39)p=0.0007

IFG &IGT

IGT

Diabetes

Limitations of clinical studies Limitations of clinical studies

about antiabout anti--diabetes drugs and cancerdiabetes drugs and cancer

�� Require longer duration of F/URequire longer duration of F/U

�� RCT: impossibleRCT: impossible

�� Retrospective observational studyRetrospective observational study

-- diabetes, diabetesdiabetes, diabetes--related related comorbiditycomorbidity, and treatment , and treatment

�� fully adjustment of confounding factors: impossiblefully adjustment of confounding factors: impossible

-- uunavailable confounding factorsnavailable confounding factors

-- allocation biasallocation bias

-- detection biasdetection bias

-- confusion of causal relationshipconfusion of causal relationship

IGF-1 System in the Development of Cancer in Diabetes


SU, insulin & CancerSU, insulin & Cancer

total n Cancer death

Cancer mortality rate (per 1,000 person-

years)(%)

Adjusted HR (95% CI)

Oral antidiabetics

MEF 6,969 245 (3.5) 6.3 1.0

Canadian population-based study n=10,309 F/U, 5.4 ± 1.9 yearsAge, 63.4 ± 13.3 years 55% men

SU 3,340 162 (4.9) 9.7 1.3 (1.1-1.6)

Insulin use

No insulin use 8,866 323 (3.6) 6.8 1.0

Insulin use 1,443 84 (5.8) 9.9 1.9 (1.5-2.4)

Adjusted for age, sex, and comorbidity

Diabetes care 29:254-258, 2006

Limitations: no data of glycemic control, BMI, or smoking

AntiAnti--cancer effect of metformin cancer effect of metformin on breast cancer cell lineson breast cancer cell lines

Cell cycle 8:909-915,2009

Metformin & CancerMetformin & Cancer

Metformin & CancerMetformin & Cancer

GP database study in Netherlands ZODIAC (Zwolle Outpatients Diabetes project Integrating Available Care) study

n=1,353 F/U, 9.6 years Age, 68 years

Gastroenterology132:2208-2225, 2007Diabetes care 33:322-326,2010

Metformin & CancerMetformin & CancerGP database study in UK

J Clin Oncol 27:3297-3302, 2009

Human insulin group Insulin glargine group

NPH insulin &/or RI Insulin glargine only

Type 1 & type 2 diabetes Type 2 diabetes only

Lower insulin secretion Higher insulin secretion

Basal, basal plus, & basal bolus Basal only

OHA 77.2% (SU 66.7%) OHA 92.1% (SU 79.8%)

LimitationsLimitations1. Allocation bias

2. No information of confounding factors(BMI, diabetes duration, smoking, and cancer type)

3. Large number of exclusion(participants who changed insulin type)322,732 patients on insulin. 195,701 excluded from analysis

4. Unexplained effect of insulin glargineon reducing all-cause mortality





Metformin & CancerMetformin & CancerGP database study in UK


Insulin and IGF-1 receptors

Ins=insulin; Ins-R=insulin receptor; IGF-1=insulin-like growth factor-1; IGF1-R=insulin-like growth factor-1 receptor

•Endogenous IGF-1 has a considerably higher

affinity for IGF-1 receptor. Therefore IGF-1

receptors will be occupied by endogenous IGF-1

• Insulin binds to insulin receptor (preferentially)

and with lower affinity to IGF-1 receptors

• Overstimulation of IGF-1 has been linked to cell proliferation, fosters retinopathy and progression thereof

Biodegradation of insulin glargine in the presence of serum, in vitro

chain A – GlyA21

chain B – LysB29-ThrB30-ArgB31-ArgB32-OH

chain A – GlyA21

Insulin glargine [M0]

Insulin GlyA21ArgB31

Insulin glargine and its metabolites

26

chain B – LysB29-ThrB30-ArgB31-OH

chain A – GlyA21

chain B – LysB29-ThrB30-OH

chain A – GlyA21

chain B – LysB29-OH

Insulin GlyA21ArgB31

[intermediate]

Insulin GlyA21 [M1]

Insulin GlyA21desB30 [M2]

Retinopathy progression (insulin glargine vs. NPH insulin)

Gastroenterology132:2208-2225, 2007Diabetologia 52:1778–88, 2009

Cancer rates in the 5-year RCT (insulin glargine vs. NPH insulin)

Patients (%) 11.112.3

RR (95% CI)

0.90 (0.64–1.26)

RR (95% CI)

0.63 (0.36–1.09)

Insulin glargine (n=524) NPH insulin (n=503)

15

Diabetologia 52:1971–3, 2009

Patients (%)

Seriousneoplasms

11.1

Allneoplasms

3.9

6.2

10

5

0

Cancer rates with insulin glargine vs. comparators in controlled trials in the sanofi-aventis adverse-event database

Database includes 31 RCTs with insulin glargine

Glargine vs NPH: 20 studies

Duration: Median ~6 months; six >6 months, one 5 yrs

Combined study population 10,880 people

Glargine: n = 5,657 exposure 4,711 person–years

Comparator: n = 5,223 exposure 4,524 person-years

Classification, n (%)Insulin glargine(n = 5,657)

Comparator(n = 5,223)

Relative risk(95% CI)


All cancers 45 (0.80) 46 (0.88) 0.90 (0.60–1.36)

Breast 4 (0.07) 6 (0.11) 0.62 (0.17–2.18)

Gastrointestinal (NOS) 6 (0.11) 4 (0.08) 1.38 (0.39–4.90)

Colon and rectum 6 (0.11) 10 (0.19) 0.55 (0.20–1.52)

Skin 12 (0.21)* 6 (0.11)† 1.85 (0.69–4.92)

Melanoma 6 (0.11) 1 (0.02)

Statement of Key regulatory and professional bodies

� FDA statement, 1 July 2009– ‘The FDA recommends that patients should not stop taking their insulin therapy without consulting a

physician since uncontrolled blood sugar level can have both immediate and long-term serious adverse effects’

� EMEA statement, 29 June 2009– ‘Patients being treated with insulin glargine are advised to continue their treatment as normal. At this

time there is no recommendation that patients should change their current treatment’� ADA statement, 26 June 2009

– ‘Patients concerned about these studies or their insulin regimen should talk to their doctor and should not stop taking their insulin on the basis of the findings reported here’

� EASD statement – ‘The EASD advises that patients do not stop taking insulin glargine based upon the information

presented on this website. If you wish to have further information you should contact your doctor’

FDA=Food and Drug Administration; EMEA=European Medicines Agency; ADA=American Diabetes Association;

EASD=European Association for the Study of Diabetes; AACE=American Association of Clinical Endocrinologists;

IDF=International Diabetes Federation; AFFSAPS=Agence Française de Sécurité Sanitaire des Produits de Santé

– ‘The EASD advises that patients do not stop taking insulin glargine based upon the information presented on this website. If you wish to have further information you should contact your doctor’

� AACE statement– ‘The AACE does not recommend that the use of any insulin be changed’

� IDF statement– ‘The International Diabetes Federation stresses that it is important that people needing insulin do not

stop taking the drug. IDF cautioned that people with diabetes should see their doctor for advice before considering any change to their treatment’

� AFFSAPS (French health safety agency) statement– ‘At present we are issuing no message about any dangers associated with Lantus…Patients taking this

medicine should continue their treatment’


GLP-1-based treatment and Cancer

Gastroenterology132:2208-2225, 2007Diabetes care 33:453–455, 2010

AntiAnti--diabetes drugs & Cancerdiabetes drugs & Cancer

Insulin analogueInsulinSU

METTZD

vs.SU

DPP-4 inhibitorGLP-1 agonist

TZD

α-GI inhibitor

In summaryIn summary,,

�� Marked increase of diabetes populationMarked increase of diabetes population

increased life expectancy of diabetesincreased life expectancy of diabetes

longer duration of antilonger duration of anti--diabetes drug exposure diabetes drug exposure

�� longlong--term surveillance for cancerterm surveillance for cancer�� longlong--term surveillance for cancerterm surveillance for cancer

�� Risk benefit ratioRisk benefit ratio

Thank you for your attention!Thank you for your attention!


Documents

Diabetes Therapy and Cancerdiabetes.or.kr/new_workshop/201001/file/S6-4_Dong-Jun KIM...Metformin & Cancer GP database study in UK J ClinOncol27:3297-3302, 2009 Humaninsulin group Insulin