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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
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
Gastroenterology132:2208-2225, 2007
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
Gastroenterology132:2208-2225, 2007
Gastroenterology132:2208-2225, 2007
Gastroenterology132:2208-2225, 2007
Gastroenterology132:2208-2225, 2007
Metformin & CancerMetformin & CancerGP database study in UK
Gastroenterology132:2208-2225, 2007
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)
Gastroenterology132:2208-2225, 2007
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’
Gastroenterology132:2208-2225, 2007
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!
Gastroenterology132:2208-2225, 2007
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