Diabetes mellitus und Krebs

Peter DiemEndokrinologie, Diabetologie und Klin.

ErnährungInselspital – Univ. Bern

Diabetes and mortality

2The Emerging Risk Factors Collaboration; NEJM 2011

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Diabetes

Cancer

• Diet• Physical activity• IGF-1• Leptin• Adiponectin• Inflammation• Sex steroids

• Hyperinsulinemia• Hyperglycemia• hyperlipidemia• Inflammation

Obesity

Diabetes and cancer risk

Breast (Larsson, Int J Can, 2007; N=36)

0.6 0.9 1 1.3 1.6 1.9 2.10 OR

1.2

1.82Pancreas (Huxley, Br J Cancer, 2005; N=16)

1.24Bladder (Larsson, Diabetologia 2006; N=15)

1.30Colorectal (Larsson, J Natl Can Inst 2007; N=16)

0.84Prostate (Kasper, Cancer Epi 2006; N=19)

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Goodwin P J et al. JCO 2002;20:42-51

Fasting insulin and outcome in early-stage breast cancer

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Distant RecurrenceFree Survival

Overall Survival

Hyperglycemia and cancer

6Jee SH et al. JAMA 2005;293:194-202

Johnson and Bowker Diabetologia 2011;54:25–31

Intensive glycemic control and cancer risk in T2DM

Weight and survival in early-stage breast cancer

BMI (kg/m2)

Esti

mat

ed R

elat

ive

Risk

of

Adve

rse

Even

t

20 30 40 50

05

1015

25 35 45 55

Distant Recurrence, p=0.0005

Death, p=0.0007

Goodwin et al.; JCO 2002 8

Human insulin

Metabolic activity ++In vitro: mitogenic activity at high concentration1

1. Le Roith; N Engl J Med 336:633–40 (1997) 2. Holt et al.; Diabet Med 20:3–15 (2003)

Mitogenic activity ++1,2

In vitro: metabolic activity

Human IGF-1

Insulin and IGF-1

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Insulin receptors and IGF-1 receptors

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Insulin action (IR-A / IR-B)

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Receptor binding of insulin analogs

12Kurtzhals P et al.; Diabetes 49:999–1005 (2000)

Human osteosarcoma cells (Saos/B10) over-expressing IGF-1R

InsulinIR

affinity (% RHI)

Metabolic pot.

(% RHI)

IGF-1 affinity (% RHI)

Mitogenicity‡

(% RHI)B10Asp 205 207 587 975Aspart 92 101 81 58Lispro 84 82 156 66Glargine 86 60 641 783A21Gly 78 88 42 34B31B32diArg 120 75 2'049 2'180Detemir 18 27 16 11

Hazard ratios for risk of all forms of cancer after various adjustments

0.6 0.8 1.0 1.2 1.4

GlargineAspartLispro

Adjustment

None

Age, gender

Age, gender, dose

Multiple covariates

Hazard ratio (95% CI) vs. human insulin

Higherrisk

Hemkens LG et al.; Diabetologia 52:1732-44 (2009) 13

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Risk of malignancy with insulinglargine versus other insulins

Study Comparator Adjusted HR(95% CI)

German database Human insulin 0.86 (0.79–0.94)

Swedish database Other insulins 1.07 (0.91–1.27)

UK database Human insulin 0.81 (0.59–1.11)

Scottish database Other insulins 1.02 (0.77–1.36)

Randomised trial Human insulin 0.63 (0.36–1.09)

Pocock SJ et al.; Lancet 374:511-3 (2009)

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Incidence rate ratio (95% CI)* Adjustment for:A: Age, BMI, smoking, age at DM onset, CVD; B: as A + gender; C: as B + age at birth of 1st child

0 1 2 3 4

Glargine alone vs other insulins

Adjustment*

All malignancy

All malignancy +in-situ tumours

Breast

GI

Prostate

B

B

C

A

B

Glargine ± other insulins vs other insulins

Higher risk

Swedish database analysis:Main results

Jonasson JM, et al.; Diabetologia 52:1745-54 (2009)

insulin glargine comparator

people malignancies people malignancies

studies (n) (n)

people (n (%))

events (n)

(n)

people (n)

events (n)

All studies 31 5657 45 (0.8) 52 5223 46 (0.9) 48

Type 1 diabetes 12 1712 6 (0.4) 7 1526 2 (0.1) 2

Type 2 diabetes 19 3945 39 (1.0) 45 3697 44 (1.2) 46

vs NPH ≤1 yr 10 2363 13 (0.6) 15 2058 13 (0.6) 14

vs NPH >1 yr 1 514 20 (3.9) 23 503 31 (6.2) 32

vs oral agents 5 693 3 (0.4) 3 728 0 (0.0) 0

vs non-NPH insulin 3 375 3 (0.8) 4 368 0 (0.0) 0

In NPH ≤1 yr is included one premix study

Results : malignancy rates (1)

16Home & Lagarenne Diabetologia 52:2499-2506 (2009)

insulin glargine comparator

people malignancies people malignancies

studies (n) (n)

people (n (%))

events (n)

(n)

people (n)

events (n)

All studies 31 5657 45 (0.8) 52 5223 46 (0.9) 48

Relative risk

0.90 (95% CI: 0.60–1.36)

Results : malignancy rates (2)

17Home & Lagarenne Diabetologia 52:2499-2506 (2009)

Metabolic and mitogenic potency of glargine metabolites

Metabolic potency Mitogenic potency

IR-Baffinity

CHO-IRautophos

Metabolicpotency

hlGF-IRautophos

Mitogenicpotencya

Glargine [M0] ~0.5 ~0.45 ~0.8 ~2.6 8–12

Insulin GlyA21ArgB31 ~0.45 ~0.44 ~0.8 ~1.4 ~2.7

Insulin GlyA21 [M1] ~0.5 ~0.6 ~0.8 <0.2 ~0.6

Insulin GlyA21desB30 [M2] ~0.5 ~0.8 ~0.8 ~0.3 ~0.6

Agin A, et al. Diabetes Metab 2007;33:205−212Sommerfeld MR et al. (2010) PLoS ONE 5(3): e9540. doi:10.1371/journal.pone.0009540

IR: insulin receptor; IR-B: insulin receptor binding; CHO-IR: cells expressing normal human insulin receptor; autophos: autophosphorylation; hIGF-IR: human IGF-1 receptor.

aSaos-2 cells.

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Metformin: Effects on insulin, IGF-1, mTOR

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Progression to solid tumour cancers in people with T2DM

Currie CJ et al.; Diabetologia 52:1766-77 (2009)

Covariate HR 95% CI p valueTreatment - Metformin 1- Sulfonylureas 1.36 1.19-1.54 <0.001- Metformin + SH 1.08 0.96-1.21 0.21- Insulin-based therapies 1.42 1.27-1.60 <0.001

Increased incidence of pancreatitis and cancer among patients given GLP-1 based therapy

oder: vom Winde verweht

Elashoff M et al. Gastroenterology, 2011 published online

Conclusion• Diabetes and obesity are associated with

increased risk of cancer• Risk associated with insulin treatment?

– Insulin is mitogenic / mutagenic – Insulin may accelerate carcinogenous process– Risk associated with Lantus (probably) similar to other

insulins• Risk associated with SU, DPP-4 inhibitors,

GLP-1 agonist?• Risk associated with Pioglitazone?• Metformin seems to protect against cancer

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