Diabetes Mellitus and Cancer

Diabetes and Cancer

Mathew John, MD, DM, DNB

Providence Endocrine & Diabetes Specialty Centre

Trivandrum, India

www.endocrinologydiabetes.com

http://www.guardian.co.uk/society/2008/oct/06/health.cancer

Agenda

Diabetes and Cancer

Insulin, its receptor , IGF-1 and cancer pathogenesis

Diabetes therapies and cancer Diabetes therapies and cancer

Insulin and Analogs

Metformin

Glitazones

ARB

Introduction

Worldwide cancer is the 2nd and diabetes in the 12 th common cause of death

Cancer and diabetes are diagnosed within the same Cancer and diabetes are diagnosed within the same individual more frequently than would be expected by chance, even after adjusting for age

Causes of CancerEstimate percentage of total cancer deaths attributable to established causes of cancer

Dileep G. Bal, M.D., Diet and Cancer

Diabetes and CancerA Metaanalysis

Vigneri et al . Endocrine-related Cancer. E pub ahead of print 2009. Source: http://erc.endocrinology-journals.org, Accessed 4th September 2009

Risk factors for diabetes and cancer

Non modifiable

Age

Sex

Race/Ethnicity

Modifiable

Diet

Overweight/Obesity

Physical activity

Smoking Smoking

Alcohol

GIOVANNUCCI E ,Diabetes and Cancer A consensus report Diabetes Care 33:16741685, 2010

Risk factors for Diabetes & Cancer

D

I

A

B

E

T

E

S

Non modifiable

Age

Sex

Race/Ethnicity

Modifiable

Diet

Overweight/Obesity

Physical activity

Smoking

C

A

N

C

E

R

D

I

A

B

E

T

E

S

Smoking

Alcohol

Made by data from GIOVANNUCCI E ,Diabetes and Cancer A consensus report Diabetes Care 33:16741685, 2010

Obesity and Cancer

The cancers most consistently associated with overweight and obesity are those of the

Breast

Colon/rectum

Endometrium

Liver

Growing body of evidence suggests that weight gain is associated with an increased risk of some cancers, breast cancer in particular

Endometrium

Pancreas

Esophagus,


Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies

Summary risk estimates by cancer sites in men Summary risk estimates by cancer sites in women

Lancet 2008; 371: 56978

Diet and Cancer

Picture removed Picture removed

Fruits and vegetables Red meat

Meat and colorectal cancer

Processed meat Red meat

Sandhu MS et al. CEBP 2001;10:439- 446

Vegetables and Colorectal CancerProspective Cohort Studies


Whole grains & cancerProspective cohort studies


Epidemiological studies of physical activity and colon and colorectal cancer risk

Prospective studies

CM. Friedenreich Physical Activity and Cancer Prevention: From Observational to Intervention Research Cancer Epidemiology, Biomarkers & Prevention Vol. 10, 287301, April 2001

Tobacco Smoking

Tobacco smoking accounts for 71% of all trachea, bronchus, and lung cancer deaths

Smoking is also an Smoking is also an independent risk factor for the development of diabetes


Alcohol

Moderate alcohol consumption increases the risk of many types of cancer including those of the oral cavity, pharynx, larynx, esophagus, liver, colon/rectum, and female breastand female breast

Excess alcohol consumption is also a risk factor for diabetes


Diabetes & CancerInterpreting associations

Many risk factors for CANCER are also risk factors for

DIABETES

Exercise caution in interpreting associations between

DIABETES and CANCER DIABETES and CANCER

Pathogenesis of Cancer


The link

The most plausible hypothesis linking diabetes and

diabetes therapies to cancer is via the

Insulin and IGF-1 receptor

M. Pollak, D. Russell-Jones Insulin analogues and cancer risk: cause for concern or cause ce le` bre?Int J Clin Pract, April 2010, 64, 5, 628636

Insulin IGF-1

Cancer cells express Insulin receptor isoform A and IGF-1 receptors

Insulin, IGF-1

Insulin Receptor

IGF-1 Receptor

Metabolic effectsGlucose transport Glycogen synthesis Protein synthesis

Growth effectsRNA & DNA synthesisCell proliferation Cell survival

and IGF-1 receptors

Insulin receptor can induce Mitogeneis

Insulin receptor, IGF-1 receptors and hybrid receptors

Diabetes therapies and cancer

Insulin & Insulin Analogs

Metformin

Thiazolidinediones

Secreatgogues

GLP-1 associated agents GLP-1 associated agents

Angiotensin receptor blockers

Differences between insulins in receptor binding properties.

AnalogueInsulin receptor

affinity (%)Insulin receptor

off-rate (%)Metabolic potency

(lipogenesis) (%)IGF-I receptor

affinity (%)Mitogenic

potency (%)

Human insulin 100 100 100 100 100

B10Asp 205 20 14 1* 207 14 287 50 975 173B10Asp 205 20 14 1* 207 14 287 50 975 173

Aspart 92 6 81 8* 101 2 81 9 58 22

Lispro 84 6 100 11 82 3 156 16 66 10Glargine 86 3 152 13 60 3 641 51 783 132

A21Gly 78 10 162 11 88 3 42 11 34 12

B31B32diArg 120 4 75 8 75 5 2049 202 2180 390

Detemir 46 5/18 2 204 9 ca 27 16 1 ca 11

Kurtzhals P, Schffer L, Srensen A et al. Correlations of receptor binding and metabolic and mitogenicpotencies of insulin analogs designed for clinical use. Diabetes 2000; 49: 9991005

Insulin-Receptor Interaction

Insulin/ Insulin Analog

IGF-1 Receptor

InsulinReceptor(IR)

Different insulin analogs have different affinities to insulin

receptor and IGF-1 receptor

Mitogenic potential of insulin

Increased duration at IR

Increased affinity at IGF-1 R

Other experimental data

Pancreatic cancer cell line responded similarly to HI and Glargine

Erbel S, Diabetes Care 2008, 31: 1105

Colorectal, breast and prostate cell lines showed proliferative changes and resistance to apoptosis with proliferative changes and resistance to apoptosis with Glargine, Detemir,Lispro but not Human Insulin

Weinstein D, Diabetes Metab Res Rev 25: 41-49

Growth of malignant cell line MCF7 was strongly promoted by insulin Glargine , but not other insulins

Shukla A, Endocr Rel Cancer 2009 16: 429

Smith U, Gale EAM Diabetologia 2009; published online July 14. DOI:10.1007/ s00125-009-1441-5.

EASD requests investigators in Sweden, Scotland & UK to conduct similar population based studies

A cohort study from Germany shows dose dependent cancer risk with Lantus

(N=127031)

Significant increase in incidence of Ca. Breast

in women usingGlargine monotherapy

(N=114841)

Significant increase in incidence of all cancers

in people usingGlargine monotherapy

(N=49197)

No increased risk of cancer with

insulin analogues(N=10067)

Sweden Scotland UK

EASD communicates possible link between glargine and cancer

Criticism to studies

Observational study

Biological implausibility : short duration 1.31 years

Unexplained improvement of Glargine on all cause mortality

No difference between cancer risk in crude analysis

Different tumors : unlikely that one agent will produce different tumors

Smith U, Gale EAM Diabetologia 2009; published online July 14. DOI:10.1007/ s00125-009-1441-5.

Glargine : metaanalysis of

randomised controlled trials

31 studies, 12 in type 1 diabetes and 19 in type 2 diabetes. Twenty compared insulin Glargine with NPH insulin

Studies were generally of 6 months duration, except for trial Studies were generally of 6 months duration, except for trial reference number 4016 (n=1,017), which had a duration of 5 years.

Insulin Glargine was not associated with an increased incidence of cancer, including breast cancer, compared with the comparator group

P. D. Home & P. Lagarenne. Published online: 15 September 2009

Insulin glargine & malignancy : prospective studies

Ehninger G, Schmidt AH Putting Insulin Glargine and Malignancies into PerspectiveThe Oncologist 2009;14:11691174

Current recommendation

FDA

FDA recommends that patients should not stop taking their insulin

therapy without consulting a physician

American Association of Clinical EndocrinologistsAmerican Association of Clinical Endocrinologists

The AACE does not recommend that the use of any insulin be

changed.

The European Association for the Study of Diabetes(EASD)

Patients with diabetes taking Lantus should continue to do so, although

some might wish to consider alternative types of insulin

Accessed from FDA/AACE/EASD websites on 5/12/2009

Metformin

In laboratory models

Inhibit cell proliferation,

Reduce colony formation

Partial cell cycle arrest in cancer cell lines

Metformin and cancer prevention Mechanism

Activation of AMP kinase

Inhibits genes involved in gluconeogenesis

Chong CR, Chabner BA. Mysterious Metformin The Oncologist 2009;14:11781181

AMPK has role in tumor suppression

Metformin reduces cancer risk in type 2 diabetes

Chong CR, Chabner BA. Mysterious Metformin The Oncologist 2009;14:11781181

Metformin & Cancer Mortality

Adjusted HR of Metformin use for cancer mortality was 0.43 (0.230.80)

The hazard for cancer The hazard for cancer mortality decreased by 42% for every 1-g increase in the Metformin dose.

Landman GWD et al. Metformin Associated With Lower Cancer Mortality in Type 2 DiabetesZODIAC-16 Diabetes Care. 2010 Feb;33(2):322-6.

Thiazoliinediones and Cancer

In vitro studies

Inhibiting growth

Inducing apoptosis and cell differentiation

Rodent studies

PPAR gamma agonists have tumorogenic properties

differentiation

Inhibits invasion

Ohta K, Endo T, Haraguchi K, Hershman JM, Onaya T. J Clin Endocrinol Metab 2001;86:21702177Rubenstrunk A, Hanf R, Hum DW, Fruchart JC, Staels B. Biochim Biophys Acta 2007;1771:10651081Liu H, Zang C, Fenner MH. et al. PPAR gamma ligands and ATRA inhibit the invasion of human breast cancer cells in vitro. Breast Cancer Res Treat 2003; 79: 6374.Govindarajan R, Ratnasinghe L, Simmons DL. et al. Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes. J Clin Oncol 2007; 12: 14761481.

They have found 33% reduction in lung cancer risk among TZD users (RR 0.67; 95%; CI: 0.510.87)

Pioglitazone and bladder tumors

Bladder tumors were seen in male rats receiving a dose of pioglitazone

Ten-year, observational cohort study as well as a nested case-control study

No statistically significant association between any No statistically significant association between any Pioglitazone exposure and increased bladder cancer risk in the study (HR= 1.2, 95% CI: 0.9-1.5)

Risk of bladder cancer increased with increasing dose and duration of Pioglitazone use, reaching statistical significance after 24 months of exposure

http://www.fda.gov/Drugs/DrugSafety/ucm226214.htm

Insulin secretagogues

Limited studies linking secreatgogue use to malignancy

Very few cancer cases among users

GLP-1 associated agents

Liraglutide increased risk of medullary thyroid cancer in rats and mice in preclinical tests

In transgenic rodent model, the DPP-4 inhibitor sitagliptin was demonstrated to increase pancreatic sitagliptin was demonstrated to increase pancreatic ductal hyperplasia

No increase in human cancer incidence with these agents

Pathogenesis of CancerInsulin and Analogs


Insulin is unlikely to be Mutagenic Insulin is likely to be

mitogenic ( IR A and IGF1 Receptor

ARB and Cancer

Cancer occurrence reported in all included trials of Angiotensin-receptor blockers

Sipahi I ,Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomized controlled trials Lancet Oncol 2010; 11: 62736

ARB and Cancer

ARBs are associated with a modestly increased risk of new cancer occurrence

RAAS is involved in regulation of cell proliferation, tumour growth, angiogenesis, and metastasistumour growth, angiogenesis, and metastasis

AT1R blockade with an ARB (which is associated

with unopposed AT2R stimulation) and direct stimulation

of AT2R are capable of stimulating tumour angiogenesis

in vivo.

Sipahi I ,Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomized controlled trials Lancet Oncol 2010; 11: 62736

Messages

Diabetes, obesity and insulin resistance are independently associated with cancer

The association between diabetes and cancer is confounded by different agentsconfounded by different agents

Insulin interaction with Insulin receptor and IGF-1 receptor forms the basis

Insulin analogs are likely to be mitogenic (not mutagenic)

Thank you

www.providence.co.in: for patient information materials

twitter.com/providenceendo : for slide presentations

Disclaimer

The material for these slides were derived from various sources including picturesand cartoons from the world wide web. I have tried my best to acknowledge allpossible sources and references. However, if I have overlooked any particularreference, it is not done intentionally. Anyone reproducing materials from thispresentations should acknowledge the author of the original work. The case given isimaginary and is given only to support the purpose of this talk. Any similarity topublished case report/ patient is unintentional.

Health & Medicine

Diabetes Mellitus and Cancer