Diabetes and Cancer The 2013-14 Diabetes Algorithm • Daniel Einhorn • President, American College of Endocrinology • Medical Director, Scripps Whittier Diabetes Institute • Clinical Professor of Medicine, UCSD

Links to websites • Diabetes and Cancer Consensus Statement: https://www.aace.com/files/positionstatements/revised-with-appendix.pdf • AACE Comprehensive Diabetes Management Algorithm Consensus Statement: https://www.aace.com/files/algorithm-07-11-2013.pdf • Algorithm slides: https://www.aace.com/files/aace_algorithm_slides.pptx

Diabetes and Cancer Consensus Conference Endocrine Practice

• Epidemiology of the associations among obesity, insulin resistance, diabetes, and cancer • Biologic links between diabetes and cancer • Do diabetes treatments influence risk of cancer or its prognosis?

Obesity is linked to specific cancers • Every year 100,500 new cases of cancer are caused by Obesity: • • • • • • •

Breast, 33,000. Endometrial, 20,700 Kidney, 13,900 Colorectal, 13,200 Pancreas, 11,900. Esophagus, 5,800. Gallbladder, 2,000.

American Institute for Cancer Research: Reported USA TODAY 11-5-09

Cancer Deaths Associated with Obesity

Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Calle EE et al. N Engl J Med. 2003;348:1625-1638.

Fasting Plasma Triglycerides and Premenopausal Breast Cancer Risk •

premenopausal women scheduled for breast surgery

•

biopsies classified according to level of breast cancer risk (NP, PDWA, AH/C’s, IC)

•

monotonic increase fasting TG with increasing risk level

•

102 NP, 102 IC (N0)

Breast Cancer Risk According to Plasma TG Quintile

TG (mg/ml)

RR Breast Cancer * (95% CI)

1

0.34-0.62

1.0

2

0.63-0.78

0.75 (0.31-1.90)

3

0.79-0.95

1.13 (0.45-2.84)

4

0.96-1.23

1.64 (0.64-4.20)

5

1.24-2.61

2.48 (0.91-6.75)

* age, weight adjusted, p=0.007 Goodwin PJ et al. Nutrition and Cancer 1997

Fasting Insulin and Breast Cancer Risk • Case-control design • 99 premenopausal T1-3, N0-1, M0 BC • 99 age-matched premenopausal controls with non-proliferative breast biopsies Insulin Quintile

Level (pmol/L)

Odds Ratio (95% CI) for Breast Cancer (age, weight adjusted)

I

≤ 35

1.0

II

>35 - ≤41

1.19 (0.49 – 2.89)

III

>41 - ≤47

1.33 (0.53 – 3.35)

IV

>47 - ≤58

1.19 (0.48 – 2.93)

V

>58 - ≤180

3.72 (1.32 – 10.5)

P (insulin) = 0.02 (2-tail) Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Del Giudice ME. Breast Cancer Res Treat. 1998;47:110-120.

Insulin Receptor Expression and Breast Cancer Survival

Mathieu et al. Proc Assoc Am Physicians. 1997 ;109(6):565-71

BMI & Cancer Risk (men)

Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Renehan AG et al. Lancet. 2008;371:569-578.

BMI & Cancer Risk (women)

Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Renehan AG et al. Lancet. 2008;371:569-578.

BMI & risk of second primary cancer

Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Druesne-Pecollo N et al. Breast Cancer Res Treat. 2012;135:647-654.

BMI (post-diagnosis) & breast cancer Breast cancer-specific survival

Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Niraula S et al. Breast Cancer Res Treat. 2012;134:769-781.

Diabetes and Cancer Mortality • Post-operative cancer patients with T2DM have ~85% higher overall mortality compared to patients without T2DM – adjusted for confounders the increased mortality is ~50%

Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Barone BB et al. Diabetes Care. 2010;33:931-939.

Glycemia-cancer relationship: Men

Stocks T et al., PLoS Medicine 2009;6: e1000201

Glycemia-cancer relationship: Women

Stocks T et al., PLoS Medicine 2009;6: e1000201

MOLECULAR MECHANISMS

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How Can the Metabolic Syndrome, Obesity, and Type 2 Diabetes Affect Cancer Development and Metastases? Nutrients IGF-I Leptin Adiponectin Cytokines Chemokines Estrogen

Diabetes

Obesity

Hyperinsulinemia Hyperglycemia Hyperlipidemia

Cancer

Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

LeRoith D. Presented at: AACE Annual Meeting; May 2013.

Multistage Carcinogenesis

Promotion Promotion

Progression

Initiation Initiation Normal Normal

Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Study Subject Estimated Lag Time Mice

20 to 50 weeks

Humans

20 to 50 years

Adapted from: Hursting SD et al. JNCI. 1999;91:215-225. Abel EL et al. Nat Protoc. 2009;4:1350-1362. Loeb LA et al. Cancer Res. 2008;68:6863-6872.

Cellular Requirements for Tumor Biosynthesis • Tumor cells depend on multiple energy sources not just glucose • Genetic mutations and altered metabolism also support tumor growth

Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Vander Heiden MG et al. Science. 2009;324:1029-1033. Christofk HR et al. Nature. 2008;452:230-233.

Insulin resistance

Mammary epithelium: ↑↑↑ IR ↑ IGF-IR ↑ IR/IGF-IR

↑ Insulin

Blood and tissue: ↓ IGFBP-1

−IGF-1/2 serum and/or tissue bioavailability

↓ Apoptosis ↑ Proliferation ↑ IGF

↑ Tumor development IGF-IR IR IR/IGF-IR hybrids

from Derek LeRoith

Obesity, Insulin, and IGF-1 • Increased BMI has been directly related to increased insulin and free insulin-like growth factor-1 (IGF-1) levels.

Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Roberts DL et al. Annu Rev Med. 2010;61:301-316.

Pathways Linking Obesity with Breast Cancer

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Dannenberg A. Presented at: AACE Consensus Conference on Diabetes and Cancer; September 2012.

Potential Mechanisms Linking Diabetes and Cancer

Macrophage infiltration of adipose tissue  IL-6, IL1-beta

Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Calle EE et al. Nat Rev Cancer. 2004;4:579-591.

Insulin, Insulin-like Growth Factors, and Receptors IGF-I

IGF-2

Insulin

ß

ß

IGF-I Receptor

Cell Survival, Growth, Proliferation Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

αα

αα

αα ß

ß

ß

ß

Insulin Insulin Receptor-A Receptor-B High expression in fetal and neoplastic tissues

Metabolic Effects LeRoith D. Presented at: AACE Consensus Conference on Diabetes and Cancer; September 2012.

Hyperinsulinemia and Cancer (Indirect Effects) Indirect Effects

↑IGF-1 ↓IGFBP-1/2

↑Aromatase ↓SHBG ↑Estrogen

↑Glucose ↑Free fatty acids ↑Amino acids Figure 2B Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Obesity

↑Inflammatory Adipokines; TNF, IL-6 ↓Protective Adipokines; Adiponectin

↓AMP-kinase

↑Protein translation mTOR/p70S6K Fantus IG. Presented at: AACE Consensus Conference on Diabetes and Cancer; September 2012.

DIABETES MANAGEMENT & CANCER RISK Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Metformin Associated with Lower Cancer Risk in Type 2 Diabetes

Diabetes Care 33:322-326, 2010

Metformin Associated with Lower Cancer Risk in Type 2 Diabetes

Diabetes Care 33:322-326, 2010

Effect of Metformin in WHI •

Women’s Health Initiative – No diabetes 2,926 – Diabetes metformin 104 – Diabetes other tx 129

•

Hazard Ratio adjusting for age, firstdegree relative with breast cancer, benign breast disease, age at menarche, age at menopause, parity, age at first birth, education, No. of months of breastfeeding, smoking, alcohol consumption, body mass index, physical activity, duration of use of estrogen alone, duration of use of estrogen plus progesterone, bilateral oophorectomy, mammogram within 2 years of baseline P=0.04 Chlebowski et al. J Clin Oncol 2012;30:2844

Metformin: esophageal adenocarcinoma pathologic complete response

Skinner et al. Acta Oncologica, 2012

TZD, metformin: prostate ca survival

He et al. Ann Oncol 2011;22:2640-5

Insulin Therapy and Cancer

Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Malignant Neoplasm in Diabetic Patients with Different Insulin Doses (Glargine vs. Human Insulin) • N=127,031 T1 and T2 insulin-treated patients. 95,804 human insulin, 23,855 glargine, followed up to 4.4 years (mean 1.6 years), cancer-free in preceding 3 years. Incidence per 1,000 patient-years (95% CI) 40 U/d

Glargine

18.6 (16.5-20.7)

20.3 (17.9-22.9)

52.6 (42.9-63.8)

Human Insulin

17.3 (16.1-18.6)

23.6 (22.3-25.0)

31.0 (29.6-32.3)

Note high rates of new cancer in the study Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Hemkens LG et al. Diabetologia. 2009;52:1732-1744.

ORIGIN Trial Results

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Presented at: 72nd Scientific Sessions of the American Diabetes Association, 2012.

The ORIGIN Trial: Lack of Association of Insulin Glargine with Malignancy Insulin

Control

P-value

Cancer death

3.0%

3.0%

N.S.

Breast cancer

0.4%

0.4%

N.S.

Lung cancer

1.3%

1.1%

N.S.

Colon cancer

1.2%

1.1%

N.S.

Prostate cancer

2.1%

2.2%

N.S.

Melanoma

0.2%

0.3%

N.S.

Other cancer

3.7%

3.9%

N.S.

Total cancers

8.9%

9.0%

N.S.

N.S., not significant Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

ORIGIN Trial Investigators, Gerstein HC et al. N Engl J Med. 2012;367:319-328.

Meta-analysis: Insulin Glargine and Cancer Risk • Findings from an European Medicines Agency (EMA)commissioned database study indicate significantly decreased risk of all cancer and prostate cancer (glargine vs. non-glargine use). Cancer Type

Cancer Incidence Summary Relative Risk (95% CI)

All cancer

0.90 (0.82 – 0.99)

Colorectal

0.84 (0.74 – 0.95)

Breast

1.11 (1.00 – 1.22)

Prostate

1.30 (1.00 – 1.28)

Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Boyle P et al. Presented at: 72nd Session of the American Diabetes Association. 2012. Poster 1332-P.

Meta-analysis: Insulin Glargine and Cancer Risk • Data from the Inovalon MORE 2 registry and the Kaiser Permanente Northern California (KPNC) database showed no significant increased risk of all cancer incidence (glargine Database All Cancer Incidence vs. NPH use) Hazard Ratio (95% CI) Inovalon MORE 2 Registry

1.12 (0.95 – 1.32)

KPNC

0.90 (0.90 – 1.00)

Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Sturmer T et al. Diabetes Care. 2013 July 22 [Epub ahead of print]. Habel L. Presented at: 72nd Session of the American Diabetes Association. 2012. CT-SY13.

GLP-1 Agonists and Calcitonin • Plasma calcitonin levels did not increase in patients with T2DM treated with liraglutide or comparator for two years in the Phase III LEAD-2 & -3 trials (Figures A, B, and C) • Plasma calcitonin also did not increase in LEAD-6 (liraglutide vs. exenatide BID)

Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Bjerre Knudsen L et al. Endocrinology. 2010;151:1473-1486. Hegedüs L et al. J Clin Endocrinol Metab. 2011;96:853-860.

Thyroid Neoplasms in RCTs • No great disparity in the incidence of thyroid neoplasms has been observed between GLP-1 receptor agonists and placebo or active comparator. GLP-1 Agonist

Treatment Group Incidence Rate

Liraglutide

Liraglutide

1.3 cases per 1000 patient-years

Placebo

1.0 cases per 1000 patient-years

Exenatide BID

0.3 cases per 100 patient-years

Comparator

0 cases per 100 patient-years

Exenatide BID

BID, twice daily; GLP, glucagon-like peptide; RCT, randomized controlled trial

Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Novo Nordisk. VICTOZA (liraglutide) U.S. Prescribing Information, April 2012. MacConell L et al. Diabetes Metab Syndr Obes. 2012;5:29-41.

GLP-1 agonists increase β-cell mass in rodents

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Spranger J et al. Gastroenterology. 2011;141:20-23.

Do TZDs  bladder cancer?

Pioglitazone studies

Rosiglitazone studies

Colmers et al. CMAJ 2012; 184:E675-E683

i3 Database Analysis of Bladder Cancer and Nine Other Cancers: Overall Conclusions • In a US population of T2DM adults > 45 years from the i3 InVision health claims database, the risk of bladder cancer with PIO is similar to that with Insulin • The risk of developing nine other common cancers (prostate, female breast, lung, pancreatic, endometrial, non-Hodgkin’s lymphoma, colorectal, kidney and malignant melanoma) associated with the use of PIO is 22% lower than the risk associated with the use of Insulin. • Although a large number of covariates was used in the models, residual confounders may potentially remain. Perez A, et al. Presented at: 72nd Scientific Sessions of the American Diabetes Association. Philadelphia, PA. June 8-12, 2012. Abstract 930-P.

Cancer reporting from clinical trials • Analyses of individual trials – – – – –

ORIGIN ADVANCE PROACTIVE RECORD ADOPT

• Metaanalyses

– Rosiglitazone metaanalysis – Intensive treatment trials metaanalysis

• Sample size considerations

CLINICAL IMPLICATIONS OF CANCERS IN OBESE & DIABETIC PATIENTS 1. ANNUAL MAMMOGRAM AND RELATED BREAST SCREENING FOR BREAST CANCER BY AGE 40 2. PATIENTS WITH PCOS, MAY REQUIRE EARLIER CANCER SCREENING, PERHAPS AS SOON AS AGE 30 . 3. EARLIER SCREENING COLONOSCOPY SHOULD BE ENCOURAGED BY AGE 40. 4. REGULAR SKILLED SKIN EVALUATIONS 5. IN PATIENTS WITH MALIGNANCIES IN CERTAIN ORGANS, THOSE ANTI-DIABETIC AGENTS WHICH MAY BE ASSOCIATED WITH EXCESS MALIGNANCY RISK IN THOSE ORGANS SHOULD BE AVOIDED. 6. PATIENTS WITH DIABETES UNDERGOING TREATMENT FOR MALIGNANCIES SHOULD HAVE RIGOROUS DIABETES CONTROL. FOR PATIENTS IN-HOSPITAL, AGGRESSIVE GLYCEMIC MANAGEMENT HAS BEEN ASSOCIATED WITH IMPROVED OUTCOMES.

And There is Still More for 2014-15 • • • • • • •

Cancer Sleep apnea Depression Dental disease Osteoporosis Fatty Liver Disease Dementia of Multiple Etiologies

Agenda • Diabetes and Cancer • New Diabetes Treatment Algorithm • New Class of Diabetes Medication

The Role of SGLT-2 Inhibitors in the Management of Patients with Type 2 Diabetes

January 10, 2013 FDA Advisory Committee Recommends Approval of Canagliflozin for Treatment of Adults with Type 2 Diabetes

http://pharmalive.com/News/index.cfm (accessed 1/14/2013)

SGLT-2 Inhibitor – kidney is target organ Renal glucose reabsorption Gluco se Proximal tubule S1 segment

SGLT2 ~90% glucose reabsorp tion SGLT-1 ~10% glucose reabsorp tion

Collectin g ducts S3 segment

SGLT-2 Inhibitor – Mechanism of Action Gluco se

SGLT2 Inhib itors Glucosur ia Loss of calories

Qualities that Make these Clinically Attractive • • • • • • • • •

1) one tablet 2) once daily 3) anytime (AM recommended) 4) lower BG as well as any pill 5) no hypoglycemia 6) weight loss (3-5% body weight) 7) blood pressure lowering 8) non-insulin-dependent MOA 9) minimal LDL and no TG elevation

Qualities that Make them Less Attractive • • • • • • •

1) bladder and genital infections 2) dehydration/hypotension 3) need good renal function 4) insurance hassles of being new 5) the unknowns with a new med 6) ? bladder cancer signal with dapa 7) LDL elevation (2-3 mg/dl)

A1c Lowering: Canagliflozin vs Sitagliptin Metformin + Canagliflozin Dose-Ranging Study Mean Baseline A1C (%)

7.71 8.01 7.81 7.57 7.70 7.71 7.62

*

*

*

* * Rosenstock J, et al. Abstract 77-OR. ADA 2010.

* *P˂.001 vs. placebo calculated using LS means

Weight Loss: Canagliflozin vs Sitagliptin Mean Baseline Weight (kg)

Metformin + Canagliflozin Dose-Ranging Study 85.5 87.5 87.7 87.7 87.8 86.3 87

* * *

**

* *

** **

Rosenstock J, et al. Abstract 77-OR. ADA 2010.

* *P˂.001 vs. placebo calculated using LS means

Canagliflozin monotherapy vs Placebo in Patients with T2D – Effect on A1c

Stenlöf et al, Diabetes Obes Metab. 2012 Dec 26. [Epub ahead of print]

Canagliflozin monotherapy vs Placebo in Patients with T2D - % to goal and PPG

Stenlöf et al, Diabetes Obes Metab. 2012 Dec 26. [Epub ahead of print]

Canagliflozin monotherapy vs Placebo in Patients with T2D Weight Change

Stenlöf et al, Diabetes Obes Metab. 2012 Dec 26. [Epub ahead of print]

Canagliflozin Trials • Symptomatic genital infections in 3-8% canagliflozin arms – 2% placebo – 2% SITA

• Urinary tract infections in 3-9% canagliflozin arms – 6% placebo – 2% SITA

• Hypoglycemia in 0-6% canagliflozin arms – 2% placebo – 5% SITA

Rosenstock J, et al. Abstract 77-OR. ADA 2010.

SUMMARY: SGLT2 INHIBITION IN DIABETES cotransporter 2 (SGLT2) is the major cotransporter  Sodium–glucose involved in reabsorption of filtered glucose in the tubular nephron of the kidney

 Chronic hyperglycaemia in patients with diabetes mellitus might

upregulate glucose reabsorption in the kidneys above normal levels

inhibitors lower the threshold for glycosuria by lowering the  SGLT2 maximum transport capacity or, more likely, by reducing the affinity of the transporter for glucose without causing hypoglycaemia

 SGLT2 inhibitors cause proximal diuresis and calorie leakage into the urine; therefore, the benefits of these agents could include blood pressure lowering and weight control

 Increased risk of genitourinary infections is a consistent adverse effect of SGLT2 inhibitors

Perspectives on SGLT2 Inhibition • Advantages – Improved glycemic control – Weight loss (75g urine glucose = 300kcal/d) – Low risk of hypoglycemia – Blood pressure lowering – One pill once daily

• Concerns – Polyuria – Electrolyte disturbances – Bacterial urinary tract infections – Fungal genital infections – Malignancies (?)

Summary of Diabetes Trifecta 2013 • Diabetes and Cancer

– Diabetes = more and worse cancer – Diabetes treatments likely don’t cause cancer

• New Diabetes Control Algorithm

– Incorporates pre-diabetes, obesity, and insulin – Prescriptive statemenst of what to use, when, and how

• New Class of Agents to Treat Diabetes

– Simple, effective, weight loss, no hypos, compatible – But new always brings hassles and risks – we’ll see