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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/position-statements/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

Calle EE et al. N Engl J Med. 2003;348:1625-1638. Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

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)

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

P (insulin) = 0.02 (2-tail)

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

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

Insulin Receptor Expression and Breast Cancer Survival

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

BMI & Cancer Risk (men)

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

BMI & Cancer Risk (women)

Renehan AG et al. Lancet. 2008;371:569-578. Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

BMI & risk of second primary cancer

Druesne-Pecollo N et al. Breast Cancer Res Treat. 2012;135:647-654. Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

BMI (post-diagnosis) & breast cancer

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

Breast cancer-specific survival

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

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%

Barone BB et al. Diabetes Care. 2010;33:931-939. Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

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

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

How Can the Metabolic Syndrome, Obesity, and Type 2 Diabetes Affect Cancer Development and

Metastases?

Hyperinsulinemia Hyperglycemia Hyperlipidemia

Nutrients IGF-I Leptin Adiponectin Cytokines Chemokines Estrogen

Obesity Diabetes

Cancer

LeRoith D. Presented at: AACE Annual Meeting; May 2013. Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Normal

Initiation

Promotion Progression

Promotion

Initiation

Normal

Multistage Carcinogenesis

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.

Study Subject Estimated Lag Time Mice 20 to 50 weeks Humans 20 to 50 years

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

Cellular Requirements for Tumor Biosynthesis

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

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

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

Insulin resistance ↑ Insulin

Blood and tissue: ↓ IGFBP-1

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

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

↑ IGF

↓ Apoptosis ↑ Proliferation

↑ 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.

Roberts DL et al. Annu Rev Med. 2010;61:301-316. Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Pathways Linking Obesity with Breast Cancer

Dannenberg A. Presented at: AACE Consensus Conference on Diabetes and Cancer; September 2012. Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Potential Mechanisms Linking Diabetes and Cancer

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

Calle EE et al. Nat Rev Cancer. 2004;4:579-591. Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Insulin, Insulin-like Growth Factors, and Receptors

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

Metabolic Effects Cell Survival,

Growth, Proliferation

IGF-I Insulin

Insulin Receptor-A

ß ß

α α

ß ß

α α

Insulin Receptor-B

IGF-I Receptor

ß ß

α α

High expression in fetal and neoplastic

tissues

IGF-2

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

Indirect Effects

↑IGF-1 ↓IGFBP-1/2 ↑Aromatase

↓SHBG ↑Estrogen

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

↑Glucose ↑Free fatty acids ↑Amino acids

↓AMP-kinase

↑Protein translation mTOR/p70S6K

Figure 2B

Hyperinsulinemia and Cancer (Indirect Effects)

Fantus IG. Presented at: AACE Consensus Conference on Diabetes and Cancer; September 2012. Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

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, first-

degree 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.

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

Incidence per 1,000 patient-years (95% CI)

<20 U/d 20-40 U/d >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.

ORIGIN Trial Results

Presented at: 72nd Scientific Sessions of the American Diabetes Association, 2012. Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

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.

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

N.S., not significant

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

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).

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

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.

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 vs. NPH use)

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.

Database All Cancer Incidence 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.

GLP-1 Agonists and Calcitonin

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

• 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.

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 Exenatide BID 0.3 cases per 100 patient-years

Comparator 0 cases per 100 patient-years

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

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.

GLP-1 agonists increase β-cell mass in rodents

Spranger J et al. Gastroenterology. 2011;141:20-23. Copyright © 2013 AACE. May not be reprinted in any form without express written permission from AACE.

Do TZDs bladder cancer?

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

Pioglitazone studies Rosiglitazone studies

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

Glucose

Proximal tubule

S1 segment

SGLT2 ~90%

glucose reabsorption

SGLT-1 ~10%

glucose reabsorption

S3 segment

Collecting ducts

SGLT-2 Inhibitor – Mechanism of Action

Glucose

SGLT-2

Inhibitors

Glucosuria 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

*P˂.001 vs. placebo calculated using LS means Rosenstock J, et al. Abstract 77-OR. ADA 2010.

Metformin + Canagliflozin Dose-Ranging Study Mean Baseline

A1C (%) 7.71 8.01 7.81 7.57 7.70 7.71 7.62

*

*

*

* *

*

Weight Loss: Canagliflozin vs Sitagliptin

Metformin + Canagliflozin Dose-Ranging Study

*P˂.001 vs. placebo calculated using LS means Rosenstock J, et al. Abstract 77-OR. ADA 2010.

Mean Baseline Weight (kg)

* *

*

*

*

*

*

*

* *

*

*

85.5 87.5 87.7 87.7 87.8 86.3 87

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

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

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.

Sodium–glucose cotransporter 2 (SGLT2) is the major cotransporter 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

SGLT2 inhibitors lower the threshold for glycosuria by lowering the 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

SUMMARY: SGLT2 INHIBITION IN DIABETES

Perspectives on SGLT2 Inhibition

• Concerns – Polyuria – Electrolyte disturbances – Bacterial urinary tract

infections – Fungal genital infections – Malignancies (?)

• Advantages – Improved glycemic

control – Weight loss (75g urine

glucose = 300kcal/d) – Low risk of hypoglycemia – Blood pressure lowering – One pill once daily

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