Joslin Diabetes Center Advances in Diabetes and Thyroid Disease 2013 Critical Literature Analysis: 3 Recent Journal Articles

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1 Critical Literature Review: Diabetes Therapeutics November 7 th, 2013 Jason Gaglia MD, MMSc Assistant Investigator, Joslin Diabetes Center Assistant Professor, Harvard Medical School Specific Therapeutics to be Discussed Insulin Glargine and Cancer Risk Pioglitizone and Bladder Cancer Risk Incretin Mimetics, Pancreatitis, and Pancreatic Cancer Development of Insulin Analogs Sequences of Various Insulins (natural and analogs) A-Chain Position B-Chain Position Insulin A-8 A-10 A-21 B-3 B-10 B-28 B-29 B30 B-31/32 Human Thr Ilc Asn Asn His Pro Lys Thr N/A Bovine Ala Val Asn Asn His Pro Lys Ala N/A Porcine Thr Ilc Asn Asn His Pro Lys Ala N/A (also dog) Aspart Thr Ilc Asn Asn His Asp Lys Thr N/A Glulisine Thr Ilc Asn Lys His Pro Glu Thr N/A Lispro Thr Ilc Asn Asn His Lys Pro Thr N/A Detemir Thr Ilc Asn Asn His Pro Lys Myristic acid N/A Glargine Thr Ilc Gly Asn His Pro Lys Thr Arg/Arg B10Asp Thr Ilc Asn Asn Asp Pro Lys Thr N/A 1

2 Mitogenic Potential of Insulin Analogs Insulin B10Asp was the first of the insulin analogs developed. It has higher affinity for the insulin and IGF-1 receptors than native insulin, and higher mitogenicity in vitro. Insulin (U/kg/day) Mammary Tumors Saline Human 200 B10Asp 12.5 B10Asp 50 B10Asp 200 Benign % 0 44% Malignant % 23% Female rats were injected for one year with saline or insulin as indicated. A dosedependent increase in incidence of mammary tumors was found on necropsy. No other neoplastic lesions were found. Jorgensen LN et al. Diabetologia. 1992;35(Suppl 1):A3. Conclusions/interpretation Considering the overall relationship between insulin dose and cancer, and the lower dose with glargine, the cancer incidence with glargine was higher than expected compared with human insulin. Our results based on observational data support safety concerns surrounding the mitogenic properties of glargine in diabetic patients. Prospective long-term studies are needed to further evaluate the safety of insulin analogs, especially glargine. Hemkens LG et al. Diabetologia. 2009;52: Mitogenic Potential of Insulin Analogs Analog Insulin Receptor Affinity (%) Insulin Receptor Off-Rate (%) Metabolic Potency (Lipogenesis) (%) IGF-1 Receptor Affinity (%) Mitogenic Potency (%) Human B10Asp 205 ± ± ± ± ± 173 Aspart 92 ± 6 81 ± ± 2 81 ± 9 58 ± 22 Lispro 84 ± ± ± ± ± 10 Glargine 86 ± ± ± ± ± 132 A21Gly 78 ± ± ± 3 42 ± ± 12 B31B32diArg 120 ± 4 75 ± 8 75 ± ± ± 390 Adapted from Kurtzhals PK et al. Diabetes. 2000;49:

3 Back to the Article Hemkens and colleagues utilized a large German insurance dataset to compare the rate of diagnosis of malignant tumors in patients treated with human insulin versus the insulin analogs aspart, lispro, and glargine. Those treated with multiple types of insulin were excluded. Included 127,031 individuals (39% of all those using insulin) 95,804 (75.4%) exclusively on human insulin 23,855 (18.8%) insulin glargine alone 4,103 (3.2%) insulin aspart alone 3,269 (2.6%) insulin lispro alone Hemkens LG et al. Diabetologia. 2009;52: The German Study (continued) First time insulin users, no evidence of malignancy for prior 3 years Type of diabetes (1 or 2) was not specified in the registry, weight not specified in the registry Primary outcome was malignancy of any type; secondary outcome was all cause mortality Mean follow up was 1.63 years for malignancy (maximum 4.41) and 1.67 years for mortality (maximum 4.41) Median age about 67 years Hemkens LG et al. Diabetologia. 2009;52: Crude Malignancy and Mortality Rates Insulin Time (yrs) Malignancy Rate (per 100 pt-yrs) Insulin Dose (U) Mortality Rate (per 100 pt-yrs) Mean ± SD Human ± Aspart 1.44* ± Lispro ± Glargine 1.31* ± *Mean duration of follow-up for glargine and aspart was shorter as these insulins were introduced to the German market later. Hemkens LG et al. Diabetologia. 2009;52:

4 HRs for Malignant Neoplasms Referenced to Human Insulin Covariate Aspart Lispro Glargine None 0.86 ( ) 0.85 ( ) 0.85 ( ) Final Model P=0.30 P=0.96 P< U 1.00 ( ) 0.99 ( ) 1.09 ( ) 30 U 1.02 ( ) 0.98 ( ) 1.19 ( ) 50 U 1.04 ( ) 0.98 ( ) 1.31 ( ) Hemkens LG et al. Diabetologia. 2009;52: HRs for Mortality Referenced to Human Insulin Covariate Aspart Lispro Glargine None 0.63 ( ) 0.75 ( ) 0.68 ( ) Final Model P=0.14 P=0.47 P< U 0.91 ( ) 0.96 ( ) 0.76 ( ) 30 U 0.90 ( ) 0.95 ( ) 0.96 ( ) 50 U 0.89 ( ) 0.94 ( ) 1.20 ( ) Hemkens LG et al. Diabetologia. 2009;52: Metabolism of Insulin Glargine Native insulin Insulin glargine A21Gly insulin A21Gly-des-30B-Thr After subcutaneous injection, insulin glargine is metabolized by sequential cleavage at the carboxy terminus of the B chain, yielding products including A21Gly and A21Gly-des- 30B-Thr insulins. On average about 50% of insulin recovered from fat from the site of injection are these two cleavage products and these products are also present and produced in the circulation after injection. A21Gly insulin has relatively low mitogenic potency. Kuerzel GU et al. Curr Med Res Opin. 2003;18: Agin A et al. Diabetes Metab. 2007;33: Kurtzhals PK et al. Diabetes. 2000;49:

5 Mitogenic Potential of Insulin Analogs Analog Insulin Receptor Affinity (%) Insulin Receptor Off-Rate (%) Metabolic Potency (Lipogenesis) (%) IGF-1 Receptor Affinity (%) Mitogenic Potency (%) Human B10Asp 205 ± ± ± ± ± 173 Aspart 92 ± 6 81 ± ± 2 81 ± 9 58 ± 22 Lispro 84 ± ± ± ± ± 10 Glargine 86 ± ± ± ± ± 132 A21Gly 78 ± ± ± 3 42 ± ± 12 B31B32diArg 120 ± 4 75 ± 8 75 ± ± ± 390 Adapted from Kurtzhals PK et al. Diabetes. 2000;49: Limitations of Observational Studies Large potential for bias The clinical decisions that determine each patient s treatment are not random Difficult to adjust for confounders Residual selection bias may distort any true differences (or lack thereof) Issues of reverse causality Multiple hypothesis testing may produce spurious results Small RCT Post Hoc Analysis Original study designed to assess ocular complications of diabetes with insulin glargine compared to NPH insulin (no difference seen) 1017 patients randomized and treated: 514 insulin glargine, 503 NPH insulin Cumulative exposure was greater than 4 years Baseline demographics between the two groups were similar No difference in number of neoplasms between the two groups (57 or 11.1% for insulin glargine and 62 or 12.3% for NPH insulin) Rosenstock J et al. Diabetologia. 2009;52:

6 RCT ORIGIN Trial Insulin glargine versus placebo in patients with impaired fasting glucose or newly diagnosed type 2 diabetes. 12,537 people randomized with median follow-up of 6.2 years. Median insulin use at year 6 was 0.4 U/kg. No significant difference in cancers (HR 1.00; 95% CI, 0.88 to 1.13; P=0.97) or death from cancers (HR 0.94; 95% CI, 0.77 to 1.15; P=0.52). ORIGIN Trial Investigators. N Engl J Med. 2012;367: Specific Therapeutics to be Discussed Insulin Glargine and Cancer Risk Pioglitizone and Bladder Cancer Risk Incretin Mimetics, Pancreatitis, and Pancreatic Cancer 6

7 Background Data on TZDs and Cancer PPAR ligands alter cell proliferation and differentiation in human cancer cell lines, including bladder cancer cells. Early studies suggested antitumor effects of PPAR activation in human cancer cell lines In male rats, pioglitazone treatment associated with more bladder tumors compared to placebo (not seen in female rats, mice of either sex or other organs). Bladder tumors reported with combined PPAR and agonists in rats. _Product_Information/human/000285/WC pdf. Suzuki et al. Toxicol Sci. 2010; PMID The European Data Retrospective cohort study using data from the French National Health Insurance Plan with 1.5 million patients with diabetes, followed for up to 4 years ( ). No difference in unadjusted analysis. After adjusting for age, sex, and use of other anti-diabetic medications (but not smoking), statistically significant increase in the risk for bladder cancer in patients exposed to pioglitazone compared to other anti-diabetic agents (HR 1.22; 95% CI 1.03 to 1.43). The results showed a dose effect related to cumulative dose >28,000 mg (HR 1.75; 95% CI 1.22 to 2.5) and for exposures longer than 1 year (HR 1.34; 95% CI 1.02 to 1.75). Neumann J et al. Diabetologia. 2012;55: nd_events/news_and_events.jsp&mid=wc0b01ac058004d5c1&jsenabled=true The American Data Planned five-year interim analysis (1/1997 through 4/2008) of tenyear, observational cohort study in patients with diabetes who are members of Kaiser Permanente Northern California (KPNC) health plan which includes 193,099 patients with diabetes. No difference in unadjusted analysis. After adjustments including age, sex, race/ethnicity, diabetes medications, A1C, and smoking, use of pioglitazone was not associated with risk of bladder cancer (HR 1.2 [95% CI ]). However, in the a priori category of >24 months of therapy, there was an increased risk (1.4 [ ]). Ninety-five percent of cancers diagnosed among pioglitazone users were detected at early stage. Lewis JD et al. Diabetes Care. 2011;34:

8 Diabetes and Excess Cancer Risk Type 2 diabetes, significant excess cancer risk: Breast 20% Colorectal 30% Endometrium 110% Liver 150% Bladder 24% Pancreas 40% Type 1 diabetes, modest excess cancer risk: Stomach Cervix Endometrium Larson SC et al. Int J Cancer. 2007;121: (2007). Larson SC et al. J Natl Cancer Inst. 2005;97: Huxley R et al. Br J Cancer. 2005;92: ). Zendehdel K et al. J Natl Cancer Inst. 2003;95: El- Serag HB et al. Clin Gastroenterol Hepatol. 2006;4: Larson SC et al. Eur J Cancer. 2008;44: Adami HO et al. Cancer Causes Control. 1991;2: Ferrera A et al. Diabetes Care. 2011;34: Other Studies: Azoulay et al. Nested case control study. Pioglitazone associated with increased rate of bladder cancer 1.83 [95% CI ]. Function of duration, exposed > 24 months 1.99 [95% CI 1.14 to 3.45] and dosage, > 28,000 mg 2.54 [95% CI 1.05 to 6.14]. Participants prescribed thiazolidinediones were more likely to be obese, to have ever smoked, and to have uncontrolled diabetes. Wei et al. Propensity score matched cohort study. 23,548 exposed to pioglitizone and 184,166 other diabetes medications. Pioglitazone did not increase the risk of bladder cancer. HR 1.16 [95% CI 0.83 to 1.62]. Chang et al. Case-control study. Pioglitazone use not associated with bladder cancer, associated with significantly lower risk of liver cancer OR 0.83 [95% CI ]. Protective effects were stronger for higher cumulative dosage and longer duration. Azoulay L et al. BMJ. 2012;344e3645. Wei L et al. Br J Clin Parmacol. 2013;75: Change CH et al. Hepatology. 2012;55:

9 Aging Obesity Diet Physical Inactivity Smoking Diabetes and Cancer: Shared Risk Factors Is There Any Evidence from Randomized Controlled Trials? PROactive: Adverse Events Dormandy JA et al. Lancet. 2005;366:

10 June 15, 2011 Specific Therapeutics to be Discussed Insulin Glargine and Cancer Risk Pioglitizone and Bladder Cancer Risk Incretin Mimetics, Pancreatitis, and Pancreatic Cancer April 19, 2012 Public Citizen, representing more than 250,000 members and supporters nationwide, hereby petitions the Food and Drug Administration (FDA), pursuant to the Federal Food, Drug, and Cosmetic Act (FDCA) 21 U.S.C. 355(e) and 21 C.F.R , to immediately remove from the market the diabetes drug liraglutide (Victoza; Novo Nordisk) because the known increased risks of thyroid cancer and pancreatitis, both of which occurred in people enrolled in preapproval clinical trials, outweigh any documented clinical benefits. 10

11 Incretin Mimetics and Cancer (medullary thyroid) Long term dosing with GLP 1 receptor agonists causes C cell hyperplasia and tumor formation in rodents. 20 months of liraglutide treatment (at >60 times human exposure levels) did not lead to C cell hyperplasia in monkeys. GLP 1R Expression in Normal Thyroid Normal Thyroid GLP 1R Localization Method Species Mouse Rat Human Autoradiographic Ligand Binding 3/5 5/5 12/12 8/8 1/18 0/13 0/6 In situ Hybridization ND ND 0/10 Immunohistochemistry /9* *Histologically normal thyroid without multinodular goiter or inflammation. Staining noted in multinodular goiter (3/3) and/or thyroid with lymphocytic infiltrate (3/4). Körner M et al. J Nucl Med. 2007;48: Knudsen LB et al. Endocrinology. 2010;151: Gier B et al. J Clin Endocrinol Metab. 2012;97: Waser B et al. Neuroendocrinology. 2011;94: GLP 1R Expression Method Tumor Type RET Autoradiographic Ligand Binding Pancreatic Adenocarcinoma Immunohistochemistry Medullary Thyroid carcinonma 5/18 10/36 Papillary Thyroid carcinoma Pheo germline mutations ND 0/21 12/20 ND 6/12* 3/17 ND ND 5/5 *With 10% positive cells and calcitonin colocalization otherwise 11/12 total. Reactive C-cell hyperplasia 1/4 with 10% positive cells and calcitonin colocalization otherwise 4/4 total. Körner M et al. J Nucl Med. 2007;48: Gier B et al. J Clin Endocrinol Metab. 2012;97: Waser B et al. Neuroendocrinology. 2011;94:

12 Calcitinon Levels in LEAD Studies 10 9 Upper Normal Range Males Upper Normal Range Females Liraglutide 0.6 mg Liraglutide 1.2 mg Liraglutide 1.8 mg Active comparator Placebo /28 39/ /65 76/78 91/92 Weeks 104 Hegedüs L et al. J Clin Endocrinol Metab, 2010;96: Incretin Mimetics and Cancer (medullary thyroid) No evidence of C cell stimulation as assessed by calcitonin analysis after 2 years of human liraglutide exposure. No evidence of an increase in medullary thyroid cancer after 840,000 patient years of exanatide exposure in humans. Knudsen LB et al. Endocrinology. 2010;151: Hegedüs L et al. J Clin Endocrinol Metab, 2010;96: January 25, 2010 It is not known if Victoza could cause thyroid tumors or a very rare type of thyroid cancer called medullary thyroid cancer in people. For this reason, Victoza should not be used as the first line treatment for diabetes until additional studies are completed that support expanded use. Victoza should not be used in people already at risk for medullary thyroid cancer, such as those who have medullary thyroid cancer in the family or those with a rare genetic condition known as Multiple Endocrine Neoplasia syndrome type 2. Required company to conduct a 5 year epidemiological study to evaluate thyroid and other cancer risks and establish a cancer registry to monitor the rate of medullary thyroid cancer in the United States over the next 15 years. 12

13 Incretin Mimetics and Pancreatitis Pancreatitis and Type 2 Diabetes Incidence per 100,000 patient-years Noel RA et al. Diabetes Care. 2009; 32: Acute Pancreatitis with Liraglutide versus Active Comparator Liraglutide Active comparator Safety analysis set (n) Total exposure (years) Events (n) 5 1 Events/1000 patient years Liraglutide injection prescribing information, Novo Nordisk,

14 March 14, 2013 The U.S. Food and Drug Administration (FDA) is evaluating unpublished new findings by a group of academic researchers that suggest an increased risk of pancreatitis, or inflammation of the pancreas, and pre-cancerous cellular changes called pancreatic duct metaplasia in patients with type 2 diabetes treated with a class of drugs called incretin mimetics. These findings were based on examination of a small number of pancreatic tissue specimens taken from patients after they died from unspecified causes. FDA has asked the researchers to provide the methodology used to collect and study these specimens and to provide the tissue samples so the Agency can further investigate potential pancreatic toxicity associated with the incretin mimetics. FDA previously warned the public about postmarketing reports of acute pancreatitis, including fatal and serious nonfatal cases, associated with the use of the incretin mimetic drugs exenatide and sitagliptin. A recently published study that examined insurance records also found the use of exenatide or sitagliptin could double the risk of developing acute pancreatitis. The Warnings and Precautions section of the drug labels and the patient Medication Guides for incretin mimetics contain warnings about the risk of acute pancreatitis. FDA has not previously communicated about the potential risk of pre-cancerous findings of the pancreas with incretin mimetics. Further, FDA has not concluded these drugs may cause or contribute to the development of pancreatic cancer. Results The mean age of included individuals was 52 years, and 57.45% were male. Cases were significantly more likely than controls to have hypertriglyceridemia (12.92% vs 8.35%), alcohol use (3.23% vs 0.24%), gallstones (9.06% vs 1.34), tobacco abuse (16.39% vs 5.52%), obesity (19.62% vs 9.77%), biliary and pancreatic cancer (2.84% vs 0%), cystic fibrosis (0.79% vs 0%), and any neoplasm (29.94% vs 18.05%). After adjusting for available confounders and metformin hydrochloride use, current use of GLP-1 based therapies within 30 days (adjusted odds ratio, 2.24 [95% CI, ]) and recent use past 30 days and less than 2 years (2.01 [ ]) were associated with significantly increased odds of acute pancreatitis relative to the odds in nonusers. Conclusions and Relevance In this administrative database study of US adults with type 2 diabetes mellitus, treatment with the GLP-1 based therapies sitagliptin and exenatide was associated with increased odds of hospitalization for acute pancreatitis. Singh S et al. JAMA Internal Med. 2013; Online Feb 25. Unadjusted Numbers Characteristic Cases n=1269 Controls n=1269 Ratio (cases/controls) Hypertriglyceridemia 164 (12.9) 106 (8.4) 1.5 Alcohol use 41 (3.2) 30 (0.2) 1.4 Gallstones 115 (9.1) 17 (1.3) 6.8 Tobacco use 208 (16.4) 70 (5.5) 3.0 Obesity 249 (19.6) 124 (9.8) 2 Biliary/pancreatic ca 36 (2.8) 0 Cystic fibrosis 10 (0.8) 0 Current GLP 1 therapy 55 (4.3) 42 (3.3) 1.3 Recent GLP 1 therapy 72 (5.7) 48 (3.8) 1.5 Singh S et al. JAMA Internal Med. 2013; Online Feb

15 The American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association believe that the study by Singh et al, Glucagon-like Peptide 1-Based Therapies and Risk of Hospitalization for Acute Pancreatitis in Type 2 Diabetes Mellitus, published online February 25th in JAMA Internal Medicine does not provide the basis for changing treatment in people with diabetes. Fortunately, there will be new data available relatively soon which will allow physicians to definitively assess risks and benefits of this class of medicines. The analysis is a retrospective study using data from an administrative database. This type of analysis is not considered as robust as a prospective randomized controlled clinical trial, the gold standard for evaluating treatments. There are currently nine ongoing, prospective, controlled trials of GLP-1 based therapy with over 65,000 subjects, which should provide answers to these important safety questions. While there are risks and benefits associated with any therapy, the retrospective analysis indicates GLP-1 based therapies are associated with a relatively small excess risk of hospitalization for acute pancreatitis, with only two additional cases per 100 patients over a three-year period. This same population of adults, between the ages of with type 2 diabetes, had a greater risk of hospitalization for acute pancreatitis if they used tobacco, consumed alcohol or were obese. As with any therapy, we encourage patients to speak with their doctors to assess which treatments are best for them and to not stop therapy on their own without consulting their doctors. Proposed Pancreatitis Mechanisms High risk population (obesity, diabetes, tobacco, alcohol, gallstones, hypertriglyceridemia) Weight loss Increased pancreatic duct cell replication and acinar to ductal metaplasia Development of Pancreatic Cancer Normal Premalignant (PanIN) Cancer KRAS2 p16/cdkn2a TP53 SMAD4 BRCA2 Gier B and Butler P. JAMA Intern Med. 2013; Online March 5 15

16 Animal and In Vitro Studies Novo Nordisk In mice, after 2 years microscopic pancreatitis in 3/158 (2%) control and 17/555 (3%) liraglutide tx. In rats, after 2 years no pancreatitis 0/100 control, 0/299 tx. In monkeys after 2 years no pancreatitis 0/10 control, 0/19 tx. In 87 week monkey study at 6 mg/kg/day no PanIN in ductal epithelium seen (0/10 animals). Peter Butler In rats, treatment with exendin 4 induces expansion of pancreatic duct glands without pancreatitis. In rats, after exendin 4 tx mucinous metaplasia and columnar cell atypia resembling low grade PanIN is seen (no carcinomas). In Pdx1 Kras mice after exendin 4 there was extensive acinar to ductal metaplasia and increased PanIN. Treatment of human pancreatic duct cells (HPDE) induced cyclin D1. Metformin was protective in Kras mutant HPDE cells (pcreb/creb). Nyborg N et al. Diabetes. 2012;61: Gier B et al. Diabetes. 2012;61: Marked Expansion of Exocrine and Endocrine Pancreas with Incretin Therapy in Humans with Increased Exocrine Pancreas Dysplasia and the Potential for Glucagon-Producing Neuroendocrine Tumors Controversy exists regarding the potential regenerative influences of incretin therapy on pancreatic cells versus possible adverse pancreatic proliferative effects. Examination of pancreata from age matched organ donors with type 2 diabetes (DM) treated by incretin therapy (n=8) or other therapy (n=12) and non diabetic controls (n=14) reveals a ~40% increased pancreatic mass in DM treated with incretin therapy with both increased exocrine cell proliferation (p<0.0001) and dysplasia (increased pancreatic intraepithelia neoplasia, p<0.01). Pancreas in DM treated with incretin therapy was notable for α cell hyperplasia and glucagon expressing microadenomas (3/8) and a neuroendocrine tumor. β-cell mass was reduced by approximately 60% in those with DM, yet a 6 fold increase was observed in incretin treated subjects although diabetes persists. Endocrine cells co-staining for insulin and glucagon were increased in DM compared to non diabetic controls (p<0.05) and markedly further increased by incretin therapy (p<0.05). In conclusion, in humans, incretin therapy resulted in a marked expansion of the exocrine and endocrine pancreatic compartments, the former being accompanied by increased proliferation and dysplasia, the latter by α cell hyperplasia with the potential for evolution into neuroendocrine tumors. Butler AE et al. Diabetes. 2013;Mar 22 Epub. PMID Male, 2 Female 7 Januvia, 1 Byetta Over 50: 5/8 (63%) Butler AE et al. Diabetes. 2013;Mar 22 Epub. PMID

17 4 Male, 8 Female 4 insulin treated 5 no treatment Over 50: 2/12 (17%) Butler AE et al. Diabetes. 2013;Mar 22 Epub. PMID Male, 7 Female Over 50: 4/14 (29%) Butler AE et al. Diabetes. 2013;Mar 22 Epub. PMID Sitagliptin Effects on the Pancreas? A 1.5 cm α-cell/glucagon producing neuroendocrine tumor (Grade 1, World Health Organization, 2010) not appreciated in life was identified in the body of the pancreas after resection at brain death. Glucagon-producing microadenomas were also detected in the same case (6185) and two other incretin treated cases (6157 and 6206). Increase in the presence of pancreatic intraepithelial neoplasia (PanINs) (11.9±2.6 vs 4.9±1.7, DM-I vs DM, PanINs/mm 2 x 103, p<0.01). Butler AE et al. Diabetes. 2013;Mar 22 Epub. PMID

18 Beta Cell % Then and Now Butler AE et al. Diabetes. 2003;52: PMID Butler AE et al. Diabetes. 2013;Mar 22 Epub. PMID PanINs are rarely seen before age 35, but are found in 60% by age 45 and in 75% of individuals by age 55. Harja E et al. Diabetes Technology & Therapeutics. 2013;8: Andea A et al. Mod Pathol. 2003;16: What are the risk factors for pancreatic cancer: Age The risk of developing pancreatic cancer increases as people age. Almost all patients are older than 45. Nearly 9 in 10 are at least 55 years old and almost 7 in 10 are at least 65 years old. The average age at the time of diagnosis is 71. Sex Men are 30% more likely to develop pancreatic cancer than women. Race African Americans are more likely to develop pancreatic cancer. Smoking About 20% to 30% of exocrine pancreatic cancer cases are thought to be caused by cigarette smoking. Other: Chronic Pancreatitis, Obesity, Diabetes, Cirrhosis, Family History, Occupational Exposures, Heavy Alcohol Consumption 18

19 Critiques after the Butler Paper Harja et al. From this, we conclude that the data and the implications of the data, as expressed by Butler et al., are vastly overstated and seemingly irresponsibly articulated. Their analysis seems to be more of an alarmist perspective, creating controversy rather than a neutral and fact-based approach. At the core of the discussion are limited numbers and many confounders related to subject history, presentation, and other subject-specific factors that make their conclusions invalid. European Medicines Agency No new concerns for GLP-1 therapies identified on the basis of available evidence. FDA had conversations with EMA and was aware of their analyses regarding the potential pancreatic effects of GLP-1 based therapies. Our general view is that their conclusions are consistent with our current understanding of the data. Harja E et al. Diabetes Technology & Therapeutics. 2013;8: European Medicines Agency. July 26, Where are we now? European Medicines Agency two large independent studies have been under way since 2011 to study the risk profile of diabetes treatment in general, and more specifically their risk profile in relation to the pancreas. First results of these studies, which are funded by the European Commission, are expected in the spring of Food and Drug Administration FDA's review is ongoing as pancreatitis and pancreatic cancer data are being collected in the cardiovascular outcome trials being conducted with this class of drugs. Additionally, there is an ongoing epidemiological study. 19