Redacted study protocol Incidence of Thyroid Neoplasm and Pancreatic Cancer in Type 2 Diabetes Mellitus Patients who Initiate Once Weekly Exenatide Compared with Other Antihyperglycemic Drugs Redacted protocol based on original protocol version 3 of August 14, 2013 LAY SUMMARY Many patients with diabetes mellitus, increased sugar levels, are treated with medicines. Different types of medicines are available. The present study is intended to monitor the occurrence of two types of cancer with weekly exenatide. Anonymised electronic health care records will be used to monitor the weekly exenatide users and compare them to patients using other types of medication. 1 BACKGROUND Diabetes mellitus is a major public health problem worldwide and especially in the United Kingdom (UK). According to Diabetes UK, approximately 2.8 million people in the UK had diabetes in 2010 [1]. Type 2 diabetes (T2DM) accounts for 90-95% of diagnosed cases of diabetes and is associated with older age, obesity, family history of diabetes, gestational diabetes, impaired glucose metabolism, physical inactivity. Diabetes is a leading cause of blindness, end-stage renal disease, non-traumatic lower limb amputation, and is a major risk factor for coronary artery disease and stroke [2]. Interventions that improve glycemic control reduce microvascular complications involving the eyes, kidneys and nerves, and may reduce macrovascular complications such as myocardial infarction [3]. Many of the traditional diabetes medications (such as sulfonylureas (SU), metformin, α-glucosidase inhibitors, thiazolidinediones (TZDs), and insulin) lower blood glucose, but they may also produce hypoglycemia, gastrointestinal symptoms, or weight gain. The American Diabetes Association recommends a hemoglobin A1C goal of less than 7%, but many diabetic patients are unable to achieve this goal by using oral drug combinations or diet and exercise. Most patients with T2DM will eventually require combination therapy to maintain glycemic control. Several newer treatments have been developed that provide valuable alternatives to improve long-term glycemic control for T2DM [4]. Exenatide, an incretin-mimetic, is one of the newer treatment alternatives available (initially approved by the Food and Drug Administration on 28 April 2005). Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist that enhances glucose-dependent insulin secretion by pancreatic beta cells, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. Review of recent data on the newer antidiabetic agents has noted signals of pancreatitis and pancreatic and thyroid malignancies with GLP-1 drugs. Acute pancreatitis has been reported as a rare adverse effect of exenatide therapy principally in suspected adverse drug reaction reports, however, this increased association was not supported by recent pharmacoepidemiologic studies [5; 6]. In rodent toxicology studies, “C-cell hyperplasia” and C-cell carcinoma (the rodent equivalent of human medullary thyroid cancer (MTC) were detected with the long-acting glucagon like peptide 1 (GLP-1) receptor agonist class (for example, liraglutide and exenatide]). A GLP-1 receptor-mediated mode of action has been proposed with respect to carcinogenicity in the rodent thyroid [7]. It is important to note that in the thyroid of various species, including rodents, monkeys, and humans, GLP-1 receptors are expressed only on C-cells, not on other thyroid cell types [8]. Accordingly, across multiple preclinical studies of all GLP-1 receptor agonists in rodents, which included near-lifetime treatment at relatively high exposure multiples, there was no evidence of an increase in thyroid tumors of cell types other than C-cells. Data both from clinical studies (approximately 5400 patient-years of exposure in long-term studies) and postmarketing exposure (approximately 1.7 million patient-years) have shown no evidence for an increased risk of thyroid malignancy in general; no case of MTC has been reported with either exenatide formulation (available as daily injection [Byetta] or weekly injection [Bydereon]). Furthermore, in primates, there is no detectable stimulation of calcitonin release by GLP-1 receptor activation. These data provide additional support for a lack of relevance of the rodent C-cell findings to humans. 2 The current study is being conducted to meet a request made by the European Medicines Agency prior to approving exenatide once weekly for marketing in the European Union. 2 OBJECTIVES The objective of this study is to estimate and compare the incidence of thyroid neoplasm and pancreatic cancer among initiators of exenatide once weekly compared with users of other oral antidiabetic agents (OADs). 2.1 Primary Objectives: ● To conduct individual medical review of cases of newly diagnosed thyroid or pancreas cancer among initiators of exenatide once weekly ● To estimate the absolute and relative incidence of newly diagnosed thyroid cancer among initiators of exenatide once weekly compared with matched control cohort of other OADs ● To estimate the absolute and relative incidence of newly diagnosed pancreas cancer among initiators of exenatide once weekly compared with matched control cohort of other OADs 2.2 Secondary Objectives: ● Describe the incidence of medullary thyroid cancer (MTC) among initiators of exenatide once weekly and matched control cohort of other OADs ● Estimate the incidence of new-onset benign thyroid neoplasm among initiators of exenatide once weekly compared to a matched control cohort of other OADs ● To conduct individual medical review of cases of newly diagnosed thyroid or pancreas cancer among initiators of exenatide (weekly or daily) ● To estimate the absolute and relative incidence of newly diagnosed thyroid cancer among initiators of exenatide (weekly or daily) compared with matched control cohort of other OADs ● To estimate the absolute and relative incidence of newly diagnosed pancreas cancer among initiators of exenatide (weekly or daily) compared with matched control cohort of other OADs 3 METHODS 3.1 Overview of Study Design This will be a retrospective cohort study of initiators of exenatide once weekly and matched control cohort of other OAD. The data sources will include the Clinical Practice Research Datalink (CPRD) and the linked Hospital Episode Statistics (HES), death certificates and cancer registry. Exenatide once weekly initiators will be matched to two control cohorts of prevalent OAD users based on age, sex and practice and on propensity scores. This will be a hypothesis testing study. 3.2 Data Sources The study will be conducted in the Clinical Practice Research Datalink (CPRD) and linked Hospital Episode Statistics (HES), death certificates and Cancer Registry. The CPRD comprises computerized medical records of general practitioners (GPs) including about 12 million patients from 1987 onwards of which approximately 3.6 million are currently active. GPs play a gatekeeper role in the UK health care system, as they are responsible for primary health care and specialist referrals. Patients are semi- permanently affiliated to a practice, which centralizes the medical information from the GPs, specialist referrals and hospitalizations. The data recorded in the CPRD include demographic information, 3 prescription details, clinical events, preventive care provided, specialist referrals, laboratory results, hospital admissions and death. Practices that want to contribute data to CPRD are carefully selected and trained in the software used to record medical data. Only those practices that meet quality standards are then used for research (about 10% of the practices that send data to CPRD do not meet the quality standards). Furthermore, validation studies are conducted regularly by comparing CPRD data to written notes of general practitioners. No other UK database restricts the data only to practices providing high quality data or with procedures for measuring and maintaining data quality and with frequent validation studies. The CPRD currently contains the complete anonymized patient medical records from GPs who agree to adhere to “Recording Guidelines” that are subject to detailed quality control checks of data at both practice and individual patient level. CPRD can now be linked individually and anonymously to other NHS datasets in England (appropriate approvals have been obtained for this; investigators have no access to patient identifiers). Currently, > 300 GP practices in England are participating in this linkage (about 50% of CPRD in the UK and 65% of the practices in England). Data from the following sources will be used for this study (for patients in practices participating in the linkages): CPRD Hospital Episode Statistics (HES). These data contain details of the date, main discharge diagnosis, procedures and duration of hospitalisation, as provided by the hospitals for all admissions to NHS hospitals in England. The patients include private patients and those resident outside of England, who were treated in NHS hospitals, as well as care delivered by treatment centres (including those in the independent sector) funded by the NHS. All NHS trusts in England, including acute hospitals, primary care trusts and mental health trusts are included. ONS Death certificates. The ONS Death certificate data contains the date and cause of death for England and Wales, along with the primary and secondary causes of death. Cancer registry. Cancer registration in England is conducted by nine regional registries,