PracticeUpdate: Conference Series | ADC 2018

ISSN 2208-150X (Print) ISSN 2208-1518 (Online)

AUSTRALASIAN DIABETES CONGRESS 2018 22–24 AUGUST 2018 • ADELAIDE • SOUTH AUSTRALIA

THE BEST OF ADC 2018 National Diabetes Registry to Analyze Clinical Benefits of Subsidized CGM • ‘Problematic Hypoglycemia in Adults With T1D Can Be Avoided’ • Is Targeting Mitochondrial Dysfunction Worth Considering as a Prevention Strategy for Kidney Disease in T1D? • Biodegradable Temporising Matrix as an Alternative Intracutaneous Site for Islet Transplantation • ‘There Is More to Neuropathy Than Hyperglycemia Alone in T2D’

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Choose JANUVIA as your DPP4i of choice in T2DM

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DPP4i = dipeptidyl peptidase 4 inhibitor, T2DM = type 2 diabetes mellitus

Study Designs Nauck MA et al. 2007 2 A randomised, double-blind, parallel-group study evaluating the effect of adding sitagliptin (100 mg once daily) vs glipizide (≤20 mg/day) to metformin in 1,172 patients with type 2 diabetes inadequately controlled with ≥1500 mg/day metformin (HbA1c ≥6.5% to ≤10%). The primary analysis assessed non-inferiority for HbA1c change from baseline at week 52 using a PP approach (patients who completed all 52 weeks of treatment and did not have any reason for exclusion). Arjona Ferreira JC et al. Am J Kidney Dis 2013 3 A randomised, double-blind, parallel-arm study assessing the efficacy and safety of sitagliptin and glipizide monotherapy in patients with T2DM and end-stage renal disease on dialysis therapy (baseline HbA1c=7.8%). Patients (n=129) received sitagliptin 25 mg once daily or glipizide (n=64) initiated at 2.5 mg daily and titrated in 2-week intervals to a potential maximum dose of 10 mg twice daily. Primary endpoints were change in HbA1c level from baseline and tolerability with sitagliptin. Arjona Ferreira JC et al. Diabetes Care 2013 4 A randomised, double-blind, parallel-group study comparing the efficacy and safety of sitagliptin with glipizide in patients with T2DM mellitus and moderate-to-severe chronic renal insufficiency and inadequate glycaemic control. Patients (n=426) received sitagliptin 50 mg once daily for moderate renal insufficiency, sitagliptin 25 mg once daily for severe renal insufficiency or glipizide 2.5 mg once daily (adjusted for glycaemic control to a 10 mg twice a day maximum dose). Primary endpoint was change from baseline in HbA1C at week 54. Green JB et al. 2015 5 A multinational, randomised, double-blind, placebo-controlled, event-driven trial that assessed the long-term CV safety of adding sitagliptin to usual care, as compared with usual care alone, in 14,671 patients ≥50 years old with T2DM and established CVD. ^ Patients were randomised to sitagliptin + usual care* (n=7,332), placebo + usual care* (n=7,339) with median follow up of 3 years. Starting dose of once-daily sitagliptin was 100 mg or 50 mg for patients with eGFR 30–50 mL/min/1.73m 2 ; if eGFR fell to <30 mL/ min/1.73m 2 , the dose was reduced to once daily sitagliptin 25 mg; if eGFR showed sustained recovery, dose was uptitrated. Primary endpoint: composite CV outcome (CV death, nonfatal MI, nonfatal stroke, or hospitalisation for unstable angina). ^Established cardiovascular disease was defined as a history of major coronary artery disease, ischaemic cerebrovascular disease, or atherosclerotic peripheral arterial disease. *Antihyperglycemic medication could have included metformin, sulfonylurea, pioglitazone, or insulin with or without metformin, excluding other DPP-4 inhibitors and GLP-1 RAs or thiazolidinedione (other than pioglitazone) during the preceding 3 months. CV=cardiovascular, DPP-4=dipeptidyl peptidase-4, GLP-1=glucagon-like peptide-1 receptor agonist, MI=myocardial infarction Chan JCN et al . 2008 6 A 54-week, randomised, double-blind, parallel-group study to test the safety of sitagliptin in T2DM patients with moderate (CrCl ≥30 to <50 mL/min) or severe renal insufficiency (CrCl <30 mL/min). The trial included a 12-week double-blind, placebo-controlled phase in which patients (baseline HbA1c=7.7%) with normal renal function were randomised to sitagliptin 100 mg/day (n=65), 50 mg/day with moderate and 25 mg/day with severe renal insufficiency or placebo (n=26) and a 42-week extension in which all patients were eligible for active therapy (patients either continued treatment with sitagliptin or patients on placebo transitioned to glipizide). PLEASE REVIEW THE PRODUCT INFORMATION BEFORE PRESCRIBING. PRODUCT INFORMATION IS AVAILABLE AT WWW.MSDINFO.COM.AU/JANUVIAPI Copyright © 2018 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, U.S.A. All rights reserved. Merck Sharp & Dohme (Australia) Pty Limited. Level 1, Building A, 26 Talavera Road, Macquarie Park NSW 2113. DIAB-1268045-0000. First Issued August 2018. Bloe Agency MSD13139. References: 1. JANUVIA Approved Product Information, April 2017. 2. Nauck MA et al. Diabetes Obes Metab 2007;9(2):194–205. 3. Arjona Ferreira JC et al. Am J Kidney Dis 2013;61(4): 579-587. 4. Arjona Ferreira JC et al. Diabetes Care 2013;36(5): 1067-1073. 5. Green JB et al. N Engl J Med 2015; 373(3): 232–242. 6. Chan JCN et al. Diabetes Obes Metab 2008;10:545–555. 7. Melizide (glipizide) Approved Product Information, October 2015. Indications: To improve glycaemic control in patients ≥ 18 years old with Type 2 Diabetes Mellitus. Either as monotherapy (when metformin cannot be used and when dietary and exercise measures have failed), or as dual combination therapy with metformin or with a sulfonylurea, or with a thiazolidinedione where its use is considered appropriate, or as triple combination therapy with metformin and a sulfonylurea, or as add-on to insulin (with or without metformin). Contraindications: Hypersensitivity to any component. Precautions: Not for Type 1 Diabetes Mellitus or diabetic ketoacidosis. Acute pancreatitis (discontinue treatment), renal insufficiency, hypoglycaemia in combination with a sulfonylurea or with insulin, hypersensitivity, bullous pemphigoid (discontinue treatment). Pregnancy (Cat B3), lactation, children. Interactions: No clinically significant interactions observed with sitagliptin and metformin, glibenclamide, simvastatin, rosiglitazone, warfarin, oral contraceptives, digoxin or cyclosporine (see full PI). Adverse reactions: URTI, headache, hypoglycaemia, nasopharyngitis. Postmarketing Experience: Hypersensitivity reactions, bullous pemphigoid, Acute pancreatitis, Worsening renal function (including acute failure), constipation, vomiting, headache, arthralgia, myalgia, pain in extremity, back pain (see full PI). Dosage: 100 mg once daily with or without food. Adjust dose for moderate/severe renal insufficiency. Moderate renal insufficiency (CrCl ≥ 30 to < 50 mL/min): 50 mg once daily. Severe renal insufficiency (CrCl < 30 mL/min) or with end-stage renal disease: 25 mg once daily (see full PI). To reduce the risk of hypoglycaemia, consider reduced dose of sulfonylurea/insulin when used in combination. Based on PI amended: JANUVIA : 06 April 2017. PBS INFORMATION: Dual, Triple, Insulin add on therapy listings. Authority required (Streamlined). Refer to PBS Schedule for full authority information. Initial combination therapy is not listed on the PBS. Sitagliptin monotherapy is not listed on the PBS.

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© Australian Diabetes Society

Contents

ADC 2018 • 22–24 August 2018 • Adelaide, South Australia

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2 National Diabetes Registry to Analyze Clinical Benefits of Subsidized CGM By the PracticeUpdate Editorial Team Comment by Peter Colman MBBS, FRACP, MD 2 Australasian Diabetes Congress 2018 Highlights By Sof Andrikopoulos PhD , Louise Maple- Brown PhD & Josephine Forbes PhD 4 ‘Problematic Hypoglycemia in Adults With T1D Can Be Avoided’ By the PracticeUpdate Editorial Team 6 Can Oral Insulin Delay Progression to T1D? By the PracticeUpdate Editorial Team 7 Update on Intranasal Insulin Trial II (INIT II) to Prevent Type 1 Diabetes By the PracticeUpdate Editorial Team 8 Preventing Type 1 Diabetes: What We Know Interview with John Wentworth MBBS, PhD, FRACP 9 Once-Weekly Dulaglutide Noninferior to Once-Daily Liraglutide in Patients With Type 2 Diabetes By the PracticeUpdate Editorial Team

10 Is Targeting Mitochondrial Dysfunction Worth Considering as a Prevention Strategy for Kidney Disease in T1D? By the PracticeUpdate Editorial Team Comment by Josephine Forbes PhD 11 Clinical Islet Transplantation in Australia By Toby Coates MBBS, PhD, FRACP 12 Research Uncovers Potential Role of Gut Microbiome in T1D Pathogenesis By the PracticeUpdate Editorial Team 13 Biodegradable Temporising Matrix as an Alternative Intracutaneous Site for Islet Transplantation By Toby Coates MBBS, PhD, FRACP & John Greenwood MBCHB, MD, DHLTHSC, FRCS(ENG), FRCS(PLAST), FRACS 14 CVD-REAL 2: SGLT2 Inhibitors Associated With Lower CV Risk vs Other Glucose- Lowering Drugs By the PracticeUpdate Editorial Team 15 Adding Liraglutide to Standard of Care Lowers Risk of Glycemic Deterioration in T2D Patients at High CV Risk By the PracticeUpdate Editorial Team 16 ‘There Is More to Neuropathy Than Hyperglycemia Alone in T2D’ By the PracticeUpdate Editorial Team Comment by Josephine Forbes PhD

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ADC 2018 • PRACTICEUPDATE CONFERENCE SERIES

National Diabetes Registry to Analyze Clinical Benefits of Subsidized CGM Research highlights the role of ADDN as a key resource to help track and improve diabetes care in the long term. BY THE PRACTICEUPDATE EDITORIAL TEAM

T he Australasian Diabetes Data Network (ADDN) is planning to ana- lyze the effectiveness of continuous glucose monitoring (CGM) devices in helping children and young adults with type 1 diabetes (T1D) to better manage their blood glucose levels and reduce the incidences of hypoglycemia. The Australian government currently pro- vides access to subsidized CGM through the National Diabetes Services Scheme (NDSS) to assist children and young adults under the age of 21 who face difficulty in managing their T1D. According to ADDN Principal Investigator Peter Colman, MBBS, FRACP, MD, while the NDSS collects usage information, it does not track clinical outcomes associ- ated with the use of CGM. “This is a unique opportunity to connect ADDN and NDSS datasets to look at individuals who have received CGM via the subsidy and to evaluate their usage and clinical outcomes. It’s something that we’re really excited about,” said Dr. Colman, who is an Endocrinologist

in the Department of Diabetes and Endocrinology at Royal Melbourne Hospital in Melbourne, Australia. “We know anecdotally that our younger patients like using CGM, that they are comfortable with it, but what we don’t know are the effects of continuous mon- itoring on these patients’ blood glucose control and whether it helps lower the incidences of hypoglycemia. “What we would also like to find out is whether CGM benefits certain groups of patients more than others. And that is an example of how data in ADDN can help us focus on tailoring different types of treatment to different groups of patients with type 1 diabetes.” Dr. Colman said information from ADDN pediatric data collection centers are now providing a snapshot profile of the chil- dren and young adults who have received subsidized CGM. The ADDN is a prospective, longitudinal diabetes database established in 2012 by the Australasian Paediatric Endocrinology Group with funding from the Juvenile

Other highlights of the meeting include Professor Sultan Linjawi’s presentation on the role of technology in the management of type 2 diabetes, Professor TimDavis who showed evidence for the role of SGLT2 inhibitors in type 1 diabetes, and Professor Alex Brown’s session on improving health outcomes in Indigenous communities. It is clear that this year's annual scientific meeting addressed topics that were relevant to researchers and clinicians in diabetes. Diabetes Research Foundation with the aim of improving patient-centered research. The first phase of ADDN col- lected clinical data from children and adolescents attending pediatric diabetes centers across the country. In 2015, with support from the Australian Diabetes Society, ADDN expanded to include data from adult diabetes centers, further enhancing capacity to follow young patients as they transition from pediatric services to adult care. The ADDN registry currently has data for over 10,000 patients from 13 diabetes centers across Australia and New Zealand, with the aim of increasing this number to 14,000 patients by the end of 2018. The registry also plans to include more participating centers and to build on national and international collaborations. Major projects currently underway that

Australasian Diabetes Congress 2018 Highlights By SOF ANDRIKOPOULOS, PhD, CEO of the Australian Diabetes Society, LOUISE MAPLE-BROWN, PhD, Menzies School of Health Research, Darwin & JOSEPHINE FORBES, PhD, Mater Research Institute–The University of Queensland, Brisbane. T he Australian Diabetes Congress 2018 saw over 1400 delegates from Australia and New Zealand, as well Stephanie Amiel, who discussed the role of the brain in hypoglycemia; and Professor Peter Tontonoz, who presented on lipid metabolism and its effects on glu- cose metabolism.

as 50 endocrinologists from China, attend and participate in an excellent program that covered many topics pertinent to understanding the cause and better man- agement of diabetes. Key presentations from international ple- nary speakers included that by Professor Jeremy Grimshaw, who discussed healthcare systems and implementation of systematic reviews to improve care for people with diabetes; Professor

Other significant presentations were by the Kellion Award recipient Professor Jonathan Shaw, who discussed the role of epidemiology in diabetes, and the Ranji and Amara Wikramanayake Clinical Diabetes Research Award recipient Associate Professor Barbora de Courten, who presented on the role of supple- ments in the management of diabetes.

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PRACTICEUPDATE CONFERENCE SERIES • ADC 2018

Comment ADDN: Facilitating Research and Benchmarking to Improve Diabetes Care INTERVIEW WITH PETER COLMAN MBBS, FRACP, MD

Dr. Peter Colman

" There are newer types of medication and technology, but there are also things we can do systematically across states and clinics in terms of how we actually deliver care to our patients that will ultimately help improve outcomes. " could potentially feed data into ADDN are the EXTEND (tocilizumab in T1D) and ENDIA (Environmental Determinants of Islet Autoimmunity) clinical trials, as well as TrialNet. Registry also reveals that a large proportion of patients with T1D struggle to reach glycemic targets Less than a third of children and adults with T1D in Australia are achieving target glycemic control, latest data from the ADDN registry reveal. Data released in the March 2018 benchmarking report showed that, among 4791 children and adolescents with T1D, only 14% (n=661) achieved HbA1c <7.0% while 44% (n=2107) had HbA1c between 7.5 and <9.0% and 23% (n=1119) ≥9.0%. Mean HbA1c was 8.3%. Among 1760 adults with T1D, 14% (n=254) had HbA1c <7.0%, while 28% (n=489) had HbA1c between 7.5% and <9.0% and 23% (n=399) ≥9.0%. Mean HbA1c was 8.4%. “We know that a patient’s outcome, in terms of developing microvascular and macrovascular complications, is better when their HbA1c is less than 7%. However, the reality is that many of our patients with type 1 diabetes do not achieve that,” Dr. Colman said. “The question then is ‘how do we address this?’” Dr. Colman said analysis of the ADDN registry data will help the continuous and long-term assessment of treatment pathways and inform changes in guidelines and health policy. “There are newer types of medication and technology, but there are also things we can do systematically across states and clinics in terms of how we actually deliver care to our patients that will ultimately help improve outcomes,” he added.

Dr. Colman is Principal Investigator of the ADDN Study Group, and an Endocrinologist at the Department of Diabetes and Endocrinology at Royal Melbourne Hospital in Melbourne, Australia. T he ADDN is a very well-designed database that provides information across the country on how we’re doing when it comes to look- ing after people with T1D. It was initially set up as a register that would collect people with T1D for clinical trials. Over time – and it’s now into its second phase – while clinical trials are still a focus, it’s become an important registry for looking at benchmarking and quality of care data provided by diabetes centres across the population of people with T1D. It gives us the ability to look at patient outcomes from the time of diagnosis in childhood or early adulthood through to their adult life, and to look at the devel- opment of complications. The ADDN is the only registry of its kind in Australia. We can now tell, for instance, the percentage of people on insulin pumps or on multi-dose insulin, and then compare the information across centres nationally and internationally. We know that we have fewer people on insulin pumps in Australia compared with the US or Europe. And while the average HbA1c in our T1D population is probably better than that in the US, it’s not as good as data coming out of Austrian or Swedish registries. But we know, with a certain level of confidence, that we’re tracking close to these international centres in terms of glycemic control. The other important aspect of the ADDN is that it’s a resource for the whole community. Its main purpose is to improve the care and outcomes of people with diabetes, and to stimulate research. ADDN data are essentially available to any researcher.

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‘Problematic Hypoglycemia in Adults With T1D Can Be Avoided’ Structured education and clinician support may allay patients’ fear of hypoglycemia. BY THE PRACTICEUPDATE EDITORIAL TEAM

A n Australian health psychologist has called for more open discussion about hypoglycemia in the clinic, saying it needs to become part of routine conversation between clinicians and their patients with type 1 diabetes (T1D). Severe hypoglycemia is currently thought to affect 1 in 5 patients in specialist T1D centers. Severe hypoglycemia is independent of HbA1c. Patients with T1D often fear hypoglycemia and take compensatory measures to cope with their risk of hypoglycemia. “These fears are common among adults with type 1 diabetes and also among their family mem- bers,” said Jane Speight, PhD, CPsychol FBPsP, Foundation Director of the Australian Centre for Behavioural Research in Diabetes. Dr. Speight, who also holds the Chair in Behavioural and Social Research in Diabetes at Deakin University in Victoria, Australia, said that talking about hypoglycemia and any related fears can be challenging for some patients, but clinicians can handle these discussions in a sensitive and nonjudgemental way to allay these fears. “Talking about hypoglycemia can be challenging and some patients are reluctant to talk about it. “They fear being blamed for doing something wrong. Some even fear the perceived nega- tive consequences, such as losing their driving license, if they have these conversations with us,” Dr. Speight said.

She added that, on the flip side, many health pro- fessionals feel that they do not have the tools to offer support to adults with T1D to deal with their fear of hypoglycemia. In the HypoCOMPaSS trial published in 2014, 96 adults with long-standing T1D with impaired awareness of hypoglycemia and suffering recur- rent severe hypoglycemia said that they worried about their blood glucose (58%) and the long-term complications of diabetes (51%). They also said that they worried about not rec- ognizing high blood glucose (30%), diabetic ketoacidosis (25%), and their doctor’s reaction to their high blood glucose (24%). These patients also exhibited compensatory behaviors, such as taking extra insulin if blood glucose exceeded 7 mmol/L, intentionally keeping blood glucose low, and undertreating low blood glucose. Some even said that they were comfort- able with hypoglycemia and exercising if blood glucose is high. “These are quite concerning behaviors and worries among this group of people who have recurrent severe hypoglycemia,” Dr. Speight said. In her own interviews with 17 adults with long-stand- ing T1D and recurrent severe hypoglycemia, Dr. Speight found that these patients exhibited psychological as well as behavioural issues aimed at preventing hypoglycemia. They included not acting or acting too late to raise low glucose levels, not having an appro- priate action plan to guide self-care, and being

" It’s time to restore balance about risks. Yes, complications are serious but we need to share the good news with our patients that all reductions in HbA1c can reduce the risk of long-term complications. They also need to be aware that hypoglycemia is not inevitable – it’s not a necessary evil . " PRACTICEUPDATE CONFERENCE SERIES • ADC 2018 4

There are currently 21 centers around Australia where clinicians can refer their patients or attend education sessions themselves. “It’s time to restore balance about risks. Yes, complications are serious but we need to share the good news with our patients that all reductions in HbA1c can reduce the risk of long-term complications. “They also need to be aware that hypo- glycemia is not inevitable – it’s not a necessary evil,” Dr. Speight said.

embarrassed to treat their diabetes in public. Some even had an absolute focus on avoiding hyperglycemia. “This showed us the determination of these patients in wanting to keep their glucose levels in the lower range because people were telling them that they needed to. “We’ve been shouting loud and clear about people’s risk of long-term compli- cations when their glucose levels are high. But what we’ve not been saying very well to our patients is what can be done to manage their risk of hypoglycemia. “This really is the elephant in the room, and we need to be talking more about it,” Dr. Speight said. In 2017, the National Diabetes Services Scheme released the handbook Diabetes and Emotional Health: A Handbook for Health Professionals Supporting Adults with Type 1 or Type 2 Diabetes to help support and encourage healthcare pro- fessionals to ask patients about their actual experiences of hypoglycemia dur- ing consultations. Structured education can improve patients’ glycemic control and hypoglycemia risk Dr. Speight also explained that patients with T1D can benefit from a structured education program, such as DAFNE in the UK and OzDAFNE in Australia.

DAFNE is a 5-day outpatient group edu- cation program that provides participants with the tools needed to self-manage their insulin doses. Studies of OzDAFNE have found that rates of severe hypoglycemia are reduced by about half in those who have completed the program. “Patients who are having problems with hypoglycemia can clearly ben- efit from attending a DAFNE course,” Dr. Speight said.

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Can Oral Insulin Delay Progression to T1D? BY THE PRACTICEUPDATE EDITORIAL TEAM O ral insulin therapy does not delay or prevent progression in people who are autoantibody-positive and have a rel- ative with type 1 diabetes (T1D), according to trial findings

pancreas function, which was defined as a normal first-phase insulin response (FPIR) to intravenous glucose. “The rationale was if you were using immunotherapy you wanted to get in as early as you can in the disease process because if you leave it later … the response is not going to be as effective,” said Dr. Wentworth. DPT-1 results showed that treatment with 7.5 mg oral insulin daily, when compared with placebo, had no significant effect in prevent- ing progression to T1D. However, a post hoc analysis suggested oral insulin treatment did have a significant effect in delaying T1D in participants with high titers of insulin autoantibodies. The TrialNet TN07 study was subsequently performed to confirm this finding. TrialNet TN07 TrialNet TN07 participants had two or more islet autoantibodies, including anti-insulin antibody, and normal glucose tolerance and a first-degree relative with T1D. Participants were divided into four strata according to their diabetes-related autoantibodies and FPIR to intravenous glucose. The primary objective of the trial was to assess the effects of oral insulin versus placebo on progression to T1D within the primary stratum. The secondary objectives were to assess the effects of treatment in each stratum and in the overall trial population. Participants in the primary stratum had ICA confirmed, or, if ICA not confirmed, had persistent glutamic acid decarboxylase (GAD) and insulinoma antigen-2 (IA-2). They also had to have a FPIR above a threshold, indicating high functioning beta cells.

presented at ADC 2018. However, contrary to the overall trial results, oral insulin delayed T1D by an average of 31 months in a pre-specified secondary stratum. The TrialNet TN07 study was a randomized, placebo-controlled trial that aimed to determine whether oral insulin prevented pro- gression from preclinical to clinical T1D. This trial was a follow-up to the Diabetes Prevention Trial–Type 1 (DPT-1). The premise of both these trials was that oral insulin treatment would dampen islet autoimmunity and prevent T1D. “Type 1 diabetes is a highly targeted immune attack and there is strong evidence that insulin is part of the process,” explained Endocrinologist and Clinician Scientist John Wentworth, MBBS, PhD, FRACP, of Royal Melbourne Hospital and the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia. Various research has indicated that insulin is a key autoantigen in T1D. Mouse model studies have also shown that insulin-toler- ization therapies prevent and treat T1D. Diabetes Prevention Trial–Type 1 In light of these data, DPT-1 was conducted in the 1990s–2000s in participants at very high risk of developing T1D. All participants were islet cell antibody (ICA)–positive and had to have good

The secondary stratum 1 had the same autoantibodies as the primary stratum but with FPIR lower than the threshold. Secondary stratum 2 were GAD- or IA-2– positive and had FPIR above the threshold, while secondary stratum 3 was identical to secondary stra- tum 2 but with FPIR below the threshold. The primary stratum showed no significant between- group differences in the primary outcome – that is, the rate of progression to T1D. However, in the secondary stratum 1 (n=55), oral insulin treatment led to an average of a 31-month delay in progression to T1D. It was a finding that was “counterintuitive and very, very interesting,” said Dr. Wentworth. “There was no effect of oral insulin to prevent type 1 diabetes in high-risk children who had strong auto- immunity and normal FPIR, although those who were approaching diagnosis were protected from diabe- tes,” he explained. The observation that oral insulin delayed disease progression in individuals with relatively poor beta- cell function raises the possibility that immune therapies might work best towards the end of the preclinical disease phase. Oral insulin treatment was also shown to be without associated significant adverse events in both the TrialNet TN07 and DPT-1 studies.

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PRACTICEUPDATE CONFERENCE SERIES • ADC 2018

Update on Intranasal Insulin Trial II (INIT II) to Prevent Type 1 Diabetes

Data show that, while nasal insulin induced an immune response, it did not halt progression to T1D. BY THE PRACTICEUPDATE EDITORIAL TEAM A ustralian researchers are leading a multinational, randomized con- trolled trial on the use of intranasal insulin to prevent the onset of type 1 dia- betes (T1D) in individuals with subclinical disease. The Intranasal Insulin Trial II (INIT II) will see all participants completing a 3-year follow-up in October 2018, at which time the median follow-up will be 57.5 months. “Previous non-obese diabetic (NOD) mouse model studies have shown that insulin delivered to the nasal mucosa induced regulatory T cells and decreased diabetes incidence,” said Leonard Harrison, MBBS, MD, DSc, FRACP, FRCPA, FAHMS, of the Walter and Eliza Hall Institute of Medical Research and the Royal Melbourne Hospital in Melbourne, Australia. He added that two human trials had shown that intranasal insulin was safe and elicited immune responses and tolerance to insulin. Against this background, INIT II was performed to determine if intranasal insulin delayed or prevented the onset of T1D in at-risk children and young adults. The trial screened over 10,000 people with T1D relatives and found 2.2% had at least two autoantibodies directed at two or more islet antigens (insulin, GAD65, IA-2). The individuals were staged through first-phase insulin response and glucose tolerance. The trial experienced quite a large dropout, according to Professor Harrison. Around 110 participants were randomized to a "low dose" or a higher dose of insulin or placebo. The estimated 5-year risk of diabetes was 40%; the trial was powered to detect a decrease of 50%. The low-dose arm was eventually discontinued, but its 18 participants con- tinue to be followed. The characteristics by treatment arm were generally similar. About 41 people (38%) developed diabetes. Comparing charac- teristics of those who developed diabetes and thosewho had not, Professor Harrison

insulin group. However, Professor Harrison remarked that he did not know why the placebo group had a low incidence of T1D. “Unfortunately, we do not know – we are intrigued by this finding.” The trial showed that intranasal insulin was safe and induced immune response, but this did not translate to a change in the development of T1D. Professor Harrison noted the importance of beginning treatment early in the dis- ease course to prevent diabetes. He said researchers are now studying nasal and oral insulin in children who are not yet autoantibody positive but are genetically at risk for T1D. oral insulin in children who are not yet autoantibody positive but are genetically at risk for T1D. " " …researchers are now studying nasal and

said the age of the former group was sig- nificantly lower. “The lower the age, the more rapidly they progressed to T1D,” he added. Insulin antibody concentrations were similar between the diabetes and non-di- abetes groups directed at two or more. HLA phenotype was significantly more frequent among those who developed diabetes, which was to be expected. No serious treatment-related adverse events were reported. Speaking about the response, Professor Harrison said intranasal insulin led to a dose-related increase in serum insulin antibody concentrations, which peaked and then declined during ongoing treat- ment in the first year. “This is quite unusual for an antibody response,” he said. “We think this is consistent with the induction of immune tolerance to exogenous insulin.” What was of concern to the researchers was the incidence of diabetes by treat- ment arm, said Professor Harrison. In the placebo group, 30% developed diabetes over a median follow-up of 1385 days ver- sus 61% in the low-dose intranasal insulin group and 36% in high-dose intranasal

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ADC 2018 • PRACTICEUPDATE CONFERENCE SERIES

Preventing Type 1 Diabetes: What We Know INTERVIEW WITH JOHN WENTWORTH MBBS, PhD, FRACP

A lot of work has gone into looking at ways to prevent close relatives of people with type 1 diabetes (T1D) from developing the disease, and to stop or slow progression in those who are in the early stages of T1D. The presence of islet autoantibodies – for example, GAD, IA-2, zinc trans- porter 8, and insulin – tell us that the immune system is activated and is attacking the pancreas. These autoantibodies are present, often for years, before T1D develops. Close relatives of a person with T1D have a 15-fold increased risk of devel- oping diabetes themselves. Approximately 1 in 40 will have two or more islet autoantibodies and will eventually progress to T1D at some stage in their life. By screening close relatives of people with T1D for these autoantibodies, we can pick out those most at risk of developing the disease. However, such targeted screening only picks up the 15% to 20% of people in the community who will eventually develop T1D. We are not capturing the other group of people who don’t have a first-degree relative with T1D but who end up getting diabetes anyway.

Dr. Wentworth is an Endocrinologist at the Royal Melbourne Hospital and Clinician Scientist at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia.

Dr. John Wentworth

" These findings raise the possibility that maybe immune therapy is best used just before a person develops T1D… "

For these reasons, there are arguments supporting blanket screening of the population to identify those at risk of developing diabetes. The justification is twofold: if we know a person is at risk, we can be alert to the signs of pro- gression and treat him or her before that person falls critically ill with high sugars and ketoacidosis; secondly, we may be able to stop someone at risk from getting T1D or at least slow the progression to diabetes.

Can immune therapy and insulin prevent T1D progression? Several immune therapies are currently being trialled for preventing or delaying the progression of T1D. These include abatacept, tocilizumab and anti-thymocyte globulin (ATG). We know that these drugs are effective against autoimmune disorders, but they can also cause problems; for example, with cytokine storm. The worry is that they are going to be too toxic for routine use in T1D, at least in the sorts of doses that are currently being used to treat other autoimmune disorders. The insulin vaccine approach, which Leonard Harrison and I presented on at this meeting, is a relatively safe way to go about preventing T1D. ( See pages 6 and 7. ) Both, the oral and intranasal, insulin approaches seem to be effective in mouse studies. However, in humans, there has been no clear benefit to people who took it – although, in the case of oral insulin, children who were very close to their diagnosis appear to be protected from progressing to T1D with oral insulin – delaying T1D diagnosis by about 2 years. These high-risk children are the ones with low first-phase insulin release and relatively low pancreas function. Leonard Harrison’s study, which had children with normal pancreas function and who had relatively early-stage T1D, found no benefit of intranasal insulin in delaying progression to T1D. These findings raise the possibility that maybe immune therapy is best used just before a person develops T1D, although that still needs to be proven in follow-up clinical studies. If that is the case, we'll need to work out how to identify antibody-positive people who are nearing the end of the preclinical disease phase and treat them to prevent progression to diabetes and insulin dependency. This is one of my research interests now. www.practiceupdate.com/c/73012

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PRACTICEUPDATE CONFERENCE SERIES • ADC 2018

Once-WeeklyDulaglutideNoninferior toOnce-Daily Liraglutide inPatientsWithType 2Diabetes Both GLP-1 receptor agonists showed strong antihyperglycemic effects, further confirming the benefits of this class of drugs for themanagement of T2D. BY THE PRACTICEUPDATE EDITORIAL TEAM

T he AWARD-6 study showed that glycemic control with once-weekly dulaglutide was not inferior to that with once-daily liraglutide in the management of type 2 diabetes (T2D). Both drugs produced robust HbA1c reductions in most patients, reaching the American Diabetes Association HbA1c target of <7.0%. Dulaglutide, a long-acting GLP-1 receptor agonist, is now available on the PBS in Australia. It has a longer plasma half-life than liraglutide and is given subcutaneously once a week. “The AWARD-6 study demonstrates strong anti- hyperglycemic profiles for both GLP-1 receptor agonists dulaglutide and liraglutide, further con- firming the benefits of this class for the treatment of type 2 diabetes,” said Tim Davis, MBBS, DPhil, FRCAP, MRCP, Professor of Medicine at the University of Western Australia, and Consultant Physician and Endocrinologist at Freemantle Hospital, in Western Australia. The AWARD-6 study compared the efficacy and safety of once-weekly dulaglutide 1.5 mg versus once-daily liraglutide 1.8 mg in 599 patients with T2D who were being treated with metformin ≥1500 mg. The primary objective of the study was to show non-inferiority in terms of glycemia (HbA1c) at 6 months compared with baseline, with a non-in- feriority margin of 0.4%. In this phase III, open-label, parallel-arm 26-week study, there was a short run-in period followed by randomization onto either the once-weekly dula- glutide or once-daily liraglutide groups. Patients in the liraglutide group underwent dose titration from 0.6 mg to 1.8 mg, usually within the first few weeks of the study, to help ensure that as many patients were on the full liraglutide dose as possible. Safety data were collected for a further 4 weeks following the main study. The baseline characteristics of patients in both groups were very similar: approximately a 50:50 female-to-male ratio, average age of 57 years, mean HbA1c of 8.1%, and mean body weight of 94.1 kg. The adjusted change from baseline at 26 weeks for a reduction in HbA1c was –1.42% in the dulaglu- tide group and –1.36% in the liraglutide group. The mean treatment difference in HbA1c was –0.06%

(95% CI, –0.19 to 0.07; P

< .0001) between

non-inferiority

the two groups. While both groups experienced significant weight reduction, liraglutide-treated patients demonstrated a 0.71-kg greater reduction than dulaglutide-treated patients (P = .01). " The adjusted change from baseline at 26 weeks for a reduction in HbA1c was –1.42% in the dulaglutide group and –1.36% in the liraglutide group. " As predicted for this class of drug, themost common treatment-related adverse events were gastroin- testinal-related. The most common adverse events for both dulaglutide and liraglutide included nau- sea (20.4% with dulaglutide, 18.0% with liraglutide), diarrhea (12.0%, 12.0%), dyspepsia (8.0%, 6.0%), and vomiting (7.0%, 8.3%). “With persistent dosing, nausea rates in both groups fell in the second half of the follow-up period to about 3–4%,” Dr. Davis said. Of the 299 patients randomized to dulaglutide and the 300 to liraglutide, 269 patients in each group finished treatment at week 26. The number of patients who discontinued the study and/or discontinued the assigned drug due to gastroin- testinal adverse events were similar (dulaglutide, 3.0%; liraglutide, 4.3%). “Retention in the study was excellent and there was no difference in the number of patients who withdrew from the study between both groups," Dr. Davis said. Meanwhile, the rate of hypoglycemia was 0.34 events per patient per year for dulaglutide and 0.52 for liraglutide. No severe hypoglycemia was reported in either group.

www.practiceupdate.com/c/73023

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ADC 2018 • PRACTICEUPDATE CONFERENCE SERIES

Is Targeting Mitochondrial Dysfunction Worth Considering as a Prevention Strategy for Kidney Disease in T1D?

This possibility was raised after young adults with T1Dwho presented with early kidney damage also

had defects in themitochondria. BY THE PRACTICEUPDATE EDITORIAL TEAM

Y oung adults with type 1 diabetes (T1D) at high risk for diabetic kidney disease (DKD) and cardiovascular disease (CVD) have been found to have mitochondrial dysfunction and other factors suggestive of early chronic kidney disease. This raised the question of whether addressing mitochondrial dysfunction could form part of a strategy to prevent DKD in patients with T1D. Current evidence suggests that DKD and CVD develop early in diabetes, and it’s the young adults in the highest tertile of the urine albumin/creatinine ratio (uACR) who are at greatest risk. And while there is evidence of dysfunctional mitochondria late in DKD, Josephine Forbes, PhD, Program Leader in Chronic Disease at Mater Research Institute–The University of Queensland in Brisbane investigated if this was the case in early kidney disease. Among young adults with T1D, her team found that those at high risk for DKD and CVD – patients with uACR ≥1.17 – had persistent elevations in uACR since their diabetes diagnosis. And while almost all the patients (99.7%) presented with hyperfiltration (CKD EPI eGFR, 135.0 [13.8] mL/min/m 2 ), it was the high-risk patients who had the highest median eGFR (P<.031 vs low-risk patients), even after adjustment for age, gender, and diabetes duration. This cross-sectional study recruited 100 young adults with T1D. Patients were on average 20 years of age, similar proportion of female to male participants, HbA1c of 12.3 mmol/L, diabetes duration of 10.7 years, and BMI of 24.5 kg/m 2 . Patients were divided into three uACR tertiles: low-risk (uACR ≤0.66 mg/mmol; n=33), medium-risk (uACR 0.67–1.16; n=33), and high-risk (uACR ≥1.17; n=34) for DKD and CVD. Professor Forbes and colleagues also found that mitochondrial function in circulating leukocytes was lower in high-risk patients compared with the low- and medium-risk groups (P=.008). The high-risk patients also had characteristics of early chronic kidney disease, including elevated circulating kidney injury molecule-1.

" This early evidence of mitochondrial

dysfunction and early kidney damage in "at risk" 15- to 25-year-olds with T1D, may provide a novel target for therapies to prevent progression to overt DKD and lower risk for future CVD. "

www.practiceupdate.com/c/73020

PRACTICEUPDATE CONFERENCE SERIES • ADC 2018 10

Clinical Islet Transplantation in Australia BY TOBY COATES MBBS, PhD, FRACP

Dr. Toby Coates Dr. Coates is Professor of Medicine and Director of Kidney and Pancreatic Islet Transplantation at the University of Adelaide, Royal Adelaide Hospital in Adelaide, South Australia. I slet transplantation is an effective therapy for selected patients with type 1 diabetes who suffer from hypoglycemic unawareness and severe metabolic instability, who have failed other technologies and therapeutic interventions. In Australia, islet transplantation is offered through the Australian Islet Consortium at three centres: Westmead Hospital in Sydney, St Vincent’s Hospital in Melbourne, and the Royal Adelaide Hospital in Adelaide. Outcomes for clinical islet transplantation have significantly improved, with 60% of recipients becoming insulin independent and some patients remaining insulin independent for up to 9 years. All patients transplanted for hypoglycemic unawareness experience a dramatic resolution of this symptom, which persists for as long as the transplanted islets produce insulin even without insulin independence. Complications of islet transplantation are min- imal and mainly relate to the side effects of immunosuppression, required to prevent trans- plant rejection and recurrence of autoimmune diabetes. An important new clinical trial to induce toler- ance for islet transplantation is now recruiting at all three sites, supported by grant funding from JDRF Australia. Practitioners can refer patients for islet transplantation by contacting the islet coordinators at each of the hospitals. Wait-listed patients are generally transplanted within a few months. Nationally Funded Centre status for the program ensures that the costs of patients travelling interstate to access islet transplantation are covered.

Comment BY JOSEPHINE FORBES PhD

Professor Forbes is Program Leader in Chronic Disease at Mater Research Institute–The University of Queensland in Brisbane, Australia. C hronic complications in people with T1D begin much earlier than previously thought. In adolescents with T1D, high-risk stratifica- tion for future kidney and CVD is possible using the highest tertile of the urinary excretion of the protein albumin (uACR), even with values within a "normal" range.

Professor Josephine Forbes

My colleagues and I showed that early kidney damage in young adults with T1D (using uACR and glomerular filtration rate), was accompanied by defects in cellular power stations, the mitochondria. The mitochondria produce energy as ATP from oxygen and substrates derived from our food, including glucose, free fatty acids, ketones, and amino acids. Interestingly, sites affected by the chronic complications of diabetes, such as kidney, nerves, and the heart, seem most reliant on the generation of high concentrations of ATP by mitochondria for their normal function. In young T1D patients at high risk of DKD and CVD, studies using typically "adult" DKD treatments have failed. Good control of blood glucose is also notoriously difficult to achieve in childhood to early adulthood. This early evidence of mitochondrial dysfunction and early kidney damage in "at risk" 15- to 25-year-olds with T1Dmay provide a novel target for therapies to prevent progression to overt DKD and lower risk for future CVD.

www.practiceupdate.com/c/73014

11 ADC 2018 • PRACTICEUPDATE CONFERENCE SERIES

Research Uncovers Potential Role of Gut Microbiome in T1D Pathogenesis BY THE PRACTICEUPDATE EDITORIAL TEAM

A n "unbalanced" gut microbiome may play a role in the pathogenesis of type 1 diabetes (T1D), say research- ers who found that children with islet autoimmunity or T1D had gut dysbiosis. They also discovered that children who presented with islet autoantibodies, who then progressed to T1D, had increased intestinal permeability compared with those who did not progress to T1D. " The discovery of a low abundance of anti- inflammatory species in type 1 diabetes and at-risk children require deeper sequencing to look at the potential for bespoke probiotic development to reduce the progression rate to T1D. " This longitudinal study was the first to characterize the gut microbiome and small intestinal permeability in Southern Hemisphere children with multiple islet autoantibodies and T1D, said Professor Jennifer Couper, Head of Paediatrics at the University of Adelaide in Adelaide, South Australia. “Intestinal permeability was previously shown to be high in type 1 diabetes … but what hadn’t previously been shown is that intestinal permeability is higher in patients who progressed to diabetes” than those who did not progress to dia- betes, Professor Couper said.

Professor Couper and her colleagues followed a small cohort of 88 children every 6 months for a median of 13 months (range, 2–34 months) to characterize gut microbiome, bacterial products, and small intestinal permeability in children with islet autoimmunity. Of these children, 18 had islet autoim- munity, while 29 had recent-onset T1D. The study included 41 age- and gen- der-matched unrelated or sibling controls. Participants’ stool samples were collected for 16S rRNA gene sequencing. Small intestinal permeability was measured using the blood lactulose:rhamnose (L/R) ratio 90 minutes after drinking a 5% lac- tulose/1% rhamnose solution. A higher L/R ratio indicates higher permeability. Short-chain fatty acids were measured by gas chromatography, and checks for progression to T1D were performed using a glucose tolerance test or postprandial glucose test every 6 months. The partici- pants’ dietary intake was evaluated using the Australian Child and Adolescent Food Frequency Questionnaire.

In terms of the gut microbiome, the alpha diversity (ie, the diversity within a sample) showed no differences among children with islet autoimmunity, T1D, and controls. However, children with two or more islet antibodies who progressed to T1D ("progressors") had lower alpha diversity (observed richness) and different beta diversity (ie, a measure of the dissimilar- ity between each sample pair) compared with those who did not progress to T1D ("non-progressors"). The relative abundance of bacteria showed there was a deficit in the anti-in- flammatory bacteria Butyricimonas and Prevotella in children with two or more islet antibodies or T1D. There was no sig- nificant difference in diet that could have explained the difference in bacteria. Progressors also had a higher L/R ratio than non-progressors. Lower alpha diver- sity related weakly to a higher L/R ratio. To the researchers’ surprise, plasma acetate – a short-chain fatty acid – was related to lower observed richness.

PRACTICEUPDATE CONFERENCE SERIES • ADC 2018 12