Endocrinology

To the Editor: We congratulate Cheung and colleagues1 on their large cluster randomised trial of routine blood glucose and automated glycated haemoglobin (HbA1c) testing in emergency departments. This trial reaffirmed the high prevalence of unrecognised diabetes in patients presenting to the emergency department, while demonstrating the feasibility of algorithmic detection. However, the rate of documented follow‐up plans in patients with suspected or newly diagnosed diabetes was low and did not benefit from the trial intervention. Cheung and colleagues1 and Hare and Shaw,2 in their accompanying editorial, suggest that this may relate to diabetes services already operating at full capacity or to overburdened staff documenting abbreviated plans at discharge. The trial highlights the difficulty in improving outcomes when multiple non‐integrated health professionals manage a condition and, hence, the importance of continuity of care. The RAPIDS trial3 was an early intervention model of care consisting of integrated continuous acute diabetes care provided by a dedicated, proactive specialist inpatient diabetes team (IDT). The intervention involved an IDT using a networked blood glucose meter system to remotely identify inpatients with diabetes (known and newly diagnosed) to directly manage these patients, compared with usual care, where diabetes management was mostly provided by parent unit teams.3 This trial showed that direct diabetes management by a dedicated IDT improved glycaemia and decreased the rate of hospital‐acquired infections. During the RAPIDS trial, in patients with newly discovered hyperglycaemia (random capillary glucose > 11.1 mmol/L without known diabetes), treatment and follow‐up plans were documented in 11/34 patients (33%) with usual care, comparable to findings by Cheung et al. However, with the IDT intervention, 22/28 patients (79%) had treatment and follow‐up plans. Similarly, in patients with newly diagnosed diabetes (HbA1c ≥ 6.5%), diabetes treatment was commenced in 8/17 patients (47%) with usual care, and in 11/12 patients (92%) with IDT intervention3 (unpublished data). It is likely that the presence of an IDT at one of the control hospitals in the trial by Cheung and colleagues contributed significantly to the improved plan documentation in that arm. We thus echo the editorial and professional society voices asserting the importance of resourcing clinical services for diabetes in Australian hospitals.4 Establishing IDTs in our hospitals will enable excellent diabetes care despite the increasing prevalence of this disease in Australia.

Spiros Fourlanos · Rahul Barmanray · Mervyn Kyi

The incidence of paediatric type 2 diabetes has increased in Australasia parallel to paediatric obesity and international guidelines available do not address the specifics for high risk ethnic groups

Alexia S Peña · Jacqueline A Curran · Michelle Fuery · Catherine George · Craig A Jefferies · Kristine Lobley · Karissa Ludwig · Ann M Maguire · Emily Papadimos · Aimee Peters · Fiona Sellars · Jane Speight · Angela Titmuss · Dyanne Wilson · Jencia Wong · Caroline Worth · Rachana Dahiya

Risk of SGLT2 inhibitor-associated diabetic ketoacidosis in type 2 diabetes: some answers, but more questions

Peter S Hamblin · Rosemary Wong · Leon A Bach

Living guidelines that incorporate new evidence as it becomes available have the potential to overcome some of the limitations inherent in static guidelines Diabetes is a complex chronic condition that affects about 1.7 million Australians and represents an estimated $15 billion per annum in direct and indirect costs to the Australian economy.1 Almost $215 million of subsidies were delivered during the 2015–16 financial year to the 1.32 million registrants of the National Diabetes Services Scheme, an Australian Government initiative that provides support to Australians living with diabetes. In 2019, an additional $100 million was announced for funding the Continuous Glucose Monitoring Initiative, which provides fully subsidised continuous glucose monitoring products to patients with diabetes who meet certain criteria.2 In 2017, almost 1.2 million hospitalisations and 11% of all deaths in Australia listed diabetes as the principal or associated cause.3 In addition to the costs associated with diabetes management and prevention, significant funding has been directed towards research into this key priority area, with the National Health and Medical Research Council (NHMRC) providing $375 million from 2013–2018 towards efforts to improve the prevention, diagnosis and management of diabetes.4 With the objective of strengthening diabetes policy and practice, the Australian Government developed the Australian National Diabetes Strategy 2016–2020, which outlines an integrated and coordinated approach for reducing the social, human and economic impact of diabetes.5 One of the key goals within this strategy involves strengthening prevention and care through the use of research, evidence and data. Indeed, developing a nationally endorsed set of diabetes guidelines, assessed against the clinical practice guidelines criteria, was a key recommendation of the Australian National Diabetes Strategy to improve complications and outcomes associated with the disease. Producing new clinical guidelines and implementing a system by which recommendations can be updated and adopted rapidly represents an important means by which this recommendation can be achieved. Clinical guidelines: is there a better way? High quality, evidence‐based clinical guidelines are integral to ensuring that health care decisions are based on the best available evidence. Unfortunately, evidence‐based clinical guideline development is an expensive and laborious undertaking in which several years can pass between inception and publication. In Australia, guidelines approved by the NHMRC are valid for 5 years from publication before they are considered outdated, following which they must be either updated or developed anew.6 These delays can result in several potential problems. First, new research is continually being generated throughout the development period, which may mean that a guideline is outdated before it is even published. Indeed, it has been demonstrated that one in five guideline recommendations are outdated within 3 years of guideline publication.7 Second, institutional memory of the decision‐making processes through which recommendations are derived can be lost, particularly if a significant period of time has transpired since the original guideline was developed. Third, changes in the policy and practice environment can shift priorities or raise new questions that were not considered when defining the original scope, resulting in the guideline failing to address some of the key current issues relating to the topic of interest (eg, the development of a new therapeutic or withdrawal of a technology from the Australian Register of Therapeutic Goods). Currently, all but one of the NHMRC‐approved diabetes clinical guidelines are outdated and have been rescinded. As a result, there is no up‐to‐date Australian guidance for clinicians caring for people with diabetes, potentially resulting in the suboptimal management and significant variation in care of this condition.8 Living guidelines Living guidelines represent an approach to guideline development in which individual recommendations are continually updated as new, relevant evidence becomes available. This is achieved through monthly searches of key databases to identify recently published research. Following analysis of the new data, an impact assessment is conducted to determine whether the evidence is of sufficient relevance, reliability and importance to justify revising recommendations.9 Updated recommendations are then published within a real‐time digital dissemination platform, providing stakeholders with access to the most up‐to‐date version of the guideline. Although the concept of living guidelines is not new, many of the processes employed in developing living guidelines have been generated through Project Transform, an innovative platform established by Cochrane to address the critical issue of evidence currency within clinical guidelines (https://community.cochrane.org/help/tools-and-software/project-transform/about-project-transform). These processes are supported by the development and refinement of machine learning algorithms (eg, randomised controlled trial classifiers), citizen science initiatives (eg, Cochrane Crowd), new methods for updating statistical analyses,10,11 and the development of online collaborative platforms for systematic review and clinical practice guideline production (eg, Covidence, MAGICApp). The application of these tools significantly reduces the workload of systematic review and guideline authors, and appears to result in the production of updated recommendations at a fraction of the resource and time costs otherwise required. In addition, the establishment of a living guideline development group improves the retention of institutional memory throughout the process of updating, and the feedback mechanisms built into the process provide a means by which the underlying scope can be adapted to changes in policy and practice in Australia (Box 1). Living evidence for diabetes Embracing the inherent potential in living guidelines, the Living Evidence for Diabetes Consortium is developing living guidelines that address key priorities relating to diabetes prevention, diagnosis and management (https://livingevidence.org.au/new-index-3#Living-Guidelines-for-Diabetes). Consisting of the Australian Diabetes Society, Diabetes Australia, the Australasian Paediatric Endocrine Group, the Australian Diabetes Educators Association and Cochrane Australia, with representation from the Royal Australian College of General Practitioners and the Australian Government Department of Health, the consortium has selected two proof‐of‐concept topics that fulfil the criteria for living guidelines (Box 2). Two systematic reviews are currently under development to underpin these guidelines, focused on the comparative safety and effectiveness of therapeutics for blood glucose control in adults with type 2 diabetes and the use of technologies (such as insulin pumps and continuous glucose monitors) for the management of type 1 diabetes in adult and paediatric populations. The need for clear guidance relating to these topics is demonstrated by the ongoing uncertainty regarding the most appropriate choice of second line therapies13 and the inception of do‐it‐yourself closed loop systems.14 Although the methods and processes required to produce living guidelines are still evolving, the development of living guidelines for diabetes represents a paradigm shift in the way recommendations are updated and shared with decision makers. Access to this resource should improve the likelihood that patients will consistently receive the best evidence‐based care available, and also provide an avenue through which guideline developers can respond to changes in policy and practice, resulting in guidelines that evolve to keep up with the current practice. Box 1 – Static guideline development (A) versus living guideline development (B) Box 2 – Requirements for converting traditional to living recommendations12 Not all recommendations are suitable for a living evidence approach. Three key requirements should be fulfilled to justify transitioning a static guideline into a living guideline: the guideline should focus on a priority topic for patient, clinical or policy decision‐making; uncertainty should exist regarding the strength and/or direction of recommendations; and there should be a high likelihood of new evidence becoming available in the near future which could increase certainty.

Heath White · Britta Tendal · Julian Elliott · Tari Turner · Sofianos Andrikopoulos · Sophia Zoungas

The treatment options for type 2 diabetes have expanded significantly in the past decade, with new classes of agents demonstrating superiority for cardiovascular outcomes

Renata Libianto · Timothy ME Davis · Elif I Ekinci

To the Editor: Over the past decades, the incidence of type 2 diabetes, rarely diagnosed in children and adolescents before the 1990s,1 has been increasing in young people in several populations, including Australia.2,3,4 Early onset type 2 diabetes appears to have a more severe phenotype compared with adult onset type 2 diabetes, and has a high prevalence of complications already present at the time of diagnosis despite the patients’ young age and short duration of the disease.5 We aimed to describe the characteristics of Western Australian children aged less than 10 years diagnosed with type 2 diabetes between June 2000 and June 2017. Demographic and clinical data for children diagnosed with type 2 diabetes during the study period were extracted from the population‐based WA Children's Diabetes Database and via manual review of hospital clinical files. Of the 193 children aged less than 16 years diagnosed with type 2 diabetes in WA during the study period, 12 children were diagnosed at less than 10 years of age, with the youngest aged 6 years and 11 months. These 12 patients had one or both parents diagnosed with type 2 diabetes, 11 children were Aboriginal Australians, one was Māori, 11 were obese (mean body mass index z‐score, 2.38; standard deviation [SD], 0.64); nine were female, and seven had one or more comorbidities. Of the 11 children examined, ten had acanthosis nigricans present on their skin. Three children presented with polyuria and polydipsia, six were unwell with other illnesses and three were asymptomatic. Type 1 diabetes antibodies were negative in seven of eight of the children tested, and the mean glycated haemoglobin level at diagnosis was 75 mmol/mol (mean, 9.0%; SD, 2.4%). Nine patients had one or more diabetes complications present at the time of diagnosis; seven had dyslipidaemia, two had an elevated albumin creatinine ratio, and three had hypertension. Our study describes the common clinical features of early onset type 2 diabetes in young children in WA, such as history of parental type 2 diabetes, Aboriginal heritage, obesity, and female sex, and provides strong evidence for the need to screen children with these risk factors for type 2 diabetes, irrespective of their age. Moreover, the high prevalence of diabetes complications present strongly supports the need for complications screening at the time of diagnosis.

Jacqueline A Curran · Aveni Haynes · Elizabeth A Davis

Routine admission screening of patients is desirable, but financial and personnel support for diabetes services is essential

Matthew JL Hare · Jonathan E Shaw

Glucose and HbA1c screening alone does not increase detection of previously unidentified diabetes in patients admitted from EDs

N Wah Cheung · Lesley V Campbell · Gregory R Fulcher · Patrick McElduff · Barbara Depczynski · Shamasunder Acharya · John Carter · Bernard Champion · Roger Chen · David Chipps · Jeff Flack · Jen Kinsella · Margaret Layton · Mark McLean · Robert G Moses · Kris Park · Ann M Poynten · Carol Pollock · Debbie Scadden · Katherine T Tonks · Mary Webber · Chris White · Vincent Wong · Sandy Middleton

To the Editor: Sodium–glucose cotransporter type 2 (SGLT2) inhibitors — dapagliflozin, empagliflozin and now ertugliflozin — have become established second line options for type 2 diabetes, with favourable potential for weight loss and cardiovascular protection.1 However, it soon became clear post‐marketing that they had potential for several pronounced side effects, including euglycaemic ketoacidosis — an unusual form of diabetic ketoacidosis where blood sugar levels remained relatively normal.2 The Therapeutic Goods Administration (TGA) first sent an alert about euglycaemic ketoacidosis in relation to SGLT2 inhibitors in 2015; subsequent alerts in 2018 from the TGA and the Australian Diabetes Society warned specifically about periprocedural risks.3,4 Austin Health has a well developed culture of adverse drug reaction reporting. A multidisciplinary committee includes representation from pharmacy, clinical pharmacology, dermatology and infectious diseases. During 2018, our adverse drug reaction committee forwarded 302 reports to the TGA, estimated to be around 15% of all reports received from Australian hospitals. Since 2016, our adverse drug reaction committee has received 12 reports of patients with diabetic ketoacidosis related to SGLT2 inhibitors, including eight in 2018. The growth in incidence locally in such a short period is alarming. Most patients (75%) had a blood sugar level of 11 mmol/L or lower at presentation. Our committee reviewed the cases in the Box to evaluate severity and causality. SGLT2 inhibitors were considered a probable cause in ten cases; the reaction was considered severe in nine cases, with one death during admission. We report our cases with the aim of increasing awareness around contributing factors, particularly concurrent illness resulting in poor oral intake. Only two of the 12 cases related to a perioperative setting, and in neither situation was the SGLT2 inhibitor withheld prior to surgery. We remind clinicians that the precipitants for diabetic ketoacidosis extend beyond the perioperative period. We advise caution when patients are experiencing other contributing factors illustrated by our case series, including acute illness, reducing insulin doses, poor oral intake, severe dehydration and low carbohydrate diet. Patients should be counselled about the signs of ketoacidosis and advised to seek medical help if they occur. SGLT2 inhibitors should be withheld if a patient is acutely unwell or undergoing surgery, and should only be restarted when the patient is eating and drinking normally.5 Box – Cases of ketoacidosis related to sodium–glucose cotransporter type 2 inhibitors Case Year Medication Dose Severity Causality Potential contributing factors 1 2016 Empagliflozin 10 mg daily Moderate Probable Low dietary intake in perioperative setting 2 2016 Dapagliflozin 5 mg twice a day Severe Probable Perioperative setting 3 2017 Dapagliflozin 10 mg daily Severe Probable Unwell for 3 days prior to presentation — patient had type 1 diabetes 4 2017 Empagliflozin 10 mg daily Severe Possible Concurrent influenza 5 2018 Empagliflozin 10 mg daily Severe Probable Narcosis leading to poor oral intake 6 2018 Empagliflozin 12.5 mg twice a day Severe Probable Weight loss since commencing — worse in the month prior to admission 7 2018 Empagliflozin 25 mg daily Moderate Probable Concurrent pneumonia 8 2018 Dapagliflozin 10 mg daily Moderate Possible Low carbohydrate diet 9 2018 Empagliflozin 10 mg daily Severe Probable Patient unwell with some vomiting for several days before admission 10 2018 Dapagliflozin 5 mg twice a day Severe Probable 5–7 days of loss of appetite 11 2018 Dapagliflozin 10 mg daily Severe (died during admission) Probable Illness for 10 days before admission Pancreatitis 12 2018 Empagliflozin 25 mg daily Severe Probable 5 days of gastroenteritis before admission Weaning insulin doses

Gina McLachlan · Claire Keith · Albert Frauman

Diagnosis of autoimmune ?-cell disorder before end-stage clinical type 1 diabetes is a key step towards the prevention of this disease

Jennifer J Couper · Leonard C Harrison

Management should be individualised, using a multidisciplinary approach

Mathis Grossmann · Sabashini K Ramchand · Frances Milat · Amanda Vincent · Elgene Lim · Mark A Kotowicz · Jill Hicks · Helena J Teede

Glucometric analysis supported by networked glucose meter technology can promote safe diabetes care in hospitals

Mervyn Kyi · Peter G Colman · Lois M Rowan · Katie A Marley · Paul R Wraight · Spiros Fourlanos

A 63- year- old man with a history of multinodular goitre presented with a sudden enlargement of the neck associated with dysphagia and dysphonia for 3 weeks

Lucien Marchand

Lactic acidosis associated with metformin use is a complex issue and the causal relationship remains open to debate

Cara Tanner · Gayathiri Wang · Nancy Liu · Sofianos Andrikopoulos · Jeffrey D Zajac · Elif I Ekinci

A 59- year- old woman with carbimazolerefractory Graves disease presented with fever and extensive necrotising rash 2 weeks after commencing propylthiouracil therapy

Brian Lam · Alexander Yuile · Suran L Fernando

A 64-year-old woman was referred to the glaucoma clinic at a tertiary eye hospital with elevated intraocular pressures

Helen HL Chan · John F Salmon

Intersectoral collaboration is needed to engage communities and design effective culturally and age‐appropriate interventions

Angela Titmuss · Elizabeth A Davis · Alex Brown · Louise J Maple‐Brown

Stopping bisphosphonate therapy in people at risk of bone fractures must be carefully considered

John A Eisman · Christopher P White

We need to move beyond managing end organ complications to reducing cardio-renal risk across the spectrum of kidney function

Brendon L Neuen · Vlado Perkovic

Ensure that cardiovascular disease risk factors are adequately controlled may reduce mortality

Wai H Lim · David W Johnson · Carmel Hawley · Charmaine Lok · Kevan R Polkinghorne · Matthew A Roberts · Neil Boudville · Germaine Wong

We have developed the first international evidence-based guideline for the diagnosis and management of polycystic ovary syndrome (PCOS), with an integrated translation program incorporating resources for health professionals and consumers

on behalf of the International PCOS Network

A new Australian strategy should finally reduce the significant national burden of diabetes-related foot disease

Peter A Lazzarini · Jaap J van Netten · Robert A Fitridge · Ian Griffiths · Ewan M Kinnear · Matthew Malone · Byron M Perrin · Jenny Prentice · Paul R Wraight