1 The management of type 1 in adults. A consensus report by the American Diabetes 2 Association (ADA) and the European Association for the Study of Diabetes (EASD).

3 4 Richard I.G. Holt1,2 5 J. Hans DeVries3,4 6 Amy Hess-Fischl5 7 Irl B. Hirsch6 8 M. Sue Kirkman7 9 Tomasz Klupa8 10 Barbara Ludwig9 11 Kirsten Nørgaard10,11 12 Jeremy Pettus12 13 Eric Renard13 14 Jay S. Skyler14 15 Frank J. Snoek15 16 Ruth S. Weinstock16 17 Anne L. Peters17

18 Affiliations

19 1Human Development and Health, Faculty of Medicine, University of Southampton, 20 Southampton, UK

21 2Southampton National Institute for Health Research Biomedical Research Centre, University 22 Hospital Southampton NHS Foundation Trust, Southampton, UK

23 3Amsterdam UMC, Internal Medicine, University of Amsterdam, Amsterdam, the 24 Netherlands

25 4Profil Institute for Metabolic Research, Neuss, Germany

26 5Kovler Diabetes Center, University of Chicago, USA

27 6UW Medicine Diabetes Institute, Seattle, USA

28 7University of North Carolina School of Medicine, Chapel Hill, USA

29 8Jagiellonian University Medical College, Kraków, Poland

30 9University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany

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31 10Steno Diabetes Center Copenhagen, Denmark

32 11University of Copenhagen, CopenhagenDenmark

33 12University of California, San Diego, USA

34 13Montpellier University Hospital, University of Montpellier, Montpellier, France

35 14University of Miami Miller School of Medicine, Miami, USA

36 15Amsterdam UMC, Medical Psychology, Vrije Universiteit, Amsterdam, the Netherlands

37 16SUNY Upstate Medical University, Syracuse, USA

38 17Keck School of Medicine of USC, Los Angeles, USA

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40 Author Contributions: R.I.G.H. and A.L.P. were co-chairs for the Consensus Statement Writing 41 Group. A.H.F., I.B.H., M.S.K., J.P., J.S.S., and R.S.W. were the writing group members for the 42 ADA. J.H.D., T.K., B.L., K.N., E.R., and F.J.S. were the writing group members for the EASD. 43 44 Acknowledgements 45 We acknowledge the support of Malaika I. Hill Mindy Saraco, Robert A. Gabbay, Petra 46 Niemann, Natasha Buckley-Mühge, Monika Gruesser, the Committee for Clinical Affairs of the 47 EASD, and the Professional Practice Committee of the ADA. We acknowledge Angus Jones for 48 his invaluable help with the diagnosis section. We also acknowledge Davida F. Kruger, Grazia 49 Aleppo, Desmond Schatz, Jane Speight, Anette Gabriele-Ziegler, and Chantal Mathieu for 50 serving as peer reviewers. 51 52 Duality of Interest 53 R.I.G.H. serves on the speakers’ bureau for and receives research support from Novo Nordisk. 54 He serves on the speakers’ bureau for Abbott, Eli Lilly, Otsuka, and Roche. He also served as 55 the editor-in-chief of Diabetic Medicine until December 2020. J.H.D. receives research funding 56 from Afon, Eli Lilly, and Novo Nordisk. He serves on advisory boards for Adocia, Novo Nordisk 57 and Zealand Pharma and is on a speaker’s bureau for Novo Nordisk. A.H.F. is an auditor for 58 the ADA’s Education Recognition Program. She is a participant in a speaker’s bureau for 59 Abbott Diabetes Care and Xeris. She is also a member of Xeris’ advisory board. I.B.H. receives 60 industry research funding from Medtronic Diabetes, Insulet and Beta Bionics. He is a 61 consultant for Bigfoot, Roche, and Abbott Diabetes Care. M.S.K. receives research funding 62 from Novo Nordisk and Bayer. K.N. receives research funding from, is a member of the 63 advisory board for, and is a stockholder in Novo Nordisk. She is an advisory board member 64 for Medtronic and Abbott Diabetes Care and receives research funding from DexCom, 65 Medtronic, and Zealand Pharma. J.P. is a consultant to Sanofi, Novo Nordisk, Eli Lilly, Zealand, 66 Mannkind, and Diasome. E.R. serves on the advisory board for Abbott, Air Liquide SI, Dexcom

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67 Inc, Insulet, Sanofi, Roche, Novo Nordisk, and Eli-Lilly. J.S.S. is a member of the board of 68 directors for Applied Therapeutics, and DexCom Inc. He serves on the scientific advisory board 69 for Abvance, ActoBiotics, Adocia, Avotres, Oramed, Orgenesis, Sanofi Diabetes, Tolerion, and 70 Viacyte. He received research support from Tolerion. He is an advisor and consultant to 71 Boehringer-Ingelheim, Dance Biopharm/Aerami Therapeutics, Enthera, Ideal Life, Imcyse, 72 Immnomolecular Therapeutics, Novo-Nordisk, Provention Bio, Sanofi Diabetes, Signos, 73 Tolerion, and VielaBio. He is a shareholder or option holder in Abvance, Avotres, Dance 74 Biopharm/Aerami Therapeutics, DexCom Inc., Ideal Life, Immnomolecular Therapeutics, 75 Oramed, and Orgenesis. F.J.S. is consultant to Abbott, Eli Lilly, Sanofi and Novo Nordisk and 76 serves on the speakers bureau for Abbott, Eli Lilly, Sanofi, and Novo Nordisk.. He has received 77 research funding from Sanofi and Novo Nordisk. R.S.W. receives research funding from Eli 78 Lilly, Medtronic, Insulet, Diasome, Kowa, Tolerion, Novo Nordisk and Boehringer Ingelheim. 79 A.L.P. serves on the advisory board for Abbott Diabetes Care, Eli Lilly and Company, Novo 80 Nordisk, Medscape and Zealand Pharmaceuticals. She has received research support from 81 Dexcom and Insulet and has received donated devices from Abbott Diabetes Care. She also 82 has stock options from Omada Health and Livongo and is a special government employee of 83 the FDA. 84 85 86 Email for correspondence: Richard Holt [email protected] 87 88 This article is being simultaneously published in Diabetes Care and Diabetologia by the 89 American Diabetes Association and the European Association for the Study of Diabetes, 90 respectively. 91 92 Key words: , diagnosis, schedule of care, , glucose monitoring, 93 hypoglycaemia, , adjunctive therapy, nutrition, exercise, psychosocial 94 care, transplantation 95 96 List of Abbreviations 97 BGM: Blood glucose monitoring 98 CGM: Continuous glucose monitoring 99 DKA: Diabetic ketoacidosis 100 DSMES: Diabetes self-management education and support 101 GMI: Glucose Management Indicator 102 HbA1c: Glycated haemoglobin A1c 103 NPH: Neutral protamine Hagedorn 104 TIR: Time in range 105 TBR: Time below range

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106 Abstract 107 108 The American Diabetes Association and the European Association for the Study of Diabetes 109 convened a writing group to develop a consensus statement on the management of type 1 110 diabetes in adults. The writing group has considered the rapid development of new 111 treatments and technologies and addressed the following topics: diagnosis, aims of 112 management, schedule of care, diabetes self-management education and support, 113 monitoring, insulin therapy, hypoglycaemia, behavioural considerations, psychosocial care, 114 diabetic ketoacidosis, pancreas and islet transplantation, adjunctive therapies, special 115 populations, inpatient management and future perspectives. Although we discuss the 116 schedule for follow-up examinations and testing, we have not included the evaluation and 117 treatment of the chronic microvascular and macrovascular complications of diabetes as these 118 are well-reviewed and discussed elsewhere. The writing group was aware of both national 119 and international guidance on type 1 diabetes and did not seek to replicate this but rather 120 aimed to highlight the major areas that healthcare professionals should consider when 121 managing adults with type 1 diabetes. Though evidence-based, recommendations in the 122 report represent the consensus opinion of the authors where the available evidence is 123 incomplete.

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124 Section 1: Introduction and rationale for the consensus report 125 Type 1 diabetes is a condition caused by autoimmune damage of the insulin-producing β cells 126 of the pancreatic islets, usually leading to severe endogenous insulin deficiency. Type 1 127 diabetes accounts for approximately 5-10% of all cases of diabetes. Although the incidence 128 peaks in puberty and early adulthood, type 1 diabetes affects all age groups with a global 129 prevalence of 5.9 per 10,000 population (1). The incidence has risen rapidly over the last 50 130 years and is currently estimated to be 15 per 100,000 per year. 131 Prior to the discovery of insulin a century ago, type 1 diabetes was associated with a life- 132 expectancy as short as a few months. Beginning in 1922, relatively crude extracts of 133 exogenous insulin, derived from animal pancreases, were used to treat people with type 1 134 diabetes. Over the ensuing decades, insulin concentrations were standardized, insulin 135 solutions became more pure, and additives (zinc, protamine) were incorporated into insulin 136 solutions to increase the duration of action. In the 1980’s, semi-synthetic and recombinant 137 human insulins were developed, resulting in reduced immunogenicity (2). In the mid-1990’s, 138 insulin analogues became available; basal insulin analogues were designed with prolonged 139 duration of action and reduced pharmacodynamic variability compared to protamine-based 140 (NPH) human insulin while rapid-acting analogues were introduced with quicker onset and 141 shorter duration than regular human insulin, resulting in reduced early postprandial 142 hyperglycaemia and less later post-meal hypoglycaemia (2). 143 The discovery of insulin transformed the lives of many people but it soon became apparent 144 that type 1 diabetes is associated with the development of long-term complications and 145 shortened life expectancy. Over the last 100 years, developments in insulin, its delivery, and 146 technologies to measure glycaemic indices have markedly changed the management of type 147 1 diabetes. Despite these advances, many people with type 1 diabetes do not reach the 148 glycaemic targets necessary to prevent or slow the progression of diabetes complications, 149 which continue to exert a high clinical and emotional burden. 150 Recognizing the on-going challenge of type 1 diabetes and the rapid development of new 151 treatments and technologies, the European Association for the Study of Diabetes (EASD) and 152 the American Diabetes Association (ADA) convened a writing group to develop a consensus 153 report on the management of type 1 diabetes in adults, aged 18 years and over. The writing 154 group was aware of both national and international guidance on type 1 diabetes and did not 155 seek to replicate this but rather aimed to highlight the major areas of care that healthcare 156 professionals should consider when managing adults with type 1 diabetes. The consensus 157 report has focused predominantly on current and future glycaemic management strategies 158 and metabolic emergencies. Recent advances in the diagnosis of type 1 diabetes have been 159 considered. Unlike many other chronic conditions, type 1 diabetes places a unique burden of 160 management on the individual with the condition. In addition to complex medication 161 regimens, other behavioural modification is also needed; all of this requires considerable 162 knowledge and skill to navigate between hyper- and hypoglycaemia. The importance of 163 diabetes self-management education and support (DSMES) and psychosocial care are rightly 164 documented in the report. While acknowledging the significance of screening, diagnosing, 165 and managing the chronic microvascular and macrovascular complications of diabetes, a 166 detailed description of the management of these complications is beyond the scope of this 167 report and where relevant the reader is directed to other publications.

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168 Two members of the writing group, one from the ADA and one from EASD, were assigned to 169 be the primary authors of each section. The chosen individuals had specific knowledge of the 170 area and were tasked with reviewing and summarizing the available literature. Each section, 171 in turn, was reviewed and approved by the entire working group. The draft consensus report 172 was peer reviewed (see “Acknowledgments”), and suggestions were incorporated as deemed 173 appropriate by the authors. Though evidence-based, the report represents the consensus 174 opinion of the authors given that the available evidence is incomplete. 175 Section 2: Diagnosis of type 1 diabetes 176 Adults with new-onset type 1 diabetes can present with a short duration of illness of 1–4 177 weeks or a more slowly evolving process that can be mistaken for . Additionally 178 monogenic diabetes can be misdiagnosed as type 1 diabetes. Most of the available data 179 discussed below are derived from white European populations and may not be representative 180 of other ethnic groups. The clinical presentation may differ, but the classical triad of thirst and 181 polydipsia, polyuria, and weight loss are common symptoms of type 1 diabetes. Accurate 182 classification of the type of diabetes has implications beyond the use of insulin treatment; 183 education, insulin regimen, use of adjuvant therapies, access to newer technologies, need for 184 psychosocial support to address the profound psychological impact of the diagnosis of 185 diabetes and concurrent disease screening may all depend on the diagnosis an individual 186 receives. Furthermore, accurate diagnosis allows an assessment of the risk of diabetes in first 187 degree relatives and appropriate counselling. Although profound insulin deficiency is the 188 hallmark of type 1 diabetes, some adults with type 1 diabetes maintain some insulin secretion 189 for years after diagnosis and may not require insulin treatment at diagnosis (3), leading to 190 diagnostic uncertainty about the type of diabetes and its management. 191 Differentiating type 1 diabetes from type 2 diabetes 192 Identifying whether an adult with newly diagnosed diabetes has type 1 diabetes may be 193 challenging where the individual has features pointing towards both type 1 diabetes and 2 194 diabetes, for example an older adult with a low or normal body mass index (BMI) or young 195 adult with an elevated BMI. Ketoacidosis, once considered pathognomonic of type 1 diabetes, 196 may occur in ketosis-prone type 2 diabetes. Misclassification of type 1 diabetes in adults is 197 common and over 40% of those developing type 1 diabetes after age 30 years are initially 198 treated as having type 2 diabetes (4–6). A misdiagnosis of type 2 diabetes can bring with it 199 stereotypes, biases and stigma, especially for those with type 1 diabetes who are overweight 200 or obese. No single clinical feature confirms type 1 diabetes in isolation (7,8). The most 201 discriminative feature is younger age at diagnosis (<35 years), with lower BMI (<25 kg/m2), 202 unintentional weight loss, ketoacidosis, and glucose >360 mg/dL (20 mmol/L) at presentation 203 also being informative. Other features classically associated with type 1 diabetes, such as 204 ketosis without acidosis, osmotic symptoms, family history, or a history of autoimmune 205 diseases are weak discriminators (6–8). 206 The very strong relationship between type 2 diabetes incidence and age means that even 207 ‘classical’ features of type 1 diabetes may have a limited predictive value in older adults, as 208 type 2 diabetes in this age group is so common (9). The majority of older adults with low BMI 209 will have type 2 diabetes (7,10,11), even more so when a person’s ethnicity is associated with 210 high type 2 diabetes risk (12). Rapid progression to insulin treatment (< 3 years) is strongly 211 suggestive of type 1 diabetes at any age (4,6,13). Controversy remains as to whether latent 212 autoimmune diabetes of adulthood (LADA) is a discrete subtype, a milder form of type 1

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213 diabetes, or a mixture of some individuals with type 1 diabetes and others with type 2 214 diabetes (14). 215 216 Differentiating type 1 diabetes from monogenic diabetes 217 Monogenic diabetes is found in approximately 4% of those diagnosed with diabetes before 218 the age of 30 years; the likelihood of monogenic diabetes rises to 20% where islet antibodies 219 are negative and C-peptide secretion is maintained (15). Monogenic diabetes is commonly 220 mistaken for type 1 diabetes because of the young age at onset. A diagnosis of monogenic 221 diabetes allows specific treatment with discontinuation of insulin in many cases and has 222 implications for family members and screening for concurrent conditions (16,17). 223 224 Investigation of an adult with suspected type 1 diabetes 225 A suggested algorithm for the investigation of adults with suspected type 1 diabetes is shown 226 in Figure 1. 227 228 Islet autoantibodies 229 An assessment of islet autoantibodies at diagnosis is recommended as the primary 230 investigation of an adult with suspected type 1 diabetes. Glutamic Acid Decarboxylase (GAD) 231 should be the primary antibody measured and, if negative, should be followed by islet 232 tyrosine phosphatase 2 (IA2) and/or Zinc transporter 8 (ZNT8) where available. Islet cell 233 antibody (ICA) measurement is no longer recommended because it is an imprecise biological 234 assay that has been superseded by the direct measurement of single antibodies (18,19). 235 In people with clinical features suggesting type 1 diabetes, the presence of one or more 236 positive islet autoantibodies is highly predictive of rapid progression and severe insulin 237 deficiency and these individuals should be considered to have type 1 diabetes, even if they 238 were not insulin requiring at diagnosis (20,21). 239 The absence of autoantibodies does not exclude type 1 diabetes, as approximately 5-10% of 240 white European people with new-onset type 1 diabetes have negative islet antibodies 241 (6,7,22), and further consideration of the diagnosis is necessary. In those diagnosed below 242 the age of 35 years, type 1 diabetes is still the most likely diagnosis, particularly if there are 243 no clinical features of type 2 diabetes or monogenic diabetes. In those aged over 35 years, 244 type 2 diabetes becomes increasingly likely with absent islet autoantibodies and older age. 245 However, it can be hard to differentiate between type 1 diabetes and type 2 diabetes based 246 on age and clinical features in non-white European populations. 247 It is important to make a clinical decision about how to treat the person with diabetes. 248 Regardless of any features of type 2 diabetes or absence of islet antibodies, if there is a clinical 249 suspicion of type 1 diabetes, the individual should be treated with insulin. However, in some 250 individuals, where the clinical course is more suggestive of type 2 diabetes, a trial of non- 251 insulin therapy may be appropriate. Those whose diabetes is treated without insulin will 252 require careful monitoring and education, so that insulin can be rapidly initiated in the event 253 of glycaemic deterioration. Type 2 diabetes and other types of diabetes should be considered

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254 in all age groups but in those aged under 35 years, negative islet antibodies should raise the 255 suspicion of monogenic diabetes. 256 257 C-peptide measurement 258 Beyond 3 years after diagnosis where there is uncertainty about diabetes type, a random C- 259 peptide measurement (with concurrent glucose) within 5 hours of eating is recommended. 260 Where a person is treated with insulin, this test should always be performed prior to insulin 261 discontinuation, to exclude severe insulin deficiency. 262 Persistent C-peptide >600 pmol/L (non-fasting) is strongly suggestive of type 2 diabetes and 263 people with C-peptide in this range are often able to replace insulin with other agents (23– 264 26). Routine C-peptide testing in those with clinically diagnosed type 1 diabetes of at least 3 265 years duration has led to reclassification in 11% of those with adult-onset diabetes (27). By 266 contrast, low or absent C-peptide confirms the diagnosis of type 1 diabetes. 267 268 Genetic testing 269 As monogenic diabetes was less likely to have been considered in the past, molecular genetic 270 testing for should be considered for all people with type 1 diabetes, 271 regardless of current age, who were diagnosed under 6 months of age as more than 80% have 272 monogenic neonatal diabetes, and the 30-50% with KATP channel mutations can replace 273 insulin with sulfonylureas (28,29). 274 Monogenic diabetes should be considered in those with one or more of the following 275 features: age at diagnosis of less than 35 years, HbA1c <58mmol/mol (7.5%) at diagnosis, one 276 parent with diabetes, and features of specific monogenic cause (e.g. renal cysts, partial 277 lipodystrophy, maternally inherited deafness, severe in the absence of 278 obesity) (30). A monogenic diabetes prediction model risk calculator 279 (https://www.diabetesgenes.org/mody-probability-calculator) (31) may also be used to 280 identify which individuals diagnosed between 6 months and 35 years are at increased risk of 281 monogenic diabetes. Those at increased risk should have islet autoantibody and C-peptide 282 testing. Molecular genetic testing should only be considered if the antibodies are negative 283 and non-fasting C-peptide is >200 pmol/l (32–34). Molecular genetic testing is not universally 284 available. 285 286 Section 3: Aims and Goals of management of type 1 diabetes 287 The aim of diabetes care and management is to support people with type 1 diabetes to live a 288 long and healthy life. The management strategies to achieve this aim broadly include: 289 • Effectively delivering exogenous insulin to maintain glucose levels as close to the 290 individual’s target range as is safely possible to prevent the development and 291 progression of diabetes complications while 292 • Minimizing episodes of hypoglycaemia, of all levels, but in particular Level 2 293 (moderate) and Level 3 (severe) hypoglycaemia and preventing episodes of diabetic 294 ketoacidosis while treating these appropriately should they occur 295 • Effectively managing cardiovascular risk factors

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296 • Providing approaches, treatments, and devices that minimize the psychosocial burden 297 of living with type 1 diabetes, and consequently diabetes-related distress, while 298 promoting psychological wellbeing 299 Management strategies should adapt to new therapies and technologies as they become 300 available according to the wishes and desires of the person with diabetes. 301 The importance of glycaemic management was demonstrated convincingly by the Diabetes 302 Control and Complications Trial (35) and the Epidemiology of Diabetes Interventions and 303 Complications follow-up study (36). With the use of intensive insulin therapy that aimed to 304 achieve levels of glycaemia close to the non-diabetes range, HbA1c was lowered by ~2% (22 305 mmol/mol) to a mean HbA1c of ~7.0% (53 mmol/mol) over a mean of 6.5 years compared with 306 standard care (mean HbA1c ~9.0% (75 mmol/mol)) (35). The risk of primary development of 307 retinopathy was reduced by 75% and progression of retinopathy slowed by 54%. The 308 development of microalbuminuria was reduced by 39% and clinical neuropathy by 60% in 309 those assigned to intensive therapy. These benefits persisted beyond the end of the trial 310 despite equivalent glucose levels (HbA1c ~8% (64 mmol/mol)) in the post-trial period, and 311 reductions in cardiovascular disease and mortality emerged with time (36). This seminal study 312 has been the basis for glycaemic target recommendations for type 1 diabetes worldwide. The 313 cost of intensive management was, however, a two- to three-fold increase in the rates of 314 severe hypoglycaemia as well as weight gain. 315 The main results of the DCCT were published in 1993 before any of the current insulin 316 analogues and diabetes technologies, except for insulin pumps, were available. Increasingly, 317 achieving and maintaining glucose levels in the target range have become possible with fewer 318 episodes of hypoglycaemia (37–40). Although the evidence of HbA1c reduction remains the 319 most robust and is the only measure that is prospectively validated, more recent studies have 320 begun to examine the relationship between time in range (TIR) and long-term complications 321 and have provided the basis for glycaemic targets with newer glucose monitoring 322 technologies (41,42). 323 The glycaemic target should be individualized considering factors that include duration of 324 diabetes, age and life expectancy, comorbid conditions, known cardiovascular disease or 325 advanced microvascular complications, impaired awareness of hypoglycaemia, and individual 326 considerations, and it may change over time. Goals should be achieved in conjunction with 327 an understanding of the person’s psychosocial needs and a reduction in diabetes distress if 328 elevated. An HbA1c goal for most adults of <7.0% (53 mmol/mol) without significant 329 hypoglycaemia is appropriate. Achievement of lower HbA1c levels than the goal of 7% (53 330 mmol/mol) may be acceptable, and even beneficial, following discussion between the person 331 with diabetes and their healthcare team if these can be achieved safely without adverse 332 effects of treatment. Less-stringent HbA1C goals (such as <8.0% [64 mmol/mol]) may be 333 appropriate for individuals with limited life expectancy or where the harms of treatment are 334 greater than the benefits. It should be recognized that any reduction in HbA1c from high initial 335 levels has significant benefit even if the “goal” is not reached. 336 Capillary blood glucose monitoring (BGM) can help people with type 1 diabetes achieve these 337 HbA1c goals. A pre-prandial capillary plasma glucose target of 80–130 mg/dL (4.4–7.2 mmol/L) 338 is appropriate for many people. Postprandial glucose may be targeted if HbA1c goals are not 339 met despite reaching pre-prandial glucose targets. Post-prandial glucose measurements 340 should be made 1–2 h after the beginning of the meal, which generally corresponds to peak

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341 levels in people with diabetes. A peak postprandial capillary plasma glucose of <180 mg/dL 342 (10.0 mmol/L) is appropriate for most people with diabetes, with higher goals in those with 343 limited life expectancy or where the harms of treatment are greater than the benefits (table 344 1). 345

346 Alternatives to the measurement of HbA1c and BGM are assessments of the glucose 347 management indicator (GMI) and time in range (TIR) from continuous glucose monitoring 348 (CGM) data. GMI is calculated based on the average sensor glucose over the last 14 days and 349 provides an approximation of a laboratory-measured HbA1c in some individuals, but it may be 350 higher or lower than actual HbA1c in others (41). In some circumstances these metrics can 351 replace HbA1c measurements. A typical GMI goal is <7.0% (53 mmol/mol). “Time-in-range” 352 (TIR) is defined as 70-180 mg/dL (3.9-10 mmol/l) in most adults and time below range (TBR) 353 as below 70 mg/dL (3.9 mmol/l) (low) as well as less than 54 mg/dL (3.0 mmol/l) (very low). 354 Other metrics are also defined (Figure 2). TIR is associated with microvascular complications 355 (41,42) and a TIR of 70% roughly corresponds to an HbA1c of 7.0% (53 mmol/mol). An 356 international consensus conference reported that for most adults with type 1 diabetes, a 357 target TIR should be above 70% with TBR less than 4%. The primary target for older people 358 with long duration of diabetes should be TBR less than 1% (43). 359 The cornerstone of type 1 diabetes therapy is insulin replacement. This is challenging because 360 of the low therapeutic window of insulin and insulin demands that vary widely according to 361 meals, exercise, and many other factors. People with type 1 diabetes have to walk a tightrope 362 between high and low glucose levels. Insulin management must be supported by adequate 363 monitoring of glucose and education and training to allow the individual with type 1 diabetes 364 to make the most of their treatment regimen. Type 1 diabetes is a demanding condition and 365 requires on-going professional medical, educational, and psychosocial support. Care may 366 differ at particular times of life, such as at the point of diagnosis, during concomitant illness 367 or pregnancy, and later in life. These issues are discussed in greater detail in the sections that 368 follow. Overall approaches for people with newly diagnosed or established type 1 diabetes 369 are shown in figures 3 and 4. 370 Section 4: Schedule of Care 371 A detailed evaluation should be obtained at the initial consultation, and more targeted 372 interval care at follow-up visits with a focus on person-centered care (Table 2) (44,45). A 373 personalized approach for visit frequency is recommended. For adults whose glycaemic 374 profile is stable and at goal, a visit once a year should be sufficient, providing that earlier and 375 more frequent appointments can be scheduled if problems arise. In contrast, more frequent 376 contact is preferred for adults who are not meeting their diabetes goals and who would 377 benefit from additional self-management education and support. More frequent contact will 378 allow additional review of glucose data and support. Additional visits can also be useful when 379 the therapeutic regimen changes, for example, when the insulin regimen is modified or when 380 a new device is started. 381 In the past, initial and follow-up visits were primarily conducted face-to-face and telemedicine 382 only used sporadically. With the onset of the COVID-19 pandemic, the use of telemedicine 383 became a necessity and there was an abrupt widespread adoption of remote visits 384 (video/audio) to deliver diabetes care. Pre-COVID-19, results from a limited number of studies 385 using telemedicine in different subgroups of people with type 1 diabetes suggested that

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386 remote monitoring, education, and provider visits have the potential to improve outcomes, 387 quality of life, and self-management; increase access to care and reduce costs; and are well- 388 accepted with improved treatment satisfaction (46–49). 389 The use of telemedicine, however, should be individualized and will vary depending upon 390 individual needs, computer literacy, and access to care (50). The healthcare professional and 391 person with diabetes should be in a private space. In advance of the visit, people with diabetes 392 should receive clear instructions on the expectations for the tele-visit, including how to 393 connect to the consultation and how to upload data from their diabetes devices (glucose 394 meters, data collecting apps, CGM devices, and insulin pumps) prior to the appointment (51). 395 When clinically indicated and appropriate, people with diabetes should be asked to weigh 396 themselves and perform home blood pressure measurements where possible. A list of all 397 medications and relevant medical reports should be available. 398 399 Section 5: Diabetes self-management education and support 400 Diabetes self-management education and support (DSMES) is an essential component of type 401 1 diabetes care. The objective of DSMES is to provide those living with type 1 diabetes with 402 the knowledge, skills, and confidence to successfully self-manage their diabetes on a daily 403 basis and thereby reduce the risks of acute and long-term complications while maintaining 404 quality of life (52). DSMES aims to empower people with type 1 diabetes, with an emphasis 405 on shared decision-making and active collaboration with the health care team. 406 407 Levels and content of diabetes self-management education and support 408 Three levels of DSMES can be distinguished. Level 3 DSMES refers to structured education 409 that meets nationally-agreed criteria, including an evidence-based curriculum, quality 410 assurance of teaching standards and regular audit. These programs are guided by learning 411 and behaviour change theories. Level 2 refers to ongoing learning that may be informal, 412 perhaps through a peer group, while level 1 comprises information and one-to-one advice. 413 Several level 3 programs have been developed for adults with type 1 diabetes and have 414 proven to be effective both in terms of improved glycaemic and psychosocial outcomes (53). 415 Most programs use a group format, increasingly supplemented with digital support, including 416 text messaging and cloud-based solutions and telemedicine (54). Structured DSMES programs 417 most often include multiple components and cover a broad range of topics from 418 pathophysiology to medical technology and healthy coping (Table 3). 419 Specific DSMES should not be confined to one particular moment but offered on a continuous 420 basis and tailored to the ever-evolving individual’s educational needs. People with type 1 421 diabetes may be diagnosed at a young age or during adulthood, and many live with type 1 422 diabetes throughout different life stages. In this context four critical times can be 423 distinguished: at diagnosis, when not meeting targets, when transitions occur, and when 424 complications develop (Figure 5) (55). DSMES should be tailored towards individuals’ needs, 425 taking into account literacy, ethnic, socio-cultural, cognitive, financial and geographical 426 factors (56). A structured, periodic assessment of educational needs and barriers should be 427 an integral part of ongoing diabetes care (Table 4). 428

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429 Section 6: Monitoring of glycaemia 430 People with type 1 diabetes should have an assessment of their glycaemia with their 431 healthcare professional as often as is clinically indicated but at least annually. Glycaemic 432 status should be assessed at least every three months in those whose therapy has changed 433 or who are not meeting glycaemic goals.

434 Glycated haemoglobin (HbA1c)

435 Monitoring of glycaemia has traditionally been by HbA1c, which has been used in most studies 436 demonstrating the effects of lowering glucose on the development and progression of 437 diabetes complications (35). A strong correlation (r>0.9) between HbA1c and average blood 438 glucose during the preceding 3 months has been demonstrated where glucose levels are 439 stable (57). In several conditions, however, HbA1c does not reflect mean glucose; these are 440 mainly situations where red blood cell turnover is altered or in the presence of 441 haemoglobinopathies (Table 5) (58). Variability exists between individuals, but the HbA1c and 442 blood glucose within an individual correlate over time (59). Although HbA1c is an indicator of 443 mean glucose, it does not inform glycaemic variability and hypoglycaemia and therefore is 444 inappropriate as the only method of glucose evaluation in type 1 diabetes (59,60). 445 Other biomarkers, such as , 1,5 anhydroglucitol, and glycated albumin provide 446 measures of mean glucose albeit with shorter durations than HbA1c. None of these are as well 447 associated with diabetes complications as HbA1c (61). 448 Capillary blood glucose monitoring 449 Capillary blood glucose monitoring (BGM) involves the use of a handheld meter and the 450 measurement of capillary blood glucose. Frequent BGM measurements are important as an 451 integrated part of to guide insulin dosage, food intake, and prevention 452 of hypoglycaemia with exercise. BGM is needed before meals for decisions about the meal 453 insulin dose. Additionally, BGM is needed to prevent and detect hypoglycaemia in several 454 situations such as before bedtime; before driving; before, during, and after exercise; and 455 when hypoglycaemic symptoms occur. The evidence for the optimal number of daily BGM is 456 lacking and may depend on variation in the person’s lifestyle. In registry studies, increased 457 testing frequency is associated with lower HbA1c (62). However, even with frequent BGM, 458 most people with type 1 diabetes will have undetected and an unacceptable high frequency 459 of hyper- and hypoglycaemia (63). Frequent measurements are often not feasible and can be 460 distressing. Seeing high or low glucose values can evoke feelings of frustration, anxiety and 461 guilt, leading many people with type 1 diabetes to measure less often than needed (64). 462 Downloading memory-capable glucose meters can be helpful in observing patterns of hyper- 463 or hypoglycaemia (65). Most meters meet the accuracy standards established by the 464 International Organization for Standardization although there is still variability with many 465 meters not meeting accuracy standards when tested independently (66). 466 Continuous Glucose Monitoring 467 Continuous glucose monitoring (CGM) devices measure interstitial glucose and have been 468 available commercially since 2006. CGM devices have evolved and improved enough in 469 accuracy to the point where most currently available sensors are “non-adjunctive” meaning 470 that a check with capillary BGM before a treatment decision is taken is not required.

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471 Currently there are two types of CGM devices. One provides a continuous value of current 472 glucose and trends to a receiver, mobile app, smartwatch, or pump (designated as real-time 473 [rt] CGM) while the other requires the glucose level to be determined by scanning a small 474 reader or smartphone across the transmitter (intermittently scanned [is]CGM). Historically, 475 rt-CGM has offered a variety of alerts, both in terms of indicating when a specific glucose level 476 is reached as well as for trends in glucose levels. IS-CGM did not have these alerts but 477 increasingly includes them. In the near future, these sensors and others in development will 478 increasingly connect to other devices, including “smart pens.” All currently available devices 479 can be uploaded to an internet cloud to allow people with diabetes and healthcare 480 professionals to easily view the data at or between clinic visits. CGMs report a reading every 481 1 to 15 minutes.

482 Based on RCT data, rt-CGM is effective for adults with type 1 diabetes in improving HbA1c 483 (particularly when high) and reducing hypoglycaemia for both those using insulin pumps or 484 multiple daily injections (38–40,67); RCTs of the original isCGM devices are more mixed but 485 observational data are supportive of their use. rt-CGM has also been found beneficial in 486 reducing the burden of hypoglycaemia in older adults with type 1 diabetes (68) and those 487 with impaired awareness of hypoglycaemia (40). Most people with type 1 diabetes can 488 benefit from this technology with appropriate initial and ongoing education, including 489 frequent observation of the glucose trends. Some people, however, may not find CGM 490 valuable as they may feel that they do not require it or find it stressful because they dislike 491 being ‘attached to a device’ or constantly reminded of their diabetes or feeling exhausted by 492 alarms (alarm fatigue). Cost considerations can also play a role. Nevertheless, CGM is the 493 standard for glucose monitoring in adults with type 1 diabetes and the choice of the device 494 should be based on individual preferences and needs as well as which devices are available 495 or reimbursed. 496 Retrospective analysis of CGM data can guide and enhance therapeutic decision-making, 497 patient understanding, and engagement in adjusting behaviours. Standardized glucose 498 reports with visual cues, such as the Ambulatory Glucose Profile (AGP) and daily tracings, 499 should be available for all CGM devices (table 6; Figure 2). 500 Although healthcare professionals should regularly review CGM data and be responsive and 501 react in a timely manner, people with type 1 diabetes should be encouraged to review their 502 own reports regularly and follow their progress over time, contacting their healthcare 503 professional as needed for worsening or changing trends. 504 People with type 1 diabetes should be warned that contact dermatitis (both irritant and 505 allergic) may occur with all CGM devices that attach to the skin (69–71). In some instances, 506 the use of an implanted sensor can help avoid skin reactions in those who are sensitive to 507 tape (72,73). 508 509 Section 7: Insulin therapy 510 The ideal regimen of insulin replacement maintains blood glucose in a near-normal state, 511 while allowing flexibility in terms of mealtimes and activity levels. Typical insulin replacement 512 regimens incorporate several components: basal insulin to restrain gluconeogenesis and 513 ketogenesis in the pre-prandial state, mealtime insulin to cover the intake of carbohydrate 514 and other macronutrients, and correction insulin to treat hyperglycaemia.

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515 Choice of regimen 516 Most people with type 1 diabetes should use regimens that mimic physiology as closely as 517 possible, irrespective of the presentation. This is best achieved with either multiple daily 518 injections (MDI) of subcutaneous basal insulin analogues and mealtime rapid-acting insulin 519 analogues or with continuous subcutaneous insulin infusion of a rapid-acting insulin analogue 520 via a pump, delivered as continuous basal insulin combined with manual mealtime boluses. 521 Trials have demonstrated that the latest basal analogues may reduce hypoglycaemia 522 compared to first-generation basal analogues and NPH insulin while rapid-acting analogues 523 achieve better mealtime coverage and less post-meal hypoglycaemia than regular human 524 insulin (74,75). Insulin analogues are therefore considered the insulins of choice. 525 Ultra-rapid analogues have a slightly earlier time of onset and peak action than rapid-acting 526 analogues. These insulins reduce post-prandial hyperglycaemia but have otherwise not been 527 shown to reduce HbA1c or hypoglycaemia to a greater extent than rapid-acting analogues (2). 528 Currently, recombinant human insulin or analogues of human insulin account for the vast 529 majority of insulin used worldwide.

530 HbA1c, time in range, and time below range are improved further when physiological MDI or 531 pump regimens are augmented with CGM usage (76), with the greatest benefits seen with 532 algorithm-driven automated basal (and in some systems correction) insulin delivery, which is 533 commonly called hybrid-closed loop therapy (77,78). 534 Despite these advantages, the costs of insulin analogues and CGM or pump therapy are 535 barriers for some people, while others do not wish to wear a device or inject multiple times 536 per day. In these cases, subcutaneous regimens of human regular and NPH insulin or pre- 537 mixed insulin, with BGM as frequently as feasible, may be used at a cost of higher glucose 538 variability with higher risk of hypoglycaemia and less flexibility of lifestyle. Figure 6 shows 539 advantages and disadvantages of more- or less-physiological insulin replacement regimens, 540 while Table 7 provides details on various regimens that might be employed. 541 Mode of delivery 542 MDI therapy can be administered using vials and insulin syringes or insulin pens, with the 543 latter providing more convenience of dosing but may be at higher cost. Smaller gauge and 544 shorter needles provide almost painless injections. Contrary to common wisdom, skin 545 thickness is not significantly increased with overweight or obesity. Needles as short as 4 mm, 546 injected at a 90-degree angle, enter the subcutaneous space with minimal risk of 547 intramuscular injection in most adults (79). The use of longer needles increases the risk of 548 intra-muscular injection. MDI regimens may be enhanced with emerging technology such as 549 bolus calculators and memory-enabled pens that keep track of insulin doses. 550 Several insulin pumps for subcutaneous insulin delivery are available in many countries. The 551 primary mechanical differences between pumps are whether they utilize external tubing to 552 connect to an infusion set or a pod directly applied to the skin and controlled via a wireless 553 connection to a controller. Current pumps include bolus calculators programmed with 554 personalized insulin-to-carbohydrate ratio and correction factors. Notably, several insulin 555 pumps now form a component of hybrid closed-loop therapy where an algorithm controls 556 basal insulin delivery, and in some cases correction boluses, based on CGM trends, while the 557 user still boluses manually (77,78). Several such systems are approved in various countries; 558 however, there are growing numbers of people with type 1 diabetes using non-regulated “do-

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559 it-yourself” systems, which use commercially available CGM systems and pumps, with open- 560 source software algorithms that communicate with both and can reverse-engineer the pump 561 control of basal and corrective doses (80). Healthcare professionals should not recommend 562 these systems, but they should respect an individual’s right to make informed choices about 563 their care and continue to offer support to the people using these systems. 564 Fully closed loop automated insulin delivery systems are currently being evaluated in clinical 565 trials being conducted by several collaborative groups in both North America and Europe (81). 566 The expectation is that some of these will receive regulatory approval in the next few years. 567 This should allow people with type 1 diabetes to achieve better glycaemic levels with minimal 568 risk of hypoglycaemia. This is a rapidly evolving area, and readers may wish to keep abreast 569 by referring to the Technology section of the ADA Standards of Care which is a living 570 document updated frequently (82). 571 572 Adverse Effects 573 The main adverse effect associated with insulin therapy is hypoglycaemia which is discussed 574 in the next section. The safety and efficacy of insulin therapy is closely related to glucose 575 monitoring and insulin dose adjustments made by the individual with diabetes, or more 576 recently, automatically through control algorithms. Therefore, education in the management 577 of insulin doses is a crucial component of this therapy, both at initiation and during follow- 578 up. This education includes rescue strategies in case of hyperglycaemic or hypoglycaemic 579 deviations, including the measurement of urine or blood ketone bodies or the prescription of 580 carbohydrate intake and glucagon, respectively. 581 Skin reactions to subcutaneous insulin therapy include local inflammation (often due to the 582 pH of or additives to the insulin), insulin-induced lipoatrophy, and insulin-induced 583 lipohypertrophy. Lipoatrophy has become rare as the purity of manufacture of human and 584 analogue insulin has improved. Lipohypertrophy typically occurs when the same sites are 585 repeatedly used for injections or pump sites and is a cause of glycaemic variability (83). People 586 with type 1 diabetes should receive instructions about proper injection technique, including 587 regular site rotation, at the time of insulin initiation with periodic reminders thereafter. 588 As described above for CGM devices, individuals should be warned about possible skin 589 reactions to pump adhesives. 590 Alternative routes of administration 591 Although subcutaneous insulin therapy has been the mainstay of treatment for almost a 592 century, this mode does not mimic physiological insulin secretion well. Healthy β cells secrete 593 a burst of insulin into the portal circulation at the onset of glucose intake, with approximately 594 half the insulin cleared by the liver and not entering the systemic circulation, whereas 595 subcutaneous insulin enters the systemic circulation with some delay and is removed 596 relatively slowly. Inhaled human insulin, available only in the U.S., has a very rapid onset of 597 action and short duration compared to subcutaneous rapid-acting analogues (2). Inhaled 598 insulin ameliorates early post-prandial hyperglycaemia well, but its short duration of action 599 results in less control of later post-prandial hyperglycaemia. Additionally, inhaled insulin can 600 cause cough or sore throat, and therapy must be monitored with periodic spirometry because 601 of possible effects on lung function.

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602 Peritoneal delivery of human regular insulin, with rapid transit to the portal system, can be 603 accomplished with implantable insulin pumps or through a port connected to an intra- 604 peritoneal catheter (available only in some countries in Europe at considerable cost). 605 Compared to subcutaneous insulin regimens, intra-peritoneal insulin infusion reduces HbA1c, 606 glycaemic variability, and hypoglycaemia (84,85). Insulin aggregation, local infections and 607 catheter occlusions are nevertheless reported complications of the devices used for this route 608 of insulin delivery. 609 610 Section 8: Hypoglycaemia 611 Hypoglycaemia is the main limiting factor in the glycaemic management of type 1 diabetes. 612 Hypoglycaemia is classified into three levels. Although these were originally developed for 613 clinical trials reporting, they are useful clinical constructs. Level 1 corresponds to a glucose 614 value below 70 mg/dL (3.9 mmol/l) and greater than or equal to 54 mg/dl (3.0 mmol/l) and is 615 named as an alert value. Level 2 is for glucose values below 54 mg/dL (3.0 mmol/l) and 616 considered as serious, clinically-important hypoglycaemia. Level 3 designates any 617 hypoglycaemia characterized by altered mental state and/or physical status needing the 618 intervention of a third party for recovery (86). Particular attention should be made to prevent 619 level 2 and 3 hypoglycaemia. Hypoglycaemia can be further sub-divided as symptomatic, 620 asymptomatic, or probable symptomatic (typical symptoms not confirmed by a measured 621 glucose). 622 Level 1 hypoglycaemia is common, with most people with type 1 diabetes experiencing 623 several episodes per week. Hypoglycaemia with glucose levels below 54 mg/dL (3.0 mmol/l) 624 occurs much more often than previously appreciated (42,87). Severe hypoglycaemia is less 625 common but occurred in 12% of adults with type 1 diabetes over a 6-month period in a recent 626 global observational analysis (88). Several studies have shown that rates of hypoglycaemia 627 have not declined even with more widespread use of insulin analogues and CGM, while other 628 studies have shown benefit with these therapeutic advances (37). 629 Risks for hypoglycaemia, particularly severe hypoglycaemia, include longer duration of 630 diabetes, older age, history of recent severe hypoglycaemia, alcohol ingestion, exercise, lower 631 education levels, lower household incomes (37), chronic kidney disease, and impaired 632 awareness of hypoglycaemia and hypoglycaemia-associated autonomic failure (89–91). Older 633 diabetes databases consistently documented that people with lower HbA1c levels had two- to 634 threefold higher rates of severe hypoglycaemia. However, in the Type 1 Diabetes Exchange 635 Clinic Registry, the risk of severe hypoglycaemia was increased not only in those whose HbA1c 636 was below 7.0% (53 mmol/mol) but also in people with an HbA1c above 7.5% (58 mmol/mol) 637 (37).

638 It is possible that the absence of a relationship between HbA1c and severe hypoglycaemia in 639 real-world settings is explained by relaxation of glycaemic targets by those with a history of 640 hypoglycaemia or confounders, such as inadequate self-management behaviours that 641 contribute to both hyper- and hypoglycaemia. A secondary analysis of the IN CONTROL trial, 642 where the primary analysis showed a reduction in severe hypoglycaemia in people using CGM, 643 demonstrated an increase in the rate of severe hypoglycaemia with lower HbA1c, similar to 644 what was reported in the DCCT (92). This implies that lowering HbA1c may still come with a 645 higher risk of severe hypoglycaemia. This risk is not inevitable and may be avoided through 646 the use of hybrid closed loop systems that result in both improvement in TIR and reduction

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647 in TBR (78). Furthermore, brief structured education with informed support in active insulin 648 dose self-adjustment underpinned by targeted blood glucose monitoring leads to sustained 649 falls in severe hypoglycaemia rates in those at high risk (93). 650 Mortality from hypoglycaemia in type 1 diabetes is not trivial. One recent trial noted more 651 than 8% of deaths for those younger than 56 years were from hypoglycaemia (94). The 652 mechanism for this is complex, including cardiac arrhythmias, activation of both the 653 coagulation system and inflammation, and endothelial dysfunction (95). What may not be as 654 well recognized is that severe hypoglycaemia is also associated with major microvascular 655 events, non-cardiovascular disease, and death from any cause (95). With regards to cognitive 656 function, in the Diabetes Control and Complications Trial, after 18 years of follow-up severe 657 hypoglycaemia in middle-aged adults did not appear to affect neurocognitive function (96). 658 However, CGM data were not available in the DCCT era and so the true extent of serious 659 hypoglycaemia over time is not known. It appears that older adults with type 1 diabetes are 660 more prone to mild cognitive impairment associated with hypoglycaemia (97), while 661 hypoglycaemia occurs more frequently in those with cognitive impairment. 662 Impaired awareness of hypoglycaemia 663 Impaired awareness of hypoglycaemia (IAH) is the reduced ability to recognize low blood 664 glucose levels that would otherwise prompt an appropriate corrective therapy (98). Its 665 prevalence is estimated close to 25% in people with type 1 diabetes but is likely 666 underestimated according to CGM data (99). IAH increases the risk of severe hypoglycaemia 667 by 6-fold (100) and may lead the person with diabetes to omit insulin injections intentionally 668 or loosen tight glucose management to prevent their occurrence. 669 The pathophysiology of IAH is still not fully understood but includes a partial or total loss of 670 sympatho-adrenal reactions to hypoglycaemia that prevent catecholaminergic stimulation of 671 hepatic glucose output and restraint of muscle glucose uptake (90). The connections between 672 autonomic neuropathy and IAH are complex since both the defect of sympatho-adrenal 673 reaction to hypoglycaemia can be a component of autonomic neuropathy and hypoglycaemia 674 itself can promote neuropathy. Indeed, recurrent hypoglycaemia is a major cause of IAH. 675 Sleep disturbance, psychological stress, and alcohol can also induce IAH (98). 676 In clinical practice, physicians should be proactive in asking people with type 1 diabetes 677 whether and at which glucose level they feel hypoglycaemia in order to identify IAH and adjust 678 individual glucose targets to prevent the occurrence of severe hypoglycaemia. The reference 679 method to assess IAH is the hyperinsulinaemic-hypoglycaemic clamp (101), although not used 680 out of a research frame due to its invasiveness, cost and time commitment from people with 681 diabetes. Self-reported awareness, however, agrees well with the autonomic glucose 682 threshold (102). The Gold and Clarke questionnaires showing a score equal or above 4 are 683 indicative of IAH (100,103) and the Pedersen-Bjergaard and HypoA-Q questionnaires can also 684 identify IAH (104,105). The UK National Institute of Health and Care Excellence recommended 685 for the first time that an assessment of hypoglycaemia, including awareness, should form part 686 of clinical consultations (106). 687 Strict avoidance of hypoglycaemia can help to restore hypoglycaemia awareness (107). CGM 688 use promotes the identification of current or impending low glucose levels that people may 689 not feel. Blood glucose awareness training, education to optimize insulin dosing and type, and 690 hypoglycaemia avoidance motivational programs all improve hypoglycaemia awareness. In 691 some situations, it may be necessary to increase the glucose target range (107,108). Several

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692 clinical trials failed to show a reduction of IAH by using CGM despite a reduced incidence of 693 severe hypoglycaemia (87,98,107–110). 694 Treatment of hypoglycaemia 695 The recommended correction of hypoglycaemia is the oral intake of approximately 15 g of 696 glucose or equivalent simple carbohydrate when a capillary blood glucose level is <70 mg/dl 697 (3.9 mmol/l). This should be repeated every 15 minutes until any symptoms have resolved 698 and the blood glucose level is above 70 mg/dl (3.9 mmol/l). A larger amount of glucose may 699 be needed if glucose levels are below 54 mg/dl (3.0 mmol/l). Lower carbohydrate intakes can 700 be used when symptoms are associated with a capillary blood glucose level above 70 mg/dl 701 (3.9 mmol/l). 702 The specific recommendations for correction of hypoglycaemia or trends for hypoglycaemia 703 according to CGM in people using automated insulin delivery systems will have to be defined 704 as this mode of therapy expands in forthcoming years. Less carbohydrate may need to be 705 ingested to correct hypoglycaemia because the automated insulin delivery system should 706 have already reduced or stopped basal insulin delivery. 707 In the case of neuroglycopaenic symptoms, including severe confusion or loss of 708 consciousness, oral glucose intake is contraindicated because of risk for aspiration. Instead, 709 glucagon via subcutaneous or intramuscular injection or nasal delivery should be given by 710 attending people. Intravenous glucose injection is a possible alternative for healthcare 711 professionals in the cases of severe hypoglycaemia. 712 After the acute symptoms have resolved, a further 20g of long-acting carbohydrate should be 713 given and the cause of the hypoglycaemic episode sought to prevent further episodes. 714 715 Section 9: Additional behavioural considerations 716 Nutrition therapy 717 Nutrition, in particular carbohydrate intake, has a major effect on glycaemia and people with 718 type 1 diabetes need to understand the effect of food on their diabetes and plan meals 719 accordingly (Table 8). People with type 1 diabetes should be referred for individualized 720 medical nutrition therapy provided by a registered dietitian who is knowledgeable and skilled 721 in providing diabetes-specific nutritional advice. Medical nutrition therapy delivered by a 722 registered dietitian is associated with a reduction HbA1C of 1.0-1.9% (11-21 mmol/mol) for 723 people with sub-optimally managed type 1 diabetes when integrated into an overall 724 management program (111). 725 There is no one eating pattern recommended for people with type 1 diabetes. The nutrition 726 approach should be individualized based on personal preferences, socioeconomic status, 727 cultural backgrounds and comorbidities. Carbohydrate counting is the most common meal 728 planning approach in type 1 diabetes. In conjunction with promoting healthy eating patterns, 729 carbohydrate counting and insulin-to-carbohydrate ratios can be a useful method for 730 adjusting meal-time insulin dosing for optimal glycaemic outcomes (112,113). While low- 731 carbohydrate and very-low carbohydrate eating patterns have become increasingly popular 732 and reduce HbA1C levels in the short-term, it is important to incorporate these in conjunction 733 with healthy eating guidelines. Additional components of the meal, including high fat and/or 734 high protein, may contribute to delayed hyperglycaemia and the need for insulin dose

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735 adjustments. Since this is highly variable between individuals, postprandial glucose 736 measurements for up to three or more hours may be needed to determine initial dose 737 adjustments (114). 738 The average BMI of individuals with type 1 diabetes is rising at a faster rate than the general 739 population, partly as a result of insulin intensification and societal factors that also affect the 740 general population such as physical inactivity. Weight loss and maintenance interventions 741 involving nutritional advice and physical activity should be offered to individuals with type 1 742 diabetes and overweight or obesity. New interactive technologies using mobile phones to 743 provide information, insulin bolus calculations based on insulin-to-carbohydrate ratios, and 744 telemedicine communications with care providers decrease both weight gain and the time 745 required for education (115). In the case of extreme low weight, unhealthy eating habits 746 should be reviewed, including the possibility of insulin omission. 747 Alcohol and recreational drug use 748 Similar to the general population, many individuals with type 1 diabetes consume alcohol, 749 although its effects on glycaemic management are not always adequately considered by those 750 with diabetes and their healthcare professionals. Increased alcohol consumption is associated 751 with a higher risk of DKA and severe hypoglycaemia (116). Some of this increase may occur 752 through the association with other risk-taking behaviour. However, excessive alcohol 753 consumption impairs cognitive function and symptom awareness, leading to a diminished 754 ability to self-manage the diabetes. Alcohol promotes ketosis, which in the context of 755 consumption of sugary alcoholic beverages may increase the risk of DKA (117). Alcohol also 756 inhibits hepatic gluconeogenesis leading to an increased risk of hypoglycaemia for up to 24 757 hours after the last drink (118). Hypoglycaemia is particularly hazardous because of the 758 potential to confuse the symptoms of hypoglycaemia with alcohol intoxication. 759 Cannabis has been legalised in multiple jurisdictions. An association between recent 760 recreational cannabis consumption and a more than double the risk of ketoacidosis has been 761 reported from countries where cannabis has been legalised, possibly related to the 762 emergence of higher potency formulations of cannabis and other synthetic cannabinoids 763 (119). Use of cocaine and other stimulant-like drugs, such as amphetamine, 764 methamphetamine, and ecstasy (or MDMA) increase glucose production and inhibit glucose 765 clearance, which increases the risk of ketoacidosis. Having a diagnosis of a substance use 766 disorder confers an increased all-cause mortality in populations with diabetes across a range 767 of substances including cocaine, opioids, and cannabis, regardless of consumption. 768 As people are unlikely to spontaneously report their alcohol or drug use to clinicians, 769 systematic screening for excess alcohol and/or drug use is recommended. Healthcare 770 professionals have a responsibility to inform people with type 1 diabetes about the effects of 771 drugs and alcohol on diabetes and related risks. Otherwise, people with diabetes will seek 772 information elsewhere, which is frequently incorrect and misleading (120). Brief interventions 773 to reduce risky drinking and drug use have been well validated in a variety of populations and 774 offer the potential to improve taking and outcome (121). In the case of 775 alcohol or drug addiction, referral to a specialized clinic is warranted. 776 Smoking 777 Since smoking increases the risk of macrovascular and microvascular complications in people 778 with diabetes, smoking cessation should be promoted in all individuals with type 1 diabetes.

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779 The direct effect of smoking on glycaemic levels in people with diabetes needs more research 780 to assess impact (122,123). 781 782 Physical Activity 783 People with type 1 diabetes should be encouraged to engage in a combination of aerobic and 784 resistance exercise on most days because exercise is associated with improved fitness, 785 increased insulin sensitivity leading to reduced insulin requirement, improved cardiovascular 786 health with better lipid profile and endothelial function, and decreased mortality (124–127). 787 Independent effects on β-cell function and HbA1c have not been established beyond doubt 788 but appear beneficial. In addition, regular physical activity is associated with reduced risk of 789 microvascular complications, osteoporosis, and cancer in people with type 1 diabetes (128). 790 Exercise also helps maintain a healthy BMI and promotes sleep quality and mental wellbeing. 791 It is important that physical activity is performed safely. The major risks are from the acute 792 effects of exercise on glucose concentrations, which depend on several factors, including the 793 baseline fitness of the individual, type, intensity and the duration of activity; the amount of 794 insulin in the circulation; the blood glucose concentration before exercise; and the 795 composition of the last meal or snack. People with type 1 diabetes should be taught about 796 the effects of exercise on glucose and how to balance exogenous insulin delivery and 797 carbohydrate intake for the different forms and intensities of exercise. 798 Glycaemic management during exercise should be made safer with CGM systems. The 799 updated consensus statement for management of exercise in type 1 diabetes highlights very 800 detailed suggestions regarding the use of trend arrows and adjustment of insulin doses and 801 carbohydrate intake (129). 802 Before recommending exercise, it is important to enquire about symptoms of cardiovascular 803 disease and undertake relevant investigation and treatment as necessary. Advice should be 804 given about appropriate footwear for those with peripheral neuropathy to avoid the risk of 805 ulceration. However, walking does not increase the risk of ulceration in people with 806 peripheral neuropathy (130). Weight-bearing exercise should be avoided in active foot 807 disease. If an individual has proliferative or severe non-proliferative 808 diabetic retinopathy, then vigorous activity requiring straining may be contraindicated 809 because of the risk of vitreous hemorrhage or retinal detachment (131). The individual should 810 be advised to consult an ophthalmologist prior to engaging in an intense exercise regimen. 811 Additional details regarding the diabetes management during physical activity or exercise 812 have been described elsewhere (132). When there is excessive physical exercise combined 813 with extreme low weight, an eating disorder should be considered. 814 Sleep 815 Proper sleep hygiene is essential for all individuals. Sleep may be disrupted in people with 816 type 1 diabetes as a result of both behavioural and physiological aspects of diabetes and its 817 management (133). They may include hyper- and hypoglycaemic episodes, blood glucose 818 variability, and loss of blood pressure decline. However, studies performed so far have not 819 determined causality. On the other hand, sleep disturbances including poor sleep quality and 820 shorter sleep duration are associated with worsening glycemic levels in type 1 diabetes 821 (134,135).

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822 823 Sick Day/Illness Management 824 Stressful events, including illness, may impact glucose levels and increase risk of DKA. More 825 frequent glucose and ketone measurements are necessary to identify insulin adjustments. It 826 is recommended that individuals develop a sick day management plan with individualized 827 guidelines with their healthcare professional (136). 828 829 Driving 830 Unrecognized hypoglycaemia and rapidly dropping glucose levels are the most relevant 831 hazards for drivers with type 1 diabetes. These risks may be reduced by the use of CGM or 832 BGM prior to driving and at 2-hourly intervals. Local regulations and recommendations should 833 be followed for driving with type 1 diabetes (137–139) . 834 835 Employment 836 837 People with type 1 diabetes can successfully undertake a wide range of employment but there 838 remains prejudice against those with diabetes that can limit employment opportunities. The 839 main concerns are associated with the risks of acute hypoglycaemia as well as certain 840 situations in which continued supply of effective insulin is not possible, for example working 841 in very hot climates. Additionally, chronic diabetes complications may affect the ability to 842 work in certain situations. For some occupations, any risk of hypoglycaemia is considered 843 unacceptable but efforts have been made to address these risks. For example, in some 844 countries people with type 1 diabetes are now working as commercial airline pilots. For this 845 reason, any person with type 1 diabetes should be supported to undertake professional 846 activity, job, or employment for which they are otherwise qualified and can do safely (140). 847 Employment circumstances should allow the safe use and storage of insulin and unrestrained 848 access to glucose monitoring and self-treatment of hyper- or hypoglycaemia. 849 850 Travel 851 Planning ahead is the key to safe and trouble-free travel for individuals with type 1 diabetes. 852 This includes preparing diabetes-related and emergency supplies which should be available 853 at hand during the travel. A plan of adjusting insulin doses, especially when traveling across 854 time zones, is essential to reduce glucose fluctuations (141). 855 Depending on the locale of travel destinations, it may be advisable to research the estimated 856 carbohydrate content of local foods to aid better insulin adjustment. Frequent glucose 857 measurement with CGM or BGM is advisable for any travel (142). Additionally, it may be 858 helpful to have note cards written in the local language to communicate that the person has 859 type 1 diabetes and may need urgent glucose administration if hypoglycaemic. 860 861 Section 10: Psychosocial Care

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862 Type 1 diabetes is a psychologically challenging chronic condition, with treatment outcomes 863 highly dependent on the person’s on-going self-care behaviours. Cognitive, emotional, and 864 social factors are critical determinants of self-care behaviours and consequently treatment 865 success (143,144). Emotional health is an important outcome of diabetes care, warranting a 866 person-centered approach (145). 867 Psychosocial problems 868 Diabetes-specific emotional distress affects 20-40% of people with type 1 diabetes and can 869 be experienced at any point in time. Two ‘critical’ times, however, are following the diagnosis 870 and when complications develop (146). Feeling powerless and overwhelmed by the daily self- 871 care demands, fear of hypoglycaemia, and worries about complications are among the most 872 cited sources of distress by persons with type 1 diabetes. Prolonged, significant diabetes 873 distress is associated with depressed mood and elevated HbA1c levels (147). 874 Lack of social support or feeling ‘policed’ by family, friends or coworkers also evokes 875 emotional distress in individuals with type 1 diabetes (148). Conversely, social support is a 876 protective factor serving as a buffer against stress. Depression and anxiety symptoms are 877 twice as prevalent among people with type 1 diabetes relative to people without diabetes, 878 negatively impacting quality of life (149–151). Anxiety and depression often co-exist and may 879 partly overlap with symptoms of diabetes distress (152). Depression is a risk factor for poor 880 self-care, hyperglycaemia, complications and excess mortality (152–154). The association 881 between generalized anxiety and sub-optimal glycaemia is less clear (155,156). 882 Given the high prevalence and impact of psychosocial problems in diabetes, screening and 883 monitoring should be integral parts of diabetes care. Validated screening tools have been 884 developed for most problem areas and are available in multiple languages. Clinicians engaging 885 in screening need to understand the psychological and social issues that may complicate 886 diabetes management, have good communication skills, and be able to refer to specialized 887 mental health services where appropriate. Recently, a working group from the International 888 Consortium for Health Outcomes Measurement (ICHOM) made recommendations for a 889 standard set of practical and validated psychosocial measures (157), including the WHO-5 890 Wellbeing Index (WHO-5) (158), Problem Areas in Diabetes scale (PAID) (159), and Patient 891 Health Questionnaire (PHQ-9) (160). For Generalized Anxiety, the Generalized Anxiety 892 Disorder-7 items (GAD-7) is recommended (161). Screening tools can help to ‘flag’ 893 psychological problems that may require follow-up or referral to a mental health specialist. 894 Assessment and periodic monitoring of emotional health combined with the necessary 895 organizational improvements are recommended and promote case-finding, emotional 896 wellbeing and patient satisfaction with care (162,163). 897 Fear of hypoglycaemia affects up to 10% of adults with type 1 diabetes, particularly among 898 those experiencing repeated episodes of severe hypoglycaemia (164). Fear of hypoglycaemia 899 may translate into avoidance behaviours aimed at keeping blood glucose at a ‘safe’ level, 900 resulting in persistent hyperglycaemia (165). In cases of problematic fear of hypoglycaemia, 901 administering the Fear of Hypoglycaemia Survey (HFS) can help to identify specific worries 902 and level of severity (166). Both disproportional high and low fear of hypoglycaemia warrant 903 attention. 904 Eating disorders, including anorexia nervosa, bulimia nervosa, and binge eating, are over- 905 represented in type 1 diabetes populations, particularly in young women (167,168) but may 906 also occur in men. Insulin omission as a weight loss strategy (’diabulimia’) often starting in

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907 teenage years warrants special attention (169,170). If indicated, screening for eating 908 disorders is advised, using a validated instrument suited for use in people with type 1 909 diabetes, e.g. the Diabetes Eating Problems Survey-Revised (DEPS-R) or Eating Disorders 910 Inventory – 3 Risk Composite (EDI-3RC) (171). 911 912 Social Determinants of Health 913 Social and financial hardships can negatively impact an individual’s mental health, motivation, 914 and capacity to engage in self-management practices, increasing the risk for elevated HbA1c 915 and complications. In a review of social determinants of health and diabetes (172), the 916 importance of the following domains is discussed: (a) Neighbourhood and physical 917 environment e.g. housing stability; (b) Built environment e.g. walkability, access to green 918 spaces; (c) Environmental exposures e.g. pollution; d) Food access, availability and 919 affordability, and; (e) Healthcare access, affordability and quality. 920 Socioeconomic challenges, particularly the inability to pay for food, insulin, other medications 921 and supplies, need to be recognized and addressed. Several screening tools are available 922 (173–178). Sample questions that have been used include: How hard is it for you to pay for 923 the very basics like food, housing, medical care, and heating? At any time since the last 924 interview or in the last 2 years have you ended up taking less insulin than was prescribed for 925 you because of cost? In the past 12 months has lack of transportation kept you from attending 926 medical appointments or from getting insulin? 927 928 Psychosocial interventions 929 All members of the diabetes care team have a responsibility for providing psychosocial care. 930 Preferably, the diabetes care team should include a psychologist or social worker to advise 931 the team and consult with people with diabetes in need of psychosocial support (179). Three 932 levels of psychosocial support can be distinguished, and diabetes teams have an important 933 role in offering diabetes self-management education and support at all three levels. 934 At the first level, people living with type 1 diabetes do not require professional mental health 935 care. They may engage in self-help programs and/or receive informal coaching as well as 936 family, peer, and community support to assist them in coping with the psychological demands 937 of self-managing type 1 diabetes as well as socioeconomic challenges. At the second level, 938 which concerns approximately one quarter of individuals with type 1 diabetes, some degree 939 of professional psychosocial support is warranted. Support for social needs can be provided 940 by a social worker and/or community organization. It is important that therapists have a good 941 understanding of diabetes treatments and integrate diabetes management in the 942 psychological treatment. Psychological therapies, including time-limited (online) Cognitive 943 Behavioural Therapy (CBT), mindfulness and interpersonal therapies are effective with regard 944 to a range of psychological outcomes, including diabetes distress and depression. The effects 945 of psychotherapy on glycaemic levels are generally small but tend to increase when diabetes 946 self-management education is incorporated in the treatment (180). Approximately 5% of the 947 adults with type 1 diabetes are in need of psychiatric treatment (level 3), which may involve 948 psychotropic medication that can impact glycaemic management. Psychiatric comorbidities, 949 such as anorexia nervosa and schizophrenia, require close collaboration between the mental 950 health specialist and diabetes care team (181,182).

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951 952 Section 11: Diabetic Ketoacidosis 953 Diabetic ketoacidosis (DKA) is a life-threatening but preventable acute complication of type 1 954 diabetes, characterized by hyperglycaemia, metabolic acidosis, and ketosis. There are times 955 when the glucose levels are normal or only minimally elevated. The underlying cause is insulin 956 deficiency, either absolute (new diagnosis of type 1 diabetes or omission of insulin in those 957 with diagnosed disease) or relative (increased counter-regulatory hormones due to infection 958 or other stressors without an adequate increase in insulin doses). 959 The prevalence of DKA and risk factors for the complication have been less well studied in 960 adults with type 1 diabetes than in children. In the USA, national surveillance of emergency 961 department visits and hospital admissions suggests a rate of 28 cases per 1000 adults with 962 diabetes per year, with a worrisome increase in emergency department visits and admissions 963 for DKA seen since 2009 (183). The U.S. Type 1 Diabetes Exchange Clinic Network reported 964 that 4.8% of participants (age 26 to 93 years) had been hospitalized for DKA in the prior year 965 (37,184). In a European (predominantly Germany and Austria) registry, adults with type 1 966 diabetes had DKA at a rate of 2.5 per 100 patient years (184). 967 As DKA occurs repeatedly in some persons with diabetes, risk factors should be identified and 968 approached in a prevention strategy. Some known risk factors are non-modifiable, such as 969 low socioeconomic status, younger age, female sex, and ethnicity (37,184), whereas others 970 associated with increased risk of DKA are potentially modifiable. These include having had 971 one previous episode of DKA, high HbA1c, low self-management skills including omission of 972 insulin therapy, psychiatric disorders, infections, somatic comorbidity, alcohol and drug 973 abuse, and less interaction with the healthcare team (185–187). Older studies demonstrated 974 a higher risk of DKA in those using insulin pumps likely due to the lack of depot insulin when 975 continuous delivery of insulin is disrupted (188). However, more recent studies have not 976 found this to be the case (37,184,189). Adjunctive use of sodium glucose cotransporter (SGLT) 977 inhibitors (see below) in adults with type 1 diabetes increases the risk of DKA by an absolute 978 rate of about 4% per year, suggesting the need for intensive diabetes self-management 979 education and monitoring (190,191). DKA in the setting of SGLT inhibitor use is often so-called 980 euglycaemic DKA, with initial case reports describing admission glucose levels of 96-224 981 mg/dL (5.3-12.4 mmol/L) (192). 982 Diabetes self-management education is an effective tool in reducing DKA risk. Additional 983 medical, behavioural health interventions and psychosocial support are often needed. 984 Telemedicine offers the potential to reach populations with decreased access to care, and 24- 985 hour access to advice about managing hyperglycaemia and ketosis/ketonemia at home can 986 reduce the risk of hospital admission (185). 987 A detailed description of the management of DKA is beyond the scope of this report but the 988 general principles of treatment are replacement of fluid, insulin, and potassium. Due to a lack 989 of rigorous evidence, there are different protocols for DKA treatment in different parts of the 990 world (193,194). For further information regarding treatment, refer to previous reviews 991 (195,196). 992 993 Section 12: Pancreas and Islet transplantation

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994 Whole organ pancreas and pancreatic islet transplantation are currently the only means of 995 clinical β-cell replacement (figure 7). Both therapeutic options can effectively prevent 996 hypoglycaemia, restore normoglycaemia, and possibly stabilize the progression of 997 complications of type 1 diabetes (197–201). However, chronic systemic immunosuppression 998 is needed in both forms to prevent allogeneic rejection. Therefore, the indication must 999 thoroughly balance risk and benefit, taking into consideration psychological factors as well 1000 (202). In the U.S., islet transplantation is not yet approved for clinical use and reimbursement. 1001 Most whole pancreas transplants are performed simultaneously with a kidney transplant 1002 (SPK). This is the “gold standard” therapy for people with type 1 diabetes and pre-final or end- 1003 stage renal disease if no contraindications (malignancies, chronic infections, insufficient self- 1004 management, and severe cardiovascular conditions) are present. Simultaneous pancreas- 1005 kidney transplants show a 5-year pancreas graft survival of 83% and are superior to pancreas 1006 transplant alone or pancreas after a kidney transplant (55 and 70% respectively) (203). With 1007 an SPK transplant, most recipients can expect amelioration of problematic hypoglycaemia for 1008 more than a decade (203–205). 1009 Pancreas transplants alone (PTA) are usually performed in people who are relatively young 1010 (<50 years) and do not have obesity (<30 kg/m2) or coronary artery disease. These selection 1011 criteria minimize operative mortality (<1%) and reduce early technical pancreas graft loss 1012 (<10%) (203,206). The main indications are a history of frequent, acute, and severe metabolic 1013 complications (hypoglycaemia, hyperglycaemia, ketoacidosis), clinical and emotional 1014 problems with exogenous insulin therapy as to be incapacitating, or consistent failure of 1015 insulin-based management including technological aids (207). 1016 Islet transplantation, a less invasive procedure, is indicated in people with excessive glycaemic 1017 lability and frequent severe hypoglycaemia despite optimal medical therapy and allows for 1018 inclusion of older people and those with coronary artery disease who would not be eligible 1019 for a whole-pancreas transplant (198,208,209). Careful patient selection and protocol 1020 optimization have led to substantial clinical improvements (198). Insulin independence can 1021 be maintained for 5 years in 50% of recipients (210,211). Although achievement of insulin 1022 independence remains an important objective, several multi-centre clinical trials of islet 1023 transplants in people with type 1 diabetes and problematic hypoglycaemia have adopted a 1024 combination of near-normal glycaemic levels (HbA1c <7.0%, 53 mmol/mol) together with the 1025 elimination of severe hypoglycaemia as the primary end point and the clinically relevant dual 1026 goal of intervention (212–214). These outcomes can translate into improved patient-reported 1027 outcomes, but research in this area is limited (215). 1028 Regardless of the β-cell replacement approach (pancreas or islets), the majority of recipients 1029 experience reliable prevention of problematic hypoglycaemia with near-normal glycaemic 1030 levels. Islet and pancreas transplants are the only approaches to date that confer both 1031 sustained recovery from hypoglycaemia-associated autonomic failure and restoration of 1032 glucose counter-regulation and, thereby, reliable protection from severe hypoglycaemia in 1033 people with longstanding type 1 diabetes (216). However, these approaches have not been 1034 compared with the newer systems of hybrid closed loop technology which might render 1035 immunosuppression requiring therapies less necessary. 1036 1037 Section 13: Adjunctive therapies

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1038 While insulin therapy is essential for people with type 1 diabetes, obtaining glycaemic goals 1039 with insulin alone is difficult because of the risks of hypoglycaemia. Furthermore, insulin 1040 therapy is often associated with undesirable weight gain which may worsen insulin resistance, 1041 does not address other pathophysiological abnormalities (apart from endogenous insulin 1042 deficiency including α-cell dysfunction), and leaves the individuals at an increased risk of 1043 cardiovascular disease. Adjunctive therapies aim to augment insulin therapy by addressing 1044 some of these critical unmet needs. 1045 To date, although several drugs have been licensed as adjunctive therapies, the evidence of 1046 their effectiveness is limited. It is not possible to make a general recommendation about their 1047 use, but they can be considered in individual cases (table 9). However, before these drugs are 1048 prescribed, insulin therapy should be optimized. 1049 Metformin 1050 Metformin has been evaluated in numerous trials in people with type 1 diabetes with hopes 1051 that its insulin-sensitizing properties would improve glycaemic management and/or reduce 1052 cardiovascular risk (217). The largest study to date assessed the use of metformin 1g twice 1053 daily in 493 people with type 1 diabetes who were treated for 3 years with a primary endpoint 1054 of changes in carotid intimal thickness, a marker of cardiovascular disease risk. The study 1055 ultimately found no difference in the primary endpoint, minimal and non-sustained effects 1056 on HbA1c, minimal effects on weight (~1 Kg reduction), and no change in total daily insulin 1057 dose (218). 1058 Pramlintide 1059 Pramlintide, an amylin analogue, is approved for therapeutic use in the U.S., but not in 1060 Europe, as an adjunctive therapy to insulin. It remains the only FDA-approved adjunctive 1061 therapy for type 1 diabetes. Injection prior to meal acts to suppress glucagon secretion, delay 1062 gastric emptying, and promote satiety (219–222). Clinical trials have shown a reduction in 1063 HbA1c (0.3-0.4%; 3-4 mmol/mol) and modest (~1 kg) weight loss (223–226). As a result of its 1064 adverse effects and need for additional injections, clinical uptake of pramlintide has been 1065 limited. However, co-formulations of amylin with insulin are currently in development, as is 1066 the possibility of use of pramlintide in pumps or artificial pancreas systems. 1067 Glucagon like peptide-1 receptor agonists 1068 Glucagon like peptide-1 receptor agonists have been explored in people with type 1 diabetes 1069 for two indications. This first aimed to ameliorate β-cell decline at the time of diagnosis and 1070 there are ongoing trials of this approach. In one study of 308 people with recently diagnosed 1071 type 1 diabetes, liraglutide when used in combination with anti-IL-21 preserved β-cell decline 1072 (227). The second is as an adjunctive therapy in established type 1 diabetes by blunting 1073 glucagon secretion, decreasing gastric emptying, and promoting satiety and weight loss (228). 1074 The largest clinical trials in people with type 1 diabetes were conducted with liraglutide and 1075 showed modest decreases in HbA1c at daily doses of 1.8 mg (~0.4%; 4 mmol/mol), decreases 1076 in weight (~5 kg), and reductions in insulin doses (229,230). However, increased rates of 1077 hypoglycaemia and ketosis were shown. Subgroup analysis in people with residual C-peptide 1078 production suggests greater HbA1c reduction and improved safety with lower risk of ketosis. 1079 Trials in people with type 2 diabetes have shown convincing reductions in cardiovascular 1080 events with human GLP-1 analogues (231); whether these benefits would also be seen in

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1081 people with type 1 diabetes is unknown. GLP-1 receptor agonists may have a role for those 1082 who have concomitant obesity. 1083 Sodium-glucose co-transporter (SGLT) inhibitors 1084 In several phase III programs in people with type 1 diabetes, the use of SGLT inhibitors 1085 reduced HbA1c, improved time in range, reduced body weight and improved blood pressure 1086 (217). However, an increased rate of diabetic ketoacidosis led to rejection of market 1087 authorization for type 1 diabetes by the FDA, whereas the European Medicines Agency has 1088 approved low-dose dapagliflozin (5mg) and sotagliflozin (200mg) for those with a BMI >27 1089 kg/m2 (232). While no risk mitigation strategies have been proven to lower the risk of DKA, a 1090 consensus statement on SGLT2 inhibitors and DKA suggested careful patient selection, 1091 appropriate insulin dose adjustment to avoid insulinopaenia, starting with a low dose of 1092 SGLT2 inhibitors and regular ketone measurements with prompt action to elevated values as 1093 sensible precautions aimed at preventing DKA (190). 1094 In people with type 2 diabetes, improved cardiovascular outcomes, mainly due to a reduction 1095 in congestive heart failure, and improved renal outcomes have been established, but the 1096 applicability of these data to people with type 1 diabetes is uncertain (233). However, 1097 increasingly, data on SGLT2 inhibitors have shown renal and heart failure benefits in people 1098 without diabetes suggesting that people with type 1 diabetes and these comorbidities may 1099 also benefit. 1100 1101 Section 14: Special populations 1102 Pregnancy including pre-conception and post-natal care 1103 Both maternal and fetal pregnancy outcomes are worse in women with type 1 diabetes 1104 compared with women without diabetes. Hyperglycaemia before and during pregnancy 1105 increases the risk of complications in the pregnant woman and developing fetus and also 1106 affects further child development. Thus, women should be supported to achieve blood 1107 glucose ranges close to those seen in pregnant women without diabetes with an HbA1c target 1108 of ≤6.5% (48 mmol/mol) (234,235). The woman should aim for fasting and pre-meals glucose 1109 concentrations below 95 mg/dL (5.3 mmol/L) and post-prandial values of below 140 mg/dL 1110 (7.8 mmol/L) 1 hour after a meal and below 120 mg/dL (6.7 mmol/L) 2 hours after a meal. 1111 Although the use of CGM is not approved in the U.S. for use of pregnancy and no studies in 1112 pregnancy have used CGM alone, the CONCEPTT trial showed that when CGM was used in 1113 conjunction with BGM, CGM was associated with better pregnancy outcomes (236). Many 1114 women rely on CGM during pregnancy and its use should be encouraged with the caveat that 1115 BGM should be performed if there are concerns that the CGM reading is inaccurate. 1116 The major limiting step to achieving normoglycaemia is hypoglycaemia which occurs more 1117 frequently in the first half of pregnancy, in part because of diminished awareness of 1118 hypoglycaemia and pregnancy associated nausea and vomiting (237). Pregnant women with 1119 type 1 diabetes are at risk of DKA at lower blood glucose levels than the non-pregnant state 1120 and should receive education on diabetic ketoacidosis prevention and detection (238). 1121 Postpartum breastfeeding, erratic sleep and eating schedules may increase the risk of 1122 hypoglycaemia and insulin dosing may require adjustment (239,240).

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1123 The management of pregnancy begins before conception as a planned pregnancy is 1124 associated with improved outcomes for both the women and offspring. Effective 1125 contraception should be used until the woman is ready for pregnancy. All women of child- 1126 bearing age with type 1 diabetes should be informed about the importance of seeking 1127 professional help prior to trying to conceive; this provides an opportunity not only to improve 1128 glycaemic management but to offer folic acid to prevent neural tube defects, screen for 1129 diabetes-related complications, and stop potentially teratogenic medications. 1130 Diabetes in pregnancy is best managed by a multidisciplinary team including a 1131 diabetologist/endocrinologist, obstetrician, dietitian, diabetes nurse/educator, and diabetes 1132 midwife. A detailed description of the management of pregnancy in women with type 1 1133 diabetes is beyond the scope of this report but is available elsewhere (241,242). 1134 1135 Older people with type 1 diabetes 1136 Insulin regimens in older adults should be individualized and patient safety is a key priority. 1137 Glycaemic targets should be based on functional status and life expectancy, rather than 1138 chronological age. As older adults with type 1 diabetes are especially vulnerable to 1139 hypoglycaemia, target glucose values should be adjusted to minimize the occurrence of 1140 hypoglycaemic events. Since in some older adults with type 1 diabetes, administration of 1141 insulin may become more difficult, simplification of insulin management may be justified in 1142 cases of individuals with complications, or functional or cognitive impairment. The use of 1143 advanced technologies in older individuals is useful and should not be discontinued or a priori 1144 excluded because of the older age (68,243). 1145 1146 People with late complications of type 1 diabetes. 1147 As there is no evidence that intensive glycaemic management slows the progression of late, 1148 microvascular complications of diabetes, glycaemic targets in individuals with advanced 1149 complications should be individualized and based on the balance of risks and benefits 1150 (35,244). Diabetes management may be particularly challenging in individuals with chronic 1151 kidney disease who may be at an increased risk of hypoglycaemia and in whom HbA1c can be 1152 falsely low (245) and in people with gastroparesis and unpredictable rates of food absorption 1153 (246). The rate of optimizing glycaemia in this group of people should also be individualized 1154 as rapid improvement may be associated with transient early worsening of retinopathy or the 1155 development of acute painful neuropathy (247,248). In people with cardiovascular 1156 complications, hypoglycaemia avoidance should be one of the management priorities (249). 1157 1158 Section 15: In-patient Management of Type 1 Diabetes 1159 There have been no large, randomized controlled trials specifically assessing glycaemic 1160 targets for in-patients with type 1 diabetes. Therefore, type 2 diabetes guidelines should be 1161 followed, which recommend target glucose ranges of 140-180 mg/dl (7.8-10.0 mmol/l) for 1162 the majority of non-critically and critically ill patients (250). However, it is important that the 1163 care team recognizes key differences between type 1 diabetes and type 2 diabetes. People 1164 with type 1 diabetes are at higher risk of hypoglycaemia, which should be avoided by careful 1165 insulin and carbohydrate matching (251). Furthermore, people with type 1 diabetes are at

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1166 high risk of developing ketosis if insulin is withheld (252). People with type 1 diabetes often 1167 find the in-patient care of their diabetes stressful and disempowering. Therefore, in-patients 1168 with type 1 diabetes should be clearly identified to avoid common errors such as omission of 1169 mealtime insulin or withholding of basal insulin for procedures or surgery. Whenever a 1170 dedicated in-patient diabetes service is available, they should be consulted for glycaemic 1171 management, diabetes self-management education and support, and discharge planning 1172 (253). Finally, the use of diabetes technology (CGM and insulin pumps) can be continued in 1173 selected, non-critically ill patients, with clear mentation, and previous training and education 1174 (254,255). Institutions should develop clear guidelines to manage in-patient type 1 diabetes 1175 safely. 1176 1177 Section 16: Emergent and Future Perspectives 1178 Both xenotransplantation and stem cells are under investigation to solve the problem of 1179 limited availability of donors for pancreas or islet transplantation (256). Stem cell strategies 1180 have used either patient specific stem cells or generic allogeneic cells. In the former, the 1181 patient’s own stem cells are reprogrammed or transdifferentiated to become β cells. By 1182 contrast, generic allogeneic cells may be used for multiple patients and centrally produced 1183 from a bank of embryonic stem cells (hESCs) or of induced pluripotent stem cells (iPSCs). One 1184 of the key issues is protecting the cells from immune attack, both rejection and recurrent 1185 autoimmunity. Three general strategies are being investigated – [1] immunosuppressive or 1186 immunomodulatory drugs, [2] use of a physical barrier e.g. encapsulation (257), and [3] gene 1187 editing for immune evasion and/or immune protection (258). Both academic and commercial 1188 groups are pursuing these approaches and some are already in clinical trials. 1189 Immunotherapy approaches are being evaluated for their potential to prevent clinical type 1 1190 diabetes, and for the preservation of β-cell function shortly after onset of clinical type 1 1191 diabetes (259). Many interventions have been tested in clinical trials, but to date the most 1192 promising results have been from the anti-CD3 monoclonal antibody teplizumab, from low- 1193 dose anti-thymocyte globulin (ATG), and from the anti-TNF drug, golimumab. These have 1194 shown promise in preserving β-cell function in recent onset type 1 diabetes, and teplizumab 1195 also has delayed the clinical onset of type 1 diabetes. Several other trials are underway with 1196 the hope of not only preserving but even improving β-cell function and being able to interdict 1197 the type 1 diabetes disease process sufficiently to prevent the development of the disease. 1198

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1199 Table 1: Glycaemic targets for most adults with type 1 diabetes 1200

HbA1c or GMI <7.0% (53 mmol/mol)

Pre-prandial capillary glucose 80–130 mg/dL (4.4–7.2 mmol/L)

1-2 hr post-prandial capillary glucose <180 mg/dL (10.0 mmol/L)

Time in range >70%

Time below range

• % of readings and time 54–69 mg/dL <4% (3.0–3.8 mmol/L) Level 1 • % of readings and time <54 mg/dL <1% (<3.0 mmol/L) Level 2

Time above range

• % of readings and time 181–250 <25% mg/dL (10.1–13.9 mmol/L) Level 1 • % of readings and time >250 mg/dL <5% (>13.9 mmol/L) Level 2

Glycaemic variability (%CV) <36%*

1201 All glycaemic targets should be individualized and agreed with the person with diabetes. 1202 HbA1c : Haemoglobin A1c; GMI: Glucose Management Indicator. *Some studies suggest that 1203 lower %CV targets (<33%) provide additional protection against hypoglycaemia. 1204 1205 1206 1207

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1208 Table 2: Schedule of Care Medical and Family Diabetes History History • Date of diagnosis • Presentation at onset • Islet autoantibodies (date) • C-peptide (date) • Episodes DKA or severe hypoglycaemia • Hypoglycaemia awareness Family history • Type 1 diabetes or type 2 diabetes in first degree relatives • Other autoimmune disorders Personal history of chronic complications • Microvascular o Retinopathy, macular edema, laser/injection therapy, Date of last retinal evaluation (exam or photos) o Peripheral neuropathy, autonomic neuropathy o Nephropathy • Macrovascular o Heart, cerebrovascular and peripheral arterial disease • Foot ulcers or amputations Personal history of common comorbidities • Autoimmune disorders (thyroid, coeliac, others)* • Hypertension • Lipid disorder • Overweight and obesity • Eating disorders • Hearing loss • Sleep disorder • Dermopathy • Fractures • Joint and soft tissue disorders o Cheiroarthropathy o Capsulitis o Carpal tunnel syndrome • Dental health Pregnancy and birth control history Immunization history

Additional Behavioral Diet and Nutrition Factors • Use of carbohydrate counting • Weight history Physical activity Smoking, alcohol, substance use

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Sleep Diabetes Management Current insulin regimen • Multiple daily injections • Insulin pump (type/model): o Settings o Back-up injection plan Other diabetes medications Blood glucose monitoring • Type of meter/strips • Frequency of use • Mean (SD), range • Pattern Continuous glucose monitoring • Type/model • Data sharing: if yes with whom • Glucometrics • Pattern Glucagon prescribed Ketone testing supplies prescribed (where available) Software/app use Psychosocial Issues Monitor psychological well-being • diabetes-specific distress • depressive symptoms • anxiety symptoms Consider also the potential presence of fear of hypoglycaemia and disordered eating Screen for social determinants of health and social support Assess cognitive status Diabetes Self- Assess and plan for meeting individual needs Management Education • Consider contraception and pregnancy planning and Support Physical Examination Height Weight, BMI: every visit Blood pressure and pulse: At least once a year Skin including injection/infusion sites • every visit if skin complaints or erratic glucose readings, otherwise annual Cardiovascular: • Annual; more often if previous abnormality or symptoms Feet • Every visit if peripheral vascular disease, neuropathy, foot complaints or history of foot ulcer; otherwise annual

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Laboratory Testing HbA1c every 3-12 months Creatinine: annual; may be more often if kidney disease Urine Albumin: Creatinine ratio: annual Lipid panel: frequency dependent on the presence of previous lipid abnormality or treatment ALT and AST: at least once and as indicated clinically Serum potassium (if taking ACE-I, ARB or diuretic) TSH, vitamin B12, coeliac screen: at least once and as indicated clinically* Goals Setting Individualized, attainable, realistic • Behavioural considerations Diet and nutrition, activity, smoking cessation Glycaemic • HbA1c, time in range, hypoglycaemia

Treatment Plan Formulate treatment plan with shared decision-making

Referrals As needed: podiatry, cardiology, nephrology, vascular surgery, others 1209 1210 * Individuals with type 1 diabetes are also at increased risk for the development of other 1211 autoimmune diseases including autoimmune thyroid disorders, pernicious anaemia, coeliac 1212 disease, collagen vascular diseases, and Addison's disease (260,261). The optimal frequency 1213 of screening for these conditions in adults has not been established. 1214

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1215 Table 3: Key content areas of Diabetes Self-Management Education and Support (DSMES). 1216 Key Content areas Examples that focus on type 1 diabetes Diabetes pathophysiology and treatment Immunology of β-cell destruction options Healthy eating Basic and advanced carbohydrate counting versus intuitive dosing Impact of composition of meals (fat, protein, glycaemic index, fiber, sugar alcohols) on glucose levels; Use of technology to enhance dosing recommendations Physical activity Impact on glucose and insulin dose recommendations Medication usage Types of available insulins Monitoring and using patient-generated Technology and its impact on the ability to health data (PGHD) have more frequent communication – reviewing CGM, pump downloads, apps Preventing, detecting and treating acute Euglycaemic DKA complications including hypoglycaemia, DKA prevention with pump use hyperglycaemia, diabetes ketoacidosis, sick day guidelines, and severe weather Glucagon use or situation crisis and diabetes supplies Ketone testing management Preventing, detecting and treating Understanding the individual risk for chronic complications including complications in type 1 diabetes immunizations and preventive eye, foot, How to prevent development and progression dental and renal examinations as of complications in the future indicated per the individual participant’s duration of diabetes and health status Healthy coping with psychosocial issues Discussing diabetes distress and burnout and concerns Problem solving Goal setting Developing personal strategies to promote health and behaviour change Problem identification and solutions Identifying and accessing resources Sick day rules 1217

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1218 Table 4: Needs assessment for Diabetes Management, Education and Support 1219 Key assessment features Health history Functional health literacy and numeracy Diabetes distress and support systems Cultural influences Health beliefs and attitudes Physical limitations Social determinants of health e.g. financial status Barriers 1220 1221

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1222 Table 5: Non-Glycaemic Factors That Alter HbA1c Levels (61) 1223 Effect on HbA1c Factor Apparent increase Age Ethnicity • HbA1c is slightly higher in African Americans than in people of white Northern European ancestry* Anaemias with decreased red cell turnover • Iron, vitamin B12, folate Severe hypertriglyceridemia Severe hyperbilirubinemia Chronic alcohol consumption Chronic salicylate consumption Chronic opioid ingestion Apparent decrease Pregnancy (second and third trimester) Anaemias of chronic disease Haemolytic anaemia Splenomegaly and splenectomy Acute blood loss Renal failure Advanced liver disease Drugs • Dapsone • Trimethoprim/ sulfamethoxazole Vitamin E ingestion Ribavirin and interferon alpha Red blood cell transfusion Apparent increase Haemoglobin variants or decrease Vitamin C ingestion 1224 1225 *Variability within races is greater than variability between races (262) 1226

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1227 Table 6: Standardized continuous glucose monitoring (CGM) metrics for clinical care 1228

Number of days CGM device is worn (recommend 14 days) Percentage of time CGM device is active (recommend 70% of data from 14 days) Mean glucose Glucose management indicator Glycaemic variability (%CV) Time above range (TAR) • % of readings and time >250 mg/dL (>13.9 mmol/L) Level 2 • % of readings and time 181–250 mg/dL (10.1–13.9 mmol/L) Level 1 Time in range (TIR) • % of readings and time 70–180 mg/dL (3.9–10.0 mmol/L) In range Time below range • % of readings and time 54–69 mg/dL (3.0–3.8 mmol/L) Level 1 • % of readings and time <54 mg/dL (<3.0 mmol/L) Level 2

1229 CV, coefficient of variation. Adapted from (43).

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Table 7: Examples of subcutaneous insulin regimens

REGIMEN TIMING AND DISTRIBUTION ADVANTAGES DISADVANTAGES ADUSTING DOSES Regimens that more closely mimic normal insulin secretion Insulin pump Basal delivery of URAA or RAA; Can adjust basal rates for varying insulin Most expensive regimen Mealtime insulin: if therapy: generally 40-60% of TDD sensitivity by time of day, for exercise, carbohydrate counting accurate, Must continuously wear one or for sick days change ICR if glucose after meal Hybrid closed Mealtime and correction: URAA more devices consistently out of target loop or RAA by bolus based on ICR Flexibility in meal timing and content Risk of rapid development of and/or correction (sensitivity Correction insulin: adjust ISF Low glucose Pump can deliver insulin in increments of ketosis, DKA with interruption factor and target glucose) and/or target glucose if suspend fractions of units of insulin delivery correction does not consistently CGM-augmented Potential for integration with CGM for Potential reactions to bring glucose into range open loop low-glucose suspend or hybrid closed- adhesives, site infections Basal rates: adjust based on loop BGM-augmented Most technically complex overnight, fasting, or daytime % Time in range highest and % time approach—harder for people glucose outside of activity of

below range lowest: hybrid closed loop > with lower numeracy or URAA/RAA bolus low glucose suspend > CGM- augmented literacy skills open loop > BGM-augmented open loop Multiple daily LAA once daily (detemir or Can use pens for all components At least four daily injections Mealtime insulin: if injections: glargine may require twice daily carbohydrate counting accurate, Flexibility in meal timing and content Most costly insulins dosing); generally 50% of TDD change ICR if glucose after meal LAA + flexible Insulin analogues cause less Smallest increments of insulin consistently out of target doses of URAA or Mealtime and correction: URAA hypoglycaemia than human insulins one unit (one-half unit with RAA at meals or RAA based on ICR and/or Correction insulin: adjust ISF some pens) correction (sensitivity factor and and/or target glucose if target glucose) LAAs may not cover strong correction does not consistently dawn phenomenon as well as bring glucose into range pump therapy LAA: based on overnight or Limited in terms of giving fasting glucose or daytime premeal doses, especially glucose outside of activity time- prelunch course or URAA or RAA injections

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REGIMEN TIMING AND DISTRIBUTION ADVANTAGES DISADVANTAGES ADUSTING DOSES Multiple daily injection regimens with less flexibility 4 injections daily Pre-breakfast: RAA ~20% of TDD May be feasible if unable to carb count Shorter duration RAA may lead Pre-breakfast RAA: based on with fixed doses to basal deficit during day; may BGM after breakfast or before Pre-lunch: RAA ~10% of TDD All meals have RAA coverage of N and RAA need twice-daily N lunch Pre-dinner: RAA ~10% of TDD N less expensive than LAAs Greater risk of nocturnal Pre-lunch RAA: based on BGM Bedtime: N ~50% of TDD hypoglycaemia with N after lunch or before dinner Requires relatively consistent Pre-dinner RAA: based on BGM mealtimes and carb intake after dinner or at bedtime Evening N: based on fasting or overnight BGM 4 injections daily Pre-breakfast: R ~20% of TDD May be feasible if unable to carb count Greater risk of nocturnal Pre-breakfast R: based on BGM with fixed doses hypoglycaemia with N after breakfast or before lunch Pre-lunch: R ~10% of TDD R can be dosed based on ICR and of N and R correction Greater risk of delayed post- Pre-lunch R: based on BGM after Pre-dinner: R ~10% of TDD meal hypoglycaemia with R lunch or before dinner All meals have R coverage Bedtime: N ~50% of TDD Requires relatively consistent Pre-dinner R: based on BGM Least expensive insulins mealtimes and carb intake after dinner or at bedtime

R must be injected at least 30 Evening N: based on fasting or minutes before meal for better overnight BGM effect Regimens with fewer daily injections Three injections Pre-breakfast: Morning insulins can be mixed in one Greater risk of nocturnal Morning N: based on pre-dinner daily: syringe hypoglycaemia with N than BGM ~40% N + ~15% R/RAA LAAs N+R or N+RAA May be appropriate for those who Morning R: based on pre-lunch Pre-dinner: cannot take injection in middle of day Greater risk of delayed post- BGM ~15% R/RAA meal hypoglycaemia with R Morning N covers lunch to some extent Morning RAA: based on post- than RAAs Bedtime: 30% N breakfast or pre-lunch BGM Same advantages of RAAs over R Requires relatively consistent

Least (N + R) or less expensive insulins mealtimes and carb intake than MDI with analogs Evening R: based on bedtime BGM

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REGIMEN TIMING AND DISTRIBUTION ADVANTAGES DISADVANTAGES ADUSTING DOSES Coverage of post-lunch glucose Evening RAA: based on Post- often sub-optimal dinner or bedtime BGM R must be injected at least 30 Evening N: based on fasting minutes before meal for better BGM effect Twice-daily “split- Pre-breakfast: Least number of injections for people Risk of hypoglycaemia in Morning N: based on pre-dinner mixed” with strong preference for this afternoon or middle of night BGM ~40% N + ~15% R or RAA from N N + R or N +RAA Insulins can be mixed in one syringe Morning R: based on pre-lunch

Fixed mealtimes and meal BGM Least (N+R) or less (N+RAA) expensive Pre-dinner: content insulins compared to analogs Morning RAA: based on post- ~30% N + ~15% R or RAA Coverage of post-lunch glucose breakfast or pre-lunch BGM Eliminates need for doses during the day often sub-optimal Evening R: based on bedtime Difficult to reach targets for BGM glycaemia without Evening RAA: based on post- hypoglycaemia dinner or bedtime BGM Evening N: based on fasting BGM

Abbreviations: N: NPH; R: regular; URAA: ultra-rapid-acting analogue; RAA: rapid-acting analogue; LAA: long-acting analogue; TDD: total daily insulin dose; CGM: continuous glucose monitoring; BGM: blood glucose monitoring; ICR: insulin-to-carbohydrate ratio; ISF: insulin sensitivity factor. DKA: diabetic ketoacidosis (263). Modified from: American Diabetes Association. Medical Management of Type 1 Diabetes (7th edition). Arlington, VA, 2017

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Table 8: Goal of Nutrition therapy for type 1 diabetes (114)

• Promote healthful eating patterns, emphasizing a variety of nutrient-dense foods in appropriate sizes to improve overall health and to:

o Improve HbA1C, blood pressure, cholesterol and aid in maintaining weight • Individualize nutrition needs based on personal and cultural preferences, health literacy, access to healthful food choices • Provide practical tools for day-to-day meal planning • Focus on matching insulin doses with meal composition through advanced carbohydrate counting

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Table 9: Adjunctive therapies for type 1 diabetes Metformin Pramlintide GLP-1 RA SGLT-2

HbA1c Reduction ~0.1% (1 mmol/mol) ~0.3% (3 mmol/mol) 0.2-0.3% (2-3 mmol/mol) 0.2-0.4% (2-4 mmol/mol)

Fasting Glucose Minimal Effect No Effect Minimal Effect Modest Decrease 15 mg/dl; 0.8 mmol/l Postprandial Minimal Effect Significant Decrease Modest Decrease Modest Decrease Glucose Time in Range No Data No Data No Data Increased (~12% at higher doses) Insulin Dose Unchanged Mealtime reductions Predominantly mealtime Mealtime and basal reductions reductions ~10% total reduction) Body Weight Modest (~1 kg) Modest (~1 kg) Significant (~5 kg) Moderate (2-3 kg) Systolic Blood No Change No Change 4 mmHg decrease (with 3-4 mmHg Decrease Pressure increase in heart rate)

Hypoglycaemia Potential increase in severe Increase in hypoglycaemia hypoglycaemia if prandial insulin doses are not decreased Side Effects GI side effects GI side effects GI side effects Genital mycotic infections Increase in ketosis Increased risk of DKA Approval Status for - US approved - EU approved low dose when type 1 diabetes in BMI ≥ 27 kg/m2 EU/US Specific groups for Women with polycystic Overweight and obesity whom treatment ovary syndrome High insulin dose may be of benefit Risk of cardiovascular and renal disease

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Figures and Legends

Figure 1: Flow chart for investigation of suspected type 1 diabetes in newly diagnosed adults, based on data from White European populations

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1: No single clinical feature confirms type 1 diabetes in isolation. The most discriminative feature is younger age at diagnosis (<35 years), with lower BMI (<25 kg/m2), unintentional weight loss, ketoacidosis, and glucose >360 mg/dL (20 mmol/L) at presentation also being informative. Other features classically associated with type 1 diabetes, such as ketosis without acidosis, osmotic symptoms, family history, or a history of autoimmune diseases are weak discriminators 2: Glutamic Acid Decarboxylase (GAD) should be the primary antibody measured and, if negative, should be followed by islet tyrosine phosphatase 2 (IA2) and/or Zinc transporter 8 (ZNT8) where available. In those diagnosed below the age of 35 years who have no clinical features of type 2 diabetes or monogenic diabetes, a negative result does not change the diagnosis of type 1 diabetes as 5-10% of people with type 1 diabetes do not have antibodies. 3: Monogenic diabetes is suggested by the presence of one or more of the following features: HbA1c <58mmol/mol (7.5%) at diagnosis, one parent with diabetes, features of specific monogenic cause (e.g. renal cysts, partial lipodystrophy, maternally inherited deafness, severe insulin resistance in the absence of obesity). Monogenic diabetes prediction model probability >5%: www.diabetesgenes.org/exeter-diabetes-app/ModyCalculator 4: Features of type 2 diabetes include overweight or obesity, absence of weight loss, absence of ketoacidosis, and less marked hyperglycaemia. Less discriminatory features include non- white ethnicity, family history, longer duration and milder severity of symptoms prior to presentation, features of the metabolic syndrome and absence of a family history of autoimmunity. 5: Type 2 diabetes should be strongly considered in older individuals. In some cases investigation for pancreatic or other types of diabetes may be appropriate. 6: A person with possible type 1 diabetes who is treated without insulin will require careful monitoring and education, so that insulin can be rapidly initiated in the event of glycaemic deterioration. Where a person is insulin treated, C-peptide must be measured prior to insulin discontinuation, to exclude severe insulin deficiency. 7: A C-peptide test is only indicated in people receiving insulin treatment. A random sample (with concurrent glucose) within 5 hours of eating can replace a formal stimulations test in the context of classification. If the result is ≥600 pmol/L the circumstances of testing do not matter. If result is <600 pmol/L and the concurrent glucose is <4 mmol/L (<72 mg/dl) or the person may have been fasting, consider repeating the test. Very low levels (<80 pmol/L) do not need to be repeated. Do not test C-peptide within 2 weeks of a hyperglycaemic emergency. 8: C-peptide values 200-600 pmol/L are usually consistent with type 1 diabetes or MODY, but may occur in insulin-treated type 2 diabetes, particularly in people with normal or low body mass index or after long duration. 9: If genetic testing does not confirm monogenic diabetes, the classification is unclear and a clinical decision should be made about treatment

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Figure 2: CGM visualization in an AGP-report. (Use AGP report from 2021 SOC)

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Figure 3: A framework for initial assessment and treatment of an individual with newly diagnosed type 1 diabetes. HbA1C: glycated haemoglobin; CGM: continuous glucose monitoring; BGM: blood glucose monitoring; TIR: time in rage; TBR: time below range; MDI: multiple daily injection. 1The availability of blood and urine ketone measurement varies across health care systems

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Figure 4: A framework for the follow-up treatment of an individual with type 1 diabetes. CGM: continuous glucose monitoring; DSMES: Diabetes self-management education and support; MDI: multiple daily injection. 1The availability of blood and urine ketone measurement varies across health care systems

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Figure 5: The four critical times when diabetes self-management education and support are particularly needed (add also when technology changing) DSMES: diabetes self-management education and support

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Figure 6: Choices of insulin regimens and glucose monitoring strategies in people with type 1 diabetes LAA: Long acting insulin analogue; RAA: rapid acting insulin analogue; URAA: ultra-rapid insulin analogue; NPH: neutral protamine Hagedorn

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Figure 7: Simplified overview of indications for beta cell replacement therapy in people with type 1 diabetes GFR: glomerular filtration rate

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