Japanese Clinical Practice Guideline for Diabetes 2019

The current guideline represents the 6th edition of the 'Japanese Clinical Practice Guideline for Diabetes' which has been revised every three years since its first appearance in 2004 to promote evidence-based, rational, efficient and consistent clinical practice in diabetes. Of note, dramatic progress has been made in recent years in diabetes research and clinical practice, which includes approval of antidiabetic agents with novel mechanisms of action along with publication of clinical trial results with these drugs, and novel diagnostic and therapeutic devices, such as continuous glucose monitoring (CGM) and sensor augmented pumps (SAP). Again, results from large-scale clinical trials in Japan, such as J-DOIT 1 to 3 and JDCP studies, have recently been reported. Further, in the last three years, new guidelines for lipid and blood pressure control have been released in a timely fashion from the Japan Atherosclerosis Society and the Japanese Society of Hypertension. Therefore, the current guideline has been compiled to include not only relevant advances in clinical practice but novel findings and new lines of evidence that have been made available to date. While the current guideline has been organized along similar lines to those of the preceding 2016 edition and using the same clinical questions (CQs) and questions (Qs) format, each CQ or Q has been closely reviewed for revision and further CQs or Qs have been added as appropriate to further promote the use of the guidelines in clinical practice. Readers are therefore referred to the 'Methods of developing the "Japanese Clinical Practice Guideline for Diabetes 2019"' for a detailed account of the guideline development processes involved to make effective use of the current guideline. It is hoped that the guideline will prove a helpful guide to evidence-based medicine (EBM) in clinical settings thereby contributing not only to prolongation of healthy lifespan but to improved quality of life in patients with diabetes. The guideline consists of general questions (cited as Qs) and clinical questions (cited as CQs) followed by explanations. Statements of recommendation were developed solely for CQs. Clinical guideline committee (CGC) members conducted systematic review (SR) of evidence from several resources to develop a statement of recommendation for CQs and presented a strength of recommendation rated as a grade. SR support team helped CGC members to make literature retrieval and confirm an evidence level for articles that they obtained. A brief criterion of the literature retrieval process was shown in this guideline. We referred to all the important articles necessary for the judgement of a statement and its strength of recommendation for CQs. Abstract tables were constructed solely for the articles necessary to recommend a statement for CQs. They contained relevant articles with PICO (Populations, Interventions, Comparators, Outcomes of interest), study design, and evidence level as defined in Table 1. The quality of evidence was also summarized based on 5 items for meta-analysis or systematic review, and 3 items for randomized controlled trial as shown in Table 1. The grade of recommendation was determined by each CGC member with consideration given to certainty of overall evidence, balance of benefits and harms, patient preferences/values, and costs (Table 2). Grades A and B stand for strong and weak recommendations, respectively. The CGC members reviewed and discussed all CQ guidelines. Votes were taken for each recommendation statement. A 75% agreement among eligible CGC members was required to approve each recommendation and its strength. Satisfies all of the following 5 items: Satisfies all of the following 3 items: I. Type 1 (Characterized by pancreatic β-cell destruction usually leading to absolute insulin deficiency) III. Diabetes due to some other specific mechanism or disease Individuals who have met the above criteria 1–3 are to be diagnosed with acute-onset (autoimmune) type 1 diabetes. Those who have met the above criteria 1, 2, and 4 are to be diagnosed with acute-onset type 1 diabetes. Those who have met the above criteria 1 and 2 but not 3 and 4 are to be re-evaluated after an interval with the diagnosis put on hold. Those who have met the criteria for fulminant type 1 diabetes are to be diagnosed as such. Some may lead to the onset of ketosis or ketoacidosis within about 1–2 weeks. The onset of fulminant type 1 diabetes may be associated with pregnancy. Exocrine pancreatic enzymes, e.g., amylase, lipase, and esterase 1, are shown to be elevated in 98% of affected individuals. Upper airway and gastrointestinal symptoms are noted in 70% of affected individuals. Fulminant type 1 diabetes is shown to be linked to HLA DRB1*04:05–DQB1*04:01. [Q2-3] How is the glycemic goal to be set for each individual patient? (Figure 5) Glucose levels in affected individuals are to be controlled as close to normal as possible. Achieving and maintaining favorable glycemic control early after initiation of treatment is likely to lead to favorable long-term outcomes in these individuals1. [Q2-4] How is the onset of chronic diabetic complications prevented or their progression delayed? Diabetes management is aimed not merely at glycemic control1 but also at ensuring continued smoking cessation and control of blood pressure and lipid levels, thereby preventing chronic diabetic complications or delaying their progression2-5. [CQ3-2] Is MNT education by registered dieticians effective? MNT education by registered dieticians is effective10, 11 (grade A: 95% agreement). As per the statement on target body weight vs total energy intake, for each patient, his/her target body weight and total energy intake is to be individually determined. Again, all values given below are primarily intended as suggested targets only and therefore need to be modified, as required, during patient consultation, in consideration of each patient's current body weight, glycemic control and other parameters. There is also a need for accumulating evidence for body weight and total energy intake determination. For elderly patients, the coefficient could be made larger than that associated with their actual level of physical activity to prevent them from developing frailty. Conversely, for obese patients in a weight loss program, the coefficient could be made lower than that associated with their actual level of physical activity. In either case, individuals whose actual body weight widely differs from their target body weight, the coefficient could be flexibly determined with consideration given to the levels of physical activity and corresponding energy coefficients to given above. Given that insulin is shown to have a wide-ranging action affecting not only glucose metabolism but lipid and protein metabolism, all of which are closely linked, energy-producing nutrients as components of MNT must be assessed for their balance and validity against each patient's disease condition, as well as associated risks including hyperglycemia. Furthermore, consideration is to be given not only to the safety of the dietary components but to Japanese cuisine culture and patient preferences, to ensure long-term implementation of MNT. However, there is no evidence available to support the effectiveness of any particular dietary nutrient ratios that contribute to long-term management of diabetes. To ensure long-term implementation of MNT in patients with diabetes, priority is to be given to honoring their eating habits and preferences thus allowing them to enjoy their meals as far as they do not defeat the purpose of MNT medically, while at the same time giving consideration to any potential risks associated with their individual diet regimens. Advantage: This Scr-based formula offers convenience by allowing renal function to be estimated with a blood test alone. With this formula, eGFR is likely to fall ± 30% of measured GFR (mGFR) in 75% of patients. Disadvantage: Adjusted for average body surface area (BSA) (1.73 m2), the formula is likely to be associated with a greater estimation error in patients of large and small build. The formula is also associated with overestimated values in patients with low muscle mass. Advantage: Secreted from all nucleated cells, cysteine C is thought less likely to be influenced by muscle mass or dietary content. Disadvantage: Adjusted for average BSA (1.73 m2), the formula is also likely to be associated with a greater estimation error in patients of large and small build. Subjective symptoms of diabetic polyneuropathy are characterized as: Findings of interest (diabetic neuropathy is to be confirmed if one of the following two has been met, despite failure to meet the criteria described above) [Q15-3] What is the office blood pressure threshold for initiating antihypertensive therapy in patients with diabetes? (Table 7, Figure 6) [CQ15-4] Is controlling office blood pressure to <130/80 mmHg effective in preventing the onset of complications in patients with diabetes and hypertension? (Figure 7) GDM is diagnosed if one or more of the following criteria have been met in a 75 g OGTT: ① Fasting blood glucose value ≥92 mg/dL ② 1-h post-OGTT glucose value ≥180 mg/dL ③ 2-h post-OGTT glucose value ≥153 mg/dL Overt diabetes in pregnancy is diagnosed if ① or ② below has been met: ① Fasting blood glucose value ≥126 mg/dL ② HbA1c ≥6.5% ① Diabetes mellitus diagnosed before pregnancy ② Pregnancy associated with unequivocal evidence of diabetic retinopathy <5.3 mmol/L*4 (<95 mg/dL) 1-h PPG <140 mg/dL Or 2-h PPG <120 mg/dL 1-h PPG <140 mg/dL Or 2-h PPG <120 mg/dL 1-h PPG <7.8 mmol/L (<140 mg/dL) Or 2-h PPG <6.4 mmol/L (115 mg/dL) [I-CQ-1] Is there any relationship between aging and impaired glucose tolerance? [I-CQ-2] What are the characteristics of diabetes in the elderly? [I-CQ-3] What are the complications associated with diabetes in the elderly? [II-CQ-1] Are the diagnostic criteria employed for diabetes in the elderly similar to those used for diabetes in adults? [II-CQ-2] Are elderly patients with diabetes susceptible to postprandial hyperglycemia? [II-CQ-3] Are elderly patients with diabetes susceptible to hyperosmolar hyperglycemic state (HHS)? [II-CQ-4] How is hypoglycemia characterized in elderly patients with diabetes? [II-CQ-5] Are elderly patients with diabetes associated with drug-related adverse events? [II-CQ-6] Is diabetes in the elderly associated with an increased incidence of atherosclerotic disease? [II-CQ-7] Is the risk of mortality increased in elderly patients with diabetes compared to that in those without? [II-CQ-8] Are elderly patients with diabetes likely to be associated with cognitive impairment or dementia? [II-CQ-9] What psychological states need to be watched for in elderly patients with diabetes? [II-CQ-10] Are elderly patients with diabetes associated with impairment of physical function? [III-CQ-1] What do elderly patients with diabetes need to be assessed for? [III-CQ-2] Why do elderly patients with diabetes need to be assessed for cognitive function? [III-CQ-3] How are elderly patients with diabetes screened for cognitive impairment? [III-CQ-4] How are elderly patients with diabetes assessed for physical function? [IV-CQ-1] What complications should elderly patients with diabetes be assessed for? [IV-CQ-2] Should elderly patients with diabetes be referred to an ophthalmologist for assessment of diabetic retinopathy? [IV-CQ-3] Should elderly patients with diabetes be assessed regularly for urinary albumin/protein values and estimated glomerular filtration rates (eGFR)? [IV-CQ-4] How are elderly patients with diabetes assessed for diabetic neuropathy and cared for? [IV-CQ-5] What infections are elderly patients with diabetes susceptible to? Summary [IV-CQ-6] Are these infections amenable to prevention with pneumococcal and influenza vaccines? [V-CQ-1] Is diabetes or hyperglycemia a likely risk factor for cognitive impairment or onset of dementia in the elderly? [V-CQ-2] Is severe hypoglycemia a likely risk factor for cognitive impairment or onset of dementia in the elderly? [V-CQ-3] Is tight glycemic control effective in reducing cognitive impairment or dementia in elderly patients with diabetes? [VI-CQ-1] Is hyperglycemia a likely risk factor for decreased ADL, sarcopenia, and falls/fractures in elderly patients with diabetes? [VI-CQ-2] Is low HbA1c or hypoglycemia a likely risk factor for falls/fractures or frailty in elderly patients with diabetes? [VI-CQ-3] Is glycemic control effective in maintaining ADL in elderly patients with diabetes? [VI-CQ-4] Is diabetes or hypoglycemia a likely risk factor for depression (depression or depressive tendency) in the elderly? [VII-CQ-1] Is glycemic control effective in inhibiting the onset or progression of complications in elderly patients with diabetes? [VII-CQ-2] Is glycemic control effective in preventing infections in elderly patients with diabetes? [VII-CQ-3] Is there any relationship between HbA1c values and the onset of macroangiopathy or mortality? [VII-CQ-4] Should tight glycemic control be implemented in elderly patients with diabetes? [VII-CQ-5] What are the considerations to be kept in mind in determining the glycemic control goal for elderly patients with diabetes? [VIII-CQ-1] Is MNT as effective for elderly patients with diabetes as for non-elderly patients? [VIII-CQ-2] What are the considerations to be kept in mind in determining adequate energy intake at initiation of therapy for elderly patients with diabetes? * While the term 'ideal body weight' was used in this section of the Japanese version of the current Guidelines in reference to the Clinical Practice Guidelines for the Management of Diabetes in the Elderly 2017, the term 'target body weight' is used, instead of 'ideal body weight', to ensure consistency with that used in the Chapter 3 on Medical nutrition therapy (MNT) of the current English-language version. [VIII-CQ-3] What are the considerations to be kept in mind in determining adequate carbohydrate, protein and lipid intakes for elderly patients with diabetes? [VIII-CQ-4] Is dietary sodium (salt) restriction effective for elderly patients? [VIII-CQ-5] Is there any relationship between vitamin/fatty acid intake and cognitive impairment in elderly patients with diabetes? [VIII-CQ-6] Is there any dietary pattern recommended for elderly patients with diabetes? [VIII-CQ-7] Is there any relationship between inadequate vitamin D/calcium intake and bone mineral density (BMD)? [VIII-CQ-8] How are elderly patients with diabetes assessed for undernutrition? [IX-CQ-1] Is physical activity/exercise effective in improving glycemic control, cognitive function, ADL, depression and QOL in elderly patients with diabetes? [X-CQ-1] What are the precautions to be kept in mind when implementing glucose-lowering therapy in elderly patients with diabetes? [X-CQ-2] Is the use of sulfonylureas (SUs) likely to cause hypoglycemia in elderly patients with diabetes? [X-CQ-3] Does metformin reduce cardiovascular death in elderly patients with diabetes? [X-CQ-4] Is metformin a risk factor for lactic acidosis in elderly patients with diabetes? [X-CQ-5] What are the precautions to be kept in mind when using oral hypoglycemic agents other than SUs or metformin, as well as GLP-1 receptor agonists, in elderly patients with diabetes? [X-CQ-6] Is multi-drug combination therapy a risk factor for hypoglycemia or falls in elderly patients with diabetes? [XI-CQ-1] What are the precautions to be kept in mind when implementing insulin therapy in elderly patients with diabetes? [XII-CQ-1] Are hypoglycemic symptoms in elderly patients with diabetes similar to those in younger adults? [XII-CQ-2] What are the risk factors for hypoglycemia in elderly patients with diabetes? [XII-CQ-3] What are the precautions against diabetes sick days characterized by the onset of fever, diarrhea, vomiting and decreased appetite? [XIII-CQ-1] Is antihypertensive management effective in reducing the onset or progression of diabetic microangiopathy and macroangiopathy in elderly patients with diabetes? [XIII-CQ-2] Is antidyslipidemic management effective in reducing the onset or progression of macroangiopathy in elderly patients with diabetes? [XIV-CQ-1] Is diabetes in elderly patients a likely risk factor for nursing home institutionalization? [XIV-CQ-2] What are the characteristics of institutionalized elderly patients with diabetes? [XV-CQ-1] What are the precautions to be kept in mind in providing terminal care for elderly patients with diabetes? [Q21-1] How are patients assessed to determine their risk of type 2 diabetes? Various risk factors have been identified for type 2 diabetes, and a risk model (risk scores) is currently being developed for type 2 diabetes in Japanese1-3. Eiichi Araki received honoraria from AstraZeneca, Daiichi Sankyo, Kowa, Mitsubishi Tanabe Pharma, MSD, Novo Nordisk, Ono Pharmaceutical and Sanofi, also received subsidies or donations from Astellas Pharma, Bayer Yakuhin, Daiichi Sankyo, Eli Lilly Japan, Kowa, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Novartis Pharma, Novo Nordisk, Pfizer Japan, Sanofi, Sumitomo Dainippon Pharma, Taisho Pharmaceutical and Takeda Pharmaceutical, and belongs to endowed departments by MSD, Ono Pharmaceutical and Terumo. Mitsuhiko Noda received subsidies or donations from Astellas Pharma, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly Japan, Mitsubishi Tanabe Pharma, MSD, Novo Nordisk Pharma, Ono Pharmaceutical, Sumitomo Dainippon Pharma, Takeda Pharmaceutical and Teijin Pharma. Hiroshi Noto received honoraria from Eli Lilly Japan and MSD. Haruhiko Osawa received research funding from Daiichi Sankyo, Ono Pharmaceutical, Sysmex, Taisho Toyama Pharmaceutical and Takeda Pharmaceutical. Yukio Tanizawa received honoraria from Astellas Pharma, MSD, Novo Nordisk Pharma, Ono Pharmaceutical and Takeda Pharmaceutical, also received research funding from Seastar, also received subsidies or donations from Astellas Pharma, Daiichi Sankyo, Eli Lilly Japan, Kyowa Kirin, Mitsubishi Tanabe Pharma, MSD, Nippon Boehringer Ingelheim, Sanofi, Sumitomo Dainippon Pharma and Takeda Pharmaceutical. Kazuyuki Tobe received honoraria from Novo Nordisk Pharma, Kowa Pharmaceutical and Astellas Pharma, also received research funding from The Uehara Memorial Foundation and The Naito Foundation, also received subsidies or donations from Mitsubishi Tanabe Pharma, Takeda Pharmaceutical, Daiichi Sankyo, MSD, Asahi Kasei Pharma, Teijin Pharma, Boehringer Ingelheim, Ono Pharmaceutical, Novo Nordisk Pharma, Eli Lilly Japan, Fuji Chemical Industries and Arkray. Narihito Yoshioka received honoraria from Novo Nordisk Pharma and Takeda Pharmaceutical. Atsushi Goto, Tatsuya Kondo, Hideki Origasa, Akihiko Taguchi have nothing to declare. The Japan Diabetes Society: Organizational Conflict of Interest Co-sponsored seminar: Abbott Diagnostics Medical, Abbott Japan, Abbott Vascular Japan, Aegerion Pharmaceuticals, Ajinomoto, AR Brown, Arkray, Arkray Global Business, Asahi Kasei Pharma, ASKA Pharmaceutical, Astellas Pharma, AstraZeneca, Bayer Yakuhin, Cosmic Corporation, Covidien Japan, Daiichi Sankyo, Eiken Chemical, Eizai, Eli Lilly Japan, Fujifilm Pharma, Fujifilm Toyama Chemical, Fukuda Colin, Fukuda Denshi, Gilead Sciences, Hakubaku, Healthy Network, Hitachi Chemical Diagnostics Systems, Horiba, InBody Japan, Johnson & Johnson, Kaken Pharmaceutical, Kissei Pharmaceutical, Kotobuki Pharmaceutical, Kowa, Kracie Pharmaceutical, Kyowa Kirin, LifeScan Japan, LSI Medience, Medtronic Japan, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Mylan EPD, Nikkiso, Nippon Becton Dickinson, Nippon Boehringer Ingelheim, Nipro, Novartis Pharma, Novo Nordisk Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Rizap Group, Roche DC Japan, Sanofi, Santen Pharmaceutical, Sanwa Kagaku Kenkyusho, SRL, Sumitomo Dainippon Pharma, Taisho Pharma, Taisho Pharmaceutical, Takeda Pharmaceutical, Terumo, Unex, Welby. Supporting member: Abbott Japan, Arkray Global Business, Astellas Pharma, AstraZeneca, Bunkodo, Chugai Pharmaceutical, Daiichi Sankyo, EA Pharma, Eizai, Eli Lilly Japan, H + B Life Science, Horiba, Japan Tobacco, Johnson & Johnson, Kaken Pharmaceutical, Kissei Pharmaceutical, Kowa, Kyowa Kirin, LifeScan Japan, Medtronic Japan, Mitsubishi Tanabe Pharma, MSD, Nippon Boehringer Ingelheim, Nipro, Novo Nordisk Pharma, Ono Pharmaceutical, PHC, Roche DC Japan, Sanofi, Sanwa Kagaku Kenkyusho, Sekisui Medical, Shionogi, SRL, Sumitomo Dainippon Pharma, Sysmex, Taisho Pharma, Taisho Pharmaceutical, Takeda Pharmaceutical, Terumo, Tosoh. Research grant: Abbott Japan, Eli Lilly Japan, MSD, Nippon Boehringer Ingelheim, Novo Nordisk Pharma, Sanofi, Takeda Pharmaceutical. Award system: Eli Lilly Japan, Novo Nordisk Pharma, Sanofi. Funding statement: The society received no specific funding for this work. The article does not contain any studies with human or animal subjects performed by any of the authors. In recent years, clear evidence has emerged from multiple meta-analyses of the available data including those from the Japanese population to demonstrate the between diabetes and In the Diabetes and the Society released their on the relationship between diabetes and from the Japan Diabetes Society and the Japanese a the first in which its for and as well as for the general The its of the on Diabetes and in To a of studies have the between diabetes and diabetes the type 2 is to be associated with an increased risk of and as well as a risk of mechanisms of in diabetes include insulin and associated hyperglycemia and chronic However, diabetes is a risk factor for to be the between glucose-lowering agents and the risk to be is thought to be that priority be given to the benefits of favorable glycemic control with these with due given to the contained in their The of the on Diabetes and this and the of glycemic control on the risk of in patients with that there is no evidence at to the between glycemic control and risk in patients with diabetes. It is that patients with and diabetes are associated with and long-term life than patients with It is also shown that diabetic patients with are less likely to therapy than patients with with and with pancreatic and diabetes whose HbA1c is or have a lower than those whose HbA1c is less than strength is determined by bone mineral density and bone The is determined by the of bone mineral in bone and the is determined by factors including bone and in bone strength is associated with an increased risk of bone The risk of developing is increased by about to in patients with type 1 patients are characterized by decreased bone mineral but the risk of bone is It is that bone quality as well as decreased bone mineral density for decreased bone strength. The of bone quality is more in patients with type 2 diabetes than those with type 1 diabetes. The risk of developing is shown to be increased to to in those with type 2 they have greater bone mineral density than those with type 1 A meta-analysis of randomized controlled trials patients with type 2 diabetes and those not e.g., that the risk of is increased to among those The risk is shown to be increased to among but not no has been about the risk of associated with the use of GLP-1 receptor agonists, metformin, or A of data from no in or with the use of between patients with type 2 diabetes and is and and for of all performed in Japan and the of the from the and performed in Japan as of the of a of with the and rates of and respectively. is a of that from a the of a is performed on patients with diabetes shown to have severe hypoglycemia despite diabetes may not its to insulin therapy for of is to reduce the of hypoglycemia and glucose values by glycemic from were conducted to a total of patients with the between 2004 and in As in studies, HbA1c was and severe hypoglycemia among those with While the need for multiple and of long-term were among the with the of which consists of with or an receptor followed by therapy with a and an or an was to lead to the from insulin therapy in all patients with type 1 diabetes from each In Japan, from was as a of care B in patients with severe hypoglycemic a similar to that of of and is currently being implemented as to the on of and the Japan Diabetes 1 was conducted to the effectiveness of in individuals at risk of diabetes in preventing diabetes. Of the in the individuals those with impaired glucose years were identified and to the and the of the study followed all subjects for years on average by of and and no in incidence of diabetes between the and but a lower incidence among those per than among those such 3 or per in the when at each study The Diabetes 2 was an study intended to to by patients with type 2 diabetes. The implemented in the study patients who were being by their to providing and their in their The results of the study that decreased by that the were In a total of patients with type 2 diabetes and to years were to current treatment therapy HbA1c blood pressure <120 mg/dL mg/dL in those with a of cardiovascular or to treatment aimed at more control therapy HbA1c blood pressure mg/dL mg/dL in those with a of cardiovascular of years, the of the study were by in the therapy while this was not from that in the therapy but were by after for all such as smoking compared to that in the therapy The JDCP study was a large-scale study of Japanese patients with type 1 and type 2 diabetes. The study was conducted to the risk factors for that they develop during The JDCP study a total of patients, years of who were being at between and The of the study the of and in the of the study are currently being reviewed by the involved in the A large-scale to be in an to patients with diabetes are being currently and diabetic complications may as a as well as to improved diabetes care and with these in a large-scale has been since as a between the Japan Diabetes Society and the for Global and the of diabetes education the of a total of and other have in the with the of patients registered some of or more patients have type 1 diabetes. 1