Guidelines for diabetes mellitus: from the perspective of diagnosis and treatment

Transcription

1 REVIEW ARTICLES Guidelines for diabetes mellitus: from the perspective of diagnosis and treatment Tomoko Nakagami 1 Yasuko Uchigata 1 1 Diabetes Center, Tokyo Women s Medical University School of Medicine ABSTRACT There are two major guidelines in the field of diabetes created under the supervision of the Japan Diabetes Society: Treatment Guide for Diabetes and Evidence-based Practice Guideline for the Treatment of Diabetes in Japan. Both are commonly used in various clinical settings related to diabetes in the country. Since the revision of diagnostic criteria of diabetes in 2010 and the global standardization of HbA1c in 2012, the aggressive use of glycated hemoglobin (HbA1c) is recommended in the diagnostic screening of diabetes in Japan, because much clinical and epidemiological data showed that the early identification and treatment of diabetes is beneficial in preventing diabetic complications and mortality. In particular, the guideline recommends the simultaneous measurement of glucose as well as HbA1c, to avoid delays or misclassifying people. Moreover, a patient-centered approach is strongly recommended. The guidelines do not include a specific regime of medications, but recommend the individualized selection of medicine based on pathophysiology and living conditions such as age, hypoglycemia, and comorbidity. Based on these considerations, three levels of HbA1c (<6, 7, and 8%) are adopted and HbA1c <7% is now widely known as a new treatment target with respect to diabetic complications. As introduced, the treatment guidelines have been updated repeatedly according to the progress of diagnosis and treatment of diabetes. However, the objectives of treatment for diabetes are consistent, which are to maintain a quality of life similar to that of healthy people, and to ensure a normal life expectancy in people living with diabetes. (HEP. 2014; 41: ) Key words guideline, diabetes, screening, diagnosis, treatment Introduction The major guideline in the field of diabetes created under the supervision of the Japan Diabetes Society is Treatment Guide for Diabetes 1), which is based on the data found in another guideline, Evidence-based Practice Guideline for the Treatment of Diabetes in Japan 2). Due to lack of space, this article focuses only on the recent revisions of the guidelines. Treatment Guide for Diabetes 1) can be used for current medical practice. The Guide was revised following the 2012 revision of the diagnostic criteria for diabetes mellitus using hemoglobin A1c (HbA1c), and the change in the goal of diabetes treatment in A further revision regarding sodium-glucose cotransporter 2 (SGLT-2) inhibitor, a new antidiabetic drug, will be made in Public comments on the revision are being collected as of February Although the treatment guidelines have been updated repeatedly to reflect progress in diagnosis and treatment, the aims of treatment for diabetes are consistent: to maintain a quality of life similar to that of healthy people, and to ensure a normal life expectancy. Received: April 2, 2014, Accepted: May 9, 2014 Corresponding author: Tomoko Nakagami 1 Address; Diabetes Center, Tokyo Women s Medical University School of Medicine 8-1 Kawada-cho, Shinjuku-ku, Tokyo , Japan TEL: , FAX: nakagami@dmc.twmu.ac.jp Guidelines on diagnostic criteria for diabetes mellitus New diagnostic criteria for diabetes mellitus were established in The differences between the previous criteria and the new criteria are as follows: HbA1c, which was previously used as a supplementary item, has become a superordinate criterion, and the diagnosis of diabetes mellitus can be made earlier using HbA1c in addition to blood glucose levels. More specifically, if any of the following four criteria is met, which include three items of blood glucose levels used in the previous criteria, the patient is considered to have a diabetic pattern : (1) fasting plasma glucose (FPG) of 126 mg/dl or higher; (2) 2-hour plasma glucose (2-h PG) followed by a 75 g oral glucose tolerance test (OGTT) of 200 mg/dl or higher; (3) random blood glucose level of 200 mg/dl or higher; and an additional criterion, (4) HbA1c of 6.5% or higher. If a retest on another day shows the diabetic pattern, diabetes is diagnosed (Fig. 1). Unlike the previous criteria, if both measurements of the blood glucose level and HbA1c in samples taken on the same day show a diabetic pattern, diabetes is diagnosed without any retest according to the new criteria. The new guideline recommends measuring blood glucose levels and HbA1c on the same day as it enables early diagnosis of diabetes mellitus. It should be noted that diabetes mellitus cannot be diagnosed based on the results of repeated measurements of only HbA1c; blood glucose levels must also be measured for such a diagnosis. HbA1c level is expressed using National Glycohemoglobin Standardization Program (NGSP) values, HEP Vol.41, No.4, 2014 (533) 21

2 Fig. 1 Flow diagram of diagnosis of diabetes. Adapted from ref 3. Fig. 2 Relationship between fasting plasma glucose and HbA1c in Hiroshima A-bomb survivors. Adapted from ref 4. which are calculated by the formula: NGSP value (%)=1.02 Japan Diabetes Society (JDS) value (%) +0.25%. Evidence for the cutoff point of HbA1c of 6.5% has been verified using data from people undergoing medical check-ups. In 6,000 or more Japanese people without known diabetes who underwent medical checkups, verification by linear regression analysis (Fig. 2) showed that FPG of 126 mg/dl corresponded to HbA1c of 6.5% 3), and 2-h PG in OGTT of 200 mg/dl corresponded to HbA1c of around 6.4% 4). Using the same data source, correlation between the prevalence of diabetic retinopathy and HbA1c was studied and the result showed that the risk of diabetic retinopathy was significantly increased when HbA1c was 6.5% or higher 3). Also, our analysis of individuals who underwent medical check-ups showed that the prevalence/risk of retinopathy was significantly increased when HbA1c was 6.5% or higher, which was independent of blood pressure (Fig. 3) 5). However, there are some issues when using HbA1c as an item in medical check-ups. First, it has been widely reported that HbA1c may not reflect the average blood glucose Fig. 3 Relationship between the prevalence of retinopathy and HbA1c in a Japanese general population: The Kurihashi Lifestyle Cohort Study. Adapted from ref 5. Table 1 Disorders and conditions associated with low HbA1c values Anemia Liver disease Dialysis Major hemorrhage Blood transfusion Chronic malaria Hemoglobinopathy Others level in some diseases or conditions (Table 1). Additionally, in 75 g OGTT (the gold standard for diagnosing diabetes), when FPG was compared with 2-h PG for diagnosing diabetes, the diagnostic result based on FPG was not consistent with the result based on 2-h PG. It has been reported that many patients were considered to show a diabetic pattern based on 2-h PG alone 6) and that in some patients with 2-h PG in the diabetic range, FPG remained in the non-diabetic range although HbA1c was much 22 (534) HEP Vol.41, No.4, 2014

3 Nakagami et al.: Guidelines for diabetes mellitus Mean±SE Fig. 4 Impact of diagnostic category on 75 g oral glucose tolerance test on HbA1c: The DECODA Study. Adapted from ref 7. lower than 6.5% 7) (Fig. 4). Therefore, the Diabetes Society recommends that 75 g OGTT should be used in specific populations. In the populations for which 75 g OGTT is strongly recommended, 75 g OGTT should be performed whenever possible to detect latent diabetes. The goal and guidelines of treatment for diabetes mellitus The new target values for control of blood glucose levels were announced in 2013 (Table 2). For all adults except pregnant women, the guideline recommends three HbA1c target ranges depending on the treatment purpose or patient s condition: less than 6.0%, less than 7.0%, and less than 8.0%. As the target ranges were established to prevent complications, HbA1c of less Table 2 Glycemic control objectives. Adapted from ref 1. Fig. 5 Glycemic control and incidence and prevalence of retinopathy in Japanese patients with type 2 diabetes: The Kumamoto Study. Adapted from ref 8. HEP Vol.41, No.4, 2014 (535) 23

4 Fig. 6 A meta-analysis of the relationship between severe hypoglycemia and the risk of death from cardiovascular diseases. Adapted from ref 18. than 7.0% was emphasized, and was adopted in the Declaration of Kumamoto 2013 in May In the Kumamoto Study 8), an intervention study of diabetic complications in 110 Japanese patients with type 2 diabetes mellitus, onset or progress of diabetic retinopathy was significantly better prevented in the conventional insulin therapy group than in the intensive insulin therapy group. It was also found that diabetic microvascular complications are unlikely to occur if HbA1c is less than 6.9% (Fig. 5). The target HbA1c has been set at less than 7.0% because it was set at less than 7.0% in the intensive therapy group in the Diabetes Control and Complication Study (DCCT) 9), a large-scale study on the prevention of vascular complications in patients with type 1 diabetes in the U.S., and in the United Kingdom Prospective Diabetes Study (UKPDS) 10), a large-scale study on the prevention of vascular complications in newly diagnosed patients with type 2 diabetes in the United Kingdom. Both studies reported that significantly more microvascular complications were prevented in the intensive therapy group than in the standard therapy group. Also, a target HbA1c of 7% in other countries was taken into consideration. Based on the result of the Kumamoto Study, FPG of less than 130 mg/dl and 2-h postprandial blood glucose level of less than 180 mg/dl, which correspond to HbA1c of less than 7%, have been adopted. The target HbA1c for glycemic control was set at less than 6.0% because the risks for both microangiopathy and macroangiopathy were lower when HbA1c was 6.0% or lower in the UKPDS 11). However, it is emphasized that HbA1c of less than 6.0% should be used as the target value only if it can be achieved with appropriate dietary modification and exercise without other pharmacologic therapies, or in the absence of adverse effects such as hypoglycemia in the setting of pharmacologic therapy. If it is difficult to achieve the target value with intensive treatment because of adverse effects such as hypoglycemia or other reasons, an HbA1c target of less than 8.0% has been adopted. This target was set because the risk of retinopathy was greatly increased when HbA1c was more than 8.0% in the DCCT 12), and when the median HbA1c was 7.9% (and microvascular complications occurred more frequently) in the conventional therapy group in the UKPDS 10). Guidelines for diabetes in Japan, unlike the guidelines in Europe and the U.S., placed emphasis on tailored therapy, though this was not clearly stated. The American Diabetes Association and the European Association for the Study of Diabetes declared the Patient Centered Approach in , 14). Three prior large-scale clinical studies on type 2 diabetes, Action to Control Cardiovascular Risk in Diabetes (ACCORD) 15), Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) 16), and Veterans Affairs Diabetes Trial (VADT) 17), and a subsequent metaanalysis 18) reported that severe hypoglycemia increased the risk of cardiovascular disease by twofold or more (Fig. 6). In particular, elderly people are unable to easily recognize hypoglycemia, and hypoglycemia-related complications, including aggravation of symptoms of depression, dementia, fracture after a fall, myocardial infarction and stroke, have been problems. Therefore, the guideline states that the treatment goal should be tailored to the patient s age, disease duration, organ dysfunction, risk of hypoglycemia, support system, etc., and it recommends treatment that matches the patient s circumstances rather than standard treatment. The initial management is dietary modification and exercise. If the target blood glucose level cannot be achieved with non pharmacologic therapy, drug therapy can be used. Currently, various drugs are on the market, and it is important to select suitable ones according to the clinical condition of individual patients. There are differences between the guidelines in Japan and those in Europe and the U.S. 13, 14). Metformin is the first-line drug in Europe and the U.S. because it is supported by substantive evidence, is safe and cheap, and has other beneficial effects such as cancer prevention. In Japan, the guidelines do not specify metformin or other drugs as the first-line drug because there are racial differences in the clinical condition of diabetes, and all available drugs are listed without a preferential ranking because it is important to select the most suitable drug based on the patient s clinical condition and symptoms (Fig. 7). In the 2013 version of the 24 (536) HEP Vol.41, No.4, 2014

5 Nakagami et al.: Guidelines for diabetes mellitus Fig. 7 Combination therapy of oral hypoglycemic agents: choice of oral hypoglycemic agents according to patient s disease condition. Adapted from ref 1. Japanese guidelines, dipeptidyl peptidase 4 (DPP-4) inhibitors as an agent that promotes insulin secretion were added. SGLT-2 inhibitors will also be added in the 2014 version or a later version. There has been a major change in the diagnosis and treatment of diabetes with the international standardization of HbA1c. In addition to the JDS value, the NGSP value has also been used together with the JDS value since It is recommended that the result of specific medical check-ups be expressed as an NGSP value alone from April 2013, and the JDS value will replace the NGSP value completely from April Recent notable topics Food Exchange Lists Dietary Guidance for Persons with Diabetes version 7 19) was published in The revised version has attracted attention because the Diabetes Society expressed their opinion about a recent notable topic, low-carbohydrate diets, in the book. The restriction of fats and carbohydrates for obese patients with type 2 diabetes and for the prevention of cardiovascular diseases has been studied and discussed for a long time in Western countries. However, it has been suggested that it is difficult to identify the effects of a specific nutrient on health because the effects of increased intake of proteins or fats caused by restriction of carbohydrates have not been studied and there are many confounding factors. Therefore, intake of carbohydrates is set at 50-60% in guidelines in the U.S., Canada, and Europe, etc. 20), and is set at 55-65% in an evidence-based recommendation based on an analysis of randomized controlled trials. It was reported that low-carbohydrate and high-protein diets led to arteriosclerosis, and a meta-analysis showed that a low-carbohydrate diet increased the overall risk of mortality in 272,216 patients without diabetes 21). However, there is not enough evidence in Japan and there is no consensus on the lower limit of intake of carbohydrates, and the intake of 60% or less seems to be appropriate. More specifically, the recommended proportions of the three major nutrients to total intake in patients with diabetes (except in stage II or more advanced nephropathy) are not biased toward any specific nutrient; similar to the current average proportion in Japanese, the proportion of carbohydrates to total calories has been set at 50-60%, that of proteins at 20%, and that of fats at 25%. Essentially, in dietary modification for type 2 diabetes, the total calorie intake is adjusted to optimize body weight and to prevent the symptoms of diabetes as well as hyperglycemia. Insulin plays a role not only in glucose metabolism but also fat and protein metabolism. These processes are closely linked to each other, and all aspects of dietary modification should be verified, as well as blood glucose control, in different disease conditions. Additionally, a revision of the staging of diabetic nephropathy was conducted in early ). The disease stage (stage I-V nephropathy) in diabetic nephropathy had been determined based on both urinary protein (albumin) and glomerular filtration rate (GFR). Stage III nephropathy (constant proteinuria stage) had been divided into the early stage or late stage of overt nephropathy. However, in the revised guideline, GFR was replaced with estimated glomerular filtration rate (egfr), with egfr of 30 mg/g Cr or higher classified as stage I-III nephropathy depending on urinary albumin amount, egfr of less than 30 mg/g Cr classified as stage IV, and disease requiring dialysis classified as stage V (Fig. 8). This classification is based on a report showing that when egfr was 30 mg/g Cr or higher, cardiovascular disease HEP Vol.41, No.4, 2014 (537) 25

6 Fig. 8 Classification of diabetic nephropathy. Adapted and translated from ref 22. and overall risk of death were increased with an increase in the amount of urinary albumin. However, when egfr of less than 30 mg/g Cr, cardiovascular disease and overall risk of death were not influenced by amount of urinary albumin and increased with deterioration of egfr 23). Summary Treatment Guide for Diabetes and Evidence-based Practice Guideline for the Treatment of Diabetes in Japan are two major guidelines for diabetes mellitus. The guidelines are repeatedly revised as the need arises. The guidelines aim to facilitate the early diagnosis of diabetes and recommend early treatment to prevent diabetic complications. Meanwhile, an individualized approach and treatment according to the patient s circumstances have been increasingly emphasized, and further revisions may be made accordingly. The authors state that they have no Conflict of Interest (COI). REFERENCES 1) Treatment Guide for Diabetes : Edited by the Japan Diabetes Society, Tokyo, Bunkodo, ) Evidence-based Practice Guideline for the Treatment of Diabetes in Japan 2013: Edited by the Japan Diabetes Society, Tokyo, Nankodo, ) Seino Y, Nanjo K, Tajima N, Kadowaki T, Kashiwagi A, Araki E, Ito C, Inagaki N, Iwamoto Y, Kasuga M, Hanafusa T, Haneda M, Ueki K: Report of the Committee on the Classification and Diagnostic Criteria of Diabetes Mellitus. Journal of the Japan Diabetes Society: 53: , ) Ito C, Maeda R, Ishida S, Sasaki H, Harada H: Correlation among fasting plasma glucose, two-hour plasma glucose levels in OGTT and HbA1c. Diabetes Res Clin Pract: 50: , ) Fukushima S, Nakagami T, Suto C, Hirose A, Uchigata Y: Prevalence of retinopathy and its risk factors in a Japanese population. J Diabetes Invest: 4: , ) Qiao Q, Nakagami T, Tuomilehto J, Borch-Johnsen K, Balkau B, Iwamoto Y, Tajima N: International Diabetes Epidemiology Group; DECODA Study Group. Diabetologia: 43: , ) The DECODA Study Group on behalf of the International Diabetes Epidemiology Group: Cardiovascular risk profile assessment in glucose intolerant Asian individuals-an evaluation of the World Health Organization two-step strategy: the DECODA Study (Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Asia). Diabetic Med: 19: , ) Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract: 28: , ) Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B: Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. N Engl J Med: 353: , ) UK Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet: 352: , ) Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR: Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ: 321: , ) The Diabetes Control and Complications Trial (DCCT) Research Group: The absence of a glycemic threshold for the development of long-term complications: the perspective of the Diabetes Control and Complications Trial. Diabetes: 45: , ) Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR: American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care: 35: , ) Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR: Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia: 55: , ) Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, 26 (538) HEP Vol.41, No.4, 2014

7 Nakagami et al.: Guidelines for diabetes mellitus Probstfield JL, Simons-Morton DG, Friedewald WT: Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med: 358: , ) ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F: Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med: 358: , ) Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD: VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med: 360: , ) Goto A, Arah OA, Goto M, Terauchi Y, Noda M: Severe hypoglycaemia and cardiovascular disease: systematic review and metaanalysis with bias analysis. BMJ: 347: f4533, ) Food Exchange Lists-Dietary Guidance for Persons with Diabetes, ver. 7: Edited by the Japan Diabetes Society, Tokyo, Bunkodo, ) Anderson JW, Randles KM, Kendall CW, Jenkins DJ: Carbohydrate and fiber recommendations for individuals with diabetes: a quantitative assessment and meta-analysis of the evidence. J Am Coll Nutr: 23: 5-17, ) Noto H, Goto A, Tsujimoto T, Noda M: Low-carbohydrate diets and all-cause mortality: a systematic review and meta-analysis of observational studies. PLoS One: 8: e55030, ) Joint Committee on Diabetic Nephropathy: Revised staging of diabetic nephropathy. The Japan Diabetes Society, (Accessed June 18, 2014, F6E F F E672E706466) (in Japanese). 23) Wada T, Haneda M, Furuichi K, Babazono T, Yokoyama H, Iseki K, Araki SI, Ninomiya T, Hara S, Suzuki Y, Iwano M, Kusano E, Moriya T, Satoh H, Nakamura H, Shimizu M, Toyama T, Hara A, Makino H: The Research Group of Diabetic Nephropathy, Ministry of Health, Labour, and Welfare of Japan. Clinical impact of albuminuria and glomerular filtration rate on renal and cardiovascular events, and all-cause mortality in Japanese patients with type 2 diabetes. Clin Exp Nephrol. DOI /s [Epub ahead of print]. HEP Vol.41, No.4, 2014 (539) 27