Standards of medical care for type 2 diabetes in China 2019

The prevalence of diabetes in China has increased rapidly from 0.67% in 1980 to 10.4% in 2013, with the aging of the population and westernization of lifestyle. Since its foundation in 1991, the Chinese Diabetes Society (CDS) has been dedicated to improving academic exchange and the academic level of diabetes research in China. From 2003 to 2014, four versions of Chinese diabetes care guidelines have been published. The guidelines have played an important role in standardizing clinical practice and improving the status quo of diabetes prevention and control in China. Since September 2016, the CDS has invited experts in cardiovascular diseases, psychiatric diseases, nutrition, and traditional Chinese medicine to work with endocrinologists from the CDS to review the new clinical research evidence related to diabetes over the previous 4 years. Over a year of careful revision, this has resulted in the present, new version of guidelines for prevention and care of type 2 diabetes in China. The main contents include epidemiology of type 2 diabetes in China; diagnosis and classification of diabetes; primary, secondary, and tertiary diabetes prevention; diabetes education and management support; blood glucose monitoring; integrated control targets for type 2 diabetes and treatments for hyperglycaemia; medical nutrition therapy; exercise therapy for type 2 diabetes; smoking cessation; pharmacologic therapy for hyperglycaemia; metabolic surgery for type 2 diabetes; prevention and treatment of cardiovascular and cerebrovascular diseases in patients with type 2 diabetes; hypoglycaemia; chronic diabetic complications; special types of diabetes; metabolic syndrome; and diabetes and traditional Chinese medicine.


| Epidemiology of diabetes in China
The prevalence of diabetes has been rising substantially over the past three decades in China. In 1980, an epidemiological survey that included 300 000 individuals from 14 provinces and municipalities nationwide showed that the prevalence of diabetes was 0.67%. 5 An epidemiological survey that included 210 000 individuals from 19 provinces and municipalities in 1994 to 1995 found that the prevalence of diabetes was 2.28% in people aged 25 to 64 years old. 6 A national nutrition and health survey in 2002 showed that the prevalence of diabetes was 4.5% in urban residents and 1.8% in rural residents aged 18 years and older. 7 In 2007 to 2008, the CDS performed an epidemiological survey in 14 provinces and municipalities in China, which showed that the prevalence of diabetes was 9.7% in Chinese adults aged 20 years and over. 8 In 2010, the Chinese Center for Disease Control and Prevention (CDC) and the Chinese Society of Endocrinology conducted a survey in Chinese populations aged 18 years and over, which showed that the prevalence of diabetes was 9.7%. 9 In 2013, the China Chronic Disease and Risk Factors Surveillance study found that the prevalence of diabetes and prediabetes was 10.4% and 16.6% in individuals aged 18 years and over, respectively (Table 1). 10,11 The epidemiological characteristics of diabetes in China are as follows: 1. The overall proportion of patients who were aware of their diabetes condition was 38.6%. 11 2. The prevalence of diabetes was significantly higher in urban than rural areas (12.0% vs 8.9%) and among men than women (11.1% vs 9.6%). 10 3. Genetic susceptibility including several susceptibility loci, such as PAX4 and NOS1AP, has been identified to increase the risk of type 2 diabetes mellitus (T2DM) by 5% to 25% in Chinese populations. 12

| Diagnosis of diabetes
This standard adopts the World Health Organization (WHO) (1999) criteria for diagnosis and classification of diabetes. Tables 2 and 3 summarize the diagnostic criteria for diabetes and the classification of metabolic status. 15 In 2011, WHO recommended that wherever conditions permit, countries and regions may consider adopting the haemoglobin A1c (HbA1c) ≥6.5% as the cutpoint for diabetes diagnosis. 16     • Controlling blood glucose, lowering blood pressure, adjusting lipids, and aspirin therapy are recommended to prevent diabetic cardiovascular and microvascular diseases in patients with T2DM with cardiovascular risk factors (A).
• Diabetes with severe complications should be referred to specialists.

| Goals for primary, secondary, and tertiary prevention of type 2 diabetes
The goal of primary prevention is to reduce risk factors and prevent the occurrence of T2DM. The goal of secondary prevention is early detection, as well as early diagnosis and treatment of T2DM to prevent diabetic complications in individuals with T2DM. Tertiary prevention aims to delay the progression of diabetic complications, reduce morbidity and mortality, and improve the patients' quality of life.

| Primary prevention
Primary prevention of T2DM includes health education in the general population to raise public awareness of diabetes prevention and treatment and promote a healthy lifestyle, including healthy diet, weight control, physical activity, salt restriction, smoking cessation, alcohol restriction, and social and psychological well-being.
Multiple randomized and controlled studies have shown that appropriate lifestyle interventions (moderate physical activity and weight management) can delay or prevent progression to T2DM among people with impaired glucose tolerance (IGT). In a study conducted in Daqing, China, those in the lifestyle intervention group were asked to increase vegetable intake and reduce intake of alcohol and monosaccharides. Those who were defined as overweight or obese (BMI >25 kg/m 2 ) were encouraged to lose weight and to increase physical activity by performing at least 20 minutes of moderately intense activity per day. After a 6-year lifestyle intervention, the cumulative incidence of T2DM risk for the subsequent 14 years decreased by 43%. 17 The lifestyle intervention groups in the Finnish

Diabetes Prevention Study 18 and the American Diabetes Prevention
Program 19 also demonstrated that lifestyle intervention could significantly reduce the risk of developing T2DM among patients with IGT.
This standard recommends that individuals with prediabetes should be encouraged to adopt healthy diet and increase physical activity to reduce the risk of diabetes. They should also receive regular follow-up that provides psychosocial support to encourage long-term adherence to a healthy lifestyle, regular monitoring of blood glucose levels, regular monitoring of cardiovascular risk factors (such as smoking, hypertension, and dyslipidaemia), and appropriate intervention measures. 4 Specific objectives for prevention among those with prediabetes are (1) among overweight or obese individuals, lowering of BMI to approximately 24 kg/m 2 or weight loss of at least 7%, (2) reduction in total daily caloric intake by at least 400 to 500 kcal (1 kcal = 4.184 kJ), (3) reduction in saturated fatty acid intake to less than 30% of total fatty acid intake, and (4) moderate-intensity physical activity for at least 150 min/week.

| Secondary prevention
Secondary prevention of T2DM includes diabetes screening and intervention in high-risk populations, chronic complication screening, and comprehensive control of blood glucose, blood pressure, and lipid in patients with diabetes.
Those in high-risk populations (Table 5) may be screened by resident health records and opportunistic screening (eg, screening that occurs during routine physical examinations or during treatment of other diseases).
For adults in the high-risk group, diabetes screening should be performed as early as possible. For children and adolescents in high-risk groups, screening should begin at age 10; however, for individuals with an earlier onset of puberty, screening should start at puberty.
Those whose initial screening results are normal are recommended to undergo screening again at least once every 3 years. 4 FPG is a simple diabetes screening method that should be used for routine screening, albeit there is risk of missed diagnosis. Individuals with abnormal FPG or random blood glucose but who have not For those with T2DM without significant diabetic vascular complications but with risk factors for cardiovascular diseases, controlling blood glucose, lowering blood pressure, adjusting lipids (mainly to reduce LDL-C), and aspirin therapy are all useful methods to prevent CVD and diabetic microvascular diseases. 4

| Tertiary prevention
The tertiary prevention aims to delay the progression of diabetic com-

| Haemoglobin A1c
Haemoglobin A1c (HbA1c) has become a gold standard for the assessment of glycaemic control over the previous 2 to 3 months and the basis for the adjustments of treatment regimens. The normal reference range is 4% to 6% with the standard HbA1c assay, which is recommended to be tested every 3 months during initial treatment and every 6 months once treatment targets are reached. However, the HbA1c value is not reliable in patients with anaemia or haemoglobin disorders. The HbA1c assay should be traceable to the Diabetes Control and Complications Trial (DCCT) reference assay.

| Glycated albumin
GA reflects the average glucose level over the previous 2 to 3 weeks, and the normal reference range is 11% to 17%. 28,29 In addition, GA can be used for differential diagnosis of stress-induced hyperglycaemia caused by acute stress. However, the GA value is not reliable in patients with conditions that affect the rate of albumin renewal, such as nephrotic syndrome and cirrhosis.

| Continuous glucose monitoring
Continuous glucose monitoring (CGM) continuously monitors interstitial glucose levels using a subcutaneous glucose sensor, which provides more comprehensive information regarding the blood glucose level and the basis for individualized diabetes care. Retrospective CGM is mainly applicable for use in the following patients or situations: 1. T1DM.

T2DM requiring intensive insulin therapy.
3. Patients with T2DM who use hypoglycaemic treatment under SMBG guidance, but still encounter one of the following situations: (1) unexplained severe or recurrent hypoglycaemia, asymptomatic hypoglycaemia, or nocturnal hypoglycaemia; (2) refractory hyperglycaemia, especially when fasting; (3) large blood glucose excursions; (4) state of hyperglycaemia maintained by individuals because of fear of hypoglycaemia. 4. GDM or diabetes in pregnancy.

Patients who need diabetes education.
Retrospective CGM data can be also used to evaluate the results of clinical studies as needed. [30][31][32][33] Real-time CGM data are indicated in children and adolescents with T1DM who have achieved HbA1c levels below 7.0%, children and adolescents with T1DM who have HbA1c levels more than 7.0% but are able to use the device on a daily basis, adult patients with T1DM who can use the device on a daily basis, nonintensive care unit inpatients with T2DM receiving insulin treatment, 34 and perioperative patients with T2DM. Table 6 shows the normal reference values for CGM in a Chinese population aged 20 to 69 years. 35,36 The 24-hour mean glucose (24hMG) is strongly correlated with HbA1c and can be calculated with the following formula: 24hMG = 1.198 × HbA1c − 0.582. Thus, when HbA1c were 6.0%, 6.5%, and 7.0%, the calculated 24hMG were 6.6, 7.2, and 7.8 mmol/L, respectively. 37 In addition, the standard "threestep" analysis is recommended for interpretation of the CGM profile and data. For analysis of data from 3-day monitoring, step 1 is to analyse nocturnal blood glucose, step 2 is to analyse preprandial glucose, and step 3 is to analyse postprandial glucose. During each step, hypoglycaemia is checked before hyperglycaemia, and reasons for it are identified so as to adjust the treatment plan. For data from 14day monitoring, step 1 is to check on-target time, step 2 is to check glucose fluctuations, and step 3 is to check hypoglycaemia.  • Lifestyle intervention is the basis for diabetes care, and drug therapy should be initiated in the event of uncontrolled blood glucose (HbA1c ≥ 7.0%) (A).
• In the event of no response to monotherapy, dual therapy, triple therapy, or multiple daily insulin injections may be prescribed (B).

| Objectives of comprehensive type 2 diabetes control
The ideal comprehensive control of T2DM varies according to the age, comorbidities, and complications of patients ( When metformin alone is unable to achieve blood glucose target, dual therapy should utilize insulin secretagogues, α-glucosidase inhibitors, dipeptidyl peptidase IV (DPP-4) inhibitors or thiazolidinediones (TZDs), sodium-glucose cotransporter 2 (SGLT2) inhibitors, insulin, or glucagon-like peptide-1 (GLP-1) receptor agonists. A combination of three types of drugs may be initiated when dual therapy is still unable to achieve a blood glucose target. Patients with uncontrolled blood glucose after triple therapy should proceed to multiple daily insulin injections (basal + prandial insulin or multiple daily injections of premixed insulin) as needed. When treating with multiple insulin injections, insulin secretagogue use should be discontinued. Figure 1 shows the treatment pathways for hyperglycaemia in T2DM.

| MEDICAL NUTRITION THERAPY
Patients with diabetes or prediabetes require individualized medical nutrition therapy, which should be provided by the guidance of a dietician who is familiar with diabetes treatment or a comprehensive integrated diabetes management team (including a diabetes educator). To achieve the metabolic control objectives for patients and satisfy their dietary preferences, reasonable quality objects should be established.
In order to control the total energy intake and distribute various nutrients in a reasonable and balanced manner, the nutrition status should be evaluated before setting quality objectives.

| EXERCISE THERAPY FOR TYPE 2 DIABETES
Exercise plays an important role in the comprehensive management of T2DM. Regular exercise helps control blood glucose, reduces cardiovascular risk factors, reduces weight, and improves overall well-being.
Moreover, exercise has a substantial primary preventive effect on populations at high risk of diabetes. Epidemiological studies have shown that regular exercise of more than 8 weeks reduced HbA1c level by 0.66% and that mortality is significantly reduced among those with diabetes who adhered to regular exercise for 12 to 14 years. The key points of exercise therapy include the following: The treatment algorithm for high blood glucose in type 2 diabetes. Note: HbA1c: glycated hemoglobin; Metformin is the preferred drug for monotherapy treatment. It may be given to obese patients receiving multiple daily insulin injections. Figure 1 reflects the primary drug treatments paths recommended based on clinical evidence of the drug's efficacy and safety, health and economic benefits and the national conditions in China

| Sulfonylureas
Sulfonylureas are insulin secretagogues whose main pharmacological effect is increasing insulin levels by stimulating insulin secretion from pancreatic β cells and therefore lowering blood glucose levels. TZDs do not cause hypoglycaemia when used alone, but they may increase the risk of hypoglycaemia when used in combination with insulin or insulin secretagogues. Weight gain and oedema are common adverse effects of TZDs, and these adverse effects are more remarkable when TZDs are used in combination with insulin. TZD use has been correlated with increased risk of fractures and heart failure. Contraindications for TZDs are heart failure (New York Heart Association heart function classification class II and above), active liver disease, transaminase elevations exceeding 2.5 times the upper limit of normal, and severe osteoporosis and fractures.
This class of medications reduces postprandial blood glucose by stimulating insulin secretion in the early phase. They can lower HbA1c by 0.5% to 1.5%. 54 These medicines must be taken immediately before a meal and can be used separately or in combination with other antidiabetic medications. For newly diagnosed patients with T2DM, combination therapy using repaglinide with metformin reduced HbA1c more significantly than repaglinide alone but with a significantly increased risk of hypoglycaemia. 55 Common adverse effects of glinides are hypoglycaemia and weight gain, but the risk and degree of hypoglycaemia are lower with glinides than with sulfonylureas. Glinides can be used in patients with renal insufficiency. 54 12.   • Insulin therapy may start with one to two daily injections in patients with T2DM (A).
• Multiple daily insulin injections (two to four injections per day) or continuous subcutaneous insulin infusion (CSII) are available for insulin therapy (A).
• Short-term (2 weeks to 3 months) intensive insulin treatment may be implemented in newly diagnosed patients with T2DM with HbA1c-9.0% or FPG ≥ 11.1 mmol/L and symptomatic hyperglycaemia (A).
Insulin therapy is an important approach for glucose control.
Patients with T1DM require insulin to sustain life, control blood glucose, and reduce the risk of diabetic complications. Insulin is also needed in patients with T2DM who do not respond to or are contraindicated for oral hypoglycaemic agents to control blood glucose and reduce the risk of diabetic complications.
Depending on the source and chemical structure, insulin can be divided into animal insulin, human insulin, and insulin analogues.
According to the pharmacokinetic properties, insulin can also be classified into rapid-acting insulin analogues, regular (short-acting) insulin, intermediate-acting insulin, long-acting insulin, long-acting insulin analogues, premixed insulin, and premixed insulin analogues. The insulin treatment paths for T2DM are shown in Figure 2.

| Efficacy evaluation of metabolic surgery
Remission of T2DM is defined as HbA1c ≤ 6.5% with lifestyle intervention alone after operation.

| Management of metabolic surgery
Metabolic surgery requires multidisciplinary teams for comprehensive preoperative, intraoperative, and postoperative management. [94][95][96] Life-long follow-up should be provided to patients after surgery, and micronutrients and nutritional status should be routinely monitored and evaluated.

| PREVENTION AND TREATMENT OF CARDIOVASCULAR AND CEREBROVASCULAR DISEASES IN PATIENTS WITH TYPE 2 DIABETES
Diabetes is an independent risk factor for cardiovascular and cerebrovascular diseases. FPG and postprandial hyperglycaemia are correlated with an increased risk of cardiovascular and cerebrovascular diseases, even when they do not reach the diagnostic criteria for diabetes. The use of aspirin has also been low. 4 Clinically, more active screening and treatment of cardiovascular risk factors and an increased prescription or recommendation of aspirin therapy are recommended.

| Screening
The risk factors of CVD should be assessed at least annually follow-  • ACEIs or ARBs are preferred treatments in patients with diabetes with hypertension and UACR >300 mg/g, or eGFR <60 mL/min/ 1.73 m 2 (A).
• ACEIs or ARBs are preferred treatments in patient with diabetes with hypertension and UACR of 30 to 300 mg/g (B).
• Recommended protein intake should be approximately 0.8 g/kg/ day in patients with diabetic kidney disease. It may be slightly higher in patients on dialysis (B).
• Renal replacement therapy should be given in patients with eGFR <30 mL/min/1.73 m 2 (A).

| Definition
Chronic kidney disease (CKD) is defined as chronic abnormalities of kidney structure and function. Diabetic kidney disease (DKD) refers to CKD that is specific to diabetes. Approximately 20% to 40% of dia-   • Well-controlled blood glucose, blood pressure, and blood lipids may prevent or delay the progression of diabetic retinopathy (A).
• Patients with moderate or severe nonproliferative retinopathy identified during screening should be referred to an ophthalmologist.

| Diagnosis and classification
Diabetic retinopathy has to be graded according to the international clinical grading standard for diabetic retinopathy (2002), in which macular oedema is included (Tables 9 and 10). 115    • Well-controlled blood glucose delays the progression of diabetic neuropathy (B).

| Definition
Diabetic neuropathy is one of the most common chronic complica-

| Treatment
The therapeutic approach to LEAD includes the prevention of pro- • Diabetic patients should receive comprehensive education on foot self-care (B).
• Multidisciplinary collaboration is required for diagnosing and treating diabetic foot ulcers (B).

| Definition
Diabetic foot refers to foot ulcers, infections, and (or) deep tissue destruction associated with distal extremity nerve abnormalities and varying degrees of peripheral vascular lesions.

| Diagnosis and classification
Once diabetic foot disease is diagnosed, it should be evaluated within clinical classification. At present, the most widely accepted classification methods are Wagner grading (Table 11) and Texas grading (Table 12). 133

| Treatment
A multidisciplinary approach is recommended to diagnose and treat diabetic foot ulcers. • It is recommended that patients with diabetes should not become pregnant until HbA1c is <6.5% in order to reduce the risk of congenital anomalies (B).
• Pregnant nondiabetic women should have one-step 75-g OGTT screening at 24 to 28 weeks of gestation (A).
• Patients should self-monitor blood glucose (FPG and postprandial glucose), with the frequency and schedule adjusted according to individual condition in order to facilitate glucose control and prevent hypoglycaemia (B).
• Lifestyle intervention is an essential component for diabetes care during pregnancy, and medications should be added in the event of uncontrolled glucose (A).
• Insulin is the preferred treatment for diabetes in pregnancy, as all oral agents lack long-term safety data (A).

| Diagnostic criteria
Diabetes in pregnancy included the following three types.    Note. This represents a consensus framework for considering treatment goals for glycaemia, blood pressure, and dyslipidaemia in older adults with diabetes. The patient characteristic categories are general concepts. Not every patient will clearly fall into a particular category. Consideration of patient and caregiver preferences is an important aspect of treatment individualization. Additionally, a patient's health status and preferences may change over time. A1C of 8.5% (69 mmol/mol) equates to an estimated average glucose of 200 mg/dL (11.1 mmol/L). Looser A1C targets above 8.5% (69 mmol/mol) are not recommended as they may expose patients to more frequent higher glucose values and the acute risks from glycosuria, dehydration, hyperglycaemic hyperosmolar syndrome, and poor wound healing. 1 mmHg = 0.133 kPa.
Abbreviation: ADL, activities of daily living. a A lower A1C goal may be set for an individual if achievable without recurrent or severe hypoglycaemia or undue treatment burden.
b Coexisting chronic illnesses are conditions serious enough to require medications or lifestyle management and may include arthritis, cancer, congestive heart failure, depression, emphysema, falls, hypertension, incontinence, stage 3 or worse chronic kidney disease, myocardial infarction, and stroke. By "multiple," we mean at least three, but many patients may have five or more.
c The presence of a single end-stage chronic illness, such as stage 3 to 4 congestive heart failure or oxygen-dependent lung disease, chronic kidney disease requiring dialysis, or uncontrolled metastatic cancer, may cause significant symptoms or impairment of functional status, and significantly reduce life expectancy. individualized glucose control target, drug treatment, and monitoring plan (A).
• Health education and lifestyle interventions are the basis for diabetes care in elderly patients. An effective and safe hypoglycaemic treatment plan should be developed to prevent hypoglycaemia.
Attention should be paid to prevent interactions among hypoglycaemic drugs (A).
• Elderly patients with diabetes commonly have multiple risk factors for ASCVD, multiple comorbidities and complications, geriatric syndrome, and muscle atrophy, and a high risk of osteoporosis and bone fracture, which require comprehensive management (A).
• It is recommended that patients with diabetes aged 65 years and above be screened for depression and cognitive function annually (B).

| Definition
Diabetes in older adults is defined as diabetes in patients aged ≥60 years regardless of whether diabetes is diagnosed before or after the age of 60 years. The goal of treatment is to reduce the disability and premature death associated with acute and chronic complications, improve quality of life, and extend expected survival.

| Treatment of senile diabetes
A comprehensive evaluation of the health status of diabetes in older adults is the basis for individualized glucose control targets and treatment strategies, as well as individualized blood lipids and blood pressure targets (Table 13). 38 Senile diabetes requires treatments with many considerations. It requires more humanistic care, and the benefits of treatment should be carefully weighed against potential risks after comprehensive evaluation.

| METABOLIC SYNDROME
Metabolic syndrome (MetS) is a clustering of medical conditions including obesity, hyperglycaemia (diabetes or impaired glucose regulation), hypertension, and dyslipidaemia (high TG and/or low HDL-C levels).

| Definitions for metabolic syndrome
MetS was defined as three or more of the following abnormalities 106