Cyclocarya paliurus Leaves Tea Improves Dyslipidemia in Diabetic Mice: A Lipidomics-Based Network Pharmacology Study

High-density lipoproteins (HDLs) protect against atherosclerosis by removing excess cholesterol from macrophages through the ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) pathways involved in reverse cholesterol transport. Factors that impair the availability of functional apolipoproteins or the activities of ABCA1 and ABCG1 could, therefore, strongly influence atherogenesis. HDL also inhibits lipid oxidation, restores endothelial function, exerts anti-inflammatory and antiapoptotic actions, and exerts anti-inflammatory actions in animal models. Such properties could contribute considerably to the capacity of HDL to inhibit atherosclerosis. Systemic and vascular inflammation has been proposed to convert HDL to a dysfunctional form that has impaired antiatherogenic effects. A loss of anti-inflammatory and antioxidative proteins, perhaps in combination with a gain of proinflammatory proteins, might be another important component in rendering HDL dysfunctional. The proinflammatory enzyme myeloperoxidase induces both oxidative modification and nitrosylation of specific residues on plasma and arterial apolipoprotein A-I to render HDL dysfunctional, which results in impaired ABCA1 macrophage transport, the activation of inflammatory pathways, and an increased risk of coronary artery disease. Understanding the features of dysfunctional HDL or apolipoprotein A-I in clinical practice might lead to new diagnostic and therapeutic approaches to atherosclerosis.

Introduction: Background to metabolomics Metabolomics is the comprehensive study of the metabolome, the repertoire of biochemicals (or small molecules) present in cells, tissues, and body fluids. The study of metabolism at the global or “-omics” level is a rapidly growing field that has the potential to have a profound impact upon medical practice. At the center of metabolomics, is the concept that a person’s metabolic state provides a close representation of that individual’s overall health status. This metabolic state reflects what has been encoded by the genome, and modified by diet, environmental factors, and the gut microbiome. The metabolic profile provides a quantifiable readout of biochemical state from normal physiology to diverse pathophysiologies in a manner that is often not obvious from gene expression analyses. Today, clinicians capture only a very small part of the information contained in the metabolome, as they routinely measure only a narrow set of blood chemistry analytes to assess health and disease states. Examples include measuring glucose to monitor diabetes, measuring cholesterol and high density lipoprotein/low density lipoprotein ratio to assess cardiovascular health, BUN and creatinine for renal disorders, and measuring a panel of metabolites to diagnose potential inborn errors of metabolism in neonates. Objectives of White Paper—expected treatment outcomes and metabolomics enabling tool for precision medicine We anticipate that the narrow range of chemical analyses in current use by the medical community today will be replaced in the future by analyses that reveal a far more comprehensive metabolic signature. This signature is expected to describe global biochemical aberrations that reflect patterns of variance in states of wellness, more accurately describe specific diseases and their progression, and greatly aid in differential diagnosis. Such future metabolic signatures will: (1) provide predictive, prognostic, diagnostic, and surrogate markers of diverse disease states; (2) inform on underlying molecular mechanisms of diseases; (3) allow for sub-classification of diseases, and stratification of patients based on metabolic pathways impacted; (4) reveal biomarkers for drug response phenotypes, providing an effective means to predict variation in a subject’s response to treatment (pharmacometabolomics); (5) define a metabotype for each specific genotype, offering a functional read-out for genetic variants: (6) provide a means to monitor response and recurrence of diseases, such as cancers: (7) describe the molecular landscape in human performance applications and extreme environments. Importantly, sophisticated metabolomic analytical platforms and informatics tools have recently been developed that make it possible to measure thousands of metabolites in blood, other body fluids, and tissues. Such tools also enable more robust analysis of response to treatment. New insights have been gained about mechanisms of diseases, including neuropsychiatric disorders, cardiovascular disease, cancers, diabetes and a range of pathologies. A series of ground breaking studies supported by National Institute of Health (NIH) through the Pharmacometabolomics Research Network and its partnership with the Pharmacogenomics Research Network illustrate how a patient’s metabotype at baseline, prior to treatment, during treatment, and post-treatment, can inform about treatment outcomes and variations in responsiveness to drugs (e.g., statins, antidepressants, antihypertensives and antiplatelet therapies). These studies along with several others also exemplify how metabolomics data can complement and inform genetic data in defining ethnic, sex, and gender basis for variation in responses to treatment, which illustrates how pharmacometabolomics and pharmacogenomics are complementary and powerful tools for precision medicine. Conclusions: Key scientific concepts and recommendations for precision medicine Our metabolomics community believes that inclusion of metabolomics data in precision medicine initiatives is timely and will provide an extremely valuable layer of data that compliments and informs other data obtained by these important initiatives. Our Metabolomics Society, through its “Precision Medicine and Pharmacometabolomics Task Group”, with input from our metabolomics community at large, has developed this White Paper where we discuss the value and approaches for including metabolomics data in large precision medicine initiatives. This White Paper offers recommendations for the selection of state of-the-art metabolomics platforms and approaches that offer the widest biochemical coverage, considers critical sample collection and preservation, as well as standardization of measurements, among other important topics. We anticipate that our metabolomics community will have representation in large precision medicine initiatives to provide input with regard to sample acquisition/preservation, selection of optimal omics technologies, and key issues regarding data collection, interpretation, and dissemination. We strongly recommend the collection and biobanking of samples for precision medicine initiatives that will take into consideration needs for large-scale metabolic phenotyping studies.

The American Diabetes Association’s (ADA’s) Standards of Medical Care in Diabetes is updated and published annually in a supplement to the January issue of Diabetes Care (1). Formerly called Clinical Practice Recommendations, the “Standards” includes the most current evidence-based recommendations for diagnosing and treating adults and children with all forms of diabetes. ADA’s grading system uses A, B, C, or E to show the evidence level that supports each recommendation (Table 1). TABLE 1. ADA Evidence Grading System for “Standards of Medical Care in Diabetes” Level of evidence Description A Clear evidence from well-conducted, generalizable randomized controlled trials that are adequately powered B Supportive evidence from well-conducted cohort studies C Supportive evidence from poorly controlled or uncontrolled studiesConflicting evidence with the weight of evidence supporting the recommendation E Expert consensus or clinical experience For additional information, please refer to the complete 2015 Standards (1). This is an abridged version of the current Standards containing only the evidence-based recommendations most pertinent to primary care. The tables, figures, and references have been renumbered from the original document. The complete 2015 Standards supplement is available at professional.diabetes.org/standards. STRATEGIES FOR IMPROVING CARE Recommendations Patient-centered communication that incorporates patient preferences, assesses literacy and numeracy, and addresses cultural barriers to care should be used. B Care should be aligned with components of the Chronic Care Model (CCM) to ensure productive interactions between a prepared proactive practice team and an informed activated patient. A Diabetes Care Concepts Patient centeredness. Because patients with diabetes are also at greatly increased risk of cardiovascular disease (CVD), a patient-centered approach should include a comprehensive plan to reduce CVD risk. Diabetes across the life span. As people with diabetes live well into older age and incidence of type 2 diabetes is on the rise in children and young adults, the demographics of diabetes are changing. There is therefore a need to improve coordination between clinical teams as patients pass through different stages of life, including pregnancy. Advocacy for patients with diabetes. Given the tremendous toll that lifestyle factors such as obesity, physical inactivity, and smoking have on the health of patients with diabetes, ongoing and energetic efforts are needed to address and change the societal determinants at the root of these problems. Care Delivery Systems The mean A1C nationally has declined. This has been accompanied by improvements in lipids and blood pressure control. Nevertheless, 33–49% of patients do not meet targets for glycemic, blood pressure, or cholesterol control, and only 14% meet targets for all three measures and nonsmoking status (2). Chronic Care Model The CCM has been shown to be effective for improving the quality of diabetes care (3). Collaborative, multidisciplinary teams are best suited to provide care for people with diabetes and to facilitate patients’ self-management (4–7). Key Objectives Optimize provider and team behavior. The care team should prioritize intensification of lifestyle and/or pharmaceutical therapy for patients with inadequate levels of blood pressure, lipid, or glucose control (8). Support patient behavior change. Successful diabetes care requires a systematic approach to supporting patients’ behavior change efforts. High-quality diabetes self-management education (DSME) and support (DSMS) have been shown to improve patient self-management, satisfaction, and glucose control (9,10). Change the care system. Optimal diabetes management requires an organized, systematic approach and the involvement of a coordinated team of dedicated health care professionals working in an environment where patient-centered high-quality care is a priority (11). When Treatment Goals Are Not Met When patients are not meeting treatment goals, reassessing the treatment regimen may require evaluation of barriers such as income, health literacy, diabetes-related distress, depression, poverty, and competing demands, including those related to family responsibilities and dynamics. CLASSIFICATION AND DIAGNOSIS OF DIABETES Diabetes can be classified into the following general categories: Type 1 diabetes (due to β-cell destruction, usually leading to absolute insulin deficiency) Type 2 diabetes (due to a progressive insulin secretory defect on the background of insulin resistance) Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third trimester of pregnancy that is not clearly overt diabetes) Specific types of diabetes due to other causes, e.g., monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young [MODY]), diseases of the exocrine pancreas (such as cystic fibrosis), and drug- or chemical-induced diabetes (such as in the treatment of HIV/AIDS or after organ transplantation) Diagnostic Tests for Diabetes Diabetes may be diagnosed based on A1C criteria or plasma glucose criteria, either the fasting plasma glucose (FPG) or the 2-h plasma glucose value after a 75-g oral glucose tolerance test (OGTT) (12,13) (Table 2). The same tests are used to screen for and diagnose diabetes and to detect individuals with prediabetes (Table 3). TABLE 2. Criteria for the Diagnosis of Prediabetes and Diabetes Prediabetes Diabetes A1C 5.7–6.4% ≥6.5% FPG 100–125 mg/dL (5.6–6.9 mmol/L) ≥126 mg/dL (7.0 mmol/L) OGTT 140–199 mg/dL (7.8–11.0 mmol/L) ≥200 mg/dL (11.1 mmol/L)* RPG ≥200 mg/dL (11.1 mmol/L)† * In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing. † Only diagnostic in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis. RPG, random plasma glucose. TABLE 3. Criteria for Testing for Diabetes or Prediabetes in Asymptomatic Adults Testing should be considered in adults who are overweight (BMI ≥25 kg/m2 or ≥23 kg/m2 in Asian Americans) and have additional risk factors: • Physical inactivity • First-degree relative with diabetes • High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander) • Women who delivered a baby weighing >9 lb or were diagnosed with GDM • Hypertension (≥140/90 mmHg or on therapy for hypertension) • HDL cholesterol level 250 mg/dL (2.82 mmol/L) • Women with polycystic ovary syndrome • A1C ≥5.7%, IGT, or IFG on previous testing • Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans) • History of CVD Type 2 Diabetes and Prediabetes Recommendations Testing to detect type 2 diabetes in asymptomatic people should be considered in adults of any age who are overweight or obese (BMI ≥25 kg/m2 or ≥23 kg/m2 in Asian Americans) and who have one or more additional risk factors for diabetes. For all patients, particularly those who are overweight or obese, testing should begin at age 45 years. B If tests are normal, repeat testing carried out at a minimum of 3-year intervals is reasonable. C In patients with prediabetes or diabetes, identify and, if appropriate, treat other CVD risk factors. B Testing to detect prediabetes and type 2 diabetes should be considered in children and adolescents who are overweight or obese and who have two or more additional risk factors for diabetes. E The modified recommendations of the ADA consensus report “Type 2 Diabetes in Children and Adolescents” (14) are summarized in Table 4. TABLE 4. Testing for Type 2 Diabetes or Prediabetes in Asymptomatic Children (≤18 Years of Age) Criteria • Overweight (BMI >85th percentile for age and sex, weight for height >85th percentile, or weight >120% of ideal for height) Plus any two of the following risk factors: • Family history of type 2 diabetes in first- or second-degree relative • Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander) • Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational-age birth weight) • Maternal history of diabetes or GDM during the child’s gestation Age of initiation: Age 10 years or at onset of puberty, if puberty occurs at a younger age Frequency: Every 3 years Gestational Diabetes Mellitus Recommendations Test for undiagnosed type 2 diabetes at the first prenatal visit in those with risk factors, using standard diagnostic criteria. B Test for GDM at 24–28 weeks of gestation in pregnant women not previously known to have diabetes. A Screen women with GDM for persistent diabetes at 6–12 weeks postpartum, using the OGTT and clinically appropriate nonpregnancy diagnostic criteria. E Women with a history of GDM should have lifelong screening for the development of diabetes or prediabetes at least every 3 years. B Women with a history of GDM found to have prediabetes should receive lifestyle interventions or metformin to prevent diabetes. A INITIAL EVALUATION AND DIABETES MANAGEMENT PLANNING Medical Evaluation A complete medical evaluation should be performed at the initial visit to: Classify diabetes Detect diabetes complications Review previous treatment and risk factor control in patients with diabetes Assist in formulating a management plan Provide a basis for continuing care Laboratory tests appropriate to the evaluation of each patient’s medical condition should be completed. A focus on the components of comprehensive care (Table 5) will enable the health care team to optimally manage the patient with diabetes. TABLE 5. Components of the Comprehensive Diabetes Evaluation Medical history • Age and characteristics of onset of diabetes (e.g., diabetic ketoacidosis, asymptomatic laboratory finding) • Eating patterns, physical activity habits, nutritional status, and weight history; growth and development in children and adolescents • Presence of common comorbidities, psychosocial problems, and dental disease • Diabetes education history • Review of previous treatment regimens and response to therapy (A1C records) • Current treatment of diabetes, including medications, medication adherence and barriers thereto, meal plan, physical activity patterns, and readiness for behavior change • Results of glucose monitoring and patient’s use of data • Diabetic ketoacidosis frequency, severity, and cause • Hypoglycemic episodes   ○ Hypoglycemia awareness   ○ Any severe hypoglycemia: frequency and cause • History of diabetes-related complications   ○ Microvascular: retinopathy, nephropathy, neuropathy (sensory, including history of foot lesions; autonomic, including sexual dysfunction and gastroparesis)   ○ Macrovascular: coronary heart disease, cerebrovascular disease, and peripheral arterial disease Physical examination • Height, weight, BMI • Blood pressure determination, including orthostatic measurements when indicated • Fundoscopic examination • Thyroid palpation • Skin examination (for acanthosis nigricans and insulin injection sites) • Comprehensive foot examination   ○ Inspection   ○ Palpation of dorsalis pedis and posterior tibial pulses   ○ Presence/absence of patellar and Achilles reflexes   ○ Determination of proprioception, vibration, and monofilament sensation Laboratory evaluation • A1C, if results not available within past 3 months • If not performed/available within past year   ○ Fasting lipid profile, including total, LDL, and HDL cholesterol and triglycerides, as needed   ○ Liver function tests   ○ Test for urine albumin excretion with spot urine albumin-to-creatinine ratio   ○ Serum creatinine and calculated glomerular filtration rate   ○ TSH in type 1 diabetes, dyslipidemia, or women over age 50 years Referrals • Eye care professional for annual dilated eye exam • Family planning for women of reproductive age • Registered dietitian for medical nutrition therapy • DSME/DSMS • Dentist for comprehensive periodontal examination • Mental health professional, if needed Management Plan People with diabetes should receive medical care from a collaborative, integrated team with expertise in diabetes. The management plan should be written with input from the patient and family, the physician, and other members of the health care team. Common Comorbid Conditions Recommendations Consider screening those with type 1 diabetes for autoimmune diseases (e.g., thyroid dysfunction, celiac disease) as appropriate. E Consider assessing for and addressing common comorbid conditions (e.g., depression, obstructive sleep apnea) that may complicate diabetes management. B Additional comorbid conditions to consider assessing include fatty liver disease, cancer, fractures, cognitive impairment, low testosterone in men, periodontal disease, and hearing impairment. FOUNDATIONS OF CARE: EDUCATION, NUTRITION, PHYSICAL ACTIVITY, SMOKING CESSATION, PSYCHOSOCIAL CARE, AND IMMUNIZATION Diabetes Self-Management Education and Support Recommendations People with diabetes should receive DSME and DSMS according to the national standards for DSME and DSMS when their diabetes is diagnosed and as needed thereafter. B Effective self-management and quality of life are the key outcomes of DSME and DSMS and should be measured and monitored as part of care. C DSME and DSMS should address psychosocial issues, as emotional well-being is associated with positive diabetes outcomes. C DSME and DSMS programs are appropriate venues for people with prediabetes to receive education and support to develop and maintain behaviors that can prevent or delay the onset of diabetes. C Because DSME and DSMS can result in cost-savings and improved outcomes B, DSME and DSMS should be adequately reimbursed by third-party payers. E Medical Nutrition Therapy For many individuals with diabetes, the most challenging part of the treatment plan is determining what to eat. It is the position of the ADA that there is not a one-size-fits-all eating pattern for individuals with diabetes. Therefore, it is important that all members of the health care team be knowledgeable about diabetes nutrition therapy and support its implementation. Goals of Nutrition Therapy for Adults With Diabetes To promote and support healthful eating patterns, emphasizing a variety of nutrient-dense foods in appropriate portion sizes, in order to improve overall health and specifically to: Attain individualized glycemic, blood pressure, and lipid goals Achieve and maintain body weight goals Delay or prevent complications of diabetes To address individual nutrition needs based on personal and cultural preferences, health literacy and numeracy, access to healthful food choices, willingness and ability to make behavioral changes, and barriers to change To maintain the pleasure of eating by providing positive messages about food choices while limiting food choices only when indicated by scientific evidence To provide the individual with diabetes with practical tools for day-to-day meal planning rather than focusing on individual macronutrients, micronutrients, or single foods Physical Activity Recommendations Children with diabetes or prediabetes should be encouraged to engage in at least 60 min of physical activity each day. B Adults with diabetes should be advised to perform at least 150 min/week of moderate-intensity aerobic physical activity (50–70% of maximum heart rate), spread over at least 3 days/week with no more than 2 consecutive days without exercise. A Evidence supports that all individuals, including those with diabetes, should be encouraged to reduce sedentary time, particularly by breaking up extended amounts of time (>90 min) spent sitting. B In the absence of contraindications, adults with type 2 diabetes should be encouraged to perform resistance training at least twice per week. A Smoking Cessation Recommendations Advise all patients not to smoke or use tobacco products. A Include smoking cessation counseling and other forms of treatment as a routine component of diabetes care. B Psychosocial Assessment and Care Recommendations Include assessment of the patient’s psychological and social situation as an ongoing part of the medical management of diabetes. B Psychosocial screening and follow-up may include, but are not limited to, attitudes about the illness, expectations for medical management and outcomes, affect/mood, general and diabetes-related quality of life, resources (financial, social, and emotional), and psychiatric history. E Routinely screen for psychosocial problems such as depression, diabetes-related distress, anxiety, eating disorders, and cognitive impairment. B Older adults (aged ≥65 years) with diabetes should be considered a high-priority population for depression screening and treatment. B Patients with comorbid diabetes and depression should receive astepwise collaborative care app-roach for the management of depression. A Immunization Recommendations Provide routine vaccinations for children and adults with diabetes as for the general population. C Annually provide an influenza vaccine to all patients with diabetes ≥6 months of age. C Administer pneumococcal polysaccharide vaccine 23 (PPSV23) to all patients with diabetes ≥2 years of age. C Adults ≥65 years of age, if not previously vaccinated, should receive pneumococcal conjugate vaccine 13 (PCV13), followed by PPSV23 6–12 months after initial vaccination. C Adults ≥65 years of age, if previously vaccinated with PPSV23, should receive a follow-up ≥12 months with PCV13. C Administer hepatitis B vaccination to unvaccinated adults with diabetes who are aged 19–59 years. C Consider administering hepatitis B vaccination to unvaccinated adults with diabetes who are aged ≥60 years. C PREVENTION OR DELAY OF TYPE 2 DIABETES Recommendations Patients with impaired glucose tolerance (IGT) A, impaired fasting glucose (IFG) E, or an A1C 5.7–6.4% E should be referred to an intensive diet and physical activity behavioral counseling program targeting loss of 7% of body weight and increasing moderate-intensity physical activity (such as brisk walking) to at least 150 min/week. Metformin therapy for prevention of type 2 diabetes may be considered in those with IGT A, IFG E, or an A1C 5.7–6.4% E, especially for those with BMI >35 kg/m2, aged 35 kg/m2 and type 2 diabetes, especially if diabetes or associated comorbidities are difficult to control with lifestyle and pharmacological therapy. B Patients with type 2 diabetes who have undergone bariatric surgery need lifelong lifestyle support and medical monitoring. B Although small trials have shown glycemic benefit of bariatric surgery in patients with type 2 diabetes and BMI 30–35 kg/m2, there is currently insufficient evidence to generally recommend surgery in patients with BMI 120/80 mmHg should be advised on lifestyle changes to reduce blood pressure. B Patients with confirmed office-based blood pressure >140/90 mmHg should, in addition to lifestyle therapy, have prompt initiation and timely subsequent titration of pharmacological therapy to achieve blood pressure goals. A Lifestyle therapy for elevated blood pressure consists of weight loss, if overweight or obese; a Dietary Approaches to Stop Hypertension (DASH)-style dietary pattern including reducing sodium and increasing potassium intake; moderation of alcohol intake; and increased physical activity. B Pharmacological therapy for patients with diabetes and hypertension should comprise a regimen that includes either an ACE inhibitor or an angiotensin receptor blocker (ARB). B If one class is not tolerated, the other should be substituted. C Multiple-drug therapy (including a thiazide diuretic and ACE inhibitor/ARB, at maximal doses) is generally required to achieve blood pressure targets. B Dyslipidemia/Lipid Management Lifestyle intervention may allow some patients to reduce CVD risk factors. Glycemic control can also benefit lipid levels, particularly in patients with high triglycerides and poor glycemic control. Initiating and intensifying statin therapy based on age and risk factors is recommended (Table 7). TABLE 7. Recommendations for Statin Treatment in People With Diabetes Age Risk factors Recommended statin dose* Monitoring with lipid panel 75 years None Moderate As needed to monitor adherence CVD risk factors Moderate or high Overt CVD High * In addition to lifestyle therapy. ** CVD risk factors include LDL cholesterol ≥100 mg/dL (2.6 mmol/L), high blood pressure, smoking, and overweight and obesity. *** Overt CVD includes those with previous cardiovascular events or acute coronary syndromes. In all patients ≥40 years of age with diabetes, moderate-intensity statin treatment should be considered in addition to lifestyle therapy. High-dose statin therapy should be considered if increased CVD risk is present (e.g., LDL cholesterol ≥100 mg/dL, high blood pressure, smoking, and overweight/obesity). In patients under 40 years of age and in those with type 1 diabetes, treatment with a moderate dose of statin should be considered if the patient has increased CVD risk and with a high dose of statin if the patient has overt CVD. Obtain a lipid panel at the time of the first diagnosis, at the first medical evaluation, and/or at age 40 years and periodically (e.g., every 1–2 years) thereafter. Once a patient is on a statin, testing for LDL cholesterol can monitor for efficacy and adherence. Extremely low, less than daily, statin doses may lower LDL cholesterol significantly (25). Statin–fibrate combination therapy is associated with an increased risk for abnormal transaminase levels, myositis, or rhabdomyolysis (26) and does not lower the risk of cardiovascular events more than simvastatin alone (27). Statin–niacin combination therapy is not recommended given the lack of efficacy and possible increase in risk of ischemic stroke and side effects (28). There is an increased risk of incident diabetes with statin use (29,30), but this increase is far outweighed by the reduction in cardiovascular events (31). Antiplatelet Agents Aspirin is effective in reducing cardiovascular morbidity and mortality in high-risk patients with previous myocardial infarction or stroke, but the benefit in primary prevention is more controversial both for patients with and without diabetes (32,33). Low-dose aspirin (75–162 mg/day) for primary prevention is reasonable for most men over age 50 years and most women over age 60 years with one or more major risk factors (smoking, hypertension, dyslipidemia, family history of premature CVD, and albuminuria). MICROVASCULAR COMPLICATIONS AND FOOT CARE Nephropathy Recommendations Optimize glucose control and blood pressure to reduce the risk or slow the progression of diabetic kidney disease (DKD). A At least once a year, quantitatively assess urinary albumin (e.g., urine albumin-to-creatinine ratio [UACR]) and estimated glomerular filtration rate (eGFR) in patients with type 1 diabetes duration of ≥5 years and in all patients with type 2 diabetes. B Complications of CKD correlate with levels of kidney function (Table 8). TABLE 8. Management of CKD in Diabetes* GFR (mL/min/1.73 m2) Recommended management All patients Yearly measurement of creatinine, urinary albumin excretion, potassium 45–60 Referral to a nephrologist if possibility for nondiabetic kidney disease exists (duration of type 1 diabetes <10 years, heavy proteinuria, abnormal findings on renal ultrasound, resistant hypertension, rapid fall in GFR, or active urinary sediment on urinalysis) Consider need for dose adjustment of medications Monitor eGFR every 6 months Monitor electrolytes, bicarbonate, hemoglobin, calcium, phosphorus, parathyroid hormone at least yearly Assure vitamin D sufficiency Consider bone density testing Referral for dietary counseling 30–44 Monitor eGFR every 3 months Monitor electrolytes, bicarbonate, calcium, phosphorus, parathyroid hormone, hemoglobin, albumin, weight every 3–6 months Consider need for dose adjustment of medications <30 Referral to a nephrologist * National Kidney Foundation. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis 2012;60:850–886 Intensive diabetes management with the goal of achieving near-normoglycemia has been shown in large prospective randomized studies to delay the onset and progression of increased urinary albumin excretion and reduced eGFR in patients with type 1 diabetes (1) and type 2 diabetes (34). Screening for increased urinary albumin excretion can be performed by UACR in a random spot urine collection; 24-h or timed collections are more burdensome and add little to prediction or accuracy (35,36). Two of three specimens collected within a 3- to 6-month period should be abnormal before considering a patient to have developed albuminuria. ACE inhibitors and ARBs provide selective benefit in slowing decline in GFR in patients with higher levels of albumin (37–40). ACE inhibitors reduce major CVD outcomes in patients with diabetes, supporting their use in patients with elevated albuminuria (a CVD risk factor) (41). ARBs reduce progression of albuminuria and end-stage renal disease in patients with type 2 diabetes (42–44), but they do not reduce risk of CVD events or albuminuria in normotensive patients with type 1 or type 2 diabetes (41). Additional blood pressure lowering can be accomplished with diuretics, calcium channel blockers, and β-blockers. Combining an ACE inhibitor and an ARB provides no additional benefit for CVD or DKD and has a higher adverse event risk (45). Thus, combined use should be avoided. Retinopathy Recommendations Optimize glycemic and blood pressure control to reduce the risk or slow the progression of retinopathy. A Adults with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 5 years after the onset of diabetes. B Patients with type 2 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist shortly after the diagnosis of diabetes. B Intensive diabetes management with the goal of achieving near-normoglycemia has been shown in large prospective randomized studies to prevent and/or delay the onset and progression of diabetic retinopathy (34,46). Because retinopathy is estimated to take at least 5 years to develop after the onset of hyperglycemia, patients with type 1 diabetes should have an initial dilated and comprehensive eye examination within 5 years after the diabetes diagnosis (47). These exams should be repeated annually. Photos are not a substitute for a comprehensive eye exam. Neuropathy Recommendations All patients should be screened for diabetic peripheral neuropathy (DPN) starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes and at least annually thereafter, using simple clinical tests, such as a 10-g monofilament. B Screening for signs and symptoms (e.g., orthostasis, resting tachycardia) of cardiovascular autonomic neuropathy (CAN) should be considered with more advanced disease. E Tight glycemic control is the only strategy convincingly shown to prevent or delay the development of DPN and CAN in patients with type 1 diabetes A and to slow the progression of neuropathy in some patients with type 2 diabetes. B Clinical tests for DPN include pinprick sensation, vibration threshold using 128-Hz tuning fork, and 10-g monofilament and ankle reflexes. DPN can be debilitating (48) but may be treated with pregabalin, duloxetine, and tapentadol. For persistent painful DPN, venlafaxine, amitriptyline, gabapentin, valproate, and opioids may be considered. A tailored and stepwise strategy is recommended (49). Autonomic neuropathy, particularly CAN, is an independent risk factor for cardiovascular mortality (50,51). Major clinical manifestations of autonomic neuropathy include resting tachycardia, exercise intolerance, orthostatic hypotension, gastroparesis, constipation, erectile dysfunction, impaired neurovascular function, and autonomic failure in response to hypoglycemia. In men, diabetic autonomic neuropathy may cause erectile dysfunction or retrograde ejaculation. Gastrointestinal neuropathies may involve any section of the gastrointestinal tract. Gastroparesis should be suspected in individuals with erratic glucose control and upper gastrointestinal symptoms. Constipation is the most common lower gastrointestinal symptom but can alternate with diarrhea. Gastroparesis may improve with dietary changes and prokinetic agents such as erythromycin. Due to side effects, metoclopramide is reserved for the most severe and unresponsive case. Recurrent urinary tract infections, pyelonephritis, incontinence, or palpable bladder should evoke evaluation of bladder dysfunction. Control of lipids, blood pressure, smoking, and other lifestyle factors can reduce the progression and development of CAN (52). Foot Care Recommendation For all patients with diabetes, perform an annual comprehensive foot examination to identify risk factors predictive of ulcers and amputations. The foot examination should include inspection and assessment of foot pulses. B Previous amputation, prior foot ulcer, peripheral neuropathy, foot deformity, peripheral vascular disease, visual impairment, peripheral neuropathy (especially if on dialysis), poor glycemic control, and smoking all represent high risk. Components of the screening exam include inspection of skin integrity and musculoskeletal deformity and assessment of pedal pulses. The exam should seek to identify loss of peripheral sensation (LOPS). Five simple tests (10-g monofilament, 128-Hz tuning fork, pinprick sensation, ankle reflexes, and testing vibration perception threshold with biothesiometer) can identify LOPS in the diabetic foot. Two of these tests should be performed annually. One or more abnormal tests would suggest LOPS and two or more normal tests would rule out LOPS. Screening for peripheral arterial disease (PAD) (ankle-brachial index evaluation) should include a history of claudication and assessment of pedal pulses. Screening for PAD should start at age 50 years and be considered at <50 years of age in those with PAD risk factors. Patients with high-risk foot conditions should be educated about their risk and appropriate management. This may be managed with well-fitted walking shoes that cushion the feet and redistribute pressure. Those with boney deformities may need extra wide or deep shoes. Some with more advanced disease may need custom fitted shoes. OLDER ADULTS Recommendations Older adults who are functional and cognitively intact and have significant life expectancy should receive diabetes care with goals similar to those developed for younger adults. E Glycemic goals for some older adults might reasonably be relaxed, using individual criteria, but hyperglycemia leading to symptoms or risk of acute hyperglycemic complications should be avoided in all patients. E Other cardiovascular risk factors should be treated in older adults with consideration of the time frame of benefit and the individual patient. Treatment of hypertension is indicated in virtually all older adults, and lipid-lowering and aspirin therapy may benefit those with life expectancy at least equal to the time frame of primary or secondary prevention trials. E Screening for diabetes complications should be individualized in older adults, but particular attention should be paid to complications that would lead to functional impairment. E Older adults (≥65 years of age) with diabetes should be considered a high-priority population for depression screening and treatment. B The care of older adults with diabetes is complicated by their clinical and functional heterogeneity. Providers caring for older adults with diabetes must take this heterogeneity into consideration when setting and prioritizing treatment goals (Table 9). TABLE 9. Framework for Considering Treatment Goals for Glycemia, Blood Pressure, and Dyslipidemia in Older Adults With Diabetes Patient characteristics/health status Rationale Reasonable A1C goal‡ Fasting or preprandial glucose (mg/dL) Bedtime glucose (mg/dL) Blood pressure (mmHg) Lipids Healthy (few coexisting chronic illnesses, intact cognitive and functional status) Longer remaining life expectancy <7.5% 90–130 90–150 <140/90 Statin unless contraindicated or not tolerated Complex/intermediate (multiple coexisting chronic illnesses* or 2+ instrumental ADL impairments or mild-to-moderate cognitive impairment) Intermediate remaining life expectancy, high treatment burden, hypoglycemia vulnerability, fall risk <8.0% 90–150 100–180 <140/90 Statin unless contraindicated or not tolerated Very complex/poor health (long-term care or end-stage chronic illnesses** or moderate-to-severe cognitive impairment or 2+ ADL dependencies) Limited remaining life expectancy makes benefit uncertain <8.5%† 100–180 110–200 <150/90 Consider likelihood of benefit with statin (secondary prevention more so than primary) This represents a consensus framework for considering treatment goals for glycemia, blood pressure, and dyslipidemia 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. ADL, activities of daily living. ‡ A lower A1C goal may be set for an individual if achievable without recurrent or severe hypoglycemia or undue treatment burden. * 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 (Laiteerapong N, Iveniuk J, John PM, Laumann EO, Huang ES. Classification of older adults who have diabetes by comorbid conditions, United States, 2005–2006. Prev Chronic Dis 2012;9:E100). ** The presence of a single end-stage chronic illness, such as stage 3–4 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. † A1C of 8.5% equates to an estimated average glucose of ∼200 mg/dL. Looser glycemic targets than this may expose patients to acute risks from glycosuria, dehydration, hyperglycemic hyperosmolar syndrome, and poor wound healing. Treatment Goals There are few long-term studies in older adults demonstrating the benefits of intensive glycemic, blood pressure, and lipid control. Patients who are expected to live long enough to reap the benefits of long-term intensive diabetes management, who have good cognitive and physical function, and who choose to do so via shared decision-making may be treated using therapeutic interventions and goals similar to those for younger adults with diabetes. Less intensive management goals may be appropriate for those with life-limiting complications, comorbid conditions, or substantial cognitive or functional impairment. However, glycemic goals at a minimum should avoid acute complications of diabetes, including dehydration, poor wound healing, hyperglycemic hyperosmolar coma, and hypoglycemia. DSME and ongoing DSMS are vital components of diabetes care. Benefit for older adults with diabetes is likely to result from control of other cardiovascular risk factors, particularly with respect to hypertension (53,54). There is less evidence for lipid-lowering and aspirin therapy, although the benefits of these interventions are likely to apply to older adults whose life expectancies equal or exceed the time frames seen in clinical trials. Hypoglycemia Older adults are at a higher risk of hypoglycemia for many reasons, including: Insulin deficiency Progressive renal insufficiency Unidentified cognitive deficits, causing difficulty in complex self-care activities (e.g., glucose monitoring, adjusting insulin doses) Pharmacological Therapy Special care is required in prescribing and monitoring pharmacological therapy in older adults (55). CHILDREN AND ADOLESCENTS The Centers for Disease Control and Prevention estimates that type 2 diabetes in those under 20 years of age will quadruple in 40 years (56,57). Three-quarters of all cases of type 1 diabetes are diagnosed in individuals <18 years of age. Given the current obesity epidemic, distinguishing between type 1 and type 2 diabetes in children can be difficult. The following recommendations were developed for children and adolescents with type 1 diabetes. However, the guidelines are the same for children and adolescents with type 2 diabetes with the addition of blood pressure measurement, a fasting lipid panel, assessment for albumin excretion, and dilated eye examination at type 2 diabetes diagnosis. Glycemic Control and Hypertension Recommendations An A1C goal of <7.5% is recommended across all pediatric age-groups. E Blood pressure should be measured at each routine visit. Children found to have high-normal blood pressure (SBP or DBP ≥90th percentile for age, sex, and height) or hypertension (SBP or DBP ≥95th percentile for age, sex, and height) should have blood pressure confirmed on three separate days. B The benefit of A1C control should be balanced against the risk of hypoglycemia and the developmental burden of intensive regimens for children and youth (58). Blood pressure measurements should be determined using the appropriate size cuff and with the child seated and relaxed. ACE inhibitors or ARBs should be considered first line, following appropriate reproductive counseling due to teratogenic effects. Dyslipidemia Recommendations Obtain a fasting lipid profile on children ≥2 years of age soon after the diagnosis (after glucose control has been established). E If lipids are abnormal, annual monitoring is reasonable. If LDL cholesterol values are within the accepted risk levels (<100 mg/dL [2.6 mmol/L]), a lipid profile repeated every 5 years is reasonable. E Lipids should be obtained at diagnosis of type 2 diabetes due to the presence of increased comorbid conditions (59). Annual monitoring is recommended if LDL is <100 mg/dL. For specific recommendations and additional guidance, refer to “Type 2 Diabetes in Children and Adolescents” (14). MANAGEMENT OF DIABETES IN PREGNANCY Recommendations GDM should be managed first with diet and exercise, and medications should be added if needed. A Due to alterations in red blood cell turnover that lower the normal A1C level in pregnancy, the A1C target in pregnancy is <6% if this can be achieved without significant hypoglycemia. B Medications widely used in pregnancy include insulin, metformin, and glyburide; most oral agents cross the placenta or lack long-term safety data. B Optimal glycemic goals for women with GDM and for women with preexisting type 1 or type 2 diabetes who become pregnant are available in the complete 2015 Standards (21). Insulin is the preferred agent for management due to the lack of long-term safety data for noninsulin agents. In type 2 diabetes, care with weight gain and management of comorbid conditions remains paramount (60,61). For women with GDM, screening for persistent diabetes at 6–12 weeks postpartum and every 1–3 years thereafter is recommended (62). DIABETES CARE IN THE HOSPITAL, NURSING HOME, AND SKILLED NURSING FACILITY Recommendations Diabetes discharge planning should start at hospital admission, and clear diabetes management instructions should be provided at discharge. E The sole use of sliding-scale insulin in the inpatient hospital setting is strongly discouraged. A All patients with diabetes admitted to the hospital should have their diabetes type clearly identified in the medical record. E Critically Ill Patients Insulin therapy should be initiated for treatment of persistent hyperglycemia starting at a threshold of no greater than 180 mg/dL (10 mmol/L). Once insulin therapy is started, a glucose range of 140–180 mg/dL (7.8–10 mmol/L) is recommended for the majority of critically ill patients. A More stringent goals, such as 110–140 mg/dL (6.1–7.8 mmol/L), may be appropriate for selected patients, as long as this can be achieved without significant hypoglycemia. C Critically ill patients require an intravenous insulin protocol that has demonstrated efficacy and safety in achieving the desired glucose range without increasing risk for severe hypoglycemia. E Noncritically Ill Patients If treated with insulin, generally premeal blood glucose targets of <140 mg/dL (7.8 mmol/L) with random blood glucose <180 mg/dL (10.0 mmol/L) are reasonable, provided these targets can be safely achieved. More stringent targets may be appropriate in stable patients with previous tight glycemic control. Less stringent targets may be appropriate in those with severe comorbidities. C A basal plus correction insulin regimen is the preferred treatment for patients with poor oral intake or who are taking nothing by mouth. An insulin regimen with basal, nutritional, and correction components is the preferred treatment for patients with good nutritional intake. A A hypoglycemia management protocol should be adopted and implemented by each hospital or hospital system. A plan for preventing and treating hypoglycemia should be established for each patient. Episodes of hypoglycemia in the hospital should be documented in the medical record and tracked. E Consider obtaining an A1C in patients with diabetes admitted to the hospital if the result of testing in the previous 3 months is not available. E Consider obtaining an A1C in patients with risk factors for undiagnosed diabetes who exhibit hyperglycemia in the hospital. E Patients with hyperglycemia in the hospital who do not have a prior diagnosis of diabetes should have appropriate follow-up testing and care documented at discharge. E Medical Nutrition Therapy in the Hospital No specific meal plan is endorsed by the ADA, and the term “ADA diet” should no longer be used. Consistent carbohydrate meal plans are preferred with respect to prandial insulin dosing (63). A registered dietitian, knowledgeable and skilled in medical nutrition therapy, should serve as an inpatient team member (64). Bedside Blood Glucose Monitoring Bedside point-of-care blood glucose monitoring is used to guide insulin dosing. In the patient receiving nutrition, the timing of glucose monitoring should match carbohydrate exposure. In the patient not receiving nutrition, glucose monitoring is performed every 4–6 h (65,66). More frequent blood glucose testing ranging from every 30 min to every 2 h is required for patients on intravenous insulin infusions. Discharge Planning Diabetes discharge planning, including DSME, is an important part of an overall discharge plan. An outpatient follow-up visit with the primary care provider, endocrinologist, or diabetes educator within 1 month of discharge is advised for all patients having hyperglycemia in the hospital, with clear communication of the diabetes care plan to include medication and diabetes supply (e.g., strips, lancets) reconciliation. DIABETES ADVOCACY Advocacy Position Statements For a list of ADA advocacy position statements, including “Diabetes and Driving” (67) and “Diabetes and Employment” (68), refer to the Diabetes Advocacy section of the complete 2015 Standards (69). Supplementary Material References