Treatment of T2DM

Glycemic Management in Type 2 Diabetes

The Comprehensive Care Plan

Every patient with documented type 2 diabetes (T2D) should have a comprehensive care plan (CCP), which takes into account the patient’s unique medical history, behaviors and risk factors, ethnocultural background, and environment. The ultimate goal of the CCP is to reduce the risk of diabetes complications without jeopardizing patient safety. To achieve this goal, the CCP should include the following components:1

The multidisciplinary team typically oversees the medical management of T2D, including the prescription of antihyperglycemic therapy and the delivery of diabetes self-management education (DSME). DSME is used to educate the patient on the components of therapeutic lifestyle changes, namely medical nutritional therapy (MNT) and physical activity. Each patient’s understanding of and participation in the CCP is essential to its success.1

Therapeutic Lifestyle Change

The components of therapeutic lifestyle change include:1

  • Healthful eating
  • Sufficient physical activity
  • Sufficient sleep
  • Avoidance of tobacco products
  • Limited alcohol consumption
  • Stress reduction

Nutritional Medicine

Nutritional medicine for diabetes involves counseling about general healthful eating, MNT, as well as nutritional support when appropriate (eg, in patients receiving enteral or parenteral nutrition in which medications provided for glycemic control must be synchronized with carbohydrate delivery; see AACE Inpatient Glycemic Control Resource Center for more information).1

Healthful Eating

Either the physician or a registered dietitian (RD) should discuss healthful eating recommendations in plain language at diagnosis of T2D and then periodically during follow-up office visits (Table 1). These recommendations are suitable for the general population, including people without diabetes, and focus on foods that can promote health vs foods that may promote disease or complications. Discussions should cover specific foods, dishes, meal planning, grocery shopping, and dining-out strategies.1

Table 1. AACE Healthful Eating Recommendations1

Topic

Recommendation

General eating habits

  • Eat regular meals and snacks; avoid fasting to lose weight
  • Consume plant-based diet (high in fiber, low calories/glycemic index, and high in phytochemicals/antioxidants)
  • Understand Nutrition Facts Label information
  • Incorporate beliefs and culture into discussions
  • Use mild cooking techniques instead of high-heat cooking
  • Keep physician-patient discussions informal

Carbohydrate

  • Explain the 3 types of carbohydrates—sugars, starch, and fiber—and the effects on health for each type
  • Specify healthful carbohydrates (fresh fruits and vegetables, legumes, whole grains); target 7-10 servings per day
  • Lower-glycemic index foods may facilitate glycemic control (glycemic index score <55 out of 100: multigrain bread, pumpernickel bread, whole oats, legumes, apple, lentils, chickpeas, mango, yams, brown rice), but there is insufficient evidence to support a formal recommendation to educate patients that sugars have both positive and negative health effects

Fat

  • Specify healthful fats (low mercury/contaminant-containing nuts, avocado, certain plant oils, fish)
  • Limit saturated fats (butter, fatty red meats, tropical plant oils, fast foods) and trans fat; use no- or low-fat dairy products

Protein

  • Consume most protein in foods with low saturated fats (fish, egg whites, beans); there is no need to avoid animal protein
  • Avoid or limit processed meats

Micronutrients

  • Routine supplementation is not necessary; a healthful eating meal plan can generally provide sufficient micronutrients
  • Specifically, chromium; vanadium; magnesium; vitamins A, C, and E; and CoQ10 are not recommended for glycemic control
  • Vitamin supplements should be recommended to patients at risk of insufficiency or deficiency

Medical Nutritional Therapy (MNT)

MNT involves a more detailed discussion of calories, grams, and other metrics, as well as intensive implementation of dietary recommendations aimed at optimizing glycemic control and reducing the risk for complications. Recommendations should be personalized, and in general, evaluation and teaching should be conducted by an RD or knowledgeable physician. In areas underserved by RDs, physicians should take on more responsibility with nutritional counseling and reinforcement of healthful eating patterns during patient encounters.1

Key MNT recommendations include the following:1

  • Consistency in day-to-day carbohydrate intake
  • Adjusting insulin doses to match carbohydrate intake (eg, use of carbohydrate counting)
  • Limitation of sucrose-containing or high-glycemic index foods
  • Adequate protein intake
  • “Heart-healthy” diets
  • Weight management
  • Regular physical activity
  • Increased glucose monitoring

All patients should be advised how to achieve and maintain a healthful weight, corresponding to a normal body mass index range between 18.5 to 24.9 kg/m2. Overweight individuals with T2D should strive for a 5% to 10% reduction in weight and should avoid weight gain. Recommendations should be personalized on the basis of a patient’s specific medical conditions, lifestyle, and behavior. Patients unable to maintain a healthy weight on their own should be referred to an RD or weight-loss program that has a proven success rate.

Physical Activity

Many studies have shown that regular physical activity improves glucose control in persons with T2D.2-4 Physical activity is also a main component in weight loss and maintenance programs and is particularly important in the weight maintenance phase.1,5,6 T2D patients’ physical activity regimens should consist of the following:1,6

  • 150 minutes of moderate-intensity aerobic exercise such as brisk walking or its equivalent, spread out over at least 3 days during the week, with no more than 2 consecutive days between bouts of aerobic activity
  • Moderate to vigorous resistance training 2–3 days per week
  • Daily, unstructured physical activity such as walking at least 10,000 steps over the course of the day

Patients should be advised that any physical activity is better than none, and that they should make every effort to increase their activity level. Unstructured activities include walking up or down stairs instead of using elevators, using parking spaces farther from building entrances, and the like. The use of pedometers with a goal of 10,000 steps per day can help patients improve their daily activity level.7 All physical activity routines should include flexibility and strength-training exercises with aerobic exercise.1,6 Supervised physical activity (eg, with a personal trainer) may lead to greater adherence to an exercise program and improved blood glucose control than exercise training without supervision.3

To help motivate patients, it may be useful to remind them of the following benefits of increased physical activity:1,6

  • Reduce all-cause and CV mortality
  • Reduce weight, blood pressure, and LDL-C, especially when combined with dietary changes aimed at weight loss
    • Up to 60 minutes per day may be required when relying on exercise alone for weight loss
  • Improve insulin action, blood glucose control, and fat oxidation and storage in muscle
  • Decrease the risk of falls and fractures due to enhanced muscle mass (especially resistance training)
  • Improve functional capacity and health-related quality of life, as well as reduce symptoms of depression

Additional key points to remember when counseling patients on exercise are as follows:1

  • Patients must be evaluated initially for contraindications and/or limitations to increased physical activity.
  • An exercise prescription should be developed for each patient according to both goals and limitations.
  • Additional physical activity should be started slowly and built up gradually.

Antihyperglycemic Pharmacotherapy

The goal of glycemic treatment of persons with T2DM is to achieve clinical and biochemical targets with as few adverse consequences as possible.1 Treatment recommendations from both the AACE and American Diabetes Association (ADA) emphasize this fundamental concept.8,9 These guidelines share the following key recommendations regarding the treatment of hyperglycemia:8,9

  • Glycemic goals should be individualized based on patient characteristics.
  • Antidiabetic treatment should be promptly intensified to maintain blood glucose at individual targets.
  • Combination therapy will be necessary for most patients.
  • Selection of agents should be based on individual patient medical history, behaviors, and risk factors, and environment.
  • Insulin is eventually necessary for many patients.
  • Self-monitoring of blood glucose (SMBG) is a vital tool for day-to-day management of blood sugar in all patients using insulin and many patients not using insulin.

Twelve classes of antihyperglycemic agents are available, along with several fixed-dose combinations of oral agents and fixed-ratio combinations of injectable agents, all with complementary mechanisms of action. For a complete, up-to-date list of all available agents, see the slide set Glycemic Management of Type 2 Diabetes. Efficacy and safety data for antihyperglycemic agents approved since 2004, including the dipeptidyl peptidase 4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP1) receptor agonists, sodium glucose cotransporter 2 (SGLT2) inhibitors, and newer insulin formulations, can be found in the companion slide set Glycemic Management of Type 2 Diabetes: Efficacy and Safety of Newer Antihyperglycemic Agents.

The risk-benefit profile of each class is shown in the following table; agents and combinations should be chosen to meet patients’ individual glucose control needs.

Click on image to view full-size version.

Profiles of Antidiabetic Medications table from the AACE 2017 Type 2 Diabetes Algorithm

Treatment should be intensified with the goal of safely reducing A1C to the patient’s individualized glucose target (see Type 2 Diabetes Glucose Management Goals). Agents with little or no potential for hypoglycemia or weight gain are preferred, and metformin is recommended as initial therapy for all patients unless it is contraindicated or not tolerated. A detailed discussion of each class can be found in the AACE T2D Treatment Algorithm.

Click on image to view full-size version.

Glycemic Control Algorithm from the AACE 2017 Type 2 Diabetes Algorithm

The founding principles of the algorithm are:8

  1. Lifestyle optimization is essential for all patients with diabetes. Lifestyle optimization is multifaceted, ongoing, and should engage the entire diabetes team. However, such efforts should not delay needed pharmacotherapy, which can be initiated simultaneously and adjusted based on patient response to lifestyle efforts. The need for medical therapy should not be interpreted as a failure of lifestyle management, but as an adjunct to it.
  2. Weight loss should be considered in all patients with prediabetes and T2D who also have overweight or obesity. Weight loss therapy should consist of lifestyle prescription that includes a reduced-calorie healthy meal-plan, physical activity, and behavioral interventions. Weight loss medications approved for the chronic management of obesity should also be considered if needed to obtain the degree of weight loss required to achieve therapeutic goals in prediabetes and T2D. Obesity is a chronic disease, and a long-term commitment to therapy is necessary.
  3. The A1C target should be individualized based on numerous factors, such as age, life expectancy, comorbid conditions, duration of diabetes, risk of hypoglycemia or adverse consequences from hypoglycemia, patient motivation, and adherence. An A1C level of ≤ 6.5% is considered optimal if it can be achieved in a safe and affordable manner, but higher targets may be appropriate for certain individuals and may change for a given individual over time.
  4. Glycemic control targets include fasting and postprandial glucose as determined by self-monitoring of blood glucose (SMBG).
  5. The choice of diabetes therapies must be individualized based on attributes specific to both patients and the medications themselves. Medication attributes that affect this choice include antihyperglycemic efficacy, mechanism of action, risk of inducing hypoglycemia, risk of weight gain, other adverse effects, tolerability, ease of use, likely adherence, cost, and safety in heart, kidney, or liver disease.
  6. Minimizing risk of both severe and nonsevere hypoglycemia is a priority. It is a matter of safety, adherence, and cost.
  7. Minimizing risk of weight gain is also a priority. It too is a matter of safety, adherence, and cost.
  8. The initial acquisition cost of medications is only a part of the total cost of care, which includes monitoring requirements and risks of hypoglycemia and weight gain. Safety and efficacy should be given higher priority than medication cost.
  9. This algorithm stratifies choice of therapies based on initial A1C level. It provides guidance as to what therapies to initiate and add, but respects individual circumstances that could lead to different choices.
  10. Combination therapy is usually required and should involve agents with complementary mechanisms of action.
  11. Comprehensive management includes lipid and blood pressure therapies and treatment of related comorbidities.
  12. Therapy must be evaluated frequently (eg, every 3 months) until stable using multiple criteria, including A1C, SMBG records (fasting and postprandial), documented and suspected hypoglycemia events, lipid and blood pressure values, adverse events (weight gain, fluid retention, hepatic or renal impairment, or CVD), comorbidities, other relevant laboratory data, concomitant drug administration, diabetic complications, and psychosocial factors affecting patient care. Less frequent monitoring is acceptable once targets are achieved.
  13. The therapeutic regimen should be as simple as possible to optimize adherence.

Insulin Therapy for T2D

Both AACE and the ADA/EASD recommend insulin for patients with T2D when noninsulin antihyperglycemic therapy fails to achieve the patient’s individual glycemic control target or when a patient, whether drug naive or not, has symptomatic hyperglycemia (A1C ≥9.0%).8,9

Long-acting basal insulin is generally the initial insulin choice, and the insulin analogs glargine, detemir, or degludec are strongly preferred over human NPH insulin because they have relatively peakless time-action curves and a more consistent effect from day to day, resulting in a lower risk of hypoglycemia. Concentrated insulins (eg, glargine U300 or degludec U200) may be useful for patient with a high degree of insulin resistance who require high insulin doses.8

Click on image to view full-size version.

Algorithm for Adding/Intensifying Insulin from the AACE 2017 Type 2 Diabetes Algorithm

SMBG in T2D

Noninsulin Users. Each patient should be introduced to an SMBG program upon diagnosis, along with the start of medical therapy.8,10 T2D patients not using insulin may benefit from SMBG, especially to provide feedback about the effects of their lifestyle and pharmacologic therapy, as well as alert them to episodes of hypoglycemia (if on hypoglycemic oral agents such as sulfonylureas or meglitinides).

Several studies have shown that SMBG has a positive impact on glycemia in T2D, especially when the results are used to modify behavior and/or pharmacologic treatment.11,12 Testing frequency should be personalized, but SMBG results should be used to inform decisions about whether to target FPG or PPG for any individual patient.1

Insulin Users. AACE and the ADA both recommend that SMBG should be performed by all patients using insulin.1,10,13 Glucose should be tested up to 4 times daily and before any injection of insulin. More frequent SMBG after meals or in the middle of the night may be required for insulin-taking patients with frequent hypoglycemia, patients not at A1C targets, or those with symptoms.1,10,13

CSII in T2D

CSII is recommended mainly for patients with type 1 diabetes (T1D), but patients with advanced T2D who are absolutely insulin-deficient, take 4 or more insulin injections a day, and assess their blood glucose levels 4 or more times daily are candidates for CSII. These patients must also be motivated to achieve tighter plasma glucose control and be intellectually and physically able to undergo the rigors of insulin pump therapy initiation and maintenance. Additional requirements are:1,14

  • Frequent SMBG testing
  • Mastery of carbohydrate counting, insulin correction, and adjustment formulas
  • Ability to troubleshoot problems related to pump operation and plasma glucose levels
  • Stable life situation
  • Frequent contact with members of their healthcare team, in particular their pump-supervising physician

Surgery as a Treatment Approach for T2D

Studies have confirmed that bariatric surgery can improve glycemic control or even reverse existing T2D.15,16 Some procedures, such as the Roux-en-Y gastric bypass, also have a positive effect on various neuroendocrine hormones, which may contribute to a sustained benefit.15,17

The decision to recommend bariatric surgery must be made based on the number and severity of obesity-related complications affecting each individual patient.5,8 Patients with T2D who undergo Roux-en-Y gastric bypass must have meticulous metabolic postoperative follow-up because of a risk of vitamin and mineral deficiencies and hypoglycemia.1,5

Safety and Tolerability

Safety—particularly the risk of hypoglycemia—should be the primary concern when choosing an antidiabetic therapy.8,9

Hypoglycemia

Hypoglycemia is the main limiting factor in diabetes therapy and stems from an imbalance among insulinogenic therapy, food intake, physical activity, organ function (gluconeogenesis), and counterregulation with glucagon and/or epinephrine (hypoglycemia-associated autonomic failure). Hyperinsulinemia, increased alcohol intake, starvation, and organ failure may be aggravating factors for hypoglycemia.1

Severe hypoglycemia stimulates sympathetic adrenergic discharge, causing arrhythmias or autonomic dysfunction (or both) and has long been recognized to have potential for causing mortality. Intensive glycemic control of T2D was associated with a 3- to 4-fold increase in hypoglycemia in the ACCORD, ADVANCE, and VADT trials, and in the ACCORD study, iatrogenic hypoglycemia was associated with excess mortality in both the intensively treated group and the conventionally treated group.18-22 Hypoglycemia has been implicated in the excess mortality observed in ACCORD, which occurred only in patients whose A1C remained >7% despite intensive therapy, while in the standard therapy group (A1C target 7 to 8%), mortality followed a U-shaped curve with increasing death rates at both low (<7%) and high (>8%) A1C levels.22-24

In addition to increased mortality, hypoglycemia negatively affects adherence to therapy and quality of life and also contributes to morbidity. Because hypoglycemia causes hunger, it may contribute to weight gain.1,25 A more serious consequence of recurrent hypoglycemia is brain dysfunction and increased risk of dementia, particularly in elderly individuals. Older patients are also less likely to recognize the symptoms of hypoglycemia, which can lead to a self-perpetuating cycle of recurrent hypoglycemia and hypoglycemia unawareness.26,27 Hypoglycemia unawareness is also common in patients who have marked swings in glucose levels and in these patients can be reversed by a period of intensive therapy that dampens glycemic excursions.1,25

The risk of hypoglycemia increases with the following:1,25,28

  • Age
  • Duration of diabetes
  • Duration of insulin therapy
  • Coexisting severe comorbidities
  • Hypoglycemia unawareness

Management of hypoglycemia involves appropriate choice of antihyperglycemic therapy, tailoring of insulin treatment to minimize risks, and patient education in the recognition and treatment of acute hypoglycemia (Table 2).40 It is important to remember that the features listed in Table 2 occur along a continuum, and glycemic thresholds and symptom manifestations may vary widely among individuals.

Table 2. Glycemic Thresholds, Signs, Symptoms, and Treatment of Hypoglycemia1,28

Blood Glucose (mg/dL)*

Glycemic Status

Typical Signs/Symptoms

Treatment

~50-70

Mild hypoglycemia

Neurogenic: palpitations, tremor, hunger, sweating, anxiety, paresthesia

  • Consume glucose-containing foods (fruit juice, soft drink, crackers, milk, glucose tablets); avoid foods also containing fat †
  • Repeat glucose intake if SMBG result remains low after 15 minutes
  • Consume meal or snack after SMBG has returned to normal to avoid recurrence

<50

Moderate hypoglycemia

Neuroglycopenic: behavioral changes, emotional lability, difficulty thinking, confusion

<50

Severe hypoglycemia

  • Severe confusion, unconsciousness, seizure, coma, death
  • Requires help from another individual
  • Glucagon injection, delivered by family member or other close associate
  • Victim should be taken to hospital for evaluation and treatment after any severe episode

* Glycemic thresholds vary among individuals.

† Fat may retard glucose absorption and delay recovery.

Table 3 lists antihyperglycemic agents more or less likely to cause hypoglycemia. Although agents with a low potential for hypoglycemia are preferred over oral agents that carry a higher risk of hypoglycemia (ie, sulfonylureas and meglitinides), insulin should not be withheld from patients unable to maintain glucose control on noninsulin agents because of the risk of hypoglycemia.1,8

Table 3. Antihyperglycemic Agents and Hypoglycemia8

Increased Risk of Hypoglycemia

Little to No Risk of Hypoglycemia*

  • Glinides
  • Insulin
  • Sulfonylureas
  • α-Glucosidase inhibitors
  • Bromocriptine
  • Colesevelam
  • DPP4 inhibitors
  • GLP1 receptor agonists
  • Metformin
  • SGLT2 inhibitors
  • Thiazolidinediones

* When used as monotherapy. Risk may be increased if combined with an agent likely to cause hypoglycemia.

Weight Control

As mentioned above, overweight individuals with type 2 diabetes should strive for a 5% to 10% reduction in weight and should avoid weight gain, which can be caused by several antihyperglycemic agents (Table 4).1

Table 4. Antihyperglycemic Agents and Weight Effects8

Weight Gain

Weight Neutral or Weight Loss

  • Glinides
  • Insulin
  • Sulfonylureas
  • Thiazolidinediones
  • α-Glucosidase inhibitors
  • Bromocriptine
  • Colesevelam
  • DPP4 inhibitors
  • GLP1 receptor agonists
  • Metformin
  • Pramlintide
  • SGLT2 inhibitors

For T2D patients, most of whom are overweight or obese, the risk of additional weight gain must be balanced against the benefits of the agent itself. Sulfonylureas may negate weight loss benefits of GLP1 receptor agonists, SGLT2 inhibitors, or metformin. Insulin should not be withheld from patients unable to maintain glucose control on noninsulin agents because of the risk of weight gain.1

Evidence for Other Risks Associated with Insulin Use

Evidence from prospective randomized studies do not support an association between exogenous insulin and cancer risk, which was suggested by some preliminary epidemiologic studies.1,29 In the large-scale ORIGIN (Outcome Reduction with an Initial Glargine Intervention) trial, which involved >6,000 patients receiving glargine over a median trial duration of 6 years, use of insulin glargine was not associated with an increased risk of any cancer or cancer death.30 In the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE), the rates of neoplasms were similar in the insulin degludec and glargine groups after 2 years.31

Treating T2D in Special Populations

Pediatric Patients

Once T1D and monogenic diabetes have been ruled out and a T2D diagnosis has been definitively established for a child or adolescent, diet and lifestyle modification are always the first treatment choices. However, pharmacologic therapy may be necessary. To date, metformin remains the only oral medication approved by the FDA for use in children with T2D. Insulin is effective and used widely, alone or in combination with metformin.1

The International Society of Pediatric and Adolescent Diabetes (ISPAD) published an extensive Clinical Practice Consensus Guideline for the care of diabetes in children, which is available on its Web site.

Pregnant Women with T2D

Children born to women with any form of diabetes are at greater risk of developing T2D themselves. For this reason, women of childbearing potential who have T2D should receive preconception care and guidance to try to bring A1C levels to ≤6.1%.1 A complete discussion can be found in the Pregnancy and Diabetes section of this Web site.32

Elderly Patients

Older adults are more likely to have an increased number of comorbid conditions (eg, frailty, dementia, depression, urinary incontinence) that can complicate their diabetes management. Age-related changes alone can impair vision and kidney function, reduce physical strength and stamina, and increase sensitivity to the side effects of medications.33 In addition, older patients may have impaired counter-regulatory mechanisms that make hypoglycemia unawareness and recurrent hypoglycemia more likely.34 All of these factors put older patients at an increased risk for falls.35 In addition, cognitive decline may impair patients’ understanding of and motivation for proper self-care.33,34

While relatively healthy older patients may be treated the same as younger adults with T2D, less strict glycemic goals and simpler treatment regimens are appropriate for frail patients and/or those who require a large number of medications to control other conditions, in order to minimize drug interactions and other risks of therapy. Elderly patients’ increased risk of falling should be considered before prescribing oral agents that cause hypoglycemia (glinides and sulfonylureas) or thiazolidinediones (which are associated with increased fracture risk).1

Patients Choosing to Fast

Fasting is a common religious practice that can pose a challenge to diabetes management, particularly if the fast occurs over an extended time, such as Ramadan, a holy month of Islam in which all healthy adults consume no food or fluids between sunrise and sunset. The ADA has issued a workgroup report that reviews risks and management recommendations for Ramadan, based on results of the Epidemiology of Diabetes and Ramadan (EPIDIAR) study.36 These recommendations should also be considered for patients who fast for other religious holidays or cultural reasons.

The main risks of fasting are as follows:36

  • Hypoglycemia
  • Hyperglycemia
  • Diabetic ketoacidosis
  • Dehydration and thrombosis

The risk of these outcomes depends on the severity and complications of T2D according to the categories in Table 5.

Table 5. Risk Categories for Patients Who Fast During Ramadan36

Risk Category

Features

Low

  • Glycemia well-controlled with antihyperglycemic agent that does not cause hypoglycemia (eg, metformin, thiazolidinedione, DPP-4 inhibitor, GLP-1 analog)
  • Otherwise healthy

Moderate

  • Glycemia well-controlled with glinides

High

  • Moderate hyperglycemia (A1C 7.5%-9.0%), renal insufficiency, cardiovascular complications, and/or other comorbid conditions
  • Living alone, especially if taking sulfonylureas, insulin, or drugs that affect mental activity
  • Elderly, especially with poor health

Very high

  • History of recurrent hypoglycemia, hypoglycemia unawareness, or episode of severe hypoglycemia within 3 months prior to Ramadan
  • Poor glycemic control
  • Ketoacidosis or hyperosmotic hyperglycemic coma within 3 months prior to Ramadan
  • Acute illness or chronic dialysis
  • Intense physical labor
  • Pregnancy

For the management of glycemia during extended fasts, general principles and recommendations are listed below. For a complete discussion, see the ADA Workgroup Report.36

  • Management plan individualized to meet specific patient needs
  • Frequent glucose monitoring; break the fast immediately if SMBG is <60 mg/dL or if <70 mg/dL while taking insulin or secretagogues; also break the fast if hyperglycemia occurs (>300 mg/dL)
  • Healthful eating before and after each fasting period; consider complex carbohydrates prior to fast and avoid ingesting high-carbohydrate, high-fat foods when breaking the fast
  • Avoid excessive physical activity, although normal exercise routines should be maintained
  • Avoid fasting while ill

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