Diabetes Mellitus

Manage your diabetes ABCs

Knowing your diabetes ABCs will help you manage your blood glucose, blood pressure, and cholesterol. Stopping smoking if you smoke will also help you manage your diabetes. Working toward your ABC goals can help lower your chances of having a heart attack, stroke, or other diabetes problems.

A for the A1C test
The A1C test shows your average blood glucose level over the past 3 months. The A1C goal for many people with diabetes is below 7 percent. Ask your health care team what your goal should be.

B for Blood pressure
The blood pressure goal for most people with diabetes is below 140/90 mm Hg. Ask what your goal should be.

C for Cholesterol
You have two kinds of cholesterol in your blood: LDL and HDL. LDL or “bad” cholesterol can build up and clog your blood vessels. Too much bad cholesterol can cause a heart attack or stroke. HDL or “good” cholesterol helps remove the “bad” cholesterol from your blood vessels.

Ask your health care team what your cholesterol numbers should be. If you are over 40 years of age, you may need to take a statin drug for heart health.

S for Stop smoking
Not smoking is especially important for people with diabetes because both smoking and diabetes narrow blood vessels. Blood vessel narrowing makes your heart work harder. E-cigarettes aren’t a safe option either.

If you quit smoking
• you will lower your risk for heart attack, stroke, nerve disease, kidney disease, diabetic eye disease, and amputation
• your cholesterol and blood pressure levels may improve
• your blood circulation will improve
• you may have an easier time being physically active

If you smoke or use other tobacco products, stop. Ask for help so you don’t have to do it alone. You can start by calling the national quitline at 1-800-QUITNOW or 1-800-784-8669. For tips on quitting, go to SmokeFree.gov.

Keeping your A1C, blood pressure, and cholesterol levels close to your goals and stopping smoking may help prevent the long-term harmful effects of diabetes. These health problems include heart disease, stroke, kidney disease, nerve damage, and eye disease. You can keep track of your ABCs with a diabetes care record (PDF, 568 KB). Take it with you on your health care visits. Talk about your goals and how you are doing, and whether you need to make any changes in your diabetes care plan.

Follow your diabetes meal plan
Make a diabetes meal plan with help from your health care team. Following a meal plan will help you manage your blood glucose, blood pressure, and cholesterol.

Choose fruits and vegetables, beans, whole grains, chicken or turkey without the skin, fish, lean meats, and nonfat or low-fat milk and cheese. Drink water instead of sugar-sweetened beverages. Choose foods that are lower in calories, saturated fat, trans fat, sugar, and salt. Learn more about eating, diet, and nutrition with diabetes.

Make physical activity part of your daily routine
Set a goal to be more physically active. Try to work up to 30 minutes or more of physical activity on most days of the week.

Brisk walking and swimming are good ways to move more. If you are not active now, ask your health care team about the types and amounts of physical activity that are right for you. Learn more about being physically active with diabetes.

Following your meal plan and being more active can help you stay at or get to a healthy weight. If you are overweight or obese, work with your health care team to create a weight-loss plan that is right for you.

Take your medicine
Take your medicines for diabetes and any other health problems, even when you feel good or have reached your blood glucose, blood pressure, and cholesterol goals. These medicines help you manage your ABCs. Ask your doctor if you need to take aspirin to prevent a heart attack or stroke. Tell your health care professional if you cannot afford your medicines or if you have any side effects from your medicines. Learn more about insulin and other diabetes medicines.

Check your blood glucose levels
For many people with diabetes, checking their blood glucose level each day is an important way to manage their diabetes. Monitoring your blood glucose level is most important if you take insulin. The results of blood glucose monitoring can help you make decisions about food, physical activity, and medicines.

The most common way to check your blood glucose level at home is with a blood glucose meter. You get a drop of blood by pricking the side of your fingertip with a lancet. Then you apply the blood to a test strip. The meter will show you how much glucose is in your blood at the moment.

Ask your health care team how often you should check your blood glucose levels. Make sure to keep a record of your blood glucose self-checks. You can print copies of this glucose self-check chart (PDF, 2 MB). Take these records with you when you visit your health care team.

What is continuous glucose monitoring?
Continuous glucose monitoring (CGM) is another way to check your glucose levels. Most CGM systems use a tiny sensor that you insert under your skin. The sensor measures glucose levels in the fluids between your body’s cells every few minutes and can show changes in your glucose level throughout the day and night. If the CGM system shows that your glucose is too high or too low, you should check your glucose with a blood glucose meter before making any changes to your eating plan, physical activity, or medicines. A CGM system is especially useful for people who use insulin and have problems with low blood glucose.

What are the recommended targets for blood glucose levels?
Many people with diabetes aim to keep their blood glucose at these normal levels:
• Before a meal: 80 to 130 mg/dL
• About 2 hours after a meal starts: less than 180 mg/dL

Talk with your health care team about the best target range for you. Be sure to tell your health care professional if your glucose levels often go above or below your target range.

What happens if my blood glucose level becomes too low?
Sometimes blood glucose levels drop below where they should be, which is called hypoglycemia. For most people with diabetes, the blood glucose level is too low when it is below 70 mg/dL.

Hypoglycemia can be life threatening and needs to be treated right away. Learn more about how to recognize and treat hypoglycemia.

What happens if my blood glucose level becomes too high?
Doctors call high blood glucose hyperglycemia.
Symptoms that your blood glucose levels may be too high include
• feeling thirsty
• feeling tired or weak
• headaches
• urinating often
• blurred vision

If you often have high blood glucose levels or symptoms of high blood glucose, talk with your health care team. You may need a change in your diabetes meal plan, physical activity plan, or medicines.

Know when to check for ketones
Your doctor may want you to check your urine for ketones if you have symptoms of diabetic ketoacidosis. When ketone levels get too high, you can develop this life-threatening condition. Symptoms include
• trouble breathing
• nausea or vomiting
• pain in your abdomen
• confusion
• feeling very tired or sleepy

Ketoacidosis most often is a problem for people with type 1 diabetes.

Work with your health care team
Most people with diabetes get health care from a primary care professional. Primary care professionals include internists, family physicians, and pediatricians. Sometimes physician assistants and nurses with extra training, called nurse practitioners, provide primary care. You also will need to see other care professionals from time to time. A team of health care professionals can help you improve your diabetes self-care. Remember, you are the most important member of your health care team.

Besides a primary care professional, your health care team may include
• an endocrinologist for more specialized diabetes care
• a registered dietitian, also called a nutritionist
• a nurse
• a certified diabetes educator
• a pharmacist
• a dentist
• an eye doctor
• a podiatrist, or foot doctor, for foot care
• a social worker, who can help you find financial aid for treatment and community resources
• a counselor or other mental health care professional

When you see members of your health care team, ask questions. Write a list of questions you have before your visit so you don’t forget what you want to ask. Watch a video to help you get ready for your diabetes care visit.

You should see your health care team at least twice a year, and more often if you are having problems or are having trouble reaching your blood glucose, blood pressure, or cholesterol goals. At each visit, be sure you have a blood pressure check, foot check, and weight check; and review your self-care plan. Talk with your health care team about your medicines and whether you need to adjust them. Routine health care will help you find and treat any health problems early, or may be able to help prevent them.

Talk with your doctor about what vaccines you should get  to keep from getting sick, such as a flu shot and pneumonia shot. Preventing illness is an important part of taking care of your diabetes. Your blood glucose levels are more likely to go up when you’re sick or have an infection. Learn more about taking care of your diabetes when you’re sick and during other special times, such as when you’re traveling.

Cope with your diabetes in healthy ways
Feeling stressed, sad, or angry is common when you live with diabetes. Stress can raise your blood glucose levels, but you can learn ways to lower your stress. Try deep breathing, gardening, taking a walk, doing yoga, meditating, doing a hobby, or listening to your favorite music. Consider taking part in a diabetes education program or support group that teaches you techniques for managing stress. Learn more about healthy ways to cope with stress.

Depression is common among people with a chronic, or long-term, illness . Depression can get in the way of your efforts to manage your diabetes. Ask for help if you feel down. A mental health counselor, support group, clergy member, friend, or family member who will listen to your feelings may help you feel better.

Try to get 7 to 8 hours of sleep each night. Getting enough sleep can help improve your mood and energy level. You can take steps to improve your sleep habits . If you often feel sleepy during the day, you may have obstructive sleep apnea , a condition in which your breathing briefly stops many times during the night. Sleep apnea is common in people who have diabetes. Talk with your health care team if you think you have a sleep problem.

Remember, managing diabetes isn’t easy, but it’s worth it.
November 2016

Diabetes Tests & Diagnosis

Your health care professional can diagnose diabetes, prediabetes, and gestational diabetes through blood tests. The blood tests show if your blood glucose, also called blood sugar, is too high.

Do not try to diagnose yourself if you think you might have diabetes. Testing equipment that you can buy over the counter, such as a blood glucose meter, cannot diagnose diabetes.

Who should be tested for diabetes?
Anyone who has symptoms of diabetes should be tested for the disease. Some people will not have any symptoms but may have risk factors for diabetes and need to be tested.

Testing also allows health care professionals to find prediabetes. Making lifestyle changes to lose a modest amount of weight if you are overweight may help you delay or prevent type 2 diabetes.

Type 1 diabetes
Most often, testing for type 1 diabetes occurs in people with diabetes symptoms. Doctors usually diagnose type 1 diabetes in children and young adults. Because type 1 diabetes can run in families, a study called TrialNet offers free testing to family members of people with the disease, even if they don’t have symptoms.

Type 2 diabetes
Experts recommend routine testing for type 2 diabetes if you
•are age 45 or older
•are between the ages of 19 and 44, are overweight or obese, and have one or more other diabetes risk factors
•are a woman who had gestational diabetes

1American Diabetes Association. Classification and diagnosis of diabetes. Diabetes Care. 2016;39(Suppl. 1):S13–S22.========================================
Though type 2 diabetes most often develops in adults, children also can develop type 2 diabetes. Experts recommend testing children between the ages of 10 and 18 who are overweight or obese and have at least two other risk factors for developing diabetes.
•low birthweight
•a mother who had diabetes while pregnant with them
•any risk factor mentioned in Risk Factors for Type 2 Diabetes

Gestational diabetes
All pregnant women who do not have a prior diabetes diagnosis should be tested for gestational diabetes. If you are pregnant, you will take a glucose challenge test between 24 and 28 weeks of pregnancy.

What tests are used to diagnose diabetes and prediabetes?
Health care professionals most often use the fasting plasma glucose (FPG) test or the A1C test to diagnose diabetes. In some cases, they may use a random plasma glucose (RPG) test.

Fasting plasma glucose (FPG) test
The FPG blood test measures your blood glucose level at a single point in time. For the most reliable results, it is best to have this test in the morning, after you fast for at least 8 hours. Fasting means having nothing to eat or drink except sips of water.

A1C test
The A1C test is a blood test that provides your average levels of blood glucose over the past 3 months. Other names for the A1C test are hemoglobin A1C, HbA1C, glycated hemoglobin, and glycosylated hemoglobin test. You can eat and drink before this test. When it comes to using the A1C to diagnose diabetes, your doctor will consider factors such as your age and whether you have anemia or another problem with your blood. The A1C test is not accurate in people with anemia.

If you’re of African, Mediterranean, or Southeast Asian descent, your A1C test results may be falsely high or low. Your health care professional may need to order a different type of A1C test.

Your health care professional will report your A1C test result as a percentage, such as an A1C of 7 percent. The higher the percentage, the higher your average blood glucose levels.

People with diabetes also use information from the A1C test to help manage their diabetes.

Random plasma glucose (RPG) test
Sometimes health care professionals use the RPG test to diagnose diabetes when diabetes symptoms are present and they do not want to wait until you have fasted. You do not need to fast overnight for the RPG test. You may have this blood test at any time.

What tests are used to diagnose gestational diabetes?
Pregnant women may have the glucose challenge test, the oral glucose tolerance test, or both. These tests show how well your body handles glucose.

Glucose challenge test
If you are pregnant and a health care professional is checking you for gestational diabetes, you may first receive the glucose challenge test. Another name for this test is the glucose screening test. In this test, a health care professional will draw your blood 1 hour after you drink a sweet liquid containing glucose. You do not need to fast for this test. If your blood glucose is too high—135 to 140 or more—you may need to return for an oral glucose tolerance test while fasting.

Oral glucose tolerance test (OGTT)
The OGTT measures blood glucose after you fast for at least 8 hours. First, a health care professional will draw your blood. Then you will drink the liquid containing glucose. For diagnosing gestational diabetes, you will need your blood drawn every hour for 2 to 3 hours.

High blood glucose levels at any two or more blood test times during the OGTT—fasting, 1 hour, 2 hours, or 3 hours—mean you have gestational diabetes. Your health care team will explain what your OGTT results mean.

Health care professionals also can use the OGTT to diagnose type 2 diabetes and prediabetes in people who are not pregnant. The OGTT helps health care professionals detect type 2 diabetes and prediabetes better than the FPG test. However, the OGTT is a more expensive test and is not as easy to give. To diagnose type 2 diabetes and prediabetes, a health care professional will need to draw your blood 1 hour after you drink the liquid containing glucose and again after 2 hours.

What test numbers tell me if I have diabetes or prediabetes?
Each test to detect diabetes and prediabetes uses a different measurement. Usually, the same test method needs to be repeated on a second day to diagnose diabetes. Your doctor may also use a second test method to confirm that you have diabetes.

The following table helps you understand what your test numbers mean if you are not pregnant.

Glucose values are in milligrams per deciliter, or mg/dL.
Oral glucose tolerance test (OGTT): At 2 hours after drinking 75 grams of glucose. To diagnose gestational diabetes, health care professionals give more glucose to drink and use different numbers as cutoffs.
Source: Adapted from American Diabetes Association. Classification and diagnosis of diabetes. Diabetes Care. 2016;39(1):S14–S20, tables 2.1, 2.3.

Which tests help my health care professional know what kind of diabetes I have?
Even though the tests described here can confirm that you have diabetes, they can’t identify what type you have. Sometimes health care professionals are unsure if diabetes is type 1 or type 2. A rare type of diabetes that can occur in babies, called monogenic diabetes, can also be mistaken for type 1 diabetes. Treatment depends on the type of diabetes, so knowing which type you have is important.

To find out if your diabetes is type 1, your health care professional may look for certain autoantibodies. Autoantibodies are antibodies that mistakenly attack your healthy tissues and cells. The presence of one or more of several types of autoantibodies specific to diabetes is common in type 1 diabetes, but not in type 2 or monogenic diabetes. A health care professional will have to draw your blood for this test.

If you had diabetes while you were pregnant, you should get tested no later than 12 weeks after your baby is born to see if you have type 2 diabetes.

Managing Diabetes

November 2016

You can manage your diabetes and live a long and healthy life by taking care of yourself each day.

Diabetes can affect almost every part of your body. Therefore, you will need to manage your blood glucose levels, also called blood sugar. Managing your blood glucose, as well as your blood pressure and cholesterol, can help prevent the health problems that can occur when you have diabetes.

How can I manage my diabetes?
With the help of your health care team, you can create a diabetes self-care plan to manage your diabetes. Your self-care plan may include these steps:

Ways to manage your diabetes
• Manage your diabetes ABCs.
• Follow your diabetes meal plan.
• Make physical activity part of your routine.
• Take your medicine.
• Check your blood glucose levels.
• Work with your health care team.
• Cope with your diabetes in healthy ways.

Manage your diabetes ABCs
Knowing your diabetes ABCs will help you manage your blood glucose, blood pressure, and cholesterol. Stopping smoking if you smoke will also help you manage your diabetes. Working toward your ABC goals can help lower your chances of having a heart attack, stroke, or other diabetes problems.

A for the A1C test
The A1C test shows your average blood glucose level over the past 3 months. The A1C goal for many people with diabetes is below 7 percent. Ask your health care team what your goal should be.

B for Blood pressure
The blood pressure goal for most people with diabetes is below 140/90 mm Hg. Ask what your goal should be.

C for Cholesterol
You have two kinds of cholesterol in your blood: LDL and HDL. LDL or “bad” cholesterol can build up and clog your blood vessels. Too much bad cholesterol can cause a heart attack or stroke. HDL or “good” cholesterol helps remove the “bad” cholesterol from your blood vessels.

Ask your health care team what your cholesterol numbers should be. If you are over 40 years of age, you may need to take a statin drug for heart health.

S for Stop smoking
Not smoking is especially important for people with diabetes because both smoking and diabetes narrow blood vessels. Blood vessel narrowing makes your heart work harder. E-cigarettes aren’t a safe option either.

If you quit smoking
• you will lower your risk for heart attack, stroke, nerve disease, kidney disease, diabetic eye disease, and amputation
• your cholesterol and blood pressure levels may improve
• your blood circulation will improve
• you may have an easier time being physically active

If you smoke or use other tobacco products, stop. Ask for help so you don’t have to do it alone. You can start by calling the national quitline at 1-800-QUITNOW or 1-800-784-8669. For tips on quitting, go to SmokeFree.gov.

Keeping your A1C, blood pressure, and cholesterol levels close to your goals and stopping smoking may help prevent the long-term harmful effects of diabetes. These health problems include heart disease, stroke, kidney disease, nerve damage, and eye disease. You can keep track of your ABCs with a diabetes care record (PDF, 568 KB). Take it with you on your health care visits. Talk about your goals and how you are doing, and whether you need to make any changes in your diabetes care plan.

Follow your diabetes meal plan
Make a diabetes meal plan with help from your health care team. Following a meal plan will help you manage your blood glucose, blood pressure, and cholesterol.

Choose fruits and vegetables, beans, whole grains, chicken or turkey without the skin, fish, lean meats, and nonfat or low-fat milk and cheese. Drink water instead of sugar-sweetened beverages. Choose foods that are lower in calories, saturated fat, trans fat, sugar, and salt. Learn more about eating, diet, and nutrition with diabetes.

Make physical activity part of your daily routine
Set a goal to be more physically active. Try to work up to 30 minutes or more of physical activity on most days of the week.

Brisk walking and swimming are good ways to move more. If you are not active now, ask your health care team about the types and amounts of physical activity that are right for you. Learn more about being physically active with diabetes.
Swimming or water walking is a good way to move more.
Following your meal plan and being more active can help you stay at or get to a healthy weight. If you are overweight or obese, work with your health care team to create a weight-loss plan that is right for you.

Take your medicine
Take your medicines for diabetes and any other health problems, even when you feel good or have reached your blood glucose, blood pressure, and cholesterol goals. These medicines help you manage your ABCs. Ask your doctor if you need to take aspirin to prevent a heart attack or stroke. Tell your health care professional if you cannot afford your medicines or if you have any side effects from your medicines. Learn more about insulin and other diabetes medicines.

Check your blood glucose levels
For many people with diabetes, checking their blood glucose level each day is an important way to manage their diabetes. Monitoring your blood glucose level is most important if you take insulin. The results of blood glucose monitoring can help you make decisions about food, physical activity, and medicines.
Checking and recording your blood glucose level is an important part of managing diabetes.
The most common way to check your blood glucose level at home is with a blood glucose meter. You get a drop of blood by pricking the side of your fingertip with a lancet. Then you apply the blood to a test strip. The meter will show you how much glucose is in your blood at the moment.

Ask your health care team how often you should check your blood glucose levels. Make sure to keep a record of your blood glucose self-checks. You can print copies of this glucose self-check chart (PDF, 2 MB). Take these records with you when you visit your health care team.

What is continuous glucose monitoring?
Continuous glucose monitoring (CGM) is another way to check your glucose levels. Most CGM systems use a tiny sensor that you insert under your skin. The sensor measures glucose levels in the fluids between your body’s cells every few minutes and can show changes in your glucose level throughout the day and night. If the CGM system shows that your glucose is too high or too low, you should check your glucose with a blood glucose meter before making any changes to your eating plan, physical activity, or medicines. A CGM system is especially useful for people who use insulin and have problems with low blood glucose.

What are the recommended targets for blood glucose levels?
Many people with diabetes aim to keep their blood glucose at these normal levels:
• Before a meal: 80 to 130 mg/dL
• About 2 hours after a meal starts: less than 180 mg/dL

Talk with your health care team about the best target range for you. Be sure to tell your health care professional if your glucose levels often go above or below your target range.

What happens if my blood glucose level becomes too low?

Sometimes blood glucose levels drop below where they should be, which is called hypoglycemia. For most people with diabetes, the blood glucose level is too low when it is below 70 mg/dL.

Hypoglycemia can be life threatening and needs to be treated right away. Learn more about how to recognize and treat hypoglycemia.

What happens if my blood glucose level becomes too high?
Doctors call high blood glucose hyperglycemia.

Symptoms that your blood glucose levels may be too high include
• feeling thirsty
• feeling tired or weak
• headaches
• urinating often
• blurred vision

If you often have high blood glucose levels or symptoms of high blood glucose, talk with your health care team. You may need a change in your diabetes meal plan, physical activity plan, or medicines.

Know when to check for ketones
Your doctor may want you to check your urine  for ketones if you have symptoms of diabetic ketoacidosis . When ketone levels get too high, you can develop this life-threatening condition. Symptoms include
• trouble breathing
• nausea or vomiting
• pain in your abdomen
• confusion
• feeling very tired or sleepy

Ketoacidosis most often is a problem for people with type 1 diabetes.

Work with your health care team
Most people with diabetes get health care from a primary care professional. Primary care professionals include internists, family physicians, and pediatricians. Sometimes physician assistants and nurses with extra training, called nurse practitioners, provide primary care. You also will need to see other care professionals from time to time. A team of health care professionals can help you improve your diabetes self-care. Remember, you are the most important member of your health care team.

Besides a primary care professional, your health care team may include
• an endocrinologist for more specialized diabetes care
• a registered dietitian, also called a nutritionist
• a nurse
• a certified diabetes educator
• a pharmacist
• a dentist
• an eye doctor
• a podiatrist, or foot doctor, for foot care
• a social worker, who can help you find financial aid for treatment and community resources
• a counselor or other mental health care professional

When you see members of your health care team, ask questions. Write a list of questions you have before your visit so you don’t forget what you want to ask. Watch a video to help you get ready for your diabetes care visit.

When you see your doctor, review your diabetes self-care plan and blood glucose chart.
You should see your health care team at least twice a year, and more often if you are having problems or are having trouble reaching your blood glucose, blood pressure, or cholesterol goals. At each visit, be sure you have a blood pressure check, foot check, and weight check; and review your self-care plan. Talk with your health care team about your medicines and whether you need to adjust them. Routine health care will help you find and treat any health problems early, or may be able to help prevent them.

Talk with your doctor about what vaccines you should get  to keep from getting sick, such as a flu shot and pneumonia shot. Preventing illness is an important part of taking care of your diabetes. Your blood glucose levels are more likely to go up when you’re sick or have an infection. Learn more about taking care of your diabetes when you’re sick and during other special times, such as when you’re traveling.

Cope with your diabetes in healthy ways
Feeling stressed, sad, or angry is common when you live with diabetes. Stress can raise your blood glucose levels, but you can learn ways to lower your stress. Try deep breathing, gardening, taking a walk, doing yoga, meditating, doing a hobby, or listening to your favorite music. Consider taking part in a diabetes education program or support group that teaches you techniques for managing stress. Learn more about healthy ways to cope with stress.

Depression is common among people with a chronic, or long-term, illness . Depression can get in the way of your efforts to manage your diabetes. Ask for help if you feel down. A mental health counselor, support group, clergy member, friend, or family member who will listen to your feelings may help you feel better.

Try to get 7 to 8 hours of sleep each night. Getting enough sleep can help improve your mood and energy level. You can take steps to improve your sleep habits . If you often feel sleepy during the day, you may have obstructive sleep apnea , a condition in which your breathing briefly stops many times during the night. Sleep apnea is common in people who have diabetes. Talk with your health care team if you think you have a sleep problem.

Remember, managing diabetes isn’t easy, but it’s worth it.

Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2018

CLASSIFICATION
Diabetes can be classified into the following general categories:
1. Type 1 diabetes (due to autoimmune β-cell destruction, usually leading to absolute insulin deficiency)
2. Type 2 diabetes (due to a progressive loss of β-cell insulin secretion frequently on the background of insulin resistance)
3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation)
4. 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 pancreatitis), and drug- or chemical-induced diabetes (such as with glucocorticoid use, in the treatment of HIV/AIDS, or after organ transplantation)

Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinical presentation and disease progression may vary considerably. Classification is important for determining therapy, but some individuals cannot be clearly classified as having type 1 or type 2 diabetes at the time of diagnosis. The traditional paradigms of type 2 diabetes occurring only in adults and type 1 diabetes only in children are no longer accurate, as both diseases occur in both age-groups. Children with type 1 diabetes typically present with the hallmark symptoms of polyuria/polydipsia, and approximately one-third present with diabetic ketoacidosis (DKA). The onset of type 1 diabetes may be more variable in adults, and they may not present with the classic symptoms seen in children. Occasionally, patients with type 2 diabetes may present with DKA, particularly ethnic minorities. Although difficulties in distinguishing diabetes type may occur in all age-groups at onset, the true diagnosis becomes more obvious over time.

In both type 1 and type 2 diabetes, various genetic and environmental factors can result in the progressive loss of β-cell mass and/or function that manifests clinically as hyperglycemia. Once hyperglycemia occurs, patients with all forms of diabetes are at risk for developing the same chronic complications, although rates of progression may differ. The identification of individualized therapies for diabetes in the future will require better characterization of the many paths to β-cell demise or dysfunction.

Characterization of the underlying pathophysiology is more developed in type 1 diabetes than in type 2 diabetes.
It is now clear from studies of first-degree relatives of patients with type 1 diabetes that the persistent presence of two or more autoantibodies is an almost certain predictor of clinical hyperglycemia and diabetes.
The rate of progression is dependent on the age at first detection of antibody, number of antibodies, antibody specificity, and antibody titer.
Glucose and A1C levels rise well before the clinical onset of diabetes, making diagnosis feasible well before the onset of DKA.

Three distinct stages of type 1 diabetes can be identified (Table) and serve as a framework for future research and regulatory decision-making.

Fasting is defined as no caloric intake for at least 8 h.
2-h PG test should be performed as described by the WHO, using ag lucose load containing the equivalent of 75-g anhydrous glucose dissolved in water.
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL is diagnostic for diabetes.
*In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing.
*For all three tests in prediabetes, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at the higher end of the range.

DIAGNOSTIC TESTS FOR DIABETES

Diabetes may be diagnosed based on plasma glucose criteria, either the fasting plasma glucose (FPG) or the 2-h plasma glucose (2-h PG) value during a 75-g oral glucose tolerance test (OGTT), or A1C criteria (6) (Table above).

Generally, FPG, 2-h PG during 75-g OGTT, and A1C are equally appropriate for diagnostic testing. It should be noted that the tests do not necessarily detect diabetes in the same individuals. The efficacy of interventions for primary prevention of type 2 diabetes has primarily been demonstrated among individuals who have impaired glucose tolerance (IGT) with or without elevated fasting glucose, not for individuals with isolated impaired fasting glucose (IFG) or for those with prediabetes defined by A1C criteria.

The same tests may be used to screen for and diagnose diabetes and to detect individuals with prediabetes. Diabetes may be identified anywhere along the spectrum of clinical scenarios: in seemingly low-risk individuals who happen to have glucose testing, in individuals tested based on diabetes risk assessment, and in symptomatic patients.

Fasting and 2-Hour Plasma Glucose
The FPG and 2-h PG may be used to diagnose diabetes (Table: Criteria for the diagnosis). The concordance between the FPG and 2-h PG tests is imperfect, as is the concordance between A1C and either glucose-based test. Numerous studies have confirmed that compared with FPG and A1C cut points, the 2-h PG value diagnoses more people with diabetes.

A1C

Recommendations
• To avoid misdiagnosis or missed diagnosis, the A1C test should be performed using a method that is certified by the NGSP and standardized to the Diabetes Control and Complications Trial (DCCT) assay. B Level of evidence

• Marked discordance between measured A1C and plasma glucose levels should raise the possibility of A1C assay interference due to hemoglobin variants (i.e., hemoglobinopathies) and consideration of using an assay without interference or plasma blood glucose criteria to diagnose diabetes. B

• In conditions associated with increased red blood cell turnover, such as sickle cell disease, pregnancy (second and third trimesters), hemodialysis, recent blood loss or transfusion, or erythropoietin therapy, only plasma blood glucose criteria should be used to diagnose diabetes. B

The A1C test should be performed using a method that is certified by the NGSP (www.ngsp.org) and standardized or traceable to the Diabetes Control and Complications Trial (DCCT) reference assay. Although point-of-care A1C assays may be NGSP certified, proficiency testing is not mandated for performing the test, so use of point-of-care assays for diagnostic purposes is not recommended but may be considered in the future if proficiency testing is performed, documented, and deemed acceptable.

The A1C has several advantages compared with the FPG and OGTT, including greater convenience (fasting not required), greater preanalytical stability, and less day-to-day perturbations during stress and illness. However, these advantages may be offset by the lower sensitivity of A1C at the designated cut point, greater cost, limited availability of A1C testing in certain regions of the developing world, and the imperfect correlation between A1C and average glucose in certain individuals. National Health and Nutrition Examination Survey (NHANES) data indicate that an A1C cut point of ≥6.5% (48 mmol/mol) identifies a prevalence of undiagnosed diabetes that is one-third of that using glucose criteria.

When using A1C to diagnose diabetes, it is important to recognize that A1C is an indirect measure of average blood glucose levels and to take other factors into consideration that may impact hemoglobin glycation independently of glycemia including age, race/ethnicity, and anemia/hemoglobinopathies.

Age
The epidemiological studies that formed the basis for recommending A1C to diagnose diabetes included only adult populations. Therefore, it remains unclear whether A1C and the same A1C cut point should be used to diagnose diabetes in children and adolescents (see p. S20 screening and testing for type 2 diabetes and prediabetes in children and adolescents for additional information).

Race/Ethnicity/Hemoglobinopathies
Hemoglobin variants can interfere with the measurement of A1C, although most assays in use in the U.S. are unaffected by the most common variants. Marked discrepancies between measured A1C and plasma glucose levels should prompt consideration that the A1C assay may not be reliable for that individual. For patients with a hemoglobin variant but normal red blood cell turnover, such as those with the sickle cell trait, an A1C assay without interference from hemoglobin variants should be used. An updated list of A1C assays with interferences is available at www.ngsp.org/interf.asp.

African Americans heterozygous for the common hemoglobin variant HbS may have, for any given level of mean glycemia, lower A1C by about 0.3% than those without the trait (11). Another genetic variant, X-linked glucose-6-phosphate dehydrogenase G202A, carried by 11% of African Americans, was associated with a decrease in A1C of about 0.8% in hemizygous men and 0.7% in homozygous women compared with those without the variant.

Even in the absence of hemoglobin variants, A1C levels may vary with race/ethnicity independently of glycemia. For example, African Americans may have higher A1C levels than non-Hispanic whites with similar fasting and postglucose load glucose levels, and A1C levels may be higher for a given mean glucose concentration when measured with continuous glucose monitoring. Though conflicting data exists, African Americans may also have higher levels of fructosamine and glycated albumin and lower levels of 1,5-anhydroglucitol, suggesting that their glycemic burden (particularly postprandially) may be higher. The association of A1C with risk for complications appears to be similar in African Americans and non-Hispanic whites.

Red Blood Cell Turnover
In conditions associated with increased red blood cell turnover, such as sickle cell disease, pregnancy (second and third trimesters), hemodialysis, recent blood loss or transfusion, or erythropoietin therapy, only plasma blood glucose criteria should be used to diagnose diabetes.

Confirming the Diagnosis
Unless there is a clear clinical diagnosis (e.g., patient in a hyperglycemic crisis or with classic symptoms of hyperglycemia and a random plasma glucose ≥200 mg/dL [11.1 mmol/L]), a second test is required for confirmation. It is recommended that the same test be repeated or a different test be performed without delay using a new blood sample for confirmation. For example, if the A1C is 7.0% (53 mmol/mol) and a repeat result is 6.8% (51 mmol/mol), the diagnosis of diabetes is confirmed. If two different tests (such as A1C and FPG) are both above the diagnostic threshold, this also confirms the diagnosis. On the other hand, if a patient has discordant results from two different tests, then the test result that is above the diagnostic cut point should be repeated, with consideration of the possibility of A1C assay interference. The diagnosis is made on the basis of the confirmed test. For example, if a patient meets the diabetes criterion of the A1C (two results ≥6.5% [48 mmol/mol]) but not FPG (<126 mg/dL [7.0 mmol/L]), that person should nevertheless be considered to have diabetes.

Since all the tests have preanalytic and analytic variability, it is possible that an abnormal result (i.e., above the diagnostic threshold), when repeated, will produce a value below the diagnostic cut point. This scenario is likely for FPG and 2-h PG if the glucose samples remain at room temperature and are not centrifuged promptly. Because of the potential for preanalytic variability, it is critical that samples for plasma glucose be spun and separated immediately after they are drawn. If patients have test results near the margins of the diagnostic threshold, the health care professional should follow the patient closely and repeat the test in 3–6 months.

Tabe 2.3: CATEGORIES OF INCREASED RISK FOR DIABETES (PREDIABETES)

Recommendations
• Screening for prediabetes and risk for future diabetes with an informal assessment of risk factors or validated tools should be considered in asymptomatic adults. B
• Testing for prediabetes and risk for future 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 (Table 2.3). B
• For all people, 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
• To test for prediabetes, fasting plasma glucose, 2-h plasma glucose during 75-g oral glucose tolerance test, and A1C are equally appropriate. B
• In patients with prediabetes, identify and, if appropriate, treat other cardiovascular disease risk factors. B
• Testing for prediabetes should be considered in children and adolescents who are overweight or obese (BMI >85th percentile for age and sex, weight for height >85th percentile, or weight >120% of ideal for height) and who have additional risk factors for diabetes (Table 2.5). E

Description
“Prediabetes” is the term used for individuals whose glucose levels do not meet the criteria for diabetes but are too high to be considered normal. Patients with prediabetes are defined by the presence of IFG and/or IGT and/or A1C 5.7–6.4% (39–47 mmol/mol) (Table 2.4).

Table 2.4—Categories of increased risk for diabetes (prediabetes)*
(Criteria for the diagnosis of prediabetes)
FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) (IFG)
OR
2-h PG during 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) (IGT)
OR
A1C 5.7–6.4% (39–47 mmol/mol)

*For all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at the higher end of the range.

Prediabetes should not be viewed as a clinical entity in its own right but rather as an increased risk for diabetes and cardiovascular disease (CVD). Criteria for testing for diabetes or prediabetes in asymptomatic adults is outlined in Table 2.3. Prediabetes is associated with obesity (especially abdominal or visceral obesity), dyslipidemia with high triglycerides and/or low HDL cholesterol, and hypertension.

Table 2.3—Criteria for testing for diabetes or prediabetes in asymptomatic adults
1. Testing should be considered in overweight or obese (BMI≥25 kg/m2 or≥23 kg/m2 in Asian Americans) adults who have one or more of the following risk factors:
• First-degree relative with diabetes
• High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander)
• History of CVD
• Hypertension (≥140/90 mmHg or on therapy for hypertension)
• HDL cholesterol level<35 mg/dL (0.90 mmol/L) and/or a triglyceride level≥250 mg/dL (2.82 mmol/L)
• Women with polycystic ovary syndrome
• Physical inactivity
• Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans)
2. Patients with prediabetes (A1C≥5.7% [39 mmol/mol], IGT, or IFG) should be tested yearly.
3. Women who were diagnosed with GDM should have lifelong testing at least every 3 years.
4. For all other patients, testing should begin at age 45 years.
5. If results are normal, testing should be repeated at a minimum of 3-year intervals, with consideration of more frequent testing depending on initial results and risk status.

Table 2.5 — Risk-based screening for type 2 diabetes or prediabetes in asymptomatic children and adolescents in a clinical setting* (*Persons aged < 18 years.)
Criteria
• Overweight (BMI>85th percentile for age and sex, weight for height>85th percentile, or weight>120% of ideal for height) A
Plus one or more additional risk factors based on the strength of their association with diabetes as indicated by evidence grades:
• Maternal history of diabetes or GDM during the child’s gestation A
• Family history of type 2 diabetes infirst- or second-degree relative A
• Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander) A
• Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational-age birth weight) B

Diagnosis of Prediabetes

IFG is defined as FPG levels between 100 and 125 mg/dL (between 5.6 and 6.9 mmol/L) (24,25) and IGT as 2-h PG during 75-g OGTT levels between 140 and 199 mg/dL (between 7.8 and 11.0 mmol/L).
It should be noted that the World Health Organization (WHO) and numerous other diabetes organizations define the IFG cutoff at 110 mg/dL (6.1 mmol/L).

As with the glucose measures, several prospective studies that used A1C to predict the progression to diabetes as defined by A1C criteria demonstrated a strong, continuous association between A1C and subsequent diabetes.

In a systematic review of 44,203 individuals from 16 cohort studies with a follow-up interval averaging 5.6 years (range 2.8–12 years), those with A1C between 5.5 and 6.0% (between 37 and 42 mmol/mol) had a substantially increased risk of diabetes (5-year incidence from 9 to 25%).
Those with an A1C range of 6.0–6.5% (42–48 mmol/mol) had a 5-year risk of developing diabetes between 25 and 50% and a relative risk 20 times higher compared with A1C of 5.0% (31 mmol/mol).
In a community-based study of African American and non-Hispanic white adults without diabetes, baseline A1C was a stronger predictor of subsequent diabetes and cardiovascular events than fasting glucose. Other analyses suggest that A1C of 5.7% (39 mmol/mol) or higher is associated with a diabetes risk similar to that of the high-risk participants in the Diabetes Prevention Program (DPP), and A1C at baseline was a strong predictor of the development of glucose-defined diabetes during the DPP and its follow-up.

Hence, it is reasonable to consider an A1C range of 5.7–6.4% (39–47 mmol/mol) as identifying individuals with prediabetes. Similar to those with IFG and/or IGT, individuals with A1C of 5.7–6.4% (39–47 mmol/mol) should be informed of their increased risk for diabetes and CVD and counseled about effective strategies to lower their risks (see Section 5 “Prevention or Delay of Type 2 Diabetes”). Similar to glucose measurements, the continuum of risk is curvilinear, so as A1C rises, the diabetes risk rises disproportionately . Aggressive interventions and vigilant follow-up should be pursued for those considered at very high risk (e.g., those with A1C >6.0% [42 mmol/mol]).

Table 2.4 summarizes the categories of prediabetes and Table 2.3 the criteria for prediabetes testing.
The ADA diabetes risk test is an additional option for screening (Fig. 2.1) (diabetes.org/socrisktest).
For additional background regarding risk factors and screening for prediabetes, see pp. S19–S20 (screening and testing for type 2 diabetes and prediabetes in asymptomatic adults and screening and testing for type 2 diabetes and prediabetes in children and adolescents).

TYPE 1 DIABETES

Recommendations
• Plasma blood glucose rather than A1C should be used to diagnose the acute onset of type 1 diabetes in individuals with symptoms of hyperglycemia. E
• Screening for type 1 diabetes with a panel of autoantibodies is currently recommended only in the setting of a research trial or in first-degree family members of a proband with type 1 diabetes. B
• Persistence of two or more autoantibodies predicts clinical diabetes and may serve as an indication for intervention in the setting of a clinical trial. B

Diagnosis of Type 1 Diabetes
In a patient with classic symptoms, measurement of plasma glucose is sufficient to diagnose diabetes (symptoms of hyperglycemia or hyperglycemic crisis plus a random plasma glucose ≥200 mg/dL [11.1 mmol/L]). In these cases, knowing the plasma glucose level is critical because, in addition to confirming that symptoms are due to diabetes, it will inform management decisions. Some providers may also want to know the A1C to determine how long a patient has had hyperglycemia. The criteria to diagnose diabetes are listed in Table 2.2.

Immune-Mediated Diabetes
This form, previously called “insulin-dependent diabetes” or “juvenile-onset diabetes,” accounts for 5–10% of diabetes and is due to cellular-mediated autoimmune destruction of the pancreatic β-cells.
Autoimmune markers include islet cell autoantibodies and autoantibodies to GAD (GAD65), insulin, the tyrosine phosphatases IA-2 and IA-2β, and ZnT8.
Type 1 diabetes is defined by the presence of one or more of these autoimmune markers. The disease has strong HLA associations, with linkage to the DQA and DQB genes. These HLA-DR/DQ alleles can be either predisposing or protective.

The rate of β-cell destruction is quite variable, being rapid in some individuals (mainly infants and children) and slow in others (mainly adults).
Children and adolescents may present with DKA (Diabettic Ketoacidosis) as the first manifestation of the disease. Others have modest fasting hyperglycemia that can rapidly change to severe hyperglycemia and/or DKA with infection or other stress.
Adults may retain sufficient β-cell function to prevent DKA for many years; such individuals eventually become dependent on insulin for survival and are at risk for DKA. At this latter stage of the disease, there is little or no insulin secretion, as manifested by low or undetectable levels of plasma C-peptide.
Immune-mediated diabetes commonly occurs in childhood and adolescence, but it can occur at any age, even in the 8th and 9th decades of life.

Autoimmune destruction of β-cells has multiple genetic predispositions and is also related to environmental factors that are still poorly defined.
Although patients are not typically obese when they present with type 1 diabetes, obesity should not preclude the diagnosis.
Patients with type 1 diabetes are also prone to other autoimmune disorders such as Hashimoto thyroiditis, Graves disease, Addison disease, celiac disease, vitiligo, autoimmune hepatitis, myasthenia gravis, and pernicious anemia (see Section 3 “Comprehensive Medical Evaluation and Assessment of Comorbidities”).

Table 2.2 — Criteria for the diagnosis of diabetes
FPG≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.*
OR
2-h PG≥200mg/dL(11.1mmol/L) during OGTT. The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.*
OR
A1C≥6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.*
OR
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose≥200 mg/dL (11.1 mmol/L).

*In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing.

Idiopathic Type 1 Diabetes
Some forms of type 1 diabetes have no known etiologies. These patients have permanent insulinopenia and are prone to DKA, but have no evidence of β-cell autoimmunity.
Although only a minority of patients with type 1 diabetes fall into this category, of those who do, most are of African or Asian ancestry.
Individuals with this form of diabetes suffer from episodic DKA and exhibit varying degrees of insulin deficiency between episodes.
This form of diabetes is strongly inherited and is not HLA associated. An absolute requirement for insulin replacement therapy in affected patients may be intermittent.

Testing for Type 1 Diabetes Risk
The incidence and prevalence of type 1 diabetes is increasing.
Patients with type 1 diabetes often present with acute symptoms of diabetes and markedly elevated blood glucose levels, and approximately one-third are diagnosed with life-threatening DKA.
Several studies indicate that measuring islet autoantibodies in relatives of those with type 1 diabetes may identify individuals who are at risk for developing type 1 diabetes. Such testing, coupled with education about diabetes symptoms and close follow-up, may enable earlier identification of type 1 diabetes onset.
A study reported the risk of progression to type 1 diabetes from the time of seroconversion to autoantibody positivity in three pediatric cohorts from Finland, Germany, and the U.S.
Of the 585 children who developed more than two autoantibodies, nearly 70% developed type 1 diabetes within 10 years and 84% within 15 years. These findings are highly significant because while the German group was recruited from offspring of parents with type 1 diabetes, the Finnish and American groups were recruited from the general population.
Remarkably, the findings in all three groups were the same, suggesting that the same sequence of events led to clinical disease in both “sporadic” and familial cases of type 1 diabetes. Indeed, the risk of type 1 diabetes increases as the number of relevant autoantibodies detected increases.

Although there is currently a lack of accepted screening programs, one should consider referring relatives of those with type 1 diabetes for antibody testing for risk assessment in the setting of a clinical research study (www.diabetestrialnet.org).
Widespread clinical testing of asymptomatic low-risk individuals is not currently recommended due to lack of approved therapeutic interventions.
Individuals who test positive should be counseled about the risk of developing diabetes, diabetes symptoms, and DKA prevention.
Numerous clinical studies are being conducted to test various methods of preventing type 1 diabetes in those with evidence of autoimmunity (www.clinicaltrials.gov).

TYPE 2 DIABETES

Recommendations
• Screening for type 2 diabetes with an informal assessment of risk factors or validated tools should be considered in asymptomatic adults. B
• Testing for 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 (Table 2.3). B
• For all people, 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
• To test for type 2 diabetes, fasting plasma glucose, 2-h plasma glucose during 75-g oral glucose tolerance test, and A1C are equally appropriate. B
• In patients with diabetes, identify and treat other cardiovascular disease risk factors. B
• Testing for type 2 diabetes should be considered in children and adolescents who are overweight or obese (BMI >85th percentile for age and sex, weight for height >85th percentile, or weight >120% of ideal for height) and who have additional risk factors for diabetes (Table 2.5). E

Table 2.5 — Risk-based screening for type 2 diabetes or prediabetes in asymptomatic children and adolescents in a clinical setting* (*Persons aged < 18 years.)
Criteria
• Overweight (BMI>85th percentile for age and sex, weight for height>85th percentile, or weight>120% of ideal for height) A
Plus one or more additional risk factors based on the strength of their association with diabetes as indicated by evidence grades:
• Maternal history of diabetes or GDM during the child’s gestation A
• Family history of type 2 diabetes infirst- or second-degree relative A
• Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander) A
• Signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational-age birth weight) B

Description
Type 2 diabetes, previously referred to as “noninsulin-dependent diabetes” or “adult-onset diabetes,” accounts for 90–95% of all diabetes. This form encompasses individuals who have relative (rather than absolute) insulin deficiency and have peripheral insulin resistance. At least initially, and often throughout their lifetime, these individuals may not need insulin treatment to survive.

There are various causes of type 2 diabetes. Although the specific etiologies are not known, autoimmune destruction of β-cells does not occur and patients do not have any of the other known causes of diabetes. Most but not all patients with type 2 diabetes are overweight or obese. Excess weight itself causes some degree of insulin resistance. Patients who are not obese or overweight by traditional weight criteria may have an increased percentage of body fat distributed predominantly in the abdominal region.

DKA seldom occurs spontaneously in type 2 diabetes; when seen, it usually arises in association with the stress of another illness such as infection or with the use of certain drugs (e.g., corticosteroids, atypical antipsychotics, and sodium–glucose cotransporter 2 inhibitors). Type 2 diabetes frequently goes undiagnosed for many years because hyperglycemia develops gradually and, at earlier stages, is often not severe enough for the patient to notice the classic diabetes symptoms. Nevertheless, even undiagnosed patients are at increased risk of developing macrovascular and microvascular complications.

Whereas patients with type 2 diabetes may have insulin levels that appear normal or elevated, the higher blood glucose levels in these patients would be expected to result in even higher insulin values had their β-cell function been normal. Thus, insulin secretion is defective in these patients and insufficient to compensate for insulin resistance. Insulin resistance may improve with weight reduction and/or pharmacologic treatment of hyperglycemia but is seldom restored to normal.

The risk of developing type 2 diabetes increases with age, obesity, and lack of physical activity. It occurs more frequently in women with prior GDM, in those with hypertension or dyslipidemia, and in certain racial/ethnic subgroups (African American, American Indian, Hispanic/Latino, and Asian American). It is often associated with a strong genetic predisposition or family history in first-degree relatives, more so than type 1 diabetes. However, the genetics of type 2 diabetes is poorly understood. In adults without traditional risk factors for type 2 diabetes and/or younger age, consider antibody testing to exclude the diagnosis of type 1 diabetes (i.e., GAD).

Screening and Testing for Type 2 Diabetes and Prediabetes in Asymptomatic Adults
Screening for prediabetes and type 2 diabetes through an informal assessment of risk factors (Table 2.3) or with an assessment tool, such as the ADA risk test (Fig. 2.1) (diabetes.org/socrisktest), is recommended to guide providers on whether performing a diagnostic test (Table 2.2) is appropriate.
Both conditions are common and impose significant clinical and public health burdens. There is often a long presymptomatic phase before the diagnosis of type 2 diabetes. Simple tests to detect preclinical disease are readily available. The duration of glycemic burden is a strong predictor of adverse outcomes.
There are effective interventions that prevent progression from prediabetes to diabetes (see Section 5 “Prevention or Delay of Type 2 Diabetes”) and reduce the risk of diabetes complications (see Section 9 “Cardiovascular Disease and Risk Management” and Section 10 “Microvascular Complications and Foot Care”).

Approximately one-quarter of people with diabetes in the U.S. and nearly half of Asian and Hispanic Americans with diabetes are undiagnosed. Although screening of asymptomatic individuals to identify those with prediabetes or diabetes might seem reasonable, rigorous clinical trials to prove the effectiveness of such screening have not been conducted and are unlikely to occur.

A large European randomized controlled trial compared the impact of screening for diabetes and intensive multifactorial intervention with that of screening and routine care.
General practice patients between the ages of 40 and 69 years were screened for diabetes and randomly assigned by practice to intensive treatment of multiple risk factors or routine diabetes care.
After 5.3 years of follow-up, CVD risk factors were modestly but significantly improved with intensive treatment compared with routine care, but the incidence of first CVD events or mortality was not significantly different between the groups. The excellent care provided to patients in the routine care group and the lack of an unscreened control arm limited the authors' ability to determine whether screening and early treatment improved outcomes compared with no screening and later treatment after clinical diagnoses.
Computer simulation modeling studies suggest that major benefits are likely to accrue from the early diagnosis and treatment of hyperglycemia and cardiovascular risk factors in type 2 diabetes; moreover, screening, beginning at age 30 or 45 years and independent of risk factors, may be cost-effective (<$11,000 per quality-adjusted life-year gained).

Additional considerations regarding testing for type 2 diabetes and prediabetes in asymptomatic patients include the following.

Age
Age is a major risk factor for diabetes. Testing should begin at age 45 years for all patients. Screening should be considered in overweight or obese adults of any age with one or more risk factors for diabetes.

BMI and Ethnicity
In general, BMI ≥25 kg/m2 is a risk factor for diabetes. However, data suggest that the BMI cut point should be lower for the Asian American population. The BMI cut points fall consistently between 23 and 24 kg/m2 (sensitivity of 80%) for nearly all Asian American subgroups (with levels slightly lower for Japanese Americans). This makes a rounded cut point of 23 kg/m2 practical. An argument can be made to push the BMI cut point to lower than 23 kg/m2 in favor of increased sensitivity; however, this would lead to an unacceptably low specificity (13.1%).
Data from the WHO also suggest that a BMI of ≥23 kg/m2 should be used to define increased risk in Asian Americans. The finding that half of diabetes in Asian Americans is undiagnosed suggests that testing is not occurring at lower BMI thresholds.

Evidence also suggests that other populations may benefit from lower BMI cut points. For example, in a large multiethnic cohort study, for an equivalent incidence rate of diabetes, a BMI of 30 kg/m2 in non-Hispanic whites was equivalent to a BMI of 26 kg/m2 in African Americans.

Medications
Certain medications, such as glucocorticoids, thiazide diuretics, and atypical antipsychotics, are known to increase the risk of diabetes and should be considered when deciding whether to screen.

Testing Interval
The appropriate interval between screening tests is not known. The rationale for the 3-year interval is that with this interval, the number of false-positive tests that require confirmatory testing will be reduced and individuals with false-negative tests will be retested before substantial time elapses and complications develop.

Community Screening Ideally, testing should be carried out within a health care setting because of the need for follow-up and treatment. Community screening outside a health care setting is generally not recommended because people with positive tests may not seek, or have access to, appropriate follow-up testing and care. However, in specific situations where an adequate referral system is established beforehand for positive tests, community screening may be considered.
Community testing may also be poorly targeted; i.e., it may fail to reach the groups most at risk and inappropriately test those at very low risk or even those who have already been diagnosed.

Screening in Dental Practices
Because periodontal disease is associated with diabetes, the utility of screening in a dental setting and referral to primary care as a means to improve the diagnosis of prediabetes and diabetes has been explored, with one study estimating that 30% of patients ≥30 years of age seen in general dental practices had dysglycemia. Further research is needed to demonstrate the feasibility, effectiveness, and cost-effectiveness of screening in this setting.

Screening and Testing for Type 2 Diabetes and Prediabetes in Children and Adolescents
In the last decade, the incidence and prevalence of type 2 diabetes in adolescents has increased dramatically, especially in racial and ethnic minority populations. See Table 2.5 for recommendations on risk-based screening for type 2 diabetes or prediabetes in asymptomatic children and adolescents in a clinical setting. See Section 12 “Children and Adolescents” for additional information on type 2 diabetes in children and adolescents.

Some studies question the validity of A1C in the pediatric population, especially among certain ethnicities, and suggest OGTT or FPG as more suitable diagnostic tests.
However, many of these studies do not recognize that diabetes diagnostic criteria are based on long-term health outcomes, and validations are not currently available in the pediatric population. The ADA acknowledges the limited data supporting A1C for diagnosing type 2 diabetes in children and adolescents. Although A1C is not recommended for diagnosis of diabetes in children with cystic fibrosis or symptoms suggestive of acute onset of type 1 diabetes and only A1C assays without interference are appropriate for children with hemoglobinopathies, the ADA continues to recommend A1C for diagnosis of type 2 diabetes in this cohort.

Prevention or Delay of Type 2 Diabetes

Recommendations
• At least annual monitoring for the development of diabetes in those with prediabetes is suggested. E
• Patients with prediabetes should be referred to an intensive behavioral lifestyle intervention program modeled on the Diabetes Prevention Program to achieve and maintain 7% loss of initial body weight and increase moderate-intensity physical activity (such as brisk walking) to at least 150 min/week. A
• Technology-assisted tools including Internet-based social networks, distance learning, and mobile applications that incorporate bidirectional communication may be useful elements of effective lifestyle modification to prevent diabetes. B
• Given the cost-effectiveness of diabetes prevention, such intervention programs should be covered by third-party payers. B

Screening for prediabetes and type 2 diabetes risk through an informal assessment of risk factors (Table 2.3) or with an assessment tool, such as the American Diabetes Association risk test (Fig. 2.1), is recommended to guide providers on whether performing a diagnostic test for prediabetes (Table 2.4) and previously undiagnosed type 2 diabetes (Table 2.2) is appropriate (see Section 2 “Classification and Diagnosis of Diabetes”).
Those determined to be at high risk for type 2 diabetes, including people with A1C 5.7–6.4% (39–47 mmol/mol), impaired glucose tolerance, or impaired fasting glucose, are ideal candidates for diabetes prevention efforts.
Using A1C to screen for prediabetes may be problematic in the presence of certain hemoglobinopathies or conditions that affect red blood cell turnover. See Section 2 “Classification and Diagnosis of Diabetes” and Section 6 “Glycemic Targets” for additional details on the appropriate use of the A1C test.

At least annual monitoring for the development of diabetes in those with prediabetes is suggested.

LIFESTYLE INTERVENTIONS
• The Diabetes Prevention Program
• Nutrition
• Physical Activity
• Technology Assistance to Deliver Lifestyle Interventions
• Cost-effectiveness

PHARMACOLOGIC INTERVENTIONS
Recommendations
• Metformin therapy for prevention of type 2 diabetes should be considered in those with prediabetes, especially for those with BMI ≥35 kg/m2, those aged <60 years, and women with prior gestational diabetes mellitus. A
• Long-term use of metformin may be associated with biochemical vitamin B12 deficiency, and periodic measurement of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy. B

Pharmacologic agents including metformin, α-glucosidase inhibitors, orlistat, glucagon-like peptide 1 (GLP-1) receptor agonists, and thiazolidinediones have each been shown to decrease incident diabetes to various degrees in those with prediabetes in research studies, though none are approved by the U.S. Food and Drug Administration specifically for diabetes prevention. One has to balance the risk/benefit of each medication.
Metformin has the strongest evidence base and demonstrated long-term safety as pharmacologic therapy for diabetes prevention. For other drugs, cost, side effects, and durable efficacy require consideration.

Metformin was overall less effective than lifestyle modification in the DPP and DPPOS, though group differences declined over time and metformin may be cost-saving over a 10-year period. It was as effective as lifestyle modification in participants with BMI ≥35 kg/m2 but not significantly better than placebo in those over 60 years of age.
In the DPP, for women with history of GDM, metformin and intensive lifestyle modification led to an equivalent 50% reduction in diabetes risk, and both interventions remained highly effective during a 10-year follow-up period. Metformin should be recommended as an option for high-risk individuals (e.g., those with a history of GDM or those with BMI ≥35). Consider monitoring B12 levels in those taking metformin chronically to check for possible deficiency (see Section 8 “Pharmacologic Approaches to Glycemic Treatment” for more details).


PREVENTION OF CARDIOVASCULAR DISEASE
Recommendation
• Screening for and treatment of modifiable risk factors for cardiovascular disease is suggested for those with prediabetes. B

People with prediabetes often have other cardiovascular risk factors, including hypertension and dyslipidemia, and are at increased risk for cardiovascular disease. Although treatment goals for people with prediabetes are the same as for the general population , increased vigilance is warranted to identify and treat these and other cardiovascular risk factors (e.g., smoking).

DIABETES SELF-MANAGEMENT EDUCATION AND SUPPORT
Recommendation
• Diabetes self-management education and support programs may be appropriate venues for people with prediabetes to receive education and support to develop and maintain behaviors that can prevent or delay the development of type 2 diabetes. B

As for those with established diabetes, the standards for diabetes self-management education and support (see Section 4 “Lifestyle Management”) can also apply to people with prediabetes. Currently, there are significant barriers to the provision of education and support to those with prediabetes. However, the strategies for supporting successful behavior change and the healthy behaviors recommended for people with prediabetes are comparable to those for diabetes. Although reimbursement remains a barrier, studies show that providers of diabetes self-management education and support are particularly well equipped to assist people with prediabetes in developing and maintaining behaviors that can prevent or delay the development of diabetes.

PHARMACOLOGIC THERAPY FOR TYPE 1 DIABETES

Recommendations
• Most people with type 1 diabetes should be treated with multiple daily injections of prandial insulin and basal insulin or continuous subcutaneous insulin infusion. A
• Most individuals with type 1 diabetes should use rapid-acting insulin analogs to reduce hypoglycemia risk. A
• Consider educating individuals with type 1 diabetes on matching prandial insulin doses to carbohydrate intake, premeal blood glucose levels, and anticipated physical activity. E
• Individuals with type 1 diabetes who have been successfully using continuous subcutaneous insulin infusion should have continued access to this therapy after they turn 65 years of age. E

Insulin Therapy
Insulin is the mainstay of therapy for individuals with type 1 diabetes. Generally, the starting insulin dose is based on weight, with doses ranging from 0.4 to 1.0 units/kg/day of total insulin with higher amounts required during puberty.
The American Diabetes Association/JDRF Type 1 Diabetes Sourcebook notes 0.5 units/kg/day as a typical starting dose in patients with type 1 diabetes who are metabolically stable, with higher weight-based dosing required immediately following presentation with ketoacidosis, and provides detailed information on intensification of therapy to meet individualized needs.
The American Diabetes Association (ADA) position statement “Type 1 Diabetes Management Through the Life Span” additionally provides a thorough overview of type 1 diabetes treatment.

Education regarding matching prandial insulin dosing to carbohydrate intake, premeal levels, and anticipated activity should be considered, and selected individuals who have mastered carbohydrate counting should be educated on fat and protein gram estimation.
Although most studies of multiple daily injections versus continuous subcutaneous insulin infusion (CSII) have been small and of short duration, a systematic review and meta-analysis concluded that there are minimal differences between the two forms of intensive insulin therapy in A1C (combined mean between-group difference favoring insulin pump therapy –0.30% [95% CI –0.58 to –0.02]) and severe hypoglycemia rates in children and adults.
A 3-month randomized trial in patients with type 1 diabetes with nocturnal hypoglycemia reported that sensor-augmented insulin pump therapy with the threshold suspend feature reduced nocturnal hypoglycemia without increasing glycated hemoglobin levels. The U.S. Food and Drug Administration (FDA) has also approved the first hybrid closed-loop system pump. The safety and efficacy of hybrid closed-loop systems has been supported in the literature in adolescents and adults with type 1 diabetes.

Intensive management using CSII and continuous glucose monitoring should be encouraged in selected patients when there is active patient/family participation.

The Diabetes Control and Complications Trial (DCCT) clearly showed that intensive therapy with multiple daily injections or CSII delivered by multidisciplinary teams of physicians, nurses, dietitians, and behavioral scientists improved glycemia and resulted in better long-term outcomes. The study was carried out with short-acting and intermediate-acting human insulins.
Despite better microvascular, macrovascular, and all-cause mortality outcomes, intensive therapy was associated with a high rate of severe hypoglycemia (61 episodes per 100 patient-years of therapy).
Since the DCCT, a number of rapid-acting and long-acting insulin analogs have been developed. These analogs are associated with less hypoglycemia, less weight gain, and lower A1C than human insulins in people with type 1 diabetes. Longer-acting basal analogs (U-300 glargine or degludec) may additionally convey a lower hypoglycemia risk compared with U-100 glargine in patients with type 1 diabetes.

Rapid-acting inhaled insulin used before meals in patients with type 1 diabetes was shown to be noninferior when compared with aspart insulin for A1C lowering, with less hypoglycemia observed with inhaled insulin therapy.
However, the mean reduction in A1C was greater with aspart (–0.21% vs. –0.40%, satisfying the noninferiority margin of 0.4%), and more patients in the insulin aspart group achieved A1C goals of ≤7.0% (53 mmol/mol) and ≤6.5% (48 mmol/mol).
Because inhaled insulin cartridges are only available in 4-, 8-, and 12-unit doses, limited dosing increments to fine-tune prandial insulin doses in type 1 diabetes are a potential limitation.

Postprandial glucose excursions may be better controlled by adjusting the timing of prandial (bolus) insulin dose administration. The optimal time to administer prandial insulin varies, based on the type of insulin used (regular, rapid-acting analog, inhaled, etc.), measured blood glucose level, timing of meals, and carbohydrate consumption. Recommendations for prandial insulin dose administration should therefore be individualized.

Pramlintide
Pramlintide, an amylin analog, is an agent that delays gastric emptying, blunts pancreatic secretion of glucagon, and enhances satiety. It is FDA-approved for use in adults with type 1 diabetes. It has been shown to induce weight loss and lower insulin doses. Concurrent reduction of prandial insulin dosing is required to reduce the risk of severe hypoglycemia.

Investigational Agents

Metformin
Adding metformin to insulin therapy may reduce insulin requirements and improve metabolic control in patients with type 1 diabetes.
In one study, metformin was found to reduce insulin requirements (6.6 units/day, P < 0.001), and led to small reductions in weight and total and LDL cholesterol but not to improved glycemic control (absolute A1C reduction 0.11%, P = 0.42) (22).
A randomized clinical trial similarly found that, among overweight adolescents with type 1 diabetes, the addition of metformin to insulin did not improve glycemic control and increased risk for gastrointestinal adverse events after 6 months compared with placebo.
The Reducing With Metformin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL) trial investigated the addition of metformin therapy to titrated insulin therapy in adults with type 1 diabetes at increased risk for cardiovascular disease and found that metformin did not significantly improve glycemic control beyond the first 3 months of treatment and that progression of atherosclerosis (measured by carotid artery intima-media thickness) was not significantly reduced, although other cardiovascular risk factors such as body weight and LDL cholesterol improved. Metformin is not FDA-approved for use in patients with type 1 diabetes.

Incretin-Based Therapies
Due to their potential protection of β-cell mass and suppression of glucagon release, glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors are being studied in patients with type 1 diabetes but are not currently FDA-approved for use in patients with type 1 diabetes.

Sodium–Glucose Cotransporter 2 Inhibitors
Sodium–glucose cotransporter 2 (SGLT2) inhibitors provide insulin-independent glucose lowering by blocking glucose reabsorption in the proximal renal tubule by inhibiting SGLT2.
These agents provide modest weight loss and blood pressure reduction in type 2 diabetes. There are three FDA-approved agents for patients with type 2 diabetes, but none are FDA-approved for the treatment of patients with type 1 diabetes.
SGLT2 inhibitors may have glycemic benefits in patients with type 1 or type 2 diabetes on insulin therapy. The FDA issued a warning about the risk of ketoacidosis occurring in the absence of significant hyperglycemia (euglycemic diabetic ketoacidosis) in patients with type 1 or type 2 diabetes treated with SGLT2 inhibitors.
Symptoms of ketoacidosis include dyspnea, nausea, vomiting, and abdominal pain. Patients should be instructed to stop taking SGLT2 inhibitors and seek medical attention immediately if they have symptoms or signs of ketoacidosis.

SURGICAL TREATMENT FOR TYPE 1 DIABETES

Pancreas and Islet Transplantation
Pancreas and islet transplantation have been shown to normalize glucose levels but require life-long immunosuppression to prevent graft rejection and recurrence of autoimmune islet destruction.
Given the potential adverse effects of immunosuppressive therapy, pancreas transplantation should be reserved for patients with type 1 diabetes undergoing simultaneous renal transplantation, following renal transplantation, or for those with recurrent ketoacidosis or severe hypoglycemia despite intensive glycemic management.

Source: MEDSCAPE
Pharmacologic Therapy
Early initiation of pharmacologic therapy is associated with improved glycemic control and reduced long-term complications in type 2 diabetes.

ACCORD Study Group --- As compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions but increased 5-year mortality.

Drug classes used for the treatment of type 2 diabetes include the following:
Biguanides, Sulfonylureas, Meglitinide derivative, Alpha-glucosidase inhibitors, Thiazolidinediones (TZDs), Glucagonlike peptide–1 (GLP-1) agonists, Dipeptidyl peptidase IV (DPP-4) inhibitors, Selective sodium-glucose transporter–2 (SGLT-2) inhibitors, Insulins, Amylinomimetics, Bile acid sequestrants, Dopamine agonists,

GLP-1 agonists, DPP-4 inhibitors, and SGLT-2 inhibitors put patients with type 2 diabetes at no additional cardiovascular risk.
GLP-1 agonists actually showed significant reduction in such risk.
SGLT-2 inhibitors demonstrated a significant decrease in hospitalization for heart failure events.

Biguanides
Unlike oral sulfonylureas, metformin rarely causes hypoglycemia.
it was found to be successful at reducing macrovascular disease endpoints in obese patients.
In January 2017, the American College of Physicians (ACP) released a guideline update recommending the use of metformin as a first-line treatment for type 2 diabetes.
The ACP update also recommended consideration of the addition of a drug from one of the following classes—sulfonylureas, thiazolidinediones, dipeptidyl peptidase IV (DPP-4) inhibitors, or selective sodium-glucose transporter-2 (SGLT-2) inhibitors—to metformin when a second oral therapy is thought to be needed to aid glycemic control. However, the second recommendation was graded as "weak," with the evidence of moderate quality, by the ACP.

A study by Vashisht et al that examined data from more than 246.5 million patients found that when used along with metformin therapy for type 2 diabetes, treatment with sulfonylureas, DPP-4 inhibitors, or thiazolidinediones was equally effective in reducing the HbA1c level to 7% or below that of total hemoglobin. However, compared with DPP-4 inhibitors, there was a slightly increased risk of myocardial infarction and eye disorders associated with sulfonylureas.

Kooy et al found improvements in body weight, glycemic control, and insulin requirements when metformin was added to insulin in patients with type 2 diabetes mellitus. No improvement of an aggregate of microvascular and macrovascular morbidity and mortality was observed; however, reduced risk of macrovascular disease was evident after a follow-up period of 4.3 years. These results support continuing metformin treatment after the introduction of insulin in patients with type 2 diabetes mellitus.
Pradhan et al did not find an association between improvement of glycemic control with metformin or insulin and reduction of inflammatory biomarker levels in patients with recent-onset type 2 diabetes.

A retrospective, nationwide cohort study found that metformin is associated with a low risk of mortality in patients who have diabetes and experience heart failure compared with treatment that includes a sulfonylurea or insulin.

A study by Gross et al found no difference in benefit between drug classes in patients already on metformin and sulfonylurea. The patient's clinical circumstances must guide selection.

Sulfonylureas Sulfonylureas (eg, glyburide, glipizide, glimepiride) are insulin secretagogues that stimulate insulin release from pancreatic beta cells and probably have the greatest efficacy for glycemic lowering of any of the oral agents. However, that effect is only short-term and quickly dissipates. Sulfonylureas may also enhance peripheral sensitivity to insulin secondary to an increase in insulin receptors or to changes in the events following insulin-receptor binding.

Sulfonylureas are indicated for use as adjuncts to diet and exercise in adult patients with type 2 diabetes mellitus. They are generally well-tolerated, with hypoglycemia the most common side effect.

The first-generation sulfonylureas are acetohexamide, chlorpropamide, tolazamide, and tolbutamide; the second-generation agents are glipizide, glyburide, and glimepiride.
The structural characteristics of the second-generation sulfonylureas allow them to be given at lower doses and as once-daily regimens.

The use of glyburide was associated with highest mortality (7.5%) compared with other sulfonylureas, such as gliclazide and glimepiride (2.7%). This raises an important concern about whether the use of glyburide should be avoided.

Glucagonlike peptide–1 agonists (GLP-1 agonists)
GLP-1 agonists (ie, exenatide, liraglutide, albiglutide, dulaglutide) mimic the endogenous incretin GLP-1; they stimulate glucose-dependent insulin release, reduce glucagon, and slow gastric emptying. The use of a GLP-1 in addition to metformin and/or a sulfonylurea may result in modest weight loss. Animal data suggest that these drugs prevent beta-cell apoptosis and may in time restore beta-cell mass. The latter property, if proven in humans, would have tremendous therapeutic potential

• Exenatide
A comparison by Bunck et al of 1 year's therapy with either exenatide or insulin glargine in metformin-treated patients with type 2 diabetes found that exenatide provided significantly greater improvement in beta-cell function. Reduction in HbA1c was similar with the 2 drugs. Beta-cell function and glycemic control returned to pretreatment values following discontinuation of exenatide or insulin glargine, suggesting that long-term treatment is required to maintain the beneficial effects of these drugs.
The addition of exenatide in patients receiving insulin glargine as basal insulin helps to improve glycemic control without the risk of increased hypoglycemia or weight gain. This benefit, however, is accompanied by a significant increase in adverse events such as nausea, diarrhea, vomiting, and headache.

Exenatide has greater ease of titration (only 2 possible doses, with most patients progressing to the higher dose) than does insulin. Although the original product requires twice-daily injections, a long-acting exenatide formulation that is given once weekly (Bydureon) has been developed and has been found to provide significantly greater improvement in glycemic control than does the twice-daily formulation. Once-weekly exenatide injections result in improvements in glycemic control and body weight regardless of age, gender, race, duration of diabetes or BMI. Bydureon was approved by the FDA in January 2012.

In the DURATION-5 (Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention With Exenatide Once Weekly) study, the exenatide once-weekly formulation provided significantly greater improvement in HbA1c and FPG levels than did the twice-daily preparation. Additionally, less nausea was observed with the once-weekly exenatide formulation.

For patients with type 2 diabetes inadequately controlled with metformin, the injectable agent exenatide was found, in one clinical trial, to be more effective than insulin detemir. [166, 167] A clinical trial involving 216 patients with A1c baseline levels >7.1% despite treatment with metformin found that once-daily injections of exenatide resulted in a significantly greater number of patients achieving target A1c than treatment with detemir. At 26 weeks, 44.1% of the exenatide group had achieved an A1c of 7% or less compared to 11.4% of the detemir group.

• Liraglutide
Indicated as an adjunct to diet and exercise, liraglutide therapy is aimed at improving glycemic control in adults with type 2 diabetes. In addition, results from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) clinical trial led to liraglutide’s approval for risk reduction of major cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease. With a median follow-up of 3.8 years, risk for the trial’s composite endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke was 13.0% for patients treated with liraglutide, compared with 14.9% for those given placebo therapy.

In June 2019, liraglutide was approved by the FDA for use in children aged 10 years or older with type 2 diabetes. Approval was based on the ELLIPSE clinical trial, in which patients aged 10 years to less than 17 years received up to 1.8 mg/day of subcutaneous liraglutide or placebo. After 26 weeks, the mean HbA1c level was 0.64% lower in the liraglutide patients and 0.42% higher in the placebo patients.

Source: MEDSCAPE
Meglitinide derivatives
Meglitinides (eg, repaglinide, nateglinide) are much shorter-acting insulin secretagogues than the sulfonylureas are, with preprandial dosing potentially achieving more physiologic insulin release and less risk for hypoglycemia. Although meglitinides are considerably more expensive than sulfonylureas, they are similar in their glycemic clinical efficacy.
Meglitinides can be used as monotherapy; however, if adequate glycemic control is not achieved, then metformin or a thiazolidinedione may be added. Meglitinides may be used in patients who have allergy to sulfonylurea medications. They have a similar risk for inducing weight gain as sulfonylureas do but possibly carry less risk for hypoglycemia.

Thiazolidinediones (TZD)
eg, pioglitazone [Actos], rosiglitazone [Avandia]
Note: Rosiglitazone restrictions --- In response to data suggesting an elevated risk of myocardial infarction in patients treated with rosiglitazone, the FDA has restricted access to this drug.
TZDs act as insulin sensitizers; thus, they require the presence of insulin to work. They must be taken for 12-16 weeks to achieve maximal effect.
These agents are used as monotherapy or in combination with sulfonylurea, metformin, meglitinide, DPP-4 inhibitors, GLP-1 receptor agonists, or insulin.
They are the only antidiabetic agents that have been shown to slow the progression of diabetes (particularly in early disease).

In a study by DeFronzo et al, pioglitazone was found to reduce the progression to frank diabetes by 72% in patients with IGT. However, the drug was associated with significant edema and weight gain.

In the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial, rosiglitazone reduced the incidence of diabetes by 62%. It also improved the achievement of normoglycemia by 70% in patients with IFG and by 64% in patients with both IFG and IGT.

A study by Phung et al investigated oral agents used for prevention of type 2 diabetes and found that TZDs resulted in a greater risk reduction than biguanides. Sulfonylureas and glinides had no benefit.

TZDs generally decrease triglyceride levels and increase HDL cholesterol levels. They increase LDL cholesterol, but this increase may involve large, buoyant LDL, which may be less atherogenic.

Pioglitazone in patients unresponsive to combination therapy
Charpentier et al concluded that the early addition of pioglitazone in patients who are not responding to dual therapy is beneficial, decreasing HbA1c, as well as improving FPG levels and other surrogate markers. In this study, patients (n=299) with type 2 diabetes mellitus uncontrolled by combination therapy with metformin and a sulfonylurea or a glinide were randomly assigned to receive add-on therapy with either pioglitazone 30 mg daily or a placebo.

Among patients with a baseline HbA1c level of less than 8.5%, 44.4% of patients in the pioglitazone group achieved an HbA1c level of less than 7% after 7 months, compared with only 4.9% of patients in the placebo group. In patients with a baseline HbA1c level of 8.5% or greater, 13% of those in the pioglitazone group achieved an HbA1c level of less than 7%, while no patients in the placebo group saw the same reduction.

Adverse effects
Edema (including macular edema) and weight gain.
The use of pioglitazone for more than 2 years is weakly associated with an increased bladder cancer risk.
Constant surveillance and vigilance is needed. Ninety-five percent of these cases were detected in early stage.

Dipeptidyl peptidase IV inhibitors (DPP-4 inhibitors)
DPP-4 inhibitors (eg, sitagliptin, saxagliptin, linagliptin) are a class of drugs that prolong the action of incretin hormones. DPP-4 degrades numerous biologically active peptides, including the endogenous incretins GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibitors can be used as a monotherapy or in combination with metformin or a TZD. They are given once daily and are weight neutral.
Patients who take Januvia don’t have to deal with the risk of low blood sugar and weight gain.

A study comparing the efficacy and safety of monotherapy with sitagliptin or metformin in treatment-naive patients with type 2 diabetes found no statistical differences between the 2 drugs in terms of decreases in HbA1c and fasting glucose levels. The 1050 participants in the study had baseline HbA1c levels of 6.5-9% and received sitagliptin (100 mg qd) or metformin (1000 mg bid) for 24 weeks.
In this study, the incidence of adverse GI effects was lower with sitagliptin than with metformin (11.6% vs 20.7%). Specifically, diarrhea (3.6% vs 10.9%) and nausea (1.1% vs 3.1%) were significantly less common with sitagliptin.

A study by Pérez-Monteverde et al found that a combination of sitagliptin and metformin was associated with improved glycemic control and less weight gain when compared with pioglitazone in the treatment of patients with type 2 diabetes mellitus.

Adding linagliptin to treatment in patients with type 2 diabetes mellitus that has been inadequately controlled with a metformin and sulfonylurea combination improves glycemic control. Because it has predominantly nonrenal excretion and is a clinically nonrelevant substrate for cytochrome-450 isoenzymes, this drug possesses the benefits of having a low risk of drug-drug interaction and of being safe to use in patients with renal insufficiency

Alpha-glucosidase inhibitors
These agents delay sugar absorption and help to prevent postprandial glucose surges. Alpha-glucosidase inhibitors prolong the absorption of carbohydrates, but their induction of flatulence greatly limits their use. They should be titrated slowly to reduce gastrointestinal (GI) intolerance.

semaglutide (OZEMPIC)

Incretin mimetics Antidiabetics
Incretin mimetic (GLP-1 receptor agonist) administered as a once-weekly subcutaneous injection Used to improve glycemic control in adults with type 2 diabetes mellitus
Not recommended as a first-line therapy because of the boxed warning regarding rodent C-cell tumor findings and the uncertain relevance to humans
SUPPLIED --- Semaglutide Subcutaneous Inj Sol: 1mL, 1.34mg

■ For the treatment of type 2 diabetes mellitus in combination with diet and exercise.
Subcutaneous dosage
Initially, 0.25 mg subcutaneously once every 7 days (weekly). Administer the dose at any time of day, with or without meals. After 4 weeks increase the dose to 0.5 mg subcutaneously once weekly; the 0.25 mg dose is only for treatment initiation and is not effective for glycemic control. If additional glycemic control is needed after at least 4 weeks on the 0.5 mg/week dose, the dosage may be increased. Max: 1 mg/week subcutaneously. When semaglutide is added to insulin detemir, a reduction in the dose of insulin detemir may be needed to reduce the risk of hypoglycemia. The manufacturer of insulin detemir recommends initiating therapy with insulin detemir at 10 units subcutaneously once daily when combining with a GLP-1 receptor agonist. When initiating semaglutide, consider reducing the dose of concomitantly administered insulin secretagogues (e.g., sulfonylureas) to reduce the risk of hypoglycemia. MISSED DOSE: If a semaglutide dose is missed, administer it as soon as possible within 5 days after the missed dose. If more than 5 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, resume the regular once weekly dosing schedule. The day of weekly administration can be changed if needed, as long as the time between 2 doses is at least 2 days (more than 48 hours).
MAXIMUM DOSAGE --- 1 mg/week subcutaneously.

Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31271-1/fulltext
In this randomised, double-blind, double-dummy, phase 3a trial, we recruited patients with type 2 diabetes from 100 sites in 12 countries. Eligible patients were aged 18 years or older, with HbA 1c of 7·0–9·5% (53–80·3 mmol/mol), on a stable dose of metformin (≥1500 mg or maximum tolerated) with or without a sodium-glucose co-transporter-2 inhibitor. Participants were randomly assigned (2:2:1) with an interactive web-response system and stratified by background glucose-lowering medication and country of origin, to once-daily oral semaglutide (dose escalated to 14 mg), once-daily subcutaneous liraglutide (dose escalated to 1·8 mg), or placebo for 52 weeks.
Interpretation
Oral semaglutide was non-inferior to subcutaneous liraglutide and superior to placebo in decreasing HbA 1c, and superior in decreasing bodyweight compared with both liraglutide and placebo at week 26. Safety and tolerability of oral semaglutide were similar to subcutaneous liraglutide. Use of oral semaglutide could potentially lead to earlier initiation of GLP-1 receptor agonist therapy in the diabetes treatment continuum of care.

Choosing a First Injectable in Type 2 Diabetes: Try a GLP-1
https://www.medscape.com/viewarticle/908297
GLP-1s, not insulin, are now recommended as the first injectable for our patients with type 2 diabetes who have not reached their A1c goals with two or three oral agents. They can also help patients lose weight. They can lose 5-10 pounds with this class of medications. These agents also have a very low incidence of hypoglycemia.

When the GLP-1 receptor agonists have been compared with insulin in head-to-head trials, they are as good or better than insulin at lowering the A1c and controlling glucose. For those three reasons—efficacy, decreased hypoglycemia, and weight loss instead of weight gain—the new guidelines clearly recommend GLP-1 receptor agonists as the preferred first injectable for patients who have not achieved adequate control on two or three oral agents.

Patients were afraid of insulin because it could cause hypoglycemic episodes and it predictably caused a good bit of weight gain, about 5-10 pounds.

let's say that this applies to most people. Patients with a very high A1c, over 11%, who are symptomatic and losing weight may benefit from insulin as the first injectable. They may have an insulin deficiency, which will not be addressed by a GLP-1 alone. The other strategy we can consider for patients with very high A1c levels—over 10%, or 2% above their target—who are symptomatic as well is the fixed-ratio combination therapies that combine a GLP-1 with a basal insulin. Those are excellent choices for that group of patients because they can start at a low dose of GLP-1 combined with a low amount of insulin, thus helping to minimize weight gain and hypoglycemia as well as the gastrointestinal side effects of the GLP-1s, while providing better efficacy than you might get with either one alone.

Choosing GLP-1 Receptor Agonists or DPP-4 Inhibitors: Weighing the Clinical Trial Evidence
https://clinical.diabetesjournals.org/content/30/1/3
https://clinical.diabetesjournals.org/content/diaclin/30/1/3.full.pdf
General Recommendations
Consistent with current expert panel guideline recommendations, GLP-1 receptor agonists and DPP-4 inhibitors are useful in the management of patients with type 2 diabetes over the spectrum of A1C levels, including drug-naive patients as well as those treated with other glucose-lowering therapy. GLP-1 receptor agonists are preferred over DPP-4 inhibitors because of the greater reductions in blood glucose and A1C and the weight loss observed in most patients treated with a GLP-1 receptor agonist.

Because of their low risk of hypoglycemia, GLP-1 receptor agonists and DPP-4 inhibitors may be particularly valuable in patients with hypoglycemia unawareness or in other patients for whom hypoglycemia is a major concern.

Improvements in blood pressure and lipids make GLP-1 receptor agonists and DPP-4 inhibitors especially helpful in patients with preexisting cardiovascular disease. Because they are not appropriate as primary therapy for cardiovascular risk reduction, other measures are needed to achieve target blood pressure and lipid levels

empagliflozin (JARDIANCE)

Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors
Oral sodium-glucose co-transporter 2 (SGLT2) inhibitor
Used in adults with type 2 diabetes mellitus; also provides cardiovascular (CV) risk reduction if these patients also have CV disease
Do not use in patients with severe renal impairment due to reduced efficacy and risk for renal-related adverse events
SUPPLIED --- JARDIANCE Oral Tab: 10mg, 25mg

■ For the treatment of type 2 diabetes mellitus (T2DM) in combination with diet and exercise, and for the reduction of cardiovascular mortality due to major cardiovascular events (MACE) in T2DM patients with established cardiovascular disease.
Oral dosage
10 mg PO once daily in the morning, with or without food. May increase to 25 mg PO once daily in those who require additional glycemic control. Correct any volume depletion prior to initiation of treatment. A multicenter, multinational, randomized, double-blind parallel group trial (EMPA-REG OUTCOME study) of 7,020 adults with inadequately controlled T2DM and established, stable, atherosclerotic cardiovascular disease reported that empagliflozin treatment reduced the risk of major adverse CV events (MACE: cardiovascular death, first occurrence of non-fatal myocardial infarction, or non-fatal stroke) by 14% vs. placebo (HR 0.86, 95% CI 0.74 to 0.99).
MAXIMUM DOSAGE -- 25 mg/day PO.

PRICE. The cost of a one-month supply of empagliflozin is approximately $410. This cost is similar to other SGLT2 inhibitors and is significantly more expensive than metformin or glipizide (Glucotrol), which both cost about $5 per month.

sitagliptin (Januvia)

Janumet – a combination drug consisting of Januvia and metformin.

PHARMACOLOGIC THERAPY FOR TYPE 2 DIABETES

Recommendations
• Metformin, if not contraindicated and if tolerated, is the preferred initial pharmacologic agent for the treatment of type 2 diabetes. A
• Long-term use of metformin may be associated with biochemical vitamin B12 deficiency, and periodic measurement of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy. B
• Consider initiating insulin therapy (with or without additional agents) in patients with newly diagnosed type 2 diabetes who are symptomatic and/or have A1C ≥10% (86 mmol/mol) and/or blood glucose levels ≥300 mg/dL (16.7 mmol/L). E
• Consider initiating dual therapy in patients with newly diagnosed type 2 diabetes who have A1C ≥9% (75 mmol/mol). E
• In patients without atherosclerotic cardiovascular disease, if monotherapy or dual therapy does not achieve or maintain the A1C goal over 3 months, add an additional antihyperglycemic agent based on drug-specific and patient factors (Table 8.1). A
• A patient-centered approach should be used to guide the choice of pharmacologic agents. Considerations include efficacy, hypoglycemia risk, history of atherosclerotic cardiovascular disease, impact on weight, potential side effects, renal effects, delivery method (oral versus subcutaneous), cost, and patient preferences. E
• In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, antihyperglycemic therapy should begin with lifestyle management and metformin and subsequently incorporate an agent proven to reduce major adverse cardiovascular events and cardiovascular mortality (currently empagliflozin and liraglutide), after considering drug-specific and patient factors (Table 8.1). A*
• In patients with type 2 diabetes and established atherosclerotic cardiovascular disease, after lifestyle management and metformin, the antihyperglycemic agent canagliflozin may be considered to reduce major adverse cardiovascular events, based on drug-specific and patient factors (Table 8.1). C*
• Continuous reevaluation of the medication regimen and adjustment as needed to incorporate patient factors (Table 8.1) and regimen complexity is recommended. E
• For patients with type 2 diabetes who are not achieving glycemic goals, drug intensification, including consideration of insulin therapy, should not be delayed. B
• Metformin should be continued when used in combination with other agents, including insulin, if not contraindicated and if tolerated. A

See Section 12 for recommendations specific for children and adolescents with type 2 diabetes. The use of metformin as first-line therapy was supported by findings from a large meta-analysis, with selection of second-line therapies based on patient-specific considerations.
An ADA/European Association for the Study of Diabetes position statement “Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach” recommended a patient-centered approach, including assessment of efficacy, hypoglycemia risk, impact on weight, side effects, costs, and patient preferences. Renal effects may also be considered when selecting glucose-lowering medications for individual patients. Lifestyle modifications that improve health (see Section 4 “Lifestyle Management”) should be emphasized along with any pharmacologic therapy.

Table 8.1 Drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes

Initial Therapy
Metformin monotherapy should be started at diagnosis of type 2 diabetes unless there are contraindications. Metformin is effective and safe, is inexpensive, and may reduce risk of cardiovascular events and death.
Compared with sulfonylureas, metformin as first-line therapy has beneficial effects on A1C, weight, and cardiovascular mortality. Metformin may be safely used in patients with estimated glomerular filtration rate (eGFR) as low as 30 mL/min/1.73 m2, and the FDA recently revised the label for metformin to reflect its safety in patients with eGFR ≥30 mL/min/1.73 m2.
Patients should be advised to stop the medication in cases of nausea, vomiting, or dehydration.
Metformin is associated with vitamin B12 deficiency, with a recent report from the Diabetes Prevention Program Outcomes Study (DPPOS) suggesting that periodic testing of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy.

In patients with metformin contraindications or intolerance, consider an initial drug from another class depicted in Fig. 8.1 under “Dual Therapy” and proceed accordingly. When A1C is ≥9% (75 mmol/mol), consider initiating dual combination therapy (Fig. 8.1) to more expeditiously achieve the target A1C level.
Insulin has the advantage of being effective where other agents may not be and should be considered as part of any combination regimen when hyperglycemia is severe, especially if catabolic features (weight loss, ketosis) are present. Consider initiating combination insulin injectable therapy (Fig. 8.2) when blood glucose is ≥300 mg/dL (16.7 mmol/L) or A1C is ≥10% (86 mmol/mol) or if the patient has symptoms of hyperglycemia (i.e., polyuria or polydipsia). As the patient’s glucose toxicity resolves, the regimen may, potentially, be simplified.

Figure 8.1
Antihyperglycemic therapy in type 2 diabetes: general recommendations. *If patient does not tolerate or has contraindications to metformin, consider agents from another class in Table 8.1. #GLP-1 receptor agonists and DPP-4 inhibitors should not be prescribed in combination. If a patient with ASCVD is not yet on an agent with evidence of cardiovascular risk reduction, consider adding.

Figure 8.2
Combination injectable therapy for type 2 diabetes. FBG, fasting blood glucose; hypo, hypoglycemia. Adapted with permission from Inzucchi et al.

Combination Therapy
Although there are numerous trials comparing dual therapy with metformin alone, few directly compare drugs as add-on therapy. A comparative effectiveness meta-analysis suggests that each new class of noninsulin agents added to initial therapy generally lowers A1C approximately 0.7–1.0%. If the A1C target is not achieved after approximately 3 months and patient does not have atherosclerotic cardiovascular disease (ASCVD), consider a combination of metformin and any one of the preferred six treatment options: sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, or basal insulin (Fig. 8.1); the choice of which agent to add is based on drug-specific effects and patient factors (Table 8.1). For patients with ASCVD, add a second agent with evidence of cardiovascular risk reduction after consideration of drug-specific and patient factors (see p. S77 cardiovascular outcomes trials). If A1C target is still not achieved after ∼3 months of dual therapy, proceed to a three-drug combination (Fig. 8.1). Again, if A1C target is not achieved after ∼3 months of triple therapy, proceed to combination injectable therapy (Fig. 8.2). Drug choice is based on patient preferences (37), as well as various patient, disease, and drug characteristics, with the goal of reducing blood glucose levels while minimizing side effects, especially hypoglycemia. If not already included in the treatment regimen, addition of an agent with evidence of cardiovascular risk reduction should be considered in patients with ASCVD beyond dual therapy, with continuous reevaluation of patient factors to guide treatment (Table 8.1).

Table 8.2 lists drugs commonly used in the U.S. Cost-effectiveness models of the newer agents based on clinical utility and glycemic effect have been reported (38). Table 8.3 provides cost information for currently approved noninsulin therapies. Of note, prices listed are average wholesale prices (AWP) (39) and National Average Drug Acquisition Costs (NADAC) and do not account for discounts, rebates, or other price adjustments often involved in prescription sales that affect the actual cost incurred by the patient. While there are alternative means to estimate medication prices, AWP and NADAC were utilized to provide two separate measures to allow for a comparison of drug prices with the primary goal of highlighting the importance of cost considerations when prescribing antihyperglycemic treatments. The ongoing Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) will compare four drug classes (sulfonylurea, DPP-4 inhibitor, GLP-1 receptor agonist, and basal insulin) when added to metformin therapy over 4 years on glycemic control and other medical, psychosocial, and health economic outcomes.

Table 8.2
Pharmacology of available glucose-lowering agents in the U.S. for the treatment of type 2 diabetes

Table 8.3
Median monthly cost of maximum approved daily dose of noninsulin glucose-lowering agents in the U.S.

Rapid-acting secretagogues (meglitinides) may be used instead of sulfonylureas in patients with sulfa allergies or irregular meal schedules or in those who develop late postprandial hypoglycemia when taking a sulfonylurea. Other drugs not shown in Table 8.1 (e.g., inhaled insulin, α-glucosidase inhibitors, colesevelam, bromocriptine, and pramlintide) may be tried in specific situations but considerations include modest efficacy in type 2 diabetes, frequency of administration, potential for drug interactions, cost, and/or side effects.

Cardiovascular Outcomes Trials
There are now three large randomized controlled trials reporting statistically significant reductions in cardiovascular events for two SGLT2 inhibitors (empagliflozin and canagliflozin) and one GLP-1 receptor agonist (liraglutide) where the majority, if not all patients, in the trial had ASCVD. The empagliflozin and liraglutide trials demonstrated significant reductions in cardiovascular death. Exenatide once-weekly did not have statistically significant reductions in major adverse cardiovascular events or cardiovascular mortality but did have a significant reduction in all-cause mortality. In contrast, other GLP-1 receptor agonists have not shown similar reductions in cardiovascular events (Table 9.4). Whether the benefits of GLP-1 receptor agonists are a class effect remains to be definitively established. See antihyperglycemic therapies and cardiovascular outcomes in Section 9 “Cardiovascular Disease and Risk Management” and Table 9.4 for a detailed description of these cardiovascular outcomes trials. Additional large randomized trials of other agents in these classes are ongoing.

Of note, these studies examined the drugs in combination with metformin (Table 9.4) in the great majority of patients for whom metformin was not contraindicated or not tolerated. For patients with type 2 diabetes who have ASCVD, on lifestyle and metformin therapy, it is recommended to incorporate an agent with strong evidence for cardiovascular risk reduction especially those with proven benefit on both major adverse cardiovascular events and cardiovascular death after consideration of drug-specific patient factors (Table 8.1). See Fig. 8.1 for additional recommendations on antihyperglycemic treatment in adults with type 2 diabetes.

Insulin Therapy
Many patients with type 2 diabetes eventually require and benefit from insulin therapy. The progressive nature of type 2 diabetes should be regularly and objectively explained to patients. Providers should avoid using insulin as a threat or describing it as a sign of personal failure or punishment.

Equipping patients with an algorithm for self-titration of insulin doses based on self-monitoring of blood glucose improves glycemic control in patients with type 2 diabetes initiating insulin (42). Comprehensive education regarding self-monitoring of blood glucose, diet, and the avoidance of and appropriate treatment of hypoglycemia are critically important in any patient using insulin.

Basal Insulin Basal insulin alone is the most convenient initial insulin regimen, beginning at 10 units per day or 0.1–0.2 units/kg/day, depending on the degree of hyperglycemia. Basal insulin is usually prescribed in conjunction with metformin and sometimes one additional noninsulin agent.
When basal insulin is added to antihyperglycemic agents in patients with type 2 diabetes, long-acting basal analogs (U-100 glargine or detemir) can be used instead of NPH to reduce the risk of symptomatic and nocturnal hypoglycemia.
Longer-acting basal analogs (U-300 glargine or degludec) may additionally convey a lower hypoglycemia risk compared with U-100 glargine when used in combination with oral antihyperglycemic agents.
While there is evidence for reduced hypoglycemia with newer, longer-acting basal insulin analogs, people without a history of hypoglycemia are at decreased risk and could potentially be switched to human insulin safely. Thus, due to high costs of analog insulins, use of human insulin may be a practical option for some patients, and clinicians should be familiar with its use. Table 8.4 provides AWP and NADAC information (cost per 1,000 units) for currently available insulin and insulin combination products in the U.S. There have been substantial increases in the price of insulin over the past decade and the cost-effectiveness of different antihyperglycemic agents is an important consideration in a patient-centered approach to care, along with efficacy, hypoglycemia risk, weight, and other patient and drug-specific factors (Table 8.1).

Table 8.4
Median cost of insulin products in the U.S. calculated as AWP and NADAC per 1,000 units of specified dosage form/product

Bolus Insulin
Many individuals with type 2 diabetes may require mealtime bolus insulin dosing in addition to basal insulin. Rapid-acting analogs are preferred due to their prompt onset of action after dosing. In September 2017, the FDA approved a new faster-acting formulation of insulin aspart. The recommended starting dose of mealtime insulin is 4 units, 0.1 units/kg, or 10% of the basal dose. If A1C is <8% (64 mmol/mol) when starting mealtime bolus insulin, consideration should be given to decreasing the basal insulin dose.

Premixed Insulin
Premixed insulin products contain both a basal and prandial component, allowing coverage of both basal and prandial needs with a single injection. NPH/Regular 70/30 insulin, for example, is composed of 70% NPH insulin and 30% regular insulin. The use of premixed insulin products has its advantages and disadvantages, as discussed below in combination injectable therapy.

Concentrated Insulin Products
Several concentrated insulin preparations are currently available. U-500 regular insulin, by definition, is five times as concentrated as U-100 regular insulin and has a delayed onset and longer duration of action than U-100 regular, possessing both prandial and basal properties.
U-300 glargine and U-200 degludec are three and two times as concentrated as their U-100 formulations and allow higher doses of basal insulin administration per volume used. U-300 glargine has a longer duration of action than U-100 glargine.
The FDA has also approved a concentrated formulation of rapid-acting insulin lispro, U-200 (200 units/mL). These concentrated preparations may be more comfortable for the patient and may improve adherence for patients with insulin resistance who require large doses of insulin.
While U-500 regular insulin is available in both prefilled pens and vials (a dedicated syringe was FDA approved in July 2016), other concentrated insulins are available only in prefilled pens to minimize the risk of dosing errors.

Inhaled Insulin
Inhaled insulin is available for prandial use with a more limited dosing range. It is contraindicated in patients with chronic lung disease such as asthma and chronic obstructive pulmonary disease and is not recommended in patients who smoke or who recently stopped smoking. It requires spirometry (FEV1) testing to identify potential lung disease in all patients prior to and after starting therapy.

Combination Injectable Therapy
If basal insulin has been titrated to an acceptable fasting blood glucose level (or if the dose is >0.5 units/kg/day) and A1C remains above target, consider advancing to combination injectable therapy (Fig. 8.2).
When initiating combination injectable therapy, metformin therapy should be maintained while other oral agents may be discontinued on an individual basis to avoid unnecessarily complex or costly regimens (i.e., adding a fourth antihyperglycemic agent).
In general, GLP-1 receptor agonists should not be discontinued with the initiation of basal insulin.
Sulfonylureas, DPP-4 inhibitors, and GLP-1 receptor agonists are typically stopped once more complex insulin regimens beyond basal are used.
In patients with suboptimal blood glucose control, especially those requiring large insulin doses, adjunctive use of a thiazolidinedione or SGLT2 inhibitor may help to improve control and reduce the amount of insulin needed, though potential side effects should be considered.
Once an insulin regimen is initiated, dose titration is important with adjustments made in both mealtime and basal insulins based on the blood glucose levels and an understanding of the pharmacodynamic profile of each formulation (pattern control).

Studies have demonstrated the noninferiority of basal insulin plus a single injection of rapid-acting insulin at the largest meal relative to basal insulin plus a GLP-1 receptor agonist relative to two daily injections of premixed insulins (Fig. 8.2).
Basal insulin plus GLP-1 receptor agonists are associated with less hypoglycemia and with weight loss instead of weight gain but may be less tolerable and have a greater cost.
In November 2016, the FDA approved two different once-daily fixed-dual combination products containing basal insulin plus a GLP-1 receptor agonist: insulin glargine plus lixisenatide and insulin degludec plus liraglutide.
Other options for treatment intensification include adding a single injection of rapid-acting insulin analog (lispro, aspart, or glulisine) before the largest meal or stopping the basal insulin and initiating a premixed (or biphasic) insulin (NPH/Regular 70/30, 70/30 aspart mix, 75/25 or 50/50 lispro mix) twice daily, usually before breakfast and before dinner.
Each approach has its advantages and disadvantages. For example, providers may wish to consider regimen flexibility when devising a plan for the initiation and adjustment of insulin therapy in people with type 2 diabetes, with rapid-acting insulin offering greater flexibility in terms of meal planning than premixed insulin.
If one regimen is not effective (i.e., basal insulin plus GLP-1 receptor agonist), consider switching to another regimen to achieve A1C targets (i.e., basal insulin plus single injection of rapid-acting insulin or premixed insulin twice daily).
Regular human insulin and human NPH/Regular premixed formulations (70/30) are less costly alternatives to rapid-acting insulin analogs and premixed insulin analogs, respectively, but their pharmacodynamic profiles may make them less optimal.

Fig. 8.2 outlines these options, as well as recommendations for further intensification, if needed, to achieve glycemic goals.
If a patient is still above the A1C target on premixed insulin twice daily, consider switching to premixed analog insulin three times daily (70/30 aspart mix, 75/25 or 50/50 lispro mix).
In general, three times daily premixed analog insulins have been found to be noninferior to basal-bolus regimens with similar rates of hypoglycemia.
If a patient is still above the A1C target on basal insulin plus single injection of rapid-acting insulin before the largest meal, advance to a basal-bolus regimen with ≥2 injections of rapid-acting insulin before meals.
Consider switching patients from one regimen to another (i.e., premixed analog insulin three times daily to basal-bolus regimen or vice-versa) if A1C targets are not being met and/or depending on other patient considerations.
Metformin should be continued in patients on combination injectable insulin therapy, if not contraindicated and if tolerated, for further glycemic benefits.

Oral Diabetes Medications Summary Chart

Biguanides: Metformin (Glucophage), Metformin liquid ( Riomet)
• Metformin: usually taken twice a day with breakfast and evening meal.
How They Work: Decreases amount of glucose released from liver.
Side Effect: Bloating, gas, diarrhea, upset stomach, loss of appetite (usually within the first few weeks of starting). Take with food to minimize symptoms. Metformin is not likely to cause low blood glucose. In rare cases, lactic acidosis may occur in people with abnormal kidney or liver function.
Note: Always tell healthcare providers that it may need to be stopped when you are having a dye study or surgical procedure.

• Metformin extended release (Glucophage XR, Fortamet, Glumetza): usually taken once a day in the morning.

Sulfonylureas: Glimepiride (Amaryl), Glyburide (Diabeta, Micronase), Glipizide (Glucotrol, Glucotrol XL), Micronized glyburide (Glynase}
Take with a meal once or twice a day.
How They Work: Stimulates the pancreas to release more insulin, both right after a meal and then over several hours.
Side Effect: Low blood glucose, occasional skin rash, irritability, upset stomach.
Note: Because these medicines can cause low blood glucose, always carry a source of carbohydrate with you.
Follow your meal plan and activity program. Call your healthcare provider if your blood glucose levels are consistently low. If there is an increase in your activity level or reduction in your weight or calorie intake, the dose may need to be lowered.

Meglitinides: Repaglinide (Prandin)
D-Phenylalanine Derivatives: Nateglinide (Starlix)
Both of these medications should be taken with meals. If you skip a meal, skip the dose.
How They Work: Stimulate the pancreas to release more insulin right after a meal.
Side Effect: Effects diminish quickly and they must be taken with each meal; may cause low blood glucose.
Note: These work quickly when taken with meals to reduce high blood glucose levels.
However, they are less likely than sulfonylureas to cause low blood glucose.

DPP-4 Inhibitors: Sitagliptin (Januvia), Saxagliptin (Onglyza), Linagliptin ( Tradjenta)
Take once a day at the same time each day
How They Work: Improves insulin level after a meal and lowers the amount of glucose made by your body.
Side Effect: Stomach discomfort, diarrhea, sore throat, stuffy nose, upper respiratory infection. Do not cause low blood glucose.
Note: Can be taken alone or with metformin, a sulfonylurea or Actos.
Tell your healthcare provider if you have any side effects that bother you or that don’t go away.

Alpha-glucosidase Inhibitors: Acarbose (Precose), Miglitol (Glyset)
Take with first bite of the meal; if not eating, do not take.
How They Work: Slows the absorption of carbohydrate into your bloodstream after eating.
Side Effect: Gas, diarrhea, upset stomach, abdominal pain
Note: Take with meals, to limit the rise of blood glucose that can occur after meals; these do not cause low blood glucose.
Side effects should go away after a few weeks. If not, call your healthcare provider.

Bile Acid Sequestrants: Colesevelam (Welchol)
Take once or twice a day with a meal and liquid.
How They Work: Works with other diabetes medications to lower blood glucose.
Side Effect: Constipation, nausea, diarrhea, gas, heartburn, headache (may interact with glyburide, levothyroxine and contraceptives)
Note: Primary effect, when used either alone or with a statin, is to lower LDL cholesterol; has blood glucose-lowering effect when taken in combination with certain diabetes medications.
Before taking this medication, tell your healthcare provider if you have high triglycerides (blood fats) or stomach problems. If you take thyroid medication or glyburide, take them 4 hours before taking Welchol. Tell your healthcare provider if you have side effects that bother you or that don’t go away.

Combination Pills:
Pioglitazone & metformin) (Actoplus Met)
Glyburide & metformin (Glucovance)
Glipizide & metformin (Metaglip)
Sitagliptin & metformin (Janumet)
Saxagliptin & metformin (kombiglyze)
Repaglinide & metformin (Prandimet)
Pioglitazone & glimepiride (Duetact)

Check with your provider; usually taken once a day.
How They Work: Combines the actions of each pill used in the combination.
Side Effect: Side effects are the same as those of each pill used in the combination. Some combination pills may lead to low blood glucose levels if one of the medications contained in the combination has this effect.
Note: May decrease the number of pills you need to take.

Six types of diabetes pills

1. Glucophage
How does Glucophage work?
■ Glucophage helps your body produce less glucose from the liver. It does not cause the body to make more insulin; therefore, it rarely causes low blood glucose (hypoglycemia) when used alone.
■ Glucophage has been found to lower blood fat levels and possibly contribute to minor weight loss.

Guidelines for use
■ Take with meals one to three times a day.
■ Your healthcare provider may want you to combine Glucophage with another type of diabetes pill or insulin to further improve your control. Since it works differently than the other diabetes medications, it will not interfere with their action.

If you have forgotten to take your diabetes pills you may take them provided it has been less than 2 hours from your dosage time. If it is more than 2 hours, contact your healthcare provider. Do not take 2 doses at the next meal. If you miss a dose, note it in your record book.

Most medicines interact safely with Glucophage. However, always remind your healthcare provider what medicines you are taking and when there is a change in your medications, so that (s)he can make sure the combination is safe.

Minor side effects usually go away after your body gets used to taking the medicine for several weeks, and may include mild diarrhea, nausea, or upset stomach. Taking Glucophage with meals can lessen side effects.
Major side effects are very rare and occur mostly in people whose kidneys or liver are not working normally. The most serious side effect is lactic acidosis. It may be life threatening. Your healthcare provider will check your kidney and liver function to determine if you are at risk.

Are there situations where it is necessary to temporarily stop taking Glucophage?
Yes, there are situations that may affect your kidneys or liver function and thus put you at risk for developing lactic acidosis. To reduce this risk, your healthcare provider may need to stop the medication for a period of time. It is important that your healthcare provider know when the following problems or situations occur:
■ You have an illness resulting in dehydration (significant loss of body fluid), which may be due to severe vomiting, diarrhea and/or fever, or an inability to keep fluids down.
■ You are going to have any surgery or special X-ray procedures that require an injection of iodine contrast dye.

Who should NOT take Glucophage?
■ People who have kidney or liver problems
■ People who drink alcohol excessively
■ People with serious conditions such as a heart attack or severe infection
■ The safety of using Glucophage in pregnant women has not been established. Women who are pregnant or contemplating pregnancy should tell their healthcare provider immediately so the right medication can be prescribed.

2. Sulfonylurea Agents
There are many different Sulfonylurea agents:

Newer and stronger pills:
Brand na (glipizide)
Glucotrol XL® (glipizide extended release)
Amaryl® (glimepiride)

Older pills:
Diabinese® (chlorpropamide)
Orinase® (tolbutamide)
Tolinase® (tolazamide)

Sulfonylurea agents work to lower blood glucose by:
■ Helping the pancreas produce more insulin
■ Allowing the cells to use insulin better

Guidelines for use:
■ Take your pills daily, at the same time each day, before meals.
■ Glucotrol should be taken 30 minutes before eating. Other oral agents should be taken at the meal.
■ Oral hypoglycemic agents are often taken in combination with other diabetes pills and/or insulin to further improve your glucose control.
■ If you take Diabinese, do not use alcohol, because the combination of this medicine and alcohol may cause you to feel dizzy and sick to your stomach. Your face may feel warm and red and you could have severe low blood glucose.

If you have forgotten to take your diabetes pills, take them, provided it has been less than 2 hours from your dosage time. Write down that you delayed a dose in your record book. If it has been more than 2 hours, contact your healthcare provider. Do not take 2 doses at the next meal unless otherwise instructed. If you skip a dose, note it in your record book.

Can I take sulfonylurea agents with other medications?
Most medications interact safely with the newer sulfonylurea agents. However, always remind your healthcare provider what medicines you are taking and when there is a change in your medications. This will help ensure the combinations are safe. Ask if the new medication will affect your diabetes.

What are the side effects of sulfonylurea agents?
Hypoglycemia is the most common side effect of the sulfonylurea agents.

Other side effects, although uncommon, are listed below. Be sure to contact your healthcare provider if any of the following problems occur while you are taking your sulfonylurea agent:
■ Skin reaction
■ Dark urine
■ Stomach upset (nausea, diarrhea, tendency to pass gas)
■ Increased sensitivity to sun


Who should NOT take hypoglycemic agents?
■ Some people with kidney or liver disease or with allergies to sulfa drugs.
■ The safety of using sulfonylureas in pregnancy has not been established. If you are planning a pregnancy or become pregnant while taking sulfonylureas tell your healthcare provider immediately so the right medications can be prescribed.
■ People with type 1 diabetes.

New medications
Other new medications that work very similar to sulfonylureas by helping the pancreas make more insulin are:
■ Prandin® (repaglinide)
■ Starlix® (nateglinide)
These medication can also cause hypoglycemia. One advantage of taking these is that if a meal is skipped, the dose can be skipped.

3. Prandin
Prandin works to lower blood glucose by:
■ Helping the pancreas produce more insulin

Guidelines for use
■ Take your dose 0-30 minutes before the meal.
■ If you skip a meal, skip your dose. If you add a meal, add a dose before that meal. Be sure to clarify dosing with your healthcare provider.

If you have forgotten to take your Prandin dose, skip the dose and take your next dose at the scheduled time. Write down that you missed the dose in your record book. Do not take 2 doses at the next meal.

Can I take Prandin with other medications?
Most medications interact safely with Prandin. Some antifungal medications and antibiotics however, may effect the action of Prandin. Always remind your healthcare provider what medicines you are taking and when there is a change in your medications. This will help ensure the combinations are safe. When started on a new medication, ask your healthcare provider if the new medication will affect your diabetes.

What are the side effects of Prandin?
Low blood glucose or hypoglycemia is the most common side effect.

Who should NOT take Prandin?
■ The safety of using Prandin in pregnancy has not been established. Women using Prandin who are pregnant or contemplating pregnancy should tell their healthcare provider immediately so the right medication can be prescribed.
■ People with type 1 diabetes.
■ Some people with kidney or liver disease may need a dose adjustment.

4. DPP-4 Inhibitors: Sitagliptin (Januvia), Saxagliptin (Onglyza), Linagliptin ( Tradjenta)
Take once a day at the same time each day
How They Work: Improves insulin level after a meal and lowers the amount of glucose made by your body.
Side Effect: Stomach discomfort, diarrhea, sore throat, stuffy nose, upper respiratory infection. Do not cause low blood glucose.
Note: Can be taken alone or with metformin, a sulfonylurea or Actos.
Tell your healthcare provider if you have any side effects that bother you or that don’t go away.

5. Alpha-glucosidase Inhibitors: Acarbose (Precose), Miglitol (Glyset)
Take with first bite of the meal; if not eating, do not take.
How They Work: Slows the absorption of carbohydrate into your bloodstream after eating.
Side Effect: Gas, diarrhea, upset stomach, abdominal pain
Note: Take with meals, to limit the rise of blood glucose that can occur after meals; these do not cause low blood glucose.
Side effects should go away after a few weeks. If not, call your healthcare provider.

6. Bile Acid Sequestrants: Colesevelam (Welchol)
Take once or twice a day with a meal and liquid.
How They Work: Works with other diabetes medications to lower blood glucose.
Side Effect: Constipation, nausea, diarrhea, gas, heartburn, headache (may interact with glyburide, levothyroxine and contraceptives)
Note: Primary effect, when used either alone or with a statin, is to lower LDL cholesterol; has blood glucose-lowering effect when taken in combination with certain diabetes medications.
Before taking this medication, tell your healthcare provider if you have high triglycerides (blood fats) or stomach problems. If you take thyroid medication or glyburide, take them 4 hours before taking Welchol. Tell your healthcare provider if you have side effects that bother you or that don’t go away.

Tests for type 1 and type 2 diabetes and prediabetes

• Glycated hemoglobin (A1C) test. This blood test, which doesn't require fasting, indicates your average blood sugar level for the past two to three months. It measures the percentage of blood sugar attached to hemoglobin, the oxygen-carrying protein in red blood cells.

The higher your blood sugar levels, the more hemoglobin you'll have with sugar attached. An A1C level of 6.5 percent or higher on two separate tests indicates that you have diabetes. An A1C between 5.7 and 6.4 percent indicates prediabetes. Below 5.7 is considered normal.

If the A1C test results aren't consistent, the test isn't available, or you have certain conditions that can make the A1C test inaccurate — such as if you're pregnant or have an uncommon form of hemoglobin (known as a hemoglobin variant) — your doctor may use the following tests to diagnose diabetes:

• Random blood sugar test. A blood sample will be taken at a random time. Regardless of when you last ate, a random blood sugar level of 200 milligrams per deciliter (mg/dL) — 11.1 millimoles per liter (mmol/L) — or higher suggests diabetes.

• Fasting blood sugar test. A blood sample will be taken after an overnight fast. A fasting blood sugar level less than 100 mg/dL (5.6 mmol/L) is normal. A fasting blood sugar level from 100 to 125 mg/dL (5.6 to 6.9 mmol/L) is considered prediabetes. If it's 126 mg/dL (7 mmol/L) or higher on two separate tests, you have diabetes.

• Oral glucose tolerance test. For this test, you fast overnight, and the fasting blood sugar level is measured. Then you drink a sugary liquid, and blood sugar levels are tested periodically for the next two hours.

A blood sugar level less than 140 mg/dL (7.8 mmol/L) is normal. A reading of more than 200 mg/dL (11.1 mmol/L) after two hours indicates diabetes. A reading between 140 and 199 mg/dL (7.8 mmol/L and 11.0 mmol/L) indicates prediabetes.

If type 1 diabetes is suspected, your urine will be tested to look for the presence of a byproduct produced when muscle and fat tissue are used for energy because the body doesn't have enough insulin to use the available glucose (ketones). Your doctor will also likely run a test to see if you have the destructive immune system cells associated with type 1 diabetes called autoantibodies.

Tests for gestational diabetes

Your doctor will likely evaluate your risk factors for gestational diabetes early in your pregnancy:

• If you're at high risk of gestational diabetes — for example, if you were obese at the start of your pregnancy; you had gestational diabetes during a previous pregnancy; or you have a mother, father, sibling or child with diabetes — your doctor may test for diabetes at your first prenatal visit.

• If you're at average risk of gestational diabetes, you'll likely have a screening test for gestational diabetes sometime during your second trimester — typically between 24 and 28 weeks of pregnancy.

Your doctor may use the following screening tests:

• Initial glucose challenge test. You'll begin the glucose challenge test by drinking a syrupy glucose solution. One hour later, you'll have a blood test to measure your blood sugar level. A blood sugar level below 140 mg/dL (7.8 mmol/L) is usually considered normal on a glucose challenge test, although this may vary at specific clinics or labs.

If your blood sugar level is higher than normal, it only means you have a higher risk of gestational diabetes. Your doctor will order a follow-up test to determine if you have gestational diabetes.

• Follow-up glucose tolerance testing. For the follow-up test, you'll be asked to fast overnight and then have your fasting blood sugar level measured. Then you'll drink another sweet solution — this one containing a higher concentration of glucose — and your blood sugar level will be checked every hour for a period of three hours.

If at least two of the blood sugar readings are higher than the normal values established for each of the three hours of the test, you'll be diagnosed with gestational diabetes.