At her initial appointment with a new primary care provider, Ms. Jones, a 57-year-old woman diagnosed with type 2 diabetes mellitus (T2DM) 7 years earlier, reports that her blood glucose levels have been higher than usual for the past several years. Today, her hemoglobin A1c is 8.8%. She reports that her last A1c - calculated a year ago - was 8.4%. At that visit, her healthcare provider had encouraged her to lose weight and exercise. The provider made no changes to her oral medication regimen of metformin 2,000 mg daily, simvastatin 20 mg daily and glipizide 10 mg daily. At today's visit, Ms. Jones weighs 244 pounds and her body mass index is 33. She apologizes for failing to manage her diabetes adequately.
This is the point at which too many providers fail to take further action. It is tempting to encourage the patient to exercise, lose weight and make better food choices. That message is important, but we should do more to keep the patient on track with glycemic control. In this scenario, it is important to reinforce to Ms. Jones that T2DM is a progressive chronic disease and to explain that it is time to intensify treatment.
This scenario is typical of many encounters in primary care today, because T2DM is more prevalent than ever. T2DM is the seventh leading cause of death in this country.1 More than 25.8 million people have been diagnosed with this disease, and its incidence continues to increase.1 In 2007, U.S. healthcare costs related to diabetes were estimated at $174 billion annually; at least half were associated with the treatment of vascular complications.2
Rationale for Intensifying Treatment
Patients with T2DM have better healthcare outcomes when euglycemia is maintained within the parameters recommended by the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE). The ADA3 defines glycemic control as maintenance of an A1c below 7%, and the AACE4 recommends keeping A1c at or below 6.5%. Data show that many patients do not meet these goals, putting them at risk for developing preventable complications. These A1c goals are difficult to reach using oral agents alone because beta cell deterioration and insulin resistance, the core defects associated with T2DM, progress over time.5
Intensification of diabetes treatment is necessary for several reasons. First, cardiovascular disease and microvascular complications are in part prevented or delayed when glycemic levels are optimal. As demonstrated by the Diabetes Control and Complications Trial (DCCT),6 microvascular diseases are significantly reduced when glycemic goals are maintained. In this large multicenter trial, patients with type 1 diabetes experienced 54% lower risk for nephropathy, 60% lower risk for neuropathy, and 76% lower risk for retinopathy when A1c was maintained at or below 7%. The United Kingdom Prospective Diabetes Study (UKPDS)7 demonstrated similar results for people with T2DM. In that landmark trial, researchers documented a 21% reduction in diabetes-related deaths and a 37% reduction in microvascular complications for each 1% reduction in A1c. These seminal trials reinforced the need for reaching glycemic goals and revolutionized diabetes care in the United States.6,7
T2DM is a progressive disease that worsens over time, even with appropriate management and careful maintenance of the treatment regimen. At the time of diagnosis, approximately 50% of beta cell function may already be lost; declines of 3% to 5% occur each subsequent year.7,8 Oral medication is not sufficient to maintain euglycemia, so eventually most patients require insulin.9-11
T2DM is characterized by two main defects: insulin resistance and beta cell deterioration. As seen with Ms. Jones, beta cell function declined over time, leading to reduced insulin production. She developed significant hyperglycemia, signaling the need to intensify therapy.5
Given the burgeoning numbers of people diagnosed with T2DM and considering that most patients are managed in primary care settings, healthcare providers need to be more comfortable with initiating insulin.12 Much evidence suggests that only half of patients with T2DM will meet glycemic goals of A1c below 7%.5,13 Meanwhile, only 26% of people in the United States with diagnosed diabetes (both types) use insulin.1 That number is quite low considering the number of people with T2DM. The responsibility for delays in insulin initiation rests with both healthcare providers and patients.
Barriers to Starting Insulin
Many clinicians delay the intensification of diabetes management due to lack of sufficient knowledge about insulin agents and how to individualize therapy for each patient.8,14 Many new types of insulin analogs are now available, and choosing the correct insulin regimen can be daunting. Another issue is finding sufficient time to initiate insulin within the context of a primary care visit. Primary care offices are not always staffed to provide the patient education that is required, and finding appropriate referral services, such as a certified diabetes educator or registered dietitian, can be difficult.15-17
Another common barrier that can result in clinical inertia is assuming that the patient will be resistant or may feel too overwhelmed to initiate insulin. Consequently, the discussion about the need for insulin does not occur and the patient's hyperglycemia goes unchecked.18 Too many providers regard insulin as a treatment of last resort. Other provider concerns include the erroneous belief that insulin increases cardiovascular risks and fears about hypoglycemia and weight gain.19 Consequently, providers miss the opportunities to start insulin even when A1c approaches 9% or rises even higher. As noted by the UKPDS study, earlier initiation of insulin is necessary to prevent long-term complications because it inhibits glucotoxicity and may help preserve beta cell mass.9
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Some patients are hesitant to start insulin. Fear of needles, weight gain and hypoglycemia are commonly cited, and many patients believe that insulin therapy is a sign of personal failure or that they are disappointing their healthcare providers and families.8 Some patients may mistakenly associate insulin with late development of complications such as dialysis, amputations, or even death. Healthcare providers need to point out that starting insulin will help prevent the poor outcomes that occur when hyperglycemia is inadequately managed.18,20
When to Start Insulin
Most experts agree that therapy should be intensified when one or more oral agents fail to maintain A1c below 6.5% to 7%. Most oral agents lower A1c by 1% to 1.5%, so when the level is above 8.5% and the patient is already taking several oral agents, it is time to consider insulin. Insulin also is a recommended option for the patient who has not yet started oral therapy but has an A1c of 8.5% or greater. Insulin should be started in every patient whose A1c is greater than 10%.12,16,21-23
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The goal of insulin is to mimic the body's physiologic pulsatile release of insulin. Normally, basal insulin is released in small amounts to suppress catabolism of muscle and fat to help regulate hepatic production of glucose. Beta cells also secrete insulin to manage carbohydrate consumption and avoid postprandial hyperglycemia. In the presence of food, insulin is normally secreted in two phases. The first is to cover hepatic production of glucose and the second is to stimulate peripheral glucose uptake. Most people with T2DM lack the first-phase response, so exogenous insulin is needed to simulate this normal physiologic basal-bolus secretion.5,8 Insulin levels must be precisely controlled to maintain euglycemia and prevent hypoglycemia.9,14 The glycemic targets for A1c, fasting and postprandial blood glucose levels are listed in Table 1.
The new insulin analogs (rapid and long-acting) more closely match the normal physiologic release of endogenous insulin. Because they provide higher serum levels of insulin earlier and have a shorter duration of action than older types of insulin, the rapid-acting analogs - lispro, aspart and glulisine - provide more flexibility for patients around mealtimes.5 Additional advantages include the ability to reduce unchecked postprandial glucose excursions and to reduce the risk of severe hypoglycemia.9 See Table 2 for more details.
How to Start Insulin
The ideal regimen of insulin is the basal-bolus method because it provides the best physiologic action and best glycemic control.4,5,8 But many patients are reluctant to adopt a complicated routine in an initial attempt, so introducing a simpler routine may be preferable. Choice of insulin and regimen is influenced by many factors, including the patient's willingness to inject more than once a day, his or her ability to manage insulin injections (including vision issues), the ability to titrate and calculate doses, and coordination with the patient's lifestyle.14 Other factors to consider include patient age, work environment, cost and insurance coverage, cultural influences, and comorbidities. All of these factors influence the decision to use basal insulin once daily, premixed insulin or prandial coverage added to basal insulin.12,16,19
It is important to note that glycemic control does not need to occur immediately. In fact, it is best to titrate slowly to avoid patient dissatisfaction and dangerous hypoglycemia. Select a simple routine to get a patient started. Simplicity offers the patient a chance to gain confidence in the routine before advancing to more complex regimens with multiple daily injections.14 One of the easiest ways to start insulin is to add an evening dose of basal insulin to the patient's oral medications.4 Basal insulin includes NPH (neutral protamine Hagedorn) and long-acting analogs (insulin glargine and insulin detemir). Advantages of the analog basal insulins are their 24-hour duration, their once-daily dosing, their association with less hypoglycemia (especially at night) and their predictable effects. Insulin detemir is also associated with less weight gain than NPH or insulin glargine.4,14, 24,16
Another clear advantage to adding basal insulin is that it is relatively easy to calculate and order. When unsure about the starting dose, it is safe to start 10 units of basal insulin at bedtime as recommended by the Treat-to-Target study.12,25,26 For patients with T2DM, the initial dose of basal insulin can be weight-based at 0.15 units/kg/day (0.1 to 0.2 units/kg/day is the recommended range); however most patients require significantly more insulin due to high levels of insulin resistance.8,11 Basal insulin can be increased slowly to achieve a fasting glucose level of less than 100 mg/dL. In the Treat-to-Target study, average daily doses required to reach goals were 0.48 units/kg/day for insulin glargine and at least two oral agents. That is equivalent to approximately 44 units of glargine per day for a patient who weighs 200 pounds (200/2.2 = 91 kg; 91 × 0.48 = 44 units).
Basal insulin specifically targets fasting blood glucose, so another advantage is that it is relatively easy for the patient to titrate with minimal assistance. For NPH insulin, two delivery methods are available: The total dose can be divided in half and given 12 hours apart, or two-thirds of the dose can be given in the morning and one-third in the evening (to maximize the prandial coverage midday).14
Another routine to consider is the use of biphased, premixed insulin preparations. This provides basal and postprandial coverage in one injection. Studies indicate that this routine can help patients reach glycemic goals adequately. However, premixed preparations do not allow the "fine tuning" of administration that basal-bolus therapy does. This type of insulin is more appropriate for patients who desire a simpler routine that requires injecting insulin only twice a day; it provides basal as well as prandial coverage.3,4,19 Premixed insulin can initially be added to the largest meal of the day, and then a second dose can be added at breakfast. To calculate the starting dose of premixed insulin, use 0.2 units/kg/day as the basic formula and give it in two equal divided doses right before a meal.16 Patients who use premixed insulin need to be assessed frequently for hypoglycemia; they also should keep a fairly consistent routine.4
Choice of insulin routine depends on many factors, including provider preference and patient issues such as convenience and willingness to inject once or multiple times daily. Table 3 outlines the primary considerations. Patients can continue their oral medications after adding insulin - with the exception of sulfonylureas, due to the high risk for hypoglycemia.27 Continuation of metformin assists in improving insulin sensitivity because it reduces gluconeogenesis and the dose of insulin needed. It also assists with weight maintenance. Glucagon-like peptide (GLP-1) analogs such as exenatide can be continued with metformin.12,28
Managing and Titrating Insulin
Several methods for titrating insulin are available, and simple adjustment schedules can be easily implemented by patients. Every 3 days, if the patient's fasting glucose level is above 130 mg/dL, basal insulin can be increased by 2 units. For glucose readings that are below 70 mg/dL, basal insulin can be reduced by 10%, or 4 units. Severe reactions warrant a phone call or office visit with the prescriber.14
It is important to also consider adding prandial coverage before the basal dose reaches 0.5 units/kg/day. So, in the case of Ms. Jones, prandial insulin should be added when her basal dose approaches 45 to 55 units daily (244 pounds or 111 kg; 110 kg/2 = 55 units of insulin).
Prandial coverage can be provided by rapid-acting analog or short-acting regular insulin. As with the analog basal insulins, the rapid-acting analogs more closely mimic physiologic insulin secretion. Their clear advantage over regular insulin is that they take effect within 10 to 15 minutes, peak in 30 to 90 minutes and last for only 3 to 5 hours. Because they are absorbed more rapidly than regular insulin, the analogs can be given right before a meal and they have a more predictable duration that will help avoid hypoglycemia.16
Prandial coverage is managed in several ways.4 The easiest technique is to have the patient give a fixed amount prior to each meal, but that does not allow for adjustments based on current glucose level or the anticipated carbohydrate ingestion. To get started, the patient can take 5 units of rapid-acting insulin (or about 7% of the daily dose of the basal insulin) before each meal.4 Another technique is to have the patient calculate the premeal dose based on the glucose reading right before the meal, following a sliding scale developed for him or her. And a preferred method is to give both prandial and correctional insulin just before the meal based on the anticipated carbohydrate ingestion. This requires counting carbohydrates correctly and adjusting the insulin dose.
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Usually, predetermined insulin-to-carbohydrate ratio is used to predict the amount of insulin to be given. A common ratio is 1:10, which means that the patient will give 1 unit of insulin for each 10 grams of carbohydrates in the meal. The ratio can be changed depending on blood glucose readings and amounts of carbohydrates eaten at each meal; the patient may have a different ratio for each meal. This kind of routine is more complex and requires a highly motivated patient who can attend diabetes classes or individual sessions with a diabetes educator or dietitian.4
Adding prandial coverage requires that patients monitor blood glucose levels more frequently. The recommended routine for checking glucose levels is at least 4 times a day - before each meal and at bedtime. Patients should bring glucose logs or their glucose meter to all appointments. Using this data, the clinician can make more accurate adjustments in insulin doses to avoid hypoglycemia and prolonged excursions of hyperglycemia.3
Case 1: Basal-Bolus Insulin
Consider the following example of Mr. Smith, a 62-year-old man who was diagnosed with T2DM 4 years ago. He is currently taking insulin glargine 22 units a day and 6 units of prandial coverage three times a day, before meals. His glucose levels for several days are shown in Table 4.
Mr. Smith is experiencing higher fasting readings each morning and higher levels after supper and before bedtime. If he is taking both basal and prandial insulin, the appropriate adjustment is to increase his basal insulin by 2 units to target fasting blood glucose levels (increase to 24 units daily) and increase rapid-acting analog before supper by 1 to 2 units (increase to 7 to 8 units). Mr. Smith should continue to monitor his blood glucose levels and report them after 1 to 2 weeks for further adjustments. All patients should report episodes of hypoglycemia for immediate dose reduction, if needed.
Giving basal-bolus insulin can be more challenging, but it provides the best physiologic match to endogenous insulin profiles. It is also more flexible because it allows for variable mealtimes and routines. Approximately 50% of the total daily dose of insulin should be basal insulin and the rest should be given as prandial (divided for meals).12
Highly motivated patients with T2DM can also transition to insulin pump therapy if desired.12,29 Continuous subcutaneous insulin infusion can offer the maximum flexibility possible for meals, activity and travel. The highly motivated patient may also benefit from continuous glucose monitoring.4
Case 2: Transitioning to Insulin
Mr. Logsdon is a 49-year-old man who was diagnosed with T2DM 6 years ago. His disease is poorly controlled. His A1c at the appointment today is 9.8%. He takes metformin 2,000 mg daily and asks if he will be placed on insulin. He works in construction and wants to keep his diabetes routine simple. He is opposed to checking his blood sugar or administering insulin while at work because his coworkers and boss are not aware of his health issues. Currently he only tests his blood sugar in the morning. Mr. Logsdon weighs 226 pounds (102 kg) and has a body mass index of 33. After a quick calculation, the clinician determines that Mr. Logsdon will need approximately 20 units of insulin to start (102 kg/0.2 units = 20.4).
The clinician chooses a biphased mixed insulin so that Mr. Logsdon can test his blood glucose and inject insulin in the morning right before breakfast and before he goes to work. He can repeat the routine before supper after he gets home. For premixed insulin, the required dose can be given in two divided doses approximately 12 hours apart. The clinician starts Mr. Logsdon on an analog mix of 70%/30% insulin at 10 units in the morning before breakfast and 10 units in the evening before supper. Blood glucose levels before breakfast and supper will help guide the titration of his regimen. For high fasting glucose before breakfast, the clinician will increase the pre-supper dose of insulin. High glucose levels before supper will require a higher morning dose of insulin.4 Fine-tuned titration is not possible with this type of insulin regimen. At each visit, the clinician needs to emphasize the importance of eating only healthy foods after administering the mixed insulin, to avoid hypoglycemia.
Within 3 months, the patient reports that his blood glucose level is ranging between 108 mg/dL and 122 mg/dL each morning and between 134 mg/dL and 148 mg/dL before supper. His A1c is still elevated at 7.6%, so the clinician increases his morning and evening dose of mixed insulin by 2 units each.
The clinician also refers Mr. Logsdon to a certified diabetes educator to learn how to count carbohydrates and instructs him to eat at least 30 grams of carbohydrates after taking his insulin in the morning to avoid hypoglycemia. The clinician advises Mr. Logsdon to keep glucose tablets with him at all times and explains how to recognize signs of hypoglycemia. At the next visit, the patient will bring his meter and logs so the clinician can further titrate his insulin.
Education is essential for addressing patient concerns about T2DM and insulin administration. One of the most important points about T2DM is its progressive nature of beta cell deterioration with resultant uncontrolled A1c. Eventually, most patients require insulin, and it is best to prepare them early in the process.30 This allows more time to get accustomed to the idea and to address the common myths associated with insulin. When patients receive preparatory information early in their educational program, accepting insulin and adjusting to the routines are much more easily accomplished.12
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Patient education is also essential for safe insulin administration. Even though severe hypoglycemia is rare among patients with T2DM, the basic "survival skills" must be reviewed at the onset of insulin initiation to protect against a hypoglycemia emergency. Patients must be instructed to eat immediately after giving short-acting insulin, and the signs and symptoms of hypoglycemia must be reviewed at all visits. Patients should be advised to carry a source of glucose with them at all times, such as glucose tablets or hard candy. For patients who experience severe episodes of hypoglycemia, family members should be taught how to administer a glucagon injection in an emergency. Clinicians also should educate patients about how to take care of their diabetes when they experience illness; providing written patient education handouts helps cement this and other knowledge.4,16
Other useful tips will facilitate the transition to insulin. First, secure modern insulin delivery devices for patients so that they accept insulin more readily. Unlike vials and syringes, it is more convenient and discreet for patients to carry prefilled insulin pens.31,32 Pens provide increased flexibility for the patient because they are portable, and they can be kept out of the refrigerator for up to a month once opened.8 Make sure patients are using the smallest possible pen needles to ensure correct placement of insulin in the subcutaneous space; these are also less painful for the patient.12,16 Insulin pens are equipped with dials to easily dose insulin; the dial also makes a palpable and audible click so that people with poor vision can use them. These devices enhance patient adherence and improve accuracy in insulin dosing.13,32-36
Also instruct patients that although long-acting insulin can be injected any time of the day, the patient should inject at the same time each day. Self-monitoring of blood glucose (SMBG) results should be documented and logs or charts should be brought to each visit; alternatively, the patient can download meter results or office personnel can perform this in anticipation of the office appointment. SMBG results are essential for recognizing patterns in blood glucose readings to ensure accurate insulin titration. Patients need to engage in SMBG much more frequently when they take insulin, so appropriate adjustments can be made. The ADA recommends that patients check blood glucose levels at least three times a day if they use multiple insulin injections.3
Patients with renal or hepatic dysfunction are predisposed to hypoglycemia because gluconeogenesis and glycogenolysis are affected. The degradation of insulin also is impaired, making hypoglycemia more likely. Insulin dose should be lowered to avoid a dangerous response.
Patients with pancreatic damage or injury lose both beta cell and alpha cell function. As a result, they lose the protective effects of glucagon and face a much higher risk of serious hypoglycemia.10 Some patients lose the ability to sense hypoglycemia and are at high risk for severe consequences. Events that can lead to low blood glucose levels, such as inadequate carbohydrate intake or taking too much insulin, should be avoided at all cost. All high-risk patients should wear medical alert identification. Older adults can be at high risk for hypoglycemia. The need for tight glycemic control should be evaluated carefully, and accepting higher targets for A1c (8% or less) may be appropriate.16
Seek Full Engagement
For many patients with T2DM, the intensification of therapy is essential to maintain euglycemia. It is imperative to individualize the plan of care, and immersing the patient and his or her loved ones in the plan is helpful. Glucose goals should be shared with patients to help increase the likelihood of treatment success. Open communication and early introduction to concepts of avoiding diabetes complications can increase patient acceptance and adherence.16 Introduction of new delivery devices can help match the patient to the regimen more successfully. To help ensure that diabetes-related complications are prevented, insulin titration should continue in order to achieve recommended goals. Insulin therapy does require close monitoring, but treatment is well tolerated when patients are fully engaged in SMBG and other aspects of their care. Considering the aging of the population and the ever increasing rates of obesity and T2DM, it is vital for NPs and PAs to be comfortable with the initiation and adjustment of insulin to maintain glycemic goals and avoid or minimize diabetes-related complications.
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26. Riddle MC, et al. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetes patients. Diabetes Care. 2003;26(11):3080-3086.
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34. Davis SN, et al. Clinical impact of initiating insulin glargine with disposable pen versus vial in patients with type 2 diabetes mellitus in a managed care setting. Endocr Pract. 2011;17(6):845-852.
35. Lee LJ, et al. Predictors of initiating rapid-acting insulin analog using vial/syringe, prefilled pen, and reusable pen devices in patients with type 2 diabetes. J Diabetes Sci Technol. 2010;4(3):547-557.
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Jane Kapustin is an adult nurse practitioner who is board certified in advanced diabetes management. She is the assistant dean for the master's and DNP programs at the University of Maryland School of Nursing in Baltimore and maintains a faculty practice at the University of Maryland Medical Center for Diabetes and Endocrinology. She has completed a disclosure statement and reports no relationships related to this article.