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IMPORTANT DEFINITIONS Basal insulin: Basal insulin is insulin that is released in small, consistent increments to maintain stable blood glucose levels throughout the day. Basal insulin therapy mimics the body’s natural production of insulin, which maintains blood glucose stability during periods of fasting, such as overnight. Bolus insulin: Bolus insulin (often referred to as mealtime insulin) is short-acting or rapid-acting insulin that is used to cover meals or snacks to prevent elevations in glucose related to eating. Bolus insulin therapy mimics the body’s natural production of insulin after eating. Target blood glucose: Every patient with diabetes has individualized goals for target blood glucose levels that are agreed upon with their health care provider. Normal blood glucose values range broadly, depending on how and when they are measured. Fasting blood glucose is generally the lowest goal number (often 80 to 130 mg/dL), with post-meal blood glucose targets often being less than 180 mg/dL. All goals are individualized on the basis of patient characteristics, risk factors, needs, and preferences. SMBG: Self-monitoring of blood glucose (SMBG) involves a patient checking his or her own blood glucose level with a home monitor. SMBG is especially important for patients using insulin, because this practice allows patients to calculate insulin doses, monitor for potential adverse effects, and assess how well they are maintaining and achieving their target blood glucose levels.

BACKGROUND

Over the last decade, diabetes has reached epidemic proportions in the United States (US).¹ Since insulin's discovery in the late 1920s, this agent has served as the mainstay of type 1 diabetes (T1D) treatment, in which endogenous insulin-producing beta cells are destroyed by an autoimmune process.² Conversely, the multiple pathophysiologic defects of type 2 diabetes (T2D), including beta-cell dysfunction and insulin resistance, have led to an explosion of therapy modalities over the last 15 years. Beta-cell function decline and death begin at least 10 years before symptoms of T2D appear. By the time a patient is diagnosed with T2D, only 50% of beta-cell function remains.³ Since this dysfunction progressively deteriorates and is associated with worsening glycemic control, preservation and recovery of beta-cell functional mass is an essential consideration in treating T2D.⁴ Removing the negative effects of elevated glucose by adding exogenous insulin is one way to preserve beta-cell function.

Approximately 25% to 40% of people with T2D use insulin as part of their therapy to control their disease.⁵ Based on new data showing that certain agents have benefits on the cardiovascular system and kidneys, management guidelines for patients with T2D have changed significantly.^6,7 Unless contraindicated, metformin with lifestyle modifications remain first line therapy. After 2-3 months if A1C is above target, for patients with established atherosclerotic cardiovascular disease (ASCVD) or if chronic kidney disease (CKD) predominates, agents with benefit in these conditions are considered second line therapy (select GLP-1 receptor agonists and SGLT2 inhibitors). Basal insulin is third line therapy (see Table 1).^6,7 Basal insulin is also considered as a 3^rd or 4^th line agent in patients without established ASCVD or CKD.

Table 1. Summary of Guideline Recommendations6,7

Despite the growing number of treatment options, insulin therapy is an important part of therapy. Insulin can be combined with other oral and injectable diabetes treatments that work in different ways to effectively treat patients.^2,6,7 The main take-home message of this program is that using insulin therapy is not difficult; it produces a rapid, measurable response to therapy and can be used safely to help patients with diabetes achieve their personalized glycemic goals.

MIMICKING NATURE: PHYSIOLOGIC CONCEPT OF BASAL-BOLUS INSULIN

In people without diabetes, release of endogenous insulin made in the body is changes in response to increased glucose and decreased glucose levels.^8,9 Produced by the pancreatic beta cells, insulin is an anabolic hormone that plays an important role in glucose, protein and fat metabolism as well as in facilitating glucose metabolism and stimulating glucose storage into muscle and liver cells in the form of glycogen. It also reduces glucose made by the liver by inhibiting the secretion of the counter-regulatory hormone glucagon when plasma glucose concentrations rise. In addition, insulin converts excess glucose into fatty acids and triglycerides and promotes storage into adipose tissues. Insulin enhances the incorporation of amino acids into proteins as well.^8,9

The concept behind basal-bolus insulin replacing or attempting to mimic natural insulin secretion is illustrated in Figure 2.¹⁰ In a basal-bolus model each component represents about half of the patient’s daily insulin needs. The main function of basal insulin is to suppress glucose production in the liver between meals and overnight in addition to stimulating lipid and protein synthesis.¹¹ Long-acting and intermediate insulins are used as replacements to mimic the body’s basal insulin secretion. Typically, in a basal-bolus model, basal insulin accounts for approximately 50% of the total daily insulin needs. The overall percentage of basal insulin that contributes to the total daily dose (TDD) of insulin, however, can vary from patient to patient.

The primary function of bolus insulin is to control hyperglycemia following food consumption by storing nutrients. Rapid-acting or regular insulin is used to cover bolus insulin needs. In a typical basal-bolus model, each bolus insulin dosage replaces approximately 10% to 20% of daily insulin requirements before each meal, depending on how many carbohydrates are in the meal. Balancing carbohydrate consumption with bolus insulin replacement to avoid blood glucose that is too high or too low is the goal of bolus replacement, particularly in a patient with T1D. This usually requires multiple self-testing of blood glucose (BG) throughout the day, before meals, and 1 to 2 hours after meals or exercise and at bedtime to properly assess insulin efficacy. In patients with T1D without functioning beta cells and T2D with dysfunctional beta cells, exogenous insulin may be used as a replacement, yet the manner in which it is done is quite different.⁷ By the nature of their disease, those with T1D have to have full basal and bolus replacement at initiation, whereas patients with T2D may only require once-daily basal insulin injections for several years before requiring any bolus insulin.¹² The dosing of insulin is individualized in both type 1 and type 2 patients based on weight, insulin resistance, etc. A more detailed dosing strategy is discussed later in this module for T2D patients.

Figure 2. Mimicking Nature's Insulin: The Basal-Bolus Concept

Pharmacokinetic and Pharmacodynamic Differences of Bolus and Basal Insulins

Understanding the differences between the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of insulin products helps the provider to understand treatment rationale and dosing and how to safely monitor BG as well as how to implement pattern management.^9,13,14 Minor modifications to the insulin protein have resulted in significant differences in PK and PD parameters of formulated insulin products used to assist patients in controlling hyperglycemia. Table 2 illustrates the insulin products dividing them into bolus insulin products (shown in orange) and basal insulin products (shown in purple). Figure 3 illustrates how different insulin products work compared with the body’s own insulin.

Figure 3. Approximations of Insulin Action Profiles of Insulins

Bolus Insulin

Bolus injectable replacement insulin falls into two main categories: rapid-acting and short-acting insulins. Injectable rapid-acting insulin analogs include insulin lispro (Humalog), aspart (Novolog, Fiasp) and glulisine (Apidra).^15-17,22 Because these drugs begin to work in only a few minutes, patients should inject these insulins right before the meal or within 15 minutes of eating the meal. With rapid-acting insulin durations of 3 to 4 hours, usually the insulin is cleared before the next meal, which reduces the opportunity for insulin stacking (accumulation) and hypoglycemic events. This is an advantage over regular or short-acting insulin (Humulin R or Novolin R),^18,19 which has a longer onset and is ideally administered 30 minutes before a meal, and with a longer duration that can increase between-meal hypoglycemic risk. All currently injectable bolus insulin products can be mixed with intermediate-acting insulin (Humulin N or Novolin N).^20,21

Fast-acting insulin aspart (Fiasp) is the most recently approved bolus insulin. It contains niacinamide which leads to a more rapid absorption into the bloodstream compared to conventional aspart..²² In patients with T2D inadequately controlled with basal insulin and oral agents, faster aspart was found noninferior to conventional aspart as part of a basal-bolus regimen but showed an increase in post-meal hypoglycemia.²³ Faster aspart can be dosed at the start of a meal or within 20 minutes after starting a meal. The product is available as 100 U/mL multidose vials or FlexTouch pens.²²

In mid-December 2017, a “follow on” product called Admelog²⁴ (insulin lispro U-100) became available in the US. This agent has the identical amino acid sequence as the existing Humalog¹⁵ (insulin lispro U-100). The medication is not categorized as a biosimilar drug by the U.S. Food and Drug Administration (FDA). Rather, the FDA refers to it as a "follow-on" product.²⁴ This is mainly semantics since biosimilar products must have a "reference product" to be proposed as a biosimilar, and currently no insulin lispro products are licensed under the Public Health Service Act. Admelog is available in a vial and prefilled Solostar pen.²⁴

Inhaled insulin (Afrezza) is a bolus inhaled technosphere insulin powder product.²⁵ This agent is only used as mealtime insulin with fixed doses in increments of 4, 8, or 12 units, which can be inhaled separately or added together to the appropriate dosage, as shown in Figure 4. Baseline pulmonary function tests are required before using this product, which should not be taken by patients with asthma, chronic obstructive pulmonary disease, or who currently smoke. The most common adverse events are hypoglycemia, cough, and throat pain or irritation.²⁵

Basal Insulin

The two main types of basal insulin are intermediate-acting and long-acting. NPH, the only intermediate-acting insulin currently available, is relatively inexpensive and usually dosed once or twice daily. NPH insulin is cloudy white in color due to the zinc additive designed to increase the duration of action. NPH is the only insulin that can be mixed in the same syringe with all currently available bolus injectable insulin products. When combining insulins, the bolus insulin should be drawn up in the syringe first, followed by NPH. This order (clear before cloudy) helps preserve the PK/PD profile of the bolus insulin.^20,21

Currently, three long-acting insulin analog products exist: detemir (Levemir),²⁶ glargine (Lantus U-100; Toujeo U-300; Basaglar)^27,28 and degludec (Tresiba U-100 or U-200).²⁹ They all have a long onset and a relatively long duration of action. Detemir's peak and duration are shorter, and both increase as the dose of detemir is increased. Both glargine products and degludec are considered relatively "peakless" insulins meaning they provide relatively stable insulin coverage over at least 24 hours without a significant peak (see Figure 3), although this can vary from patient to patient. Degludec's duration of action is almost twice that of U-100 glargine, and the two of them have more predictable PK/PD profiles compared with detemir and NPH. The concentrated U-300 insulin glargine (Toujeo) is also available in a SoloStar insulin pen, for people who require higher daily dosages of insulin glargine.

When switching from one basal insulin product to another, dosage adjustments are usually necessary prevent hypoglycemia. When converting twice-a-day NPH to insulin glargine U-100 or U-300, the recommended starting dose is 80% of the total daily NPH dose administered once daily at the same time of day.^27,28 When converting between glargine and detemir, it has been found that the conversion is not one-to-one as previously thought.³⁰ Insulin glargine (U-100) appears to be between 20% and 39% stronger than detemir. A conservative approach is to increase the once-daily glargine dose used by 10% when converting from insulin glargine (U-100) to detemir. Adjustments are typically needed when converted from U-100 glargine to U-300 glargine.²⁸ For patients controlled on insulin glargine U-100 being converted to concentrated insulin glargine U-300, it is expected that the total daily dose will be higher by at least 10%.²⁸

In December 2016, Basaglar (insulin glargine U-100, which has an identical amino acid sequence as Lantus) was the first “follow on” insulin to become available in the US.³¹ Like Admelog, Basaglar is not categorized as a biosimilar drug by the FDA, yet the PK profile, efficacy, and safety are similar to Lantus. Basaglar is available in a prefilled KwikPen device.³¹

All bolus and basal insulins are manufactured as physiologic pH solutions with the exception of insulin glargine (both U-100 and U-300 formulations), which has a pH of 4. This acidic pH is necessary for glargine’s prolonged mechanism of action and may theoretically cause injection-site burning. This is not usually a concern, however.

Lastly, a concentrated U-500 formulation of regular insulin can be used for patients who require larger doses of daily insulin, but this is then considered a basal formulation.³² U-500 regular insulin is usually reserved for very insulin-resistant patients who require large volumes of insulin (200 units per day). A dedicated U-500 syringe for the use with Humulin U-500 insulin is available.³³ Previously, patients had to calculate dosing using a conversion method when drawing the U-500 insulin into U-100 syringes or tuberculin syringes. This was a cause for concern due to potential errors in dosing calculations.

Insulin Mixtures^34-39

Fixed-mixed-dose insulin products can be used twice daily in some patients with the benefits being ease of use and no mixing required. However, adjustment in fixed-mixed insulin dosages change both basal and bolus components with each dosage modification. In general, fixed-mixed insulins are not preferred if insulin components (either basal or bolus) require frequent dose changes. Table 3 lists currently available insulin mixtures.

Figure 4. Inhaled powdered insulin Dose Conversion Chart25

PRACTICAL APPROACH TO INITIATING INSULIN AND DOSING ADJUSTMENTS

Patients with T1D Using the Basal-Bolus Method

Patients with T1D usually begin insulin using the basal-bolus method, with very conservative dosing and loose glycemic goals until the individual's response is determined. Empirically, the total daily insulin dose is 0.4 to 0.5 units/kg; however, lower doses may initially be needed during the honeymoon phase when the pancreas may still have some function remaining.^40,41 In general, the daily dose is divided into 2 parts, with 50% as basal insulin (long-acting insulin or intermediate-acting NPH) and 50% as bolus insulin (mealtime insulin). The bolus insulin will be divided among 3 meals. Bolus doses may need adjustment based on the carbohydrate content of each meal. Very small adjustments are usually made one at a time until target goals are met. SMBG requirements are usually 4 to 8 times per day, if not more, especially as the individualized dose response is determined.

Using Insulin to Treat Patients with T2D

Compared with the intensive insulin regimens required by patients with T1D, initiating insulin in those with T2D is much more straightforward. The patient’s A1C can help guide initial insulin doses. The A1C, a clinical marker used to measure glycemic control, is a weighted mean of glucose concentrations from the previous 2 to 3 months. The A1C accounts for fasting plasma glucose (FPG) and postprandial glucose (PPG) concentrations. Figure 5 illustrates that not all A1C values are made up of the same FPG and PPG proportions.¹¹ At higher A1C values (greater than 9%), FPG concentration contributes more to the overall A1C than PPG. For this reason, basal insulin is often used first when treating patients with T2D. If A1C remains above goal and FPG are controlled, bolus insulin can be added to cover postprandial glucose excursions.

Figure 5

The American Diabetes Association (ADA) and European Association for the Study of Diabetes insulin-use guidelines demonstrate the use of the relative contributions of FPG and PPG of the A1C to guide initiation of insulin (see Table 4).^6,7 In general, insulin is considered third line therapy; however, insulin should be considered as the first injectable initiated if A1C is very high (> 11%); the patient is experiencing weight loss, polyuria, or polydipsia which suggest insulin deficiency; or if T1D is a possibility. A combination of a GLP-1 receptor agonist and basal insulin or basal bolus insulin should be considered if the A1C is over 10% or the patients current A1C is 2% above target goal. To improve adherence and reduce daily injections, GLP-1 receptor agonist and long acting insulin mixtures are available.

Another, quite practical way to view and approach insulin use is featured in Figure 6. The main goal with insulin use is that patients see the positive effects on their daily SMBG, and experience little or no hypoglycemia. For these reasons, start off with a low dose basal insulin and consistently titrate the daily dose upward until morning FPG values are between 80 and 130 mg/dL in most patients. The target glycemic goals (A1C and SMBG) can be set and personalized for each patient based on his or her individual factors (e.g., age, duration of diabetes, complications), and some patients, especial older ones, may require less stringent goals.^7,43

Practical Approach to Using Insulin in T2D

A rather practical method of initiation is to begin basal insulin at 10 units once daily, in the morning or at bedtime, and then increase the daily dose by 3 units every 3 days until morning FPG goals are achieved (Figure 6). Typically, goals are met within a few weeks to the first month, and patients experience reduced symptoms of hyperglycemia without low glucose events. A1C should be checked within 2 to 3 months to assess therapy. If FBG goals are met but the A1C remains above goal, additional mealtime coverage may be required. Patients should check their BG before each meal for 2 to 3 days and use these values and the pattern management in Table 5 to determine which meal contributes the most to high PPG. Bolus insulin can be added prior to that meal and adjusted as necessary until BG goals are met. Usually the post-prandial blood glucose goal is < 180mg/dL.

An alternative and preferred method to adding bolus insulin would be to consider a trial of a GLP-1 receptor agonist if the patient is not already on one. This option is useful, especially for overweight patients, as GLP-1 RAs may result in improved glycemic control without hypoglycemia and with the added benefit of weight loss. Another option is to switch the basal insulin to a fixed-mixed-insulin product administered twice a day. As described earlier, there are inherent limitations to using fixed dosing insulin. (Figure 6)

Table 5. Pattern Management:* General Insulin Dose Adjustments

*Assumes proper insulin administration, timing, regular meals, etc. CHO = carbohydrate; FPG = fasting plasma glucose; HS = at bedtime; RAI = rapid acting insulin Kroon LA, Williams C. Table 53-15.In: Alldredge BK, Corelli RL, Ernst ME, et al, eds. Koda-Kimble and Young's Applied Therapeutics: The Clinical Use of Drugs.10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2013:1223-1300.

HELPING PATIENTS WITH T2D TO MANAGE THEIR OWN INSULIN REGIMEN

Performing SMBG and understanding the meaning of the glucose values helps patients understand how their medication, exercise, and food choices impact their glucose control. Therefore, testing BG at home is essential. Because basal insulin is generally initiated first, patients should test at least once each morning before they eat. When patients have reached their glucose goals, they can potentially switch to twice-weekly testing. Figure 7 illustrates varied dosing strategies using 2 to 4 daily injections of basal and bolus injections. No matter which insulin regimen a patient is prescribed, using Table 5 as a tool to identify which insulin, meal, or snack may be causing highs or lows during different times of the day is helpful. Understanding the PK and PD of the type(s) of insulin can help when making dosage adjustments. This works for the majority of patients; however, there are some PK/PD differences to consider in some special populations.^14,42

Recommendations for Pattern Management to Guide Insulin Dose Adjustments

Clinicians can use the SMBG log to have patients track glucose values, times of day, and insulin dose as well as food and activity levels each day. At least 7 days of values should be used to help identify whether a BG pattern can be established. Additional information from the patient that may be important includes: 1. How many doses of insulin have you missed in the last week? 2. Have you noticed any foods that make your glucose readings higher? 3. Have you had any changes in meals or activities in the last week? If no significant changes are identified, then a patient may need to be referred to their provider for a insulin dose adjustment. Patient’s may need to be reminded of their glycemic targets and goal range, such as morning glucose values of 80 to 130 mg/dL, to be able to identify out-of-goal range values. Using the pattern management tool shown in Table 5 helps to identify where the insulin change may need to be made. Adjustments are made one at a time in small (approximately 10%) increments, starting with either the earliest time of high blood glucose in the day or the most crucial time, such as hypoglycemic events.

Figure 7. Examples of Insulin Dosing Regimens

American Diabetes Association. Practical Insulin: A Handbook for Prescribing Providers. 3rd ed. 2011.

INSULIN ADMINISTRATION

Properly preparing and administering the insulin dose is essential to ensure that patients receive the correct dose and to prevent injection-site reactions. Tables 6 and 7 provide stepwise insulin preparation and administration instructions. Insulin administration can be influenced by several factors listed in Table 8. As an inhaled insulin product, Afrezza is administered by inhaling at a 45-degree angle as shown in Figure 8.

Figure 8. Inhaled Insulin Administration25

WARNINGS AND PRECAUTIONS FOR THE USE OF INSULIN

With the purity of today's insulin options, injection-site reactions rarely occur. Since insulin is an anabolic hormone, fatty accumulation may occur if the patient regularly uses the same injection site. As such, it is important to remind patients to rotate their injection site and use a new needle/pen needle for each injection to avoid lipohypertrophy. The abdominal area is the preferred injection site, avoiding 1 to 2 inches around the navel, although some patients prefer injecting in the thighs or deltoids.

While weight gain may also be a concern with insulin use, coupled with a healthy diet and regular daily physical activity, insulin use does not have to result in added pounds.^45,46 Moreover, regular physical activity has been shown to improve BG control, lipids, blood pressure, cardiovascular events, mortality risk, and quality of life.⁴⁷

Hypoglycemia is among the most concerning adverse events with insulin use. Personalizing glucose target goals, self-monitoring blood glucose, and managing glucose patterns can help prevent hypoglycemia. Mild-to-moderate hypoglycemia is more common and easily treated compared with severe episodes requiring medical assistance. Research indicates an increased risk of cognitive impairment,⁴⁸ arrhythmias,⁴⁹ and cardiovascular and all-cause mortality^48-53 is associated with severe hypoglycemic episodes. Educating patients on prevention and treatment remains key for dealing with hypoglycemia. For these reasons, the ADA recommends a premeal glucose target of 80 to 130 mg/dL, instead of the previous 70 to 130 mg/dL.⁷ Several factors can contribute to hypoglycemia, including insufficient caloric intake (e.g., skipped or delayed meals, vomiting), inaccurate insulin dosage (e.g., depot effect, too high, frequent adjustments, incorrect insulin given), use of other hypoglycemic medications (i.e., insulin secretagogues), vigorous exercise, and excessive alcohol intake.

Since detecting hypoglycemia early is important, educating patients about potential symptoms is crucial. Early symptoms of hypoglycemia may include trembling, shaking, sweating, heart palpitations, or tachycardia. Other symptoms (e.g., slow mentation, difficulty concentrating, slurred speech, uncoordinated, dizziness) may occur as hypoglycemia worsens.

TREATING MILD-TO-MODERATE HYPOGLYCEMIA

Mild-to-moderate hypoglycemia can usually be reversed rapidly, often within 5 to 10 minutes. Using the "Rule of 15" described in Table 9, BG concentrations rise quickly without overtreating, which could lead to elevated glucose concentrations and an undesired BG roller coaster. As a preventative measure, people using insulin should always carry a fast-acting glucose source. For BG of less than 70 to 54 mg/dL, use 15 to 20 grams of carbohydrates. But if the glucose is below 54 mg/dL and the patient can swallow, 20 to 30 grams of carbohydrates should be consumed. Table 10 lists 15-gram amounts of effective fast-acting carbohydrates such as glucose tablets, milk, fruit juice, regular (non-diet) soft drink, sugar, raisins, hard candies, and glucose gels, with the tablets being the preferred source for treatment.

Foods high in fat such as chocolate, doughnuts, potato chips, and pizza are poor choices for treating hypoglycemia. This is mainly because fatty foods slow carbohydrate absorption, delaying glucose correction and adding unnecessary calories.⁴² However, if these foods are the only sources available, patients should use them, realizing that symptoms may take longer to resolve. Once hypoglycemia is treated and if mealtime is not within 1 hour, a light snack (e.g., crackers, a piece of fruit, a small sandwich) should be consumed to prevent further hypoglycemia.

TREATING SEVERE HYPOGLYCEMIA

Untreated mild-to-moderate hypoglycemia can lead to severe hypoglycemia and unconsciousness. Severe hypoglycemia may result in unconsciousness, coma, seizures, and the inability to swallow and should be treated with glucagon.⁵⁴ All patients with T1D must have a glucagon emergency kit. For an unconscious patient, keep in mind that the person experiencing severe hypoglycemia cannot swallow. Force-feeding food or liquid to an unconscious person is unsafe and can lead to choking.

Treatment of severe hypoglycemia requires a glucagon emergency kit, which is available only by prescription. The kit contains a 1-mg ampule of glucagon, a syringe filled with diluent, and administration directions. Glucagon, a natural counter-regulatory hormone to insulin, works quickly to increase BG concentrations. The glucagon mixing and administration instructions may seem confusing during an emergency. To prevent confusion in a stressful situation, it is vital to educate people around the patient (family, coworkers, close friends, teachers, caregivers) on how to prepare and administer glucagon before an actual emergency arises. Encourage them to practice the process of glucagon administration ahead of time so they will be prepared. Annual re-education is a practical recommendation.

Figure 9 contains a summary of the steps for treating severe hypoglycemia with glucagon. This hormone peptide may cause vomiting that lasts up to 24 hours. Unconscious individuals should, therefore, be turned on their side before glucagon is administered to prevent choking. The usual dose is 1 mg for adults and children 5 to 8 years old who weighing more than 44 pounds (20 kg), and 0.5 for children younger than 5 years of age who weigh less than 44 pounds (20 kg). Glucagon usually works within 5 to 10 minutes, but the effects are short-lived. If no response is seen after 5 to 10 minutes, a second injection may be given. If that is ineffective, the caregiver should call 911 immediately. Once the person is conscious and can swallow, the caregiver should give him or her a carbohydrate-containing liquid (e.g., juice, milk, a non-diet soft drink) followed by a carbohydrate snack (small sandwich and/or crackers with peanut butter). For the next 24 hours, regular SMBG is necessary as well as adequate food intake to replenish hepatic glycogen stores. The primary care provider should be informed of the episode.

It is important to remind patients to regularly check expiration dates on glucagon kits. It is a good practice to obtain a new glucagon kit annually. Although some patients go for years without having to use their glucagon emergency kits, it is very important that every insulin-treated patient has a kit available and keeps it easily accessible. The kits should be stored in several places, such as in the bedroom or in a purse, a desk, a briefcase, or a backpack, and those individuals around the patient should know where the kits are located.

Patients with repeated hypoglycemic episodes can develop hypoglycemia unawareness. This condition is characterized by a progressive loss of symptoms to hypoglycemia, such as sweating, tremor, anxiety, and palpitations.⁵⁵ This loss of symptoms may result in BG levels falling to potentially dangerous levels since the patient does not experience the typical signs. Hypoglycemic unawareness can in some cases be reversible by strict avoidance of hypoglycemia for even a few days.⁵⁶ This may require blood glucose targets to be higher (i.e., 90-150 mg/dL) temporarily depending on the individual patient to help avoid severe hypoglycemia.

Some medications such as beta-blockers can decrease the response to hypoglycemia by blocking most sympathetic warning symptoms, except for sweating. According to the ADA Standards of Care, the benefits of beta-blocker use in patients who have had a myocardial infarction outweigh the potential consequences of hypoglycemia.⁷ If nocturnal hypoglycemia occurs, individuals should keep a fast-acting glucose source such as a 4-ounce bottle/box or container of apple juice at the bedside for easy treatment. If nocturnal hypoglycemia recurs, the insulin regimen should be re-evaluated.

PERCEIVED BARRIERS TO INSULIN USE

Despite the advances and improved safety of newer insulin formulations, push back still persists with insulin use in many patients with T2D. A systematic review evaluating 25 studies (15 qualitative and 10 quantitative) indicated that barriers to insulin use tend to fall into 3 main categories: patient-, health care provider (HCP)-, and system-related.⁵⁷ The 3 most common barriers for patients were fear of painful injections, adverse effects of insulin, and the perception that insulin hinted at the end stages of diabetes. Patient barriers can be broken down by the provider if each is addressed and the patient is educated. Table 11 lists related barriers with practical talking points and solutions that providers can use to address patient-related barriers as well as common clinician- and health-system-related barriers.

HCP barriers include lack of knowledge and concerns about insulin's adverse events as well as fear that the patient will either not be willing to use it or have poor adherence.^57,60-63 With the advances in insulin therapy described above, adding basal insulin to an oral regimen can considerably control BG levels while minimizing risks of weight gain and hypoglycemia. HCP may need diabetes education and training that includes the pathophysiology of diabetes and the benefits and ease of insulin use in addition to patient-directed pattern management.

BREAKING DOWN THE BARRIERS: EMPOWERING PATIENTS TO CONTROL THEIR DIABETES

A more personalized care approach is recommended to help patients achieve glycemic control.⁶ Patients need information regarding the progressive nature of diabetes, factors that can control diabetes, current glycemic control status, current or potential complications, how to prevent complications, and the importance of glycemic control. A key component to diabetes control is empowering patients.^64,65 Empowerment encompasses listening, acknowledging, believing, and guiding. (Figure 10) HCPs can listen to patients' fears, concerns, and interests to help them identify a regimen that will best suit them. Acknowledging patients' concerns and discussing their issues should help them know that they have been heard, and it is helpful in breaking down barriers.

Figure 10. Empowerment Concept

Patients may need help identifying motivating factor(s) for taking control of their diabetes. What is the carrot? Is it improving their well-being by experiencing less nighttime urination, getting better sleep, having more energy, wanting to see improvement quickly, performing better at their job, living longer to experience a significant life event, or understanding the reason behind taking medications? Whatever the key element is, identifying and addressing the issue can help patients to control their diabetes. In a cross-sectional survey asking 524 patients with diabetes and caregivers about motivational factors and adherence methods used, medication education was identified as a key factor.⁶⁶ The 3 motivating factors most commonly identified as improving medication adherence were: 1. Knowing that diabetes medications work effectively to lower BG, 2. Managing those medications' adverse effects, and 3. Understanding the benefits of the agents used. To empower patients to overcome barriers to compliance, HCPs can help to educate patients about diabetes-drug indications, mechanisms of action, and therapeutic effects. Pharmacy technicians can help identify patients who would benefit from this education.

Understanding treatment options and addressing barriers are essential to helping patients adhere to insulin therapy. Empowering patients to understand that ultimately they are in charge of their diabetes is key. HCPs can provide patients with the tools, education, medication, and knowledge to assist them, but it is up to the patients to utilize this information to help control their diabetes. We can believe in them and help guide them toward achieving their goals. Empowerment is a vision that helps patients modify their behavior and make better decisions about their health care.^64,65 Using patient empowerment and motivation as key elements in a diabetes-intensive medical management tune-up clinic model has demonstrated significantly improved glycemic controlled compared with regular care supervised by a primary care provider, even in complex patients (-2.4% versus – 0.8% A1C reduction in 6 months, P < .05).⁴⁵

Once barriers are addressed with insulin therapy and patients are educated, seeing a positive impact from initiating insulin therapy is almost immediate. Finding the right dose of basal insulin plus daily SMBG is a good way for patients to see a difference in their diabetes control. Improvement in hyperglycemic symptoms of poor energy, frequent urination, and excessive thirst soon follows. Glycemic control has been shown to prevent or reduce long-term complications. Achieving diabetes control appears to have a legacy effect, with the benefits of previous glycemic control lasting over a decade in preventing complications.^66-70

IMPORTANT POINTS FOR PATIENTS USING INSULIN

Pharmacy technicians are an integral part of the pharmacy team and can identify potential counseling opportunities during interactions with patients. For patients who use insulin, ask the following open-ended questions to assess their comfort levels with insulin therapy and discern if a pharmacist consultation is needed:

• How does your insulin work?
• What difficulties do you have with your injections?
• How are you tracking your blood sugars?
• How often do you test your blood sugars? What do the results mean to you?
• How have you been feeling since you started your insulin?

The main message patients should understand is that insulin use does not have to be feared, and it can very quickly help control diabetes.

REFERENCES

1. Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2017. Atlanta, GA: US Department of Health and Human Services; 2017.
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