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Introduction to Basal Insulin Therapy: Clinical Management of Diabetes
Jasmine D. Gonzalvo, PharmD, BCPS, BC-ADM, CDE, LDE
Evaluating New-Generation Basal Insulin Therapy Participating Faculty
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Introduction to Basal Insulin Therapy: Clinical Management of Diabetes

Jasmine D. Gonzalvo, PharmD, BCPS, BC-ADM, CDE, LDE
Although most people with diabetes will need pharmacotherapy, patients should be encouraged to maintain healthy, active lifestyles at all stages of diabetes.7 The decision to begin any therapy—oral, insulin, or other injectable—should be made jointly by the patient and provider with appropriate considerations of evidence-based recommendations. The ADA recommends initiating metformin as first-line treatment for T2D at diagnosis unless contraindications exist.7 When considering add-on therapy to metformin, pharmacologic recommendations have recently changed to place preference on the medications shown to have CV benefits, such as empagliflozin or liraglutide.7 Dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium glucose co-transporter 2 (SGLT-2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists are among the newer, commonly used medication classes that have offered some advantages over sulfonylureas, alpha glucosidase inhibitors, meglitinides, and thiazolidinediones (TZDs) over the last decade.7

Although insulin therapy is the mainstay of treatment for patients with T1D, many patients with T2D may eventually require insulin therapy.7 Basal insulin regimens are often dosed once daily and are commonly added to oral diabetes medication regimens that do not provide optimal glucose management.7 The longer-acting basal analogs (U-300 glargine or degludec) may offer some advantages in comparison to U-100 glargine or detemir.7

Patient Reluctance

Although it is well established that optimal glycemic management delays or prevents serious diabetic complications, more than 50% of patients with T2D do not achieve their target A1C of less than 7.0%.18 The ADA, AACE, and IDF recommend that patients with diabetes be as near to normoglycemic as possible.3,7,19 While the use of insulin has typically been reserved for patients with worsening diabetes, studies suggest that early treatments with insulin therapy have long-term benefits. The UKPDS researchers demonstrated long-term beneficial CV effects of early intensive glycemic management, which may have included insulin, in a population newly diagnosed with T2D.20 The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial evaluated insulin glargine in patients with early T2D or prediabetes.21 Participants with prediabetes who received insulin glargine were 28% less likely to develop diabetes during the study period than those who received standard oral treatment. However, those who received insulin glargine also had higher rates of hypoglycemia and weight gain of about 1.6 kg in a 6-year period.21

Despite convincing evidence that insulin is safe and effective, many patients and physicians are reluctant to start insulin therapy.22 Fear of injections, weight gain, and hypoglycemia may be contributing factors as to why uptake is not greater. Many healthcare providers and patients are worried about hypoglycemia and its consequences. According to the ADA, risk factors for insulin-induced hypoglycemia are endogenous insulin deficiency, a history of hypoglycemia, aggressive glycemic therapy, recent moderate or intensive exercise, sleep, and renal failure.23

Hypoglycemia can increase the risk of injury and death, although reports from the Diabetes Control and Complications Trial state that severe hypoglycemia and low A1C account for only 9% of hypoglycemic episodes.24 The ADA estimates that 50% of all hypoglycemic events can be predicted by patients who self-monitor blood glucose levels.23 Despite the evidence supporting the use of insulin in patients with T2D, previous reports suggest that insulin is used in less than 50% of patients for whom it is recommended.25 Providing patient education on the signs, symptoms, and appropriate management of hypoglycemia, suggesting dietary and exercise modifications, making necessary medication adjustments, and monitoring blood glucoses frequently help to decrease the risk of hypoglycemia.23

Select Barriers to Use of Insulin Products

Some patients may not be able to afford some of the newer insulin products.25 Many of the newer insulin analogs are more costly than older formulations (such as neutral protamine Hagedorn [NPH] or regular insulin).25 Newer insulin products resemble endogenous insulin secretion patterns, and there are advantages to their use.25 It has been reported that patients are reluctant to begin insulin therapy—basal or prandial—because they perceive insulin regimens as complicated and confusing.25 To help patients understand how best to start or modify their insulin therapy, algorithms that provide a stepwise approach to basal–bolus insulin therapy and bolus dose adjustments are available.26

Basal, premixed, and basal-prandial insulin regimens using the newer insulin products are all designed to help patients safely achieve their glycemic goals, with the goal of attenuating adverse effects, such as hypoglycemia and weight gain.19 Long-acting insulins, such as U-100 insulin glargine, U-300 insulin glargine, insulin degludec, and insulin detemir, are insulin formulations with predictable pharmacokinetic and pharmacodynamic profiles.

Although weight gain is associated with insulin, results of a meta-analysis revealed that the combination of metformin with basal or basal–bolus insulin resulted in statistically significant reductions in weight gain compared with insulin monotherapy.27 Results of other randomized controlled trials demonstrated that the use of metformin with either insulin glargine or insulin detemir resulted in less weight gain than with NPH insulin.27 According to the results of the Treating To Target in Type 2 Diabetes trial, basal insulin detemir was associated with less weight gain than biphasic insulin aspart twice daily or prandial insulin aspart 3 times daily.28 Moreover, basal insulin detemir sustained its weight advantage after 3 years.28 Basal insulins have an extended rate of absorption and long duration of action, thereby minimizing the risk of hypoglycemia as compared with faster acting insulins.27

Clinical Inertia and Current Challenges in Diabetes Therapy Management

Despite substantial evidence from clinically based or well-established guidelines, some healthcare providers fail to initiate therapy for diabetes.29 Clinical inertia is defined as recognizing a problem but failing to act, start, or intensify therapy when there is substantial evidence to initiate treatment.29 Studies done in the United States, Canada, and Europe confirm that clinical inertia among healthcare providers is widespread, at 30% to 68%.29,30 A more recent study found clinical inertia rates to be as high as 57% among family physicians treating patients with diabetes; investigators reported poor glycemic control among those patients.31 Many providers exhibit clinical inertia when they do not initiate more aggressive therapy for their patients who are not reaching targeted A1C concentrations because of assumptions of nonadherence to pharmacotherapy, diet, and exercise.29

Clinical inertia can also be seen in patients who are reluctant to begin, modify, or intensify therapy because of previously experienced adverse effects, perceived risks of treatments, or the notion that there is no need to be proactive when there are no apparent symptoms of disease.29 Despite the results of less-than-optimal glucose levels, many prescribers do not advance a patient’s therapy based on perceptions that glycemic values were improving.29 Based on the results of a study examining changes in the “process” of diabetes management, patients achieved a significant reduction in A1C when clinicians intensified therapy based on protocol, which demonstrates that clinical inertia can be overcome.29

While guidelines for the management of diabetes are well established, clinical inertia is a barrier to improved patient outcomes. Better management of diabetes will require modification of current educational practices of providers and medical students.29 Several approaches to reversing clinical inertia have been recommended, including medical education programs, emphasizing the significance of medical education about dangers of clinical inertia to undergraduate and graduate students, systemic self-assessments, and regular interactions with peers or opinion leaders.32

Newer Insulin Formulations

Insulin degludec, available in 100 units/mL (U-100) and 200 (U-200) units/mL, is a once-daily injection that is characterized by its long duration of action of more than 42 hours and half-life greater than 24 hours.33 U-100 and U-200 are bioequivalent, but U-200 delivers half the volume of the U-100 formulation and allows for administration of up to 160 units in 1 dose.33 Based on the results of a phase 3 clinical trial (BEGIN, a 1-year, randomized, treat-to-target trial), insulin degludec U-100 and U-200 proved noninferior to older basal insulins in patients with T1D and T2D.33 Lower rates of severe hypoglycemia were also seen in participants receiving insulin degludec.33

There are 2 insulin glargine U-100 products (Basaglar, Lantus) which are biologically similar each other, indicating that it has no clinically meaningful differences in terms of safety, purity, and potency (ie, safety and effectiveness).34 Insulin glargine injection 100 units/mL (Basaglar) is a long-acting, once-daily basal insulin that is approved for the treatment of T1D and T2D in adults and pediatric patients.35 Based on a 24-week, phase 3 clinical trial consisting of 756 adult patients with T2D, a new biologically similar formulation of insulin glargine injection 100 units/mL (Basaglar) demonstrated noninferiority to a reference insulin glargine injection (Lantus).36 Switching from insulin glargine 100 units/mL (Lantus) to insulin glargine 100 units/mL (Basaglar) is a 1:1 dose conversion.35

Another recently approved product is insulin glargine 300 units/mL, a long-acting basal insulin product that lasts for more than 24 hours and has proven to be as safe and effective as insulin glargine 100 units/mL. It has a longer duration of glucose-lowering action than insulin glargine 100 units/mL.37 A series of multinational, open-label, parallel-group trials—known as EDITION I, II, III, and IV—led to the approval of insulin glargine 300 units/mL.37-39 Insulin glargine 300 units/mL is as effective as insulin glargine 100 units/mL in reaching optimal A1C and fasting plasma glucose (FPG) levels in patients with T1D and T2D with less risk of nocturnal or severe hypoglycemia at any time of the day.40 The TAKE CONTROL trial—patient-driven dose titration—enrolled participants with uncontrolled T2D into a 2-arm parallel-group, multicenter, multinational study.40 Despite having to increase doses of insulin glargine 300 U/mL, more than doses of insulin glargine U-100/mL, patient-driven titration of insulin glargine 300 U/mL led to similar glycemic management in participants with T2D with a lower risk of nocturnal hypoglycemia.37-39

 
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