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Supplements Evaluating New-Generation Basal Insulin Therapy
Introduction to Basal Insulin Therapy: Clinical Management of Diabetes
Jasmine D. Gonzalvo, PharmD, BCPS, BC-ADM, CDE, LDE
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Evaluating the Managed Care Implications of Longer-Acting Basal Insulin Analog Therapies
Tripp Logan, PharmD, and Bianca Daisy, PharmD

Evaluating the Managed Care Implications of Longer-Acting Basal Insulin Analog Therapies

Tripp Logan, PharmD, and Bianca Daisy, PharmD
Diabetes, particularly type 2 diabetes (T2D), has become an epidemic in the United States, with a significant portion of patients unable to meet recommended glycemic targets. All individuals with type 1 diabetes (T1D) and a significant majority of those with T2D will ultimately require insulin therapy. However, there are several barriers to its use. The introduction of the new, ultra–long-acting basal insulins degludec and glargine U-300, and the single-injection combinations of insulin degludec/liraglutide and insulin glargine U-100/lixisenatide, offer options that may overcome several of those barriers, including the high risk of hypoglycemia, glycemic variability, and relatively short duration of action. This article spotlights the outcomes of the phase 3 clinical trials for these newer formulations, as well as more recent meta-analyses and real-world studies. It also highlights the implications for managed care plans as they move to add these insulins to their formularies.
Am J Manag Care. 2018;24:-S0
An estimated 30.3 million people in the United States, or 9.4% of the population, now have diabetes, with about 1 in 4 yet to be diagnosed. The numbers are significantly higher in the 65-years-and-older population, in which  25.2% have the disease.1

The burden of diabetes can be difficult for patients and complex for the US health system. Direct medical costs for diabetes in 2012 were $176 billion, about $1 out of every $10 spent on healthcare in the United States.2 Overall medical costs for those with diabetes are, on average, 2 to 3 times higher than for those without the disease, with more than half the cost attributable to the diabetes itself. People with diabetes also have higher rates of hospitalization and longer lengths of stay than those without, accounting for about a quarter of all US hospital inpatient costs. In addition, the cost of medications has risen substantially in recent years. Today, about a third of what the United States spends on medications can be attributed to diabetes.2

A substantial percentage of diabetes-related healthcare costs are the result of complications from the disease, which includes cardiovascular disease (CVD), chronic kidney disease (CKD), neuropathy, and diabetic retinopathy. Such complications account for 25% of emergency department visits and 45% of inpatient admissions.2 Maintaining glycemic control, typically defined as a glycated hemoglobin (A1C) less than 7%, can significantly reduce the risk of these complications.3

Despite high spending and the availability of effective treatments, control of diabetes in this country remains poor. The most recent government figures show that while glycemic control has improved from 1999 through 2010, nearly half of US adults with diabetes still do not reach an A1C of less than 7%; about 20% do not have an A1C less than 8%. The percentages are even worse for patients on insulin therapy from 2007 to 2010: just 30% reached an A1C of less than 7% and just 64% reached less than 8%.4

Insulin Therapy

Traditionally, insulin therapy has been reserved as a third- or even fourth-line treatment for diabetes, used when all other options fail. However, given a greater understanding of the benefits of early insulin initiation on beta-cell preservation and reduced microvascular complications, the most recent guidelines from the American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE) recommend earlier initiation for patients with hyperglycemia uncontrolled on other antidiabetic medications.3

As the first part of this supplement noted, there are numerous barriers to the early initiation of insulin. These include the strict timing required for insulin injections, patient fear of needles, the risk of hypoglycemia, and weight gain.5-8

Many of those fears are justified. While basal insulins detemir and glargine, with reduced frequency of injection and glucose monitoring, are usually the first option used when initiating insulin therapy, they have numerous limitations, including the risks of hypoglycemia, particularly nocturnal hypoglycemia, and weight gain; inter- and intra-individual variability; and the potential for twice-daily injections.9-13

The longer-acting basal insulins degludec and glargine U-300 require a once-daily injection, have a longer and more stable pharmacokinetic profile, exhibit lower within-subject variability, do not result in significant weight gain, and carry a lower risk of hypoglycemia. There is also less involvement with the hepatic or renal systems, and they can be combined with fast-acting insulin or a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in a single injection.8,11 This improved clinical profile is leading diabetes experts to recommend the use of basal insulin much earlier in the disease state, with the addition of a GLP-1 RA (either separately or in a fixed dose) if basal insulin alone is insufficient to control A1C.14,15

This article highlights the efficacy and safety of insulins degludec and glargine U-300, as well as the combination insulin degludec/liraglutide U-100/3.6 mg/mL and glargine/lixisenatide U-100/33 mcg/mL, and discusses the managed care implications of these newer insulin formulations.

Insulin Degludec

Insulin degludec is an ultra–long-acting, once-daily insulin pen approved for use in adults, adolescents, and children with diabetes.16 Insulin degludec’s stable pharmacokinetic profile stems from the formation of multihexamers upon injection, resulting in a subcutaneous depot of insulin. This delays insulin absorption into the systemic circulation, while the insulin also binds to circulating albumin, resulting in a lengthened duration of action of more than 42 hours and a half-life of approximately 25 hours. Insulin degludec’s concentration does not vary once it reaches a steady-state concentration within 3 days of injection. In addition, its pharmacokinetics are similar even in individuals with renal and hepatic impairment, regardless of the degree of impairment.8 At the same time, this reduces glycemic variability, thus minimizing hypoglycemic and hyperglycemic excursions.17

Insulin degludec was evaluated in the BEGIN clinical trial program and an interim analysis of DEVOTE, which studied its cardiovascular (CV) safety. The BEGIN program was a series of nine 26- to 52-week,  randomized, controlled, open-label, multicenter, treat-to-target trials in patients with T1D and T2D from more than 40 countries.12,18-24 Table 1 provides an overview of the trials.12,18-25

Three trials evaluated insulin degludec against insulin glargine in basal–bolus therapy in T1D and T2D, and 4 against glargine in basal–oral therapy in participants with T2D, for a total of 7 trials.12,18-25 A basal–oral trial in patients with T2D compared insulin degludec with sitagliptin, while another in patients with T1D compared it with insulin detemir.24,26

Patients with T2D had a baseline A1C of 7% to 10%, while those with T1D had a baseline of 10% or less. The trials excluded those with a history of recurrent severe hypoglycemia (more than 1 severe episode in the past 12 months) and allowed concomitant oral antidiabetic treatments. A severe hypoglycemic episode was defined as a symptomatic event that requires assistance from another individual to resolve the episode.

The 7 trials comparing insulin degludec with insulin glargine demonstrated noninferiority in A1C reductions. Rates of confirmed hypoglycemia, particularly nocturnal confirmed hypoglycemia, were either similar with the 2 insulins or significantly lower with insulin degludec.12,18-23

Meanwhile, a meta-analysis of those 7 trials found that patients treated with insulin degludec achieved similar or significantly better fasting blood glucose (FBG) and rates of hypoglycemia than those treated with glargine, even with lower mean total insulin doses. These results held across subgroups of patients with T1D, T2D who were insulin-naïve, and T2D who received basal–bolus therapy.17

A preplanned analysis of all 7 trials found significantly lower rates of overall confirmed hypoglycemia as well as nocturnal and severe episodes in insulin-naïve patients with T2D who received insulin degludec compared with insulin glargine (estimated rate ratio [RR], 0.83 [95% CI, 0.70-0.98]; RR, 0.64 [95% CI, 0.48-0.86], and RR, 0.14 [95% CI, 0.03-0.70], respectively).27 Rates of overall confirmed and nocturnal confirmed hypoglycemic episodes were significantly lower in the overall T2D population (overall confirmed RR, 0.83; 95% CI, 0.74-0.94; nocturnal confirmed RR, 0.68, 95% CI, 0.57-0.82), while rates of nocturnal confirmed episodes were lower in the T1D population only during the maintenance treatment period (RR, 0.75; 95% CI, 0.60-0.94). Overall reduction in hypoglycemic events in the 3 groups was lowest during the maintenance treatment.27

In the time insulin degludec has been approved, real-world studies have been published and presented. One, EU-TREAT, was a European, multicenter, real-world evidence study investigating the effect of switching to insulin degludec from any other basal insulin (primarily insulin glargine U-100) in people with T1D (n = 1717) and T2D (n = 833). Six months after switching, patients experienced a significant reduction in A1C (–0.2% for T1D and –0.5% for T2D), results that were sustained at 12 months. Rates of overall hypoglycemia were also significantly lower in the 6 months after switching, with the rate of severe hypoglycemia 85% lower in T1D and 92% lower in T2D, with similar results at 12 months. There was also a significant reduction in fasting plasma glucose (FPG) in both populations that was maintained over 12 months. In addition, patients were able to significantly reduce their total daily insulin dose (–4.9 units T1D; –2.5 T2D) at 6 months, which remained stable at 12 months.28

The DEVOTE Trial

The CV safety of insulin degludec was evaluated in DEVOTE, a double-blind, treat-to-target, event-driven outcomes trial. The trial enrolled 7637 patients with T2D (85.2% had established CVD, CKD, or both) who were randomized to receive either insulin degludec U-100 or insulin glargine U-100 once daily between dinner and bedtime. The primary composite outcome in the time-to-event analysis was the first occurrence of a major CV event (death from CV causes, nonfatal myocardial infarction, or nonfatal stroke) with a prespecified noninferiority margin of 1.3. The secondary outcome was severe hypoglycemia.29

The primary outcome occurred in 8% (325) of patients in the insulin degludec group and 9.3% (356) in the insulin glargine group (hazard ratio [HR], 0.91; 95% CI, 0.78-1.06; P <.001 for noninferiority). At 24 months, the A1C was 7.5 ± 1.2% in each group, with a significantly lower mean fasting plasma glucose level in the insulin degludec group than in the insulin glargine group (128 ± 56 vs 136 ± 57 mg/dL; P <.001). The insulin degludec group experienced 40% fewer episodes of severe hypoglycemia compared with the insulin glargine group (RR, 0.60; P <.001 for superiority; odds ratio [OR], 0.73; P <.001 for superiority) with no difference in rates of other adverse events.29

Insulin Glargine U-300

Insulin glargine U-300 is another long-acting basal insulin analog pen. While it has the same molecule and metabolism as insulin glargine U-100, it delivers the same amount of insulin in just a third of the volume required. This reduced surface area results in a more prolonged and constant release of insulin into the bloodstream, with a steady state reached within 3 to 4 days of daily administration and a half-life of 19 hours. Insulin glargine U-100, in contrast, reaches a steady state after 2 to 4 days of once-daily administration and has a half-life of 12 hours. When converting from U-100 to U-300, the same number of insulin units can be used. However, when switching from U-300 to U-100, it is recommended to reduce the insulin unit by 20%.30,31

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