Insulin Degludec: What Pharmacists Should Know

The FDA approved injectable insulin degludec (Tresiba) and insulin degludec/insulin aspart (Ryzodeg 70/30) in September 2015 to improve blood glucose control in adults with type 1 or type 2 diabetes.

Insulin degludec is the third FDA-approved long-acting insulin formulation, alongside insulin glargine and insulin detemir. It became available at pharmacies nationwide in January 2016.

This article highlights several key therapeutics areas for insulin degludec that every pharmacist should know. Because Ryzodeg 70/30 isn’t slated to be launched at this time, this article will primarily focus on Tresiba.

History

Novo Nordisk originally submitted new drug applications for both Tresiba and Ryzodeg 70/30 in November 2012. An FDA Advisory Committee subsequently voted 8-4 in favor of approving insulin degludec, but required that Novo Nordisk conduct a post-marketing study to evaluate cardiovascular safety.

Three months later, the FDA said insulin degludec couldn’t be approved, citing a need for additional cardiovascular outcomes data from a dedicated clinical trial. This was prompted by the discovery of a cardiovascular safety signal in a meta-analysis of 16 randomized, controlled studies that found an increased risk of major adverse cardiovascular events (MACE) in the insulin degludec group compared with active control.

In 2015, Novo Nordisk resubmitted new drug applications for Tresiba and Ryzodeg 70/30 with interim results of the DEVOTE trial, which showed more promising safety data that met the FDA’s pre-specified risk margin. After reviewing the interim data, the FDA approved both insulin degludec products.

Nevertheless, Novo Nordisk decided to continue the DEVOTE trial to fully study the cardiovascular safety of insulin degludec. Completion is expected in December 2016, and final report submission is planned for September 2017.

Formulation

Tresiba is available as a 3-mL FlexTouch disposable prefilled pen in concentrations of 100 units/mL (U-100) and 200 units/mL (U-200).

Pharmacokinetics

Tresiba was developed to form multi-hexamers when injected into the subcutaneous tissue, resulting in a subcutaneous insulin degludec depot. Additionally, insulin degludec binds to circulating albumin. Both of these factors play a role in delaying Tresiba’s absorption and elimination, resulting in a prolonged half-life and duration of action (>42 hours).

These pharmacokinetic parameters allow for once-daily dosing without regard to meals. Unlike insulin detemir and insulin glargine, Tresiba doesn’t have to be injected at the same time each day.

Dosing

The recommended starting dose of Tresiba in insulin-naïve patients with type 1 diabetes is approximately one-third to one-half of the total daily insulin dose. The remainder of the total daily insulin dose should be administered as short-acting insulin with meals. As a general rule, 0.2 to 0.4 units of insulin per kilogram of body weight can be used to calculate the initial total daily insulin dose in insulin-naïve patients with type 1 diabetes.

The recommended starting dose of Tresiba in insulin-naïve patients with type 2 diabetes is 10 units once-daily.

In patients with type 1 and type 2 diabetes who are already taking insulin, Tresiba should be started at the same unit dose as the total daily long- or intermediate-acting insulin unit dose. The dose of Tresiba can be increased every 3 to 4 days as needed.

Tresiba should be administered subcutaneously once-daily at any time of day without regard to meals. Injection sites should be rotated to reduce the risk of lipodystrophy.

Efficacy

The efficacy of Tresiba administered once-daily at either the same time each day or any time of day in patients with type 1 diabetes was evaluated in 3 randomized, open-label, treat-to-target, active-controlled trials. Meanwhile, drug efficacy in patients with type 2 diabetes was evaluated in 6 randomized, open-label, treat-to-target, active-controlled trials. All studies ranged in duration from 26 to 52 weeks.

In 8 of the 9 total trials, insulin degludec was shown to be non-inferior to insulin glargine and insulin detemir in lowering HbA1C, with similar rates of hypoglycemia. In the ninth trial, there was a statistically significant HbA1C reduction with insulin degludec compared with sitagliptin 100 mg, but insulin degludec caused more episodes of hypoglycemia.

Safety

The most common adverse reactions associated with Tresiba in clinical trials were hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema, and weight gain. Notably, Tresiba was shown to result in a numerically smaller rate of nocturnal hypoglycemic episodes than its comparators; however, some results didn’t reach statistical significance.

Product Comparison

Drug

Formulations

Dosing frequency

Duration of action

Cost*

Insulin degludec (Tresiba)

FlexTouch pen (U-100, U-200)

QD

>42 hours

$106.52 (U-100)

$213.05 (U-200)

Insulin detemir (Levemir)

Vial or FlexTouch pen (U-100)

QD or BID

12-20 hours

$96.84

Insulin glargine (Lantus)

Vial or SoloStar pen (U-100)

QD

22-24 hours

$89.46

Insulin glargine (Toujeo)

SoloStar pen (U-300)

QD

24-36 hours

$134.19

*Cost based on average wholesale price for 1 pen, per Lexi-Drugs. Cost to the patient will vary based on insurance coverage.

Guidelines

The American Diabetes Association’s 2016 Standards of Medical Care in Diabetes recognize insulin degludec along with insulin glargine and insulin detemir, but no preference among the 3 is noted.

Conclusion

Tresiba provides patients with another long-acting insulin option to control their diabetes. Unlike insulin detemir and insulin glargine, Tresiba doesn’t have to be injected at the same time each day, which may be beneficial for adherence.