What Do You Need to Know About the Newer Insulin Analogues?

Authors:
Laura Hollar, MD, and Kim A. Carmichael, MD—Series Editor

Citation:
Hollar L, Carmichael KA. What do you need to know about the newer insulin analogues? Consultant. 2019;59(1):18-19.

Q. What is the history and prevalence of US insulin use?

A. Insulin was first isolated and extracted in 1921 and has been available since 1925.¹ Since then, substantial progress has been made in insulin preparations, from early animal insulins to human insulins in the 1980s to insulin analogues.² Novel insulin analogues continue to develop, with improving profiles in insulin administration and action.

In the United States, 30.3 million people have diabetes, with 1.5 million new cases diagnosed each year.³ Data from the Centers for Disease Control and Prevention in 2011 showed that 17.8% of patients with diabetes were using insulin alone, and 13% were using insulin and oral anti-diabetic agents.⁴ Of those using insulin, glargine was the most prescribed insulin in 2015, followed by insulin detemir. The disease’s widespread prevalence motivates continued development of superior insulin products.

Q. What are the duration of action of new forms of insulin?

A. As a review, insulins have differences in onset, peak, duration, and concentration. They are often categorized by the duration of action—rapid-acting, short-acting, intermediate-acting, and long-acting. 

Over the course of the past 20 years, the market has seen development of ultralong-acting and ultrafast-acting insulins in addition to these categories. These new insulin analogues are designed to more closely mimic the action of pancreatic β-cell insulin secretion.

Ultralong-acting insulins include insulin glargine U-300 or 300 units/mL (brand name, Toujeo, from Sanofi-Aventis) and insulin degludec (brand name, Tresiba, from Novo Nordisk).¹ Insulin degludec is available in U-100 and U-200 formulations and, unlike with glargine, the concentration does not alter its action profile. 

The half-lives of glargine-300 and degludec, respectively, are 19 hours and 25 hours.^1,5 This results in a duration of action of 32 hours or more for glargine-300 and 42 hours or more for degludec.¹ They are both dosed once daily, but their long half-life provides patients with flexibility in when the insulins are administered within the day. 

Due to the long half-life of these insulin types, the recommended interval between dose changes is 3 to 4 days. Of note, studies have shown that when transitioning to glargine-300 from glargine-100, expect an approximately 20% necessary dose increase.

Faster insulin aspart (with niacinamide; brand name, Fiasp, from Novo Nordisk) is a new ultrafast-acting insulin.³ It has a faster onset of action than insulin aspart, with at least a 2-fold higher insulin exposure in the 30 minutes after administration. Faster insulin aspart should be administered with a meal or within 20 minutes, since it can appear in the bloodstream within 2½ to 4 minutes. Ultrafast insulin lispro is in clinical trials.⁶

Q. What are the available alternatives to subcutaneous insulin analogues?

A. Insulin human inhalation powder (brand name, Afrezza, from MannKind Corp) is the only nonsubcutaneous insulin that is currently available on the US market for ambulatory use.¹ 

Compared with rapid-acting insulin aspart or lispro (but not the newer faster-acting formulations), Afrezza has a slightly faster onset, a lower peak of activity, equivalent or less-effective reduction in glycated hemoglobin (HbA_1c), and mixed results as far as lower hypoglycemia risk. Due to the risk of bronchospasm, Afrezza should not be used in smokers or patients with chronic lung disease, and all patients should be screened for these conditions with spirometry prior to initiation, at 6 months, and then annually. It is administered in single-use cartridges of 4, 8, and 12 units. Of note, in clinical trials, diabetic ketoacidosis was observed more frequently in type 1 diabetes with Afrezza vs comparators.

Q. What have studies shown about the advantages of new insulin formulations?

A. Studies of the ultralong-acting insulins so far have shown equivalent HbA_1c lowering but reduced rates of hypoglycemia compared with conventional long-acting insulins. 

Specifically, the EDITION phase 3a program compared glargine-300 with glargine-100 and showed that the 2 insulins had similar improvement in glycemic control and HbA_1c, but that glargine-300 had a lower risk of hypoglycemia and lower weight gain.^7,8 The BEGIN trials compared insulin degludec with glargine-100 and had similar results of equivalent glycemic control and significantly lower rates of nocturnal and overall hypoglycemia with degludec.⁹

The ONSET trial compared faster insulin aspart (with niacinamide) with insulin aspart.¹⁰ HbA_1c reduction was found to be noninferior, with the study reporting a slightly greater HbA_1c reduction of approximately 0.1% with faster insulin aspart vs insulin aspart. Participants who had been randomly assigned to postmeal dosing of faster insulin aspart had equivalent glycemic control and HbA_1c reductions compared with participants who had been assigned to mealtime insulin aspart dosing. There were similar rates of overall and severe hypoglycemia.

In summary, new insulin analogues show noninferiority to conventional analogues in regard to glycemic control and HbA_1c reductions. Newer ultralong-acting basal options have a lower risk of hypoglycemia. And both ultralong-acting and faster insulin aspart allow for flexibility in timing of insulin administration.

Laura Hollar, MD, is a clinical fellow in the Department of Medicine, Division of Endocrinology, Metabolism and Lipid Research, at Washington University School of Medicine in St Louis, Missouri.

Kim A. Carmichael, MD, is an associate professor of medicine in the Department of Medicine, Division of Endocrinology, Metabolism and Lipid Research, at Washington University School of Medicine in St Louis, Missouri.

References:

1. Meneghini L. New insulin preparations: a primer for the clinician. Cleve Clin J Med. 2016;​83(5 suppl 1):S27-S33.

2. Mathieu C, Gillard P, Benhalima K. Insulin analogues in type 1 diabetes mellitus: getting better all the time. Nat Rev Endocrinol. 2017;13(7):​385-399.

3. Davis A, Kuriakose J, Clements JN. Faster insulin aspart: a new bolus option for diabetes mellitus [published online July 6, 2018]. Clin Pharmacokinet. doi:10.1007/s40262-018-0696-8.

4. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017: Estimates of Diabetes and Its Burden in the United States. Atlanta, GA: Centers for Disease Control and Prevention; 2017. https://www.cdc.gov/
diabetes/pdfs/data/statistics/national-diabetes--statistics-report.pdf. Accessed December 18, 2018.

5. Becker RHA, Dahmen R, Bergmann K, Lehmann A, Jax T, Heise T. New insulin glargine 300 units•mL^–1 provides a more even activity profile and prolonged glycemic control at steady state compared with insulin glargine 100 Units•mL^–1. Diabetes Care. 2015;38(4):637-643.

6. Danne T, Heinemann L, Bolinder J. New insulins, biosimilars, and insulin therapy. Diabetes Technol Ther. 2018;20(S1):S55-S70.

7. Home PD, Bergenstal RM, Bolli GB, et al. New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 1 diabetes: a randomized, phase 3a, open-label clinical trial (EDITION 4). Diabetes Care. 2015;38(12):​2217-2225. 

8. Riddle MC, Yki-Järvinen H, Bolli GB, et al. One-year sustained glycaemic control and less hypoglycaemia with new insulin glargine 300 U/ml compared with 100 U/ml in people with type 2 diabetes using basal plus meal-time insulin: the EDITION 1 12-month randomized trial, including 6-month extension. Diabetes Obes Metab. 2015;17(9):835-842.

9. Zinman B, Philis-Tsimikas A, Cariou B, et al; NN1250-3579 (BEGIN Once Long) Trial Investigators. Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN Once Long). Diabetes Care. 2012;​35(12):2464-2471.

10. Russell-Jones D, Bode BW, De Block C, et al. Fast-acting insulin aspart improves glycemic control in basal-bolus treatment for type 1 diabetes: results of a 26-week multicenter, active-controlled, treat-to-target, randomized, parallel-group trial (Onset 1). Diabetes Care. 2017;​40(7):943-950.