Early Data on Once-Weekly Insulin; Will it Transform Treatment?

Miriam E. Tucker

June 15, 2020

The investigational once-weekly basal insulin analog icodec (Novo Nordisk) was comparable in efficacy and safety to once-daily insulin glargine U100, new research suggests. 

Julio Rosenstock, MD, of University of Texas Southwestern Medical Center at Medical City, Dallas, presented the data from the phase 2 pivotal study of icodec on June 14 during the virtual American Diabetes Association (ADA) 80th Scientific Sessions.

Insulin icodec binds to albumin to create a circulating depot with a 196-hour half-life. A once-weekly injection is designed to cover an individual's basal insulin requirements for a full week with steady insulin release. Because of its concentrated formulation, its injection volume is equivalent to that of daily glargine U100.

"Many people with type 2 diabetes are reluctant to start on insulin therapy due to the need for daily injections...I'm truly excited about the potential of such innovative treatments which could reduce the number of basal insulin injections for my patients with diabetes," Rosenstock commented in a Novo Nordisk statement.

During his presentation, he added that the product "has the potential to be a major player in the management of type 2 diabetes if eventually approved."

Asked to comment, Charles M. Alexander, MD, an endocrinologist and managing director of Alexander Associates, Gwynedd Valley, Pennsylvania, told Medscape Medical News: "It's a phase 2 study. Obviously we need to see the phase 3 data, but it's very encouraging."

Alexander, who was global medical director for diabetes in medical affairs at Merck from 2008-2015, observed: "The theory is that you have better adherence to once-weekly compared to daily [dosing], but when you actually do the studies it's very difficult to prove that."

"I think the big advantage is that the company can develop a co-formulation of [the GLP-1 receptor agonist] semaglutide and icodec in the same pen or vial...There is a convenience factor of once weekly over daily."

In fact, he noted, Novo Nordisk is already in phase 1 trials with that product, called icosema.

"Potential to Be Transformational"

The phase 2, randomized, double-blind, double-dummy, parallel-group treat-to-target trial included 247 insulin-naive patients with type 2 diabetes with A1c levels of 7.0% to 9.5% despite taking metformin, with about half also taking a dipeptidyl peptidase 4 (DPP-4) inhibitor.

They were randomized to weekly insulin icodec plus daily placebo (n = 125) or daily insulin glargine U100 plus weekly placebo (n = 122). All participants took 7 injections per week with a vial and syringe plus one injection per week with a pen injector. Doses were titrated up or down to achieve blood glucose levels 70-108 mg/dL, with glargine dose adjustments of 2 or 4 units and icodec units of 14 or 28 units.  

Participants were a mean age of 59.6 years, had a diabetes duration of 9.7 years, and 56.3% were men. Baseline A1c was 8.0% overall and fasting blood glucose was 181 mg/dL, and both were similar between the two groups.

The primary endpoint, change in A1c from baseline to week 26, dropped 1.33 percentage points with icodec and 1.15 percentage points with glargine, which was not significantly different (P = .08). Estimated mean A1c levels were 6.7% for icodec and 6.9% for glargine.

The icodec result, Rosenstock said, "is a very impressive final A1c."

The proportions of patients achieving A1c < 7% by week 26 for icodec vs glargine were 72% vs 68%, and for A1c ≤ 6.5% were 49% and 39%, respectively. Those differences weren't statistically significant due to lack of power, Rosenstock observed.

Fasting plasma glucose levels were nearly identical at 26 weeks, with drops of 58 mg/dL with icodec and 54 mg/dL with glargine (P = .34).

However, there was a significant difference in favor of icodec in the 9-point self-monitoring of blood glucose profile, with a difference in mean change from baseline to week 26 of –7.9 mg/dL (P = .01).

Lower post-breakfast and post-lunch glucose peaks at 90 minutes accounted for most of the difference, Rosenstock noted. 

Total insulin doses during the last 2 weeks of treatment with icodec vs glargine were 229 vs 284 units/week (P = .01); those translate to approximate daily doses of 33 vs 41 units/day, respectively.

Both groups gained a small amount of weight, 1.5 kg with icodec and 1.6 kg with glargine by week 26 (P = .88).

Hypoglycemia was more common with icodec than glargine, including mild (53.6% vs 37.7%), moderate or clinically significant (16.0% vs 9.8%), and severe (1 [0.8%] vs 0 participants). Corresponding event rates were 508.9 vs 210.8 per 100 patient-years (mild hypoglycemia), 52.5 vs 45.6 per 100 patient-years (moderate or clinically significant), and 1.4 vs 0 per 100 patient-years (severe) for icodec vs glargine.

The difference between the two groups in moderate or clinically significant hypoglycemia wasn't statistically significant (P = .85), and the duration of hypoglycemia wasn't longer with icodec compared with glargine, despite its longer duration of action, Rosenstock emphasized.

Rates of other adverse events were similar between groups.

"Based on the robustness of these data, further evidence on the role of weekly basal insulin icodec will be pursued in a comprehensive phase 3 clinical development program," Rosenstock explained.

If those data confirm the phase 2 results, "I believe personally that a weekly basal insulin has the potential to be transformational in the management of people with type 2 diabetes needing insulin therapy."

Rosenstock has reported receiving research support from, being on advisory boards for, and/or receiving consulting honoraria from Merck, Pfizer, Sanofi, Novo Nordisk, Eli Lilly, GlaxoSmithKline, AstraZeneca, Janssen, Genentech, Oramed, Boehringer Ingelheim, Applied Therapeutics, and Intarcia. Alexander has reported no relevant financial relationships.

ADA 2020 Scientific Sessions. Presented June 14, 2020. Abstracts 236-OR, 237-OR, 238-OR.

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