Novo's Tresiba, Insulin GLP-1 Combos Draw Interest at ADA

Results for a new insulin from Novo Nordisk, and those for competing insulin/GLP-1 combination therapies from Novo and Sanofi, packed meeting rooms and created a swarm in the poster hall Sunday at the 76^th Scientific Sessions of the American Diabetes Association (ADA) in New Orleans, Louisiana.

While the insulin degludec injection U-100, sold as Tresiba, was approved last September, results presented in Sunday’s poster session could convince FDA to update the product’s label, giving Novo Nordisk an edge in what promises to be a competitive market for both insulin and combination therapy.

Tresiba is one part of iDegLira, the insulin/GLP-1 therapy marketed overseas as Xultophy, which won unanimous support May 24, 2016, from an FDA advisory panel. Sanofi’s combination, formerly known as LixiLan but renamed iGlarLixi, received advisory panel support the next day.

Novo Nordisk previously announced topline cardiovascular results for the glucagon-like peptide-1 in its combination, liraglutide (Victoza); full results from the LEADER trial will be revealed at ADA Monday.

On Sunday, results for the 2 combinations came in consecutive presentations at a standing-room-only oral session. At the noon poster session, rows of clinicians surrounded Wendy S. Lane, MD, chief investigator of the SWITCH 1 trial, straining to hear her until someone brought a microphone.

SWITCH 1 and 2

Results presented Sunday from the SWITCH trials showed that insulin degludec resulted in lower rates of hypoglycemia in patients with type 1 and type 2 diabetes. As Todd Hobbs, MD, chief medical officer for Novo Nordisk North America explained, the trials had similar designs, which addressed concerns from FDA that the phase 3a trial included patients at low risk for hypoglycemia and, thus, the benefit of avoiding events was not included on the label.

In both trials, patients started on either insulin degludec or insulin glargine, taking 16 weeks to titrate up to the needed dose, then spent 16 weeks on maintenance. Patients then crossed over to the other therapy, first starting at 20% less than the prior dose for safety reasons, then titrating to the necessary dose over 16 weeks, and then spending another 16 weeks on the second therapy. SWITCH 1 examined patients with type 1 diabetes (T1D),¹ while SWITCH 2 examined patients with type 2 diabetes (T2D).²

Lane, of Mountain Diabetes and Endocrine Center in Asheville, North Carolina, noted the SWITCH 1 participants had to meet 1 of these criteria to qualify: at least 1 severe hypoglycemic event in the past year, moderate chronic renal failure, diabetes for at least 15 years, a hypoglycemic event in past 12 weeks. “These are the patients most at risk,” Lane said. “They are usually excluded from studies.”

Results in the maintenance period showed that insulin degludec produced the following benefits compared with insulin glargine: (1) 11% lower rate of severe of blood glucose-confirmed symptomatic hypoglycemia, (2) 36% lower rate of severe of blood glucose-confirmed symptomatic nocturnal hypoglycemia, and (3), 35% lower rate of severe hypoglycemia.¹

In SWITCH 2, results showed that insulin degludec produce the following benefits, compared with insulin glargine: (1) lower rates of severe or blood glucose-confirmed symptomatic hypoglycemia in the maintenance period (30%) and full (23%) treatment periods, (2) lower rates of severe or blood glucose-confirmed symptomatic nocturnal hypoglycemia in the maintenance (42%) or full (25%) treatment periods, and (3) a much lower rate (51%) of severe hypoglycemia across the full treatment period, involving a smaller share of patients.²

As for the effect of SWITCH on payer coverage, Hobbs said, results that show a reduction in severe hypoglycemia show the potential for a reduction in costs. “We will take that to payers,” he said. While insulin degludec enjoys “very good, broad coverage,” Hobbs said, “hopefully, we’ll be able to improve that.”

The LixiLan Studies

In a morning session, Julio Rosenstock, MD, presented results from LixiLan-O, which found that the whole is greater than the sum of its parts: lixisenatide, a GLP-1 receptor agonist found safe in its CV outcomes trial, and Sanofi’s longtime mainstay insulin glargine (Lantus): more subjects on background metformin reached a glycated hemoglobin (A1C) of < 7% with the combination (74%) than on lixisenatide (33%) or insulin glargine (59%).³

In the afternoon session, Vanita R. Aroda, MD, of Medstar Health Research Institute, presented efficacy and safety results from Lixilan-L which involved patients who were inadequately controlled on insulin alone or with 2 oral therapies. During a run-in period, patients’ mean A1C dropped from 8.5% to 8.1%. During the 30 week study, patients in the LixiLan arm had a mean A1C drop of 1.1%, while those in the insulin glargine arm dropped 0.6% on average. Patients’ weight dropped 0.7 kg in the combination therapy group and increased 0.7 kg in the insulin group. Aroda reported no additional risk of hypoglycemia and said the drug was well tolerated.⁴

Post-Hoc Analysis of iDegLira Study

Ildiko Lingvay, MD, MPH, MSCS, of the University of Texas Southwestern Medical Center followed Aroda with a post hoc analysis of DUAL V that looked at whether patients who A1C of < 7% and fasting plasma glucose (FPG) of < 130 mg/dL met other composite endpoints relevant to management of their diabetes.⁵

Two arms of patients took either the combination therapy iDegLira or insulin glargine for 26 weeks; both arms also took metformin. Results found that the odds of achieving targets of A1C < 7% and FPG < 130 mg/dL without hypoglycemia or weight gain were significantly improved for patients taking the combination therapy, and the benefit of the taking the combination increased with rising baseline A1C.

Lingvay said this is important, because patients need to see quick, early results with a new therapy, “or they don’t want to stick with it.” She had some concerns about patients’ ability to maintain control with the cut in the insulin dose. But, as Aroda noted with iGlarLixi, the combination therapy proves superior: the liraglutide mitigates the weight gain effects of insulin, while offering glycemic control.

References

1. Lane WS, Bailey TS, Gerety G, et al. SWITCH 1: reduced hypoglycemia with insulin degludec (iDeg) vs insulin glargine (iGlar), both U100, in patients with T1D at high risk of hypoglycemia: a randomized, double-blind, crossover trial. Diabetes. 2016; 65(suppl1): 87-LB.

2. Wysham C, Bhargava A, Chaykin LB, et al. SWITCH 2: reduced hypoglycemia with insulin degludec (iDeg) vs insulin glargine (iGlar), both U100, in patients with T2D at high risk of hypoglycemia: a randomized, double-blind, crossover trial. Diabetes. 2016; 65(suppl1): 90-LB.

3. Rosenstock J, Aronson R, Hanefield M et al. Clinical impact of titrable fixed-ratio combination of insulin glargine/lixisenatide vs. each component alone in type 2 diabetes inadequately controlled on oral agents: LixiLan-O trial. Diabetes. 2016; 65(suppl1):186-OR.

4. Aroda V, Rosentock J, Wysham C, et al. Efficacy and safety of the insulin glargine/lixisenatide fixed-ratio combination vs. insulin glargine in patients with T2DM: the LixiLan-L trial. Diabetes. 2016; 65(suppl1): 238-OR.

5. Lingvay I, Norwood PC, Begtrup K, Langbakke IH, Perez-Manghi FC. Patients with T2D treated with insulin degludec/liraglutide (iDegLira) have a greater chance of reaching glycemic targets without hypoglycemia and weight gain than with insulin glargine. Diabetes. 2016; 65(suppl1): 239-OR.