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Single-Shot IDegLira Bests Basal-Bolus Insulin Regimen in Diabetes

SAN DIEGO — A single daily injection of fixed-dose insulin degludec/liraglutide (IDegLira) (Xultophy 100/3.6, Novo Nordisk) could offer an alternative to multiple daily insulin injections for patients with type 2 diabetes who don't achieve glucose targets with basal insulin alone, new company-sponsored research shows.

Basal-bolus insulin therapy is currently considered the current gold standard for these patients, but this places a large burden on them, so these new results are potentially practice changing because they offer a practical solution for challenges faced by patients every day, endocrinologists here said. These include frequent injections, frequent self-monitoring of blood glucose, and the chore of carb-counting and adjusting bolus insulin doses.

Findings from the Insulin Degludec/Liraglutide vs Basal-Bolus Therapy in Patients with Type 2 Diabetes: DUAL VII trial were presented June 10 by endocrinologist Liana K Billings, MD, of NorthShore University HealthSystem, department of medicine, Evanston, Illinois, here at the American Diabetes Association (ADA) 2017 Scientific Sessions.

At 26 weeks, HbA1c levels were comparable among 252 type 2 diabetes patients randomized to once-daily IDegLira compared with 254 randomized to a basal-bolus regimen including once-daily glargine (Lantus, Sanofi) plus three or more injections of short-acting insulin aspart (Novolog, Novo Nordisk).

However, rates of hypoglycemia and weight gain were significantly lower with IDegLira, and the proportion of patients achieving an HbA1c value of less than 7% without experiencing either hypoglycemia or weight gain was over 10 times greater with the once-daily injection.

"This is one of the most robust, most impressive pieces of data I've seen" in this kind of comparative trial between a combination of basal insulin plus glucagonlike peptide-1 (GLP-1) receptor agonist vs the basal-bolus insulin gold-standard regimen, Julio Rosenstock, MD, Dallas Diabetes and Endocrine Center at Medical City, Texas, commented from the audience following Dr Billings' presentation.

Dr Rosenstock was the lead investigator for a similar and competing product, insulin glargine plus lixisenatide (LixiLan) (Soliqua 100/33, Sanofi).

Both Soliqua and Xultophy were approved by the US Food and Drug Administration in November 2016 and have been rolled out in the first half of this year. Xultophy is already available in the European Union and LixiLan was recently approved there, where it will be known as Suliqa.

Solution for a Real-life Clinical Problem?

Indeed, Harpreet Bajaj, MD, a community endocrinologist in Toronto and a research associate at Mount Sinai Hospital — who also blogs for Medscape and is a spokesperson for Diabetes Canada — called the findings "practice-changing."

"The results of the DUAL VII trial should help guide clinicians to address a real-life practice challenge," he wrote in the Medscape ADA blog.

Dr Bajaj told Medscape Medical News that neither Xultophy or Soliqua are yet on the market in Canada, but he "looks forward" to using the single-pen basal insulin and GLP-1 receptor agonist combinations "preferentially to the burdensome basal-bolus insulin therapy in patients with type 2 diabetes who need to intensify further from a basal insulin." 

Of course IDegLira is more expensive than glargine plus aspart (annual drug cost $9284 vs $8563 during the trial), but in a separate poster at the meeting, Dr Billings and colleagues offered a short-term cost-effectiveness analysis showing that the costs were roughly the same when the reduction in cost from lower use of needles and blood glucose monitoring are factored in.

"It's a bit of a paradigm shift in terms of diabetes care. It's a single injection with two medications," Dr Adam Viljoen, East and North Hertfordshire, National Health Service Trust, United Kingdom, told Medscape Medical News, explaining that the dosing is based on "dose-stepping" rather than titration and "dose steps" rather than "units."

"The big thing here is it's patient-friendly. The titration is very simple," said Dr Viljoen, who has worked on other studies of IDegLira but not this current one.

Another concern aside from cost is that the maximum insulin dose that can be given is 50 units, so that "if you can't control [glycemia] after the maximum dose, we don't know what to do….That's the downside," Dr Viljoen acknowledged.

More Bang for the Buck?

The DUAL VII study was a phase 3b, 26-week, randomized, open-label, multicenter trial conducted in 12 countries with 506 patients who were inadequately controlled (HbA1c 7%–10%) with 20 to 50 units of glargine plus metformin.

They were randomized to glargine (continued at baseline dose and titrated further) with addition of four or fewer injections of aspart insulin before meals (started at four units and titrated further) or a comparator arm of one injection per day of IDegLira starting at 16 units at any time of the day — with titration capped for the latter at 50 units/day. 

"A peculiar and practical feature of the protocol design was the requirement for only one daily self-monitoring of blood glucose in IDegLira arm vs four times daily testing as per standard of care in the basal-bolus insulin arm," Dr Bajaj noted in his blog post.

At 26 weeks, the percentage point drop in HbA1c was equal in both groups (1.48 for IDegLira vs 1.46 for glargine/aspart; P for noninferiority < .0001). About two-thirds of both groups achieved an HbA1c <7% (odds ratio, 0.91).

Total insulin dose was halved for the IDegLira group (84 vs 40 units; < .0001).

Rates of hypoglycemia were significantly lower with IDegLira (19.8% vs 52.6%, or 1.07 vs 8.17 episodes per person-year; < .0001).

The IDegLira group lost an average of 0.93 kg by 26 weeks, while the glargine/aspart patients gained an average of 2.64 kg (P < .0001).

And the IDegLira group was more than four times as likely to achieve an HbA1c of less than 7% without weight gain (43.3% vs 15.5%) and nearly three times as likely to achieve that level of control without hypoglycemia (57.6% vs 33.5%).

Altogether, the proportions achieving an HbA1c of less than 7% without either weight gain or hypoglycemia were 38.2% with IDegLira vs just 6.4% with the basal-bolus regimen, with an odds ratio of 10.39.  

As has been reported for the GLP-1 agonist class, nausea was more common in the IDegLira combo arm (11.1% vs 1.6% over the 26 weeks), but at no point in the study did more than 3% of patients experience nausea, Dr Billings noted.

In a late-breaking poster at the meeting, Dr Billings also reported that patient-reported outcomes related to diabetes management and treatment burden were improved with IDegLira.

Dr Billings is an advisor and speaker for Novo Nordisk. Disclosures for the coauthors are listed in the abstract. Dr Viljoen is an advisor for Novo Nordisk, Sanofi, and Janssen. Dr Rosenstock has served on scientific advisory boards and received honoraria or consulting fees from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Intarcia Therapeutics, Janssen, Lexicon, Merck, Novo Nordisk, and Sanofi. He has also received grants/research support from Asahi, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Hanmi Pharmaceutical, Intarcia Therapeutics, Janssen, Lexicon, MannKind, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi, and Takeda Pharmaceuticals. Dr Bajaj reports research support from and/or being on speakers' bureaus for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi, but he has not received any funding specifc to iDegLira. 

American Diabetes Association (ADA) 2017 Scientific Sessions. June 10, 2017; San Diego, California.

SOURCES:

Single-Shot IDegLira Bests Basal-Bolus Insulin Regimen in Diabetes. Medscape. June 15, 2017.


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