CHICAGO — Among the plethora of new data presented on existing and novel therapies for type 1 and type 2 diabetes at the recent American Diabetes Association (ADA) 2013 Scientific Sessions, a number of abstracts stood out as particularly interesting.
Phase 3 results were reported for 2 investigational once-weekly injectable glucagonlike peptide (GLP)-1 agonists, dulaglutide (Lilly) and albiglutide (GlaxoSmithKline), in type 2 diabetes. Also of interest is a new fixed-dose combination of another GLP-1 agonist, liraglutide, with insulin degludec — a new ultra–long-acting insulin available in the European Union but not the United States — known as IDegLira (Novo Nordisk).
Meanwhile a novel formulation of metformin, the backbone of treatment in type 2 diabetes, looks promising as a potential new product for use in people who cannot currently tolerate the drug.
And insulin itself was also the subject of much discussion; it is clear that insulin therapy is becoming increasingly sophisticated, with new rapid- and long-acting insulins, ultraconcentrated insulins, and novel delivery routes, such as transdermal and buccal. Also, the use of insulin in type 2 diabetes is generating some controversy, as reported previously by Medscape Medical News. The result is that doctors, diabetes educators, and patients will need information regarding the options available, optimal use, and tailoring to individual patient's needs. Pricing of these newer products will also be key, speakers said.
Two New Weekly GLP-1 Agonists Waiting in the Wings
There were 3 oral presentations on dulaglutide, sponsored by Lilly, 1 of which compared the safety and efficacy of 2 doses of dulaglutide (0.75 mg or 1.5 mg once weekly) with metformin 1000 mg twice daily in 807 patients with early type 2 diabetes in the AWARD-3 trial, presented by Guillermo E. Umpierrez, MD, from Emory University School of Medicine, Atlanta, Georgia. Both once-weekly doses of dulaglutide demonstrated superior glycemic control over metformin at 26 weeks, and at 52 weeks the 1.5-mg dose was superior to metformin.
In the second oral presentation, of the AWARD-1 trial, the same 2 doses of once-weekly dulaglutide were compared with another GLP-1 agonist, exenatide (Byetta, AstraZeneca/Bristol-Myers Squibb) — which was given twice daily at a dose of 10 µg but is also available in a once-weekly formulation — and placebo in patients with type 2 diabetes already taking metformin and pioglitazone. Both dulaglutide doses showed superior glycemic control compared with twice-daily Byetta or placebo. The final presentation, of the AWARD-5 trial, showed that dulaglutide at the once-weekly dose of 1.5 mg was superior to the oral dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin (Januvia, Merck), given to more than 1000 type 2 diabetes patients already taking metformin over 104 weeks.
Nausea — a known side effect of GLP-1 agonists — was the most common adverse event reported across the studies for dulaglutide. Lilly looks most likely to commercially develop the 1.5-mg dose of dulaglutide, and it is expected to be submitted to major markets for approval this year,
Meanwhile, 5 studies, Harmony 1 – 5, on another investigational once-weekly injectable GLP-1 agonist, albiglutide (GlaxoSmithKline), compared with placebo and a range of other comparators, were reported in late-breaking abstracts at the meeting.
Albiglutide, at doses of 30 mg or 50 mg once weekly, demonstrated significant reductions in HbA1c from baseline at 52 weeks compared with placebo in patients currently taking pioglitazone with or without metformin (Harmony 1) and in drug-naive patients (Harmony 2), with more nausea and injection-site reactions seen with the GLP-1 agonist than with placebo.
In Harmony 3, albiglutide was compared with sitagliptin, glimepiride, and placebo in patients inadequately controlled on metformin. At week 104, reductions in HbA1c from baseline were significantly greater for albiglutide compared with these 3 agents. In Harmony 4, albiglutide was compared with insulin glargine in patients taking metformin with or without sulfonylureas. Albiglutide was noninferior to insulin glargine, although again it resulted in more nausea and a greater likelihood of injection-site reactions.
But albiglutide failed to demonstrate even noninferiority over pioglitazone in the Harmony 5 study, which was conducted in type 2 diabetes patients currently taking metformin and glimepiride.
Albiglutide is under regulatory review for type 2 diabetes in the European Union and United States.
IDegLira: GLP-1 Agonist and Insulin Complementary
Another novel agent discussed at the meeting was IDegLira, a fixed-dose combination of the long-acting insulin degludec and liraglutide (both Novo Nordisk products). John Buse, MD, PhD, from the University of North Carolina, Chapel Hill, reported the findings from a large 3-arm, open-label, phase 3 trial comparing this combination product with the individual components alone, insulin degludec (Tresiba) or 1.8 mg of liraglutide (Victoza), in 1663 type 2 diabetes patients inadequately controlled on metformin with or without pioglitazone. IDegLira and insulin degludec were titrated to the same fasting glucose (72 – 90 mg/dL).
The primary end point, HbA1c at 26 weeks, decreased by 1.9% from 8.3% to 6.4% with IDegLira, which was greater than the reduction seen with insulin degludec (-1.4%) or liraglutide (-1.3%) alone.
"The efficacy [of IDegLira] in lowering glucose was absolutely spectacular, a 1.9% reduction in A1c," Dr. Buse told Medscape Medical News. "But the more interesting thing is that many of the aspects of GLP-1 receptor agonists and insulin are complementary.
"So when you titrate up this combination slowly, there's much less nausea, less than half of what you see with Victoza, despite an even lower A1c, a third less hypoglycemia than you see with insulin alone, and as opposed to weight gain, weight neutrality, just a hint of weight loss, at 26 weeks, so in my mind this is a demonstration of a sort-of souped-up insulin — I hate to say it, but 'insulin on steroids.' "
Dr. Buse said Novo Nordisk plans to file for approval of this combination product in Europe and will report on another version at the International Diabetes Federation meeting in Melbourne, in December.
NewMet: Novel Idea, but Will It Take Off in Practice?
Patients with renal impairment are among those unable to take metformin, because of the risk for lactic acidosis due to plasma metformin accumulation, and this is one of the target groups of the company Elcelyx Therapeutics, with its new delayed-release formulation of the drug NewMet.
The firm says it has discovered that metformin's glucose-lowering effects are predominantly due to its actions in the lower bowel and that plasma metformin exposure is not required for efficacy. NewMet, a proprietary delayed-release formulation of metformin, was thus designed to bypass the upper bowel and deliver metformin in the lower bowel, thereby dramatically reducing circulating plasma metformin levels.
The company reported data on the product in 2 posters. In the first, 1000 mg or 2000 mg of NewMet resulted in approximately a 45% to 68% reduction in plasma metformin exposure relative to 2000 mg of commercially available metformin formulations in 24 patients with type 2 diabetes. In the second poster, the company used a pharmacokinetic model and data from 44 type 2 diabetes patients, with and without renal impairment; this showed that the reductions in metformin exposure with NewMet were sufficient to justify its use in patients with renal impairment.
Dr. Buse, who is involved in the development of NewMet, said: "They basically demonstrated that, with this approach, they achieve much lower values in the circulation, around a quarter of the circulating metformin, and they have equivalent response with regard to glucose lowering and arguably even better tolerability but certainly no worse tolerability.
"They would argue that there's a huge segment of the market where that's going to have a high impact, something in the order of a third to a half of patients who could be on metformin but aren't because of issues of tolerability or kidney disease. But I think it's actually much lower. My guess is it's probably 20%, but still, it’s a lot of people. The major issue is in the setting of renal failure," he told Medscape Medical News.
Dr. Buse says that if NewMet does make it through development, the issue of how it is priced will be key. "If it’s $9 a day, I think they will have trouble selling it. But if it's $2 to $3 a day, [that might be a different matter]. This would be for people who cannot take metformin, so if they can't take it, it doesn't really matter how cheap [normal generic metformin is]. But the point is…that metformin has its primary position in the algorithm in part based on its price."
Increasing Sophistication of Insulin Market
Last but not least were reports on numerous new insulin preparations, discussed at a special symposium dedicated to this topic. There are few new data on these products at present, but physicians need to be aware that they are either already available or on the horizon, conference attendees heard.
Mary Korytkowski, MD, from the University of Pittsburgh, Pennsylvania, discussed the increasing frequency of use of concentrated insulin preparations, due to the obesity epidemic. Utilization of U-500 (Humulin-R, Lilly), which used to be considered an orphan drug, almost doubled between 2007 and 2010, she said. Newer concentrated insulins are also in clinical trials, including degludec U-200 and glargine U-300. There are significant safety issues with these new concentrated insulins, however, which include the obvious danger of overdosing.
William T. Cefalu, MD, from Pennington Biomedical Research Center, Baton Rouge, Louisiana, talked about several alternative insulin-delivery devices in development or already on the market, including transdermal (eg, a U-strip insulin patch from Transdermal Specialties, which is currently in clinical trials); buccal (eg, Ora-Lyn formulations, Generex), which still requires further modifications to achieve an ideal dose of 2 to 4 puffs per meal; and several oral insulin products that are in clinical trials. Inhaled insulin is another alternative route for delivery, but this field has experienced some setbacks, with only 1 of 4 initial companies still pursuing its development, Dr. Cefalu noted.
Finally, Thomas Donner, MD, from Johns Hopkins University School of Medicine, Baltimore, MD, discussed the new "ultra" insulins, which either have a very short time-to-peak effect or a very long duration. These include insulin degludec and other products further back in development (eg, ultrarapid prandial insulins in phase 2 or 3 trials).
Dr. Buse has consulted for Abbott Diagnostic Care, Amylin Pharmaceuticals, Andromeda, Bayhill Therapeutics, BD Research Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Catabasis, the Centers for Disease Control and Prevention, Cebix Diartis Pharmaceuticals, Elcelyx Therapeutics, Dynamics, GlaxoSmithKline, Halozyme Therapeutics, F Hoffman La Roche, i3 Research, Jaeb Center for Health Research, Johnson & Johnson, LipoScience, Medtronic, Merck, Metabolic Diagnostics Development, Metabolon, the National Institutes of Health, Novan, Novartis, Novella, Novo Nordisk, Orexigen Therapeutics, Osiris Therapeutics, Pfizer, Rhythm Pharmaceuticals, Sanofi, Takeda, ToleRx, Transpharma, and Veritas. Disclosures for the other abstract authors are listed in Supplement 1 of the June issue of Diabetes.
American Diabetes Association (ADA) 2013 Scientific Sessions. Abstract 1087-P, presented June 23, 2013; Abstract 75-LB, presented June 23, 2013; Abstract 66-OR, presented June 22, 2013; Abstract 69-OR, presented June 22, 2013; Abstract 71-OR, presented June 22, 2013; Abstract 1004-P, presented June 23, 2013; Abstract 68-OR, presented June 22, 2013; Abstract 57-LB, presented June 23, 2013; Abstract 55-LB, presented June 23, 2013; Abstract 52-LB, presented June 23, 2013; Abstract 54-LB, presented June 23, 2013; Abstract 58-LB, presented June 23, 2013; Abstract 65-OR, presented June 22, 2013; Abstract 1045-P, presented June 22, 2013.
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Cite this: Intriguing New Drug Developments at ADA Meeting - Medscape - Jul 12, 2013.