Icodec + Semaglutide Combo Shows Benefit in Type 2 Diabetes

MADRID — Novo Nordisk’s investigational once-weekly combination of insulin icodec plus semaglutide (IcoSema) could benefit people with type 2 diabetes who don’t reach target glycemic goals with either single agent alone, new research suggests.

Data for three 52-week multicenter randomized open-label trials from the company’s phase 3a COMBINE program were presented on September 11, 2024, in a 1-hour symposium at the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting. Among people with type 2 diabetes not meeting target A1c goals with their current therapy, COMBINE 1 compared IcoSema with icodec alone, COMBINE 2 compared the combination with semaglutide alone, and COMBINE 3 examined IcoSema with once-daily basal glargine and premeal insulin aspart in people not achieving glycemic targets with basal insulin alone.

All three trials met their primary endpoints for A1c reduction — superiority in COMBINE 1 and 2, and non-inferiority in COMBINE 3. All other endpoints were either superior or non-inferior except for the expected greater weight gain compared with semaglutide alone and more gastrointestinal adverse effects compared with basal insulin alone.

“People don’t very much like complexity to their regimens, and it can impact adherence…Combination therapy can help overcome the barriers in this treatment of type 2 diabetes with fewer injections, fewer finger stick glucose testing, and less complex dosing, and hopefully this can impact adherence and persistence in therapy,” Liana K. Billings, MD, director, Clinical and Genetics Research in Diabetes and Cardiometabolic Disease at NorthShore University Health System, Evanston, Illinois, said in her introductory remarks.

Both EASD and the American Diabetes Association guidelines support combination therapy, she noted, and the specific combination of a glucagon-like peptide 1 receptor agonist and a long-acting basal insulin “can result in greater glycemic lowering than the [individual] components with less weight gain, lower rates of hypoglycemia than other intensified insulin regimens, and better [gastrointestinal] tolerability.”

Moreover, Billings added, “In terms of cost, if you combine two agents together, you’re no longer paying for two. You’re going to pay for one. And so cost can be improved for the combined agents as well.”

Asked to comment, Stephanie Amiel, MBBS, MD, emeritus professor of Diabetes Research at King’s College London, London, told Medscape Medical News that although COMBINE 1 and 2 showed efficacy, “I can’t get excited about studies showing me that adding in a new treatment has better effect than just staying on a failed therapy. Combination therapy always makes me a bit nervous, as you can’t change one drug without changing the other. Weekly insulin also makes me nervous, although not for type 2 needing basal replacement…The insulin sparing and the lack of weight gain are pluses for IcoSema, but at the cost of nausea for some.”

However, Amiel added, “I was favorably impressed by COMBINE 3, where there are obvious patient-related outcomes using a once-weekly injection versus multiple daily injections, and this would be where I would start off using the product.”

In COMBINE 3, for which Novo Nordisk released top line results in January 2024, 679 people with type 2 diabetes inadequately controlled on basal-bolus insulin therapy were randomized to receive either IcoSema once-weekly or once-daily glargine U100 plus mealtime aspart, given two to four times daily as needed.

At 52 weeks, A1c reductions were similar in the two groups, −1.47 vs −1.40 percentage points with IcoSema and glargine + aspart, respectively. Time below range was lower with IcoSema (0.2% vs 0.5%; P < .0001), while time in range was similar (68.9% vs 66.3%; P = .1892). Body weight change was a loss of 3.56 kg with IcoSema vs a gain of 3.16 kg for glargine + aspart (P < .0001).

Clinically significant or severe hypoglycemia was less common with IcoSema, 10.0% vs 58.5% with glargine + aspart (P < .0001). Gastrointestinal adverse effects were more common with IcoSema, 10.0% vs 2.7% with glargine + aspart.

In COMBINE 1, IcoSema (n = 646) was statistically superior to once-weekly icodec alone (n = 645) in A1c reduction (1.55 vs 0.89 percentage points (P < .0001), body weight (−3.70 kg vs +1.89 kg; P < .0001), in clinically significant or severe hypoglycemia (7.1% vs 20.8%; P < .0001), higher time in range, and lower time above range. No new safety signals were identified, and the overall safety profile reflected those of the individual components.

And in COMBINE 2, IcoSema (n = 342) was significantly superior to semaglutide alone (n = 341) in A1c reduction (−1.35 vs 0.90 percentage points; P < .0001). However, body weight change favored semaglutide monotherapy, with a loss of 3.70 kg compared with a gain of 0.84 kg with IcoSema (P < .0001). There were no differences in clinically significant or severe hypoglycemia and similar rates of adverse events, including gastrointestinal adverse events.

Insulin icodec is currently available in Europe and Canada but not in the United States.

Publication of COMBINE in a journal is expected soon, a Novo Nordisk representative told Medscape Medical News.

Billings received consulting honoraria from Novo Nordisk, Sanofi, Bayer, Xeris, Endogenex, Dexcom, Lilly, and Pfizer. She is a principal investigator for multicenter trials with Novo Nordisk, Sanofi, Endogenex, Lilly, Inventiva, and Medtronic. Amiel has been on an advisory board for and speaking at a symposium for Vertex and speaker for Sanofi. She also has grant support from the National Institutes of Health and is vice chair of the International Hypoglycaemia Study Group. She had no disclosures with Novo Nordisk.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape Medical News, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X @MiriamETucker.