Cagrilintide with semaglutide: A way to prevent diabesity?

SAN DIEGO – Coadministration of the long-acting amylin analog cagrilintide plus the glucagonlike peptide–1 (GLP-1) agonist semaglutide, dubbed CagriSema, resulted in significantly greater weight loss, along with improved measures of glucose control, than either agent alone, in a small, short phase 2 trial of patients with type 2 diabetes.

Juan P. Frias, MD, presented the findings at the annual scientific sessions of the American Diabetes Association, which were simultaneously published in The Lancet.

“Overall, in this phase 2 trial in people with type 2 diabetes, clinically relevant improvements in glycemic control – as assessed by [hemoglobin] A1c, [time in range], and other [continuous glucose monitoring (CGM)] measures – were observed with CagriSema, as well as weight loss of a magnitude not previously reported with pharmacotherapies in this population. CagriSema also had an acceptable safety profile,” the researchers summarized.

“These data support further investigation of CagriSema in people with type 2 diabetes in longer and larger phase 3 studies,” said Dr. Frias, from Velocity Clinical Research, Los Angeles.

In reply to audience questions, he said he was “pleasantly surprised” with the low gastrointestinal adverse events, which may have been related to the slower dosing titration. He also noted that patients in the study did not receive dietary counseling, unlike in the STEP-2 trial, where weight loss with semaglutide was greater than in this study.

Time in normal blood glucose range in the CagriSema group went from 40% at baseline to 89% at week 32, Chantal Mathieu, MD, PhD, reported during a follow-up presentation that focused on the trial’s CGM findings.

“I was extremely happy that we were allowed to include CGM measurement because it does give you more information, especially in a short-term trial,” said Dr. Mathieu, from the Katholieke Universiteit Leuven (Belgium). The CGM data were collected for 10 days preceding baseline and at weeks 20 and 32.

“At this point in time, it is difficult to make a final determination” about potential future clinical applications, session chair Elisabetta Patorno, MD, DrPH, from Harvard Medical School, Boston, said in an interview. “This was a phase 2 randomized controlled trial, so more patients are needed.

“It’s very interesting what was found with the use of CGM, which makes us think whether they should always be part of [trials] versus the more traditional A1c assessment,” Dr. Patorno added.

‘Synergistic effect for both glycemic control and weight loss’

“CagriSema is the next in a series of gut hormone analogs with the potential to herald a new era in treating obesity and preventing diabesity,” the coexistence of type 2 diabetes and obesity, Caroline M. Apovian, MD, and Marie E. McDonnell, MD, both also from Harvard Medical School, wrote in an accompanying editorial in The Lancet.

Cagrilintide plus semaglutide each “effectively delay gastric emptying, suppress glucagon release, and are involved in the regulation of appetite and satiety in the brain,” they noted.

The results – a substantial difference in effect size between the combination drug and each component alone – show that “there is a synergistic effect for both glycemic control and weight loss.

“The weight loss seen in this phase 2 trial of CagriSema in 32 weeks could predict a phase 3 trial result over 1 year that might surpass that of semaglutide (14.9%) and tirzepatide (20.9%) in a population without type 2 diabetes, and might equal that of bariatric surgery (23.5%-30.4%),” they speculated.

However, it’s still early days, the editorialists cautioned. Study limitations include that it was a small trial and the mean duration of type 2 diabetes at baseline was shorter in the CagriSema group (6.4 years) than in the semaglutide or cagrilintide alone groups (9.2 years and 10.7 years, respectively).

The rate of gastrointestinal adverse events was also higher in the CagriSema group (58%) than in the other two groups (about 33%). However, the adverse events “were all mild or moderate and not severe enough to lead to participant withdrawal,” they noted. “Remarkably, only one participant, from the semaglutide group, withdrew due to adverse events during the 32-week trial across all groups.

“Although bariatric surgery remains the most effective treatment for severe obesity, offering the most robust weight reduction, remission of type 2 diabetes, and reduced cardiovascular mortality,” the study suggests that “combination metabolic hormonal therapy could offer all three of these outcomes in the near future,” Dr. Apovian and Dr. McDonnell wrote.

92 patients randomized to three treatments

In the study, researchers randomized 92 adults with type 2 diabetes and a body mass index of at least 27 kg/m² taking metformin alone (73%) or metformin plus a sodium-glucose cotransporter 2 inhibitor (27%), at 17 sites in the United States, between August and October 2021.

Patients were a mean age of 58 years and 64% were men. Mean A1c was 8.4% and mean bodyweight was 106 kg (234 lb).

They were randomized 1:1:1 to receive up to maximal once-weekly doses of 2.4 mg semaglutide and 2.4 mg cagrilintide (CagriSema, given in two injector pens), 2.4 mg semaglutide (plus placebo), or 2.4 mg cagrilintide (plus placebo).

Both cagrilintide and semaglutide are manufactured by the Danish company Novo Nordisk. Semaglutide is already approved in the United States for type 2 diabetes, as Ozempic, and as the weight-loss drug Wegovy. Cagrilintide is not yet approved.

Treatment doses were escalated every 4 weeks from 0.25 to 0.5 to 1.0 to 1.7 mg to a maintenance dose of 2.4 mg at 16 weeks. Patients then entered a 16-week maintenance phase followed by a 5-week follow-up period.

Among the key findings, the reduction in A1c at 32 weeks, compared with baseline (primary outcome), was –2.2% with CagriSema, –1.8% with semaglutide, and –0.9% with cagrilintide, but was not significantly greater with CagriSema versus semaglutide (–0.4%; P = .07).

However, in a secondary outcome, there was a significantly greater difference in A1c at 32 weeks with CagriSema versus cagrilintide (–1.3%; P < .0001). Moreover, 89% of patients in the CagriSema group reached an A1c less than 7%.

In other secondary outcomes, there was a significantly greater reduction in body weight at 32 weeks with CagriSema versus cagrilintide or semaglutide, with 71% of patients in the CagriSema group achieving greater than 10% reduction in body weight. Patients in the CagriSema group also had clinically relevant improvements in blood pressure, lipids, and high-sensitivity C-reactive protein.

Adverse events – reported in 68% of patients with CagriSema versus 71% with semaglutide and 80% with cagrilintide – were mostly mild or moderate gastrointestinal events, consistent with those seen in these two drug classes.

At week 32, time in range was 89% with CagriSema versus 76% with semaglutide and 72% with cagrilintide.

“Our phase 2 clinical trial is the first study to report efficacy and safety data for treatment with the combination of a GLP-1 agonist and an amylin analog in participants with type 2 diabetes,” the researchers summarize. “These data support further investigation of CagriSema in this population in longer and larger phase 3 studies.”

This trial was sponsored by Novo Nordisk. Dr. Frias, Dr. Mathieu, Dr. Apovian, and Dr. McDonnell reported financial relationships with a number of companies.

A version of this article first appeared on Medscape.com.