LAI287/semaglutide (NN1535) / Novo Nordisk - LARVOL DELTA

CGM-Based Outcomes in Adults with T2D Receiving IcoSema vs. Comparators—Post Hoc Analysis of COMBINE 1 and 3 (ADA 2025) - "Introduction and Objective: IcoSema is a once-weekly combination therapy of insulin icodec (icodec) + semaglutide... Between weeks 48-52, TiTR was significantly higher with IcoSema vs icodec and similar vs BBT. More participants on IcoSema vs comparators achieved the CGM composite outcome, CV% was <36% and median overall hypoglycemia duration was similar between arms."

Clinical • Retrospective data • Hypoglycemia • Metabolic Disorders • Type 2 Diabetes Mellitus

CGM-Derived Model-Based Postprandial Glucose with IcoSema vs. Other Insulin Regimens—A Post Hoc Analysis of COMBINE 1 and 3 (ADA 2025) - "Introduction and Objective: This post hoc analysis investigated whether IcoSema, a once-weekly (OW) combination therapy of basal insulin icodec and the GLP-1 analog semaglutide currently in development, offers a postprandial glucose (PPG) control benefit vs other insulin-based regimens. COMBINE 1 and 3, two 52-week, phase 3a trials, investigated IcoSema vs OW basal insulin (icodec; COMBINE 1) or basal-bolus therapy (glargine U100 + aspart; COMBINE 3) in adults with T2D who were inadequately controlled on daily basal insulin... Based on post hoc modelling using CGM data, IcoSema showed statistically significantly better PPG control vs OW basal insulin and similar PPG control vs basal-bolus therapy."

Retrospective data • Metabolic Disorders

A1C and Hypoglycemia Outcomes with Once-Weekly IcoSema vs. Comparators in T2D by Kidney Function (ADA 2025) - "For IcoSema vs comparators, A1C reductions, combined clinically significant or severe hypoglycemia rates, and achievement of A1C <7% without weight gain and combined clinically significant or severe hypoglycemia were generally consistent across kidney function subgroups."

Hypoglycemia • Metabolic Disorders • Severe Hypoglycemia • Type 2 Diabetes Mellitus

Novo Nordisk to present array of new portfolio data including studies with semaglutide and CagriSema, expanding evidence in obesity and diabetes care at ADA 2025 (PRNewswire) - "Novo Nordisk today announced that new data from its industry-leading cardiometabolic portfolio will be showcased at the upcoming American Diabetes Association (ADA) 85th Scientific Sessions taking place in Chicago, June 20 – 23, 2025. A total of 29 abstracts will be presented, including trials investigating the efficacy and safety of CagriSema in people with overweight/obesity (REDEFINE 1) and those with overweight/obesity and type 2 diabetes (REDEFINE 2). Further, new data will complement the extensive body of cardiometabolic and kidney evidence for semaglutide in people with type 2 diabetes through analyses of the SOUL, STRIDE and FLOW trials, as well as insights from additional real-world studies in adults with obesity."

Clinical data • Obesity • Peripheral Arterial Disease • Type 2 Diabetes Mellitus

Once-weekly IcoSema versus multiple daily insulin injections in type 2 diabetes management (COMBINE 3): an open-label, multicentre, treat-to-target, non-inferiority, randomised, phase 3a trial. (PubMed, Lancet Diabetes Endocrinol) - P3 | "Once-weekly IcoSema achieved non-inferior HbA1c reduction and superiority in change in bodyweight, weekly total insulin dose, and hypoglycaemia rates versus daily BBT, suggesting that there is a potentially beneficial treatment intensification option for adults with type 2 diabetes."

Head-to-Head • Journal • P3 data • Alzheimer's Disease • Cognitive Disorders • Diabetes • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Metabolic Disorders • Severe Hypoglycemia • Type 2 Diabetes Mellitus

IcoSema and the evolution of fixed-ratio insulin-GLP-1 receptor agonist therapies. (PubMed, Lancet Diabetes Endocrinol) - No abstract available

Journal

Once‑weekly IcoSema versus once‑weekly insulin icodec in type 2 diabetes management (COMBINE 1): an open‑label, multicentre, treat‑to‑target, randomised, phase 3a trial. (PubMed, Lancet Diabetes Endocrinol) - P3 | "In adults with inadequately controlled type 2 diabetes on daily basal insulin therapy, once‑weekly IcoSema showed superiority to once-weekly icodec alone in changes in HbA1c and in overall lower rate of combined clinically significant or severe hypoglycaemia. IcoSema might provide an option for insulin therapy intensification in adults with type 2 diabetes."

Journal • P3 data • Diabetes • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Metabolic Disorders • Severe Hypoglycemia • Type 2 Diabetes Mellitus

COMBINE 2 is better than one: shaping the future of therapeutics in inadequately controlled type 2 diabetes. (PubMed, Expert Rev Clin Pharmacol) - "The recently published COMBINE 2 trial reported that switching to weekly combination therapy of basal insulin icodec and semaglutide (IcoSema), compared with semaglutide, results in greater HbA1c reduction, similar risk of clinically significant or severe hypoglycemia, and comparable gastrointestinal tolerability, but unfavorable weight change among individuals with T2DM inadequately controlled with GLP-1 RA therapy, with or without additional oral glucose-lowering drugs. IcoSema represents an effective, safe, and convenient therapeutic choice for treatment intensification in individuals with T2DM inadequately controlled with GLP-1 RA therapy."

Journal • Review • Diabetes • Metabolic Disorders • Severe Hypoglycemia • Type 2 Diabetes Mellitus

Glucose-Lowering Agents Developed in the Last Two Decades and Their Perioperative Implications. (PubMed, Pharmaceuticals (Basel)) - "There have been other developments as well. For instance, Imeglimin, a variant of metformin available in Japan and India, Icodec, a once-weekly basal insulin formulation, and IcoSema, a once-weekly combination of Icodec plus semaglutide, are all being explored, although in their early stages or facing approval challenges."

Journal • Review • Anesthesia • Cardiovascular • Congestive Heart Failure • Diabetes • Genetic Disorders • Heart Failure • Metabolic Disorders • Obesity

Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial. (PubMed, Diabetologia) - P3 | "In people living with type 2 diabetes inadequately managed with GLP-1 RA therapy, with or without additional oral glucose-lowering medications, switching to once-weekly IcoSema in comparison with once-weekly semaglutide 1.0 mg demonstrated superiority in HbA1c reduction, similar rates of clinically significant or severe hypoglycaemia, and similar frequency of gastrointestinal adverse events. However, weight change from baseline to week 52 was statistically significantly in favour of semaglutide 1.0 mg."

Journal • Alzheimer's Disease • Cognitive Disorders • Diabetes • Gastrointestinal Disorder • Hypoglycemia • Metabolic Disorders • Severe Hypoglycemia • Type 2 Diabetes Mellitus

Evaluating semaglutide + LAI-287 (IcoSema) for the treatment of diabetes mellitus type II. (PubMed, Expert Opin Pharmacother) - "The key trials from the clinical development process of insulin icodec, semaglutide, and IcoSema are reviewed with important endpoints highlighted. Once-weekly IcoSema offers glycemic efficacy that is non-inferior to glargine+aspart, similar risk of hypoglycemia, significant reduction in body weight, the convenience of use, and favorable safety profile with most adverse events being gastrointestinal."

Journal • Review • Diabetes • Gastrointestinal Disorder • Hypoglycemia • Metabolic Disorders • Type 2 Diabetes Mellitus

Pharmacokinetic Properties of a Once-Weekly Fixed-Ratio Combination of Insulin Icodec and Semaglutide Compared with Separate Administration of Each Component in Individuals with Type 2 Diabetes Mellitus. (PubMed, Clin Drug Investig) - P1 | "The combination of icodec and semaglutide in IcoSema leads to a higher and earlier maximum semaglutide concentration, which will guide the dose recommendations for IcoSema."

Journal • PK/PD data • Diabetes • Gastrointestinal Disorder • Metabolic Disorders • Type 2 Diabetes Mellitus

IcoSema's leap forward: new data from COMBINE 3 paves the way. (PubMed, J Basic Clin Physiol Pharmacol) - No abstract available

Journal

A Research Study to See How Well New Weekly Medicine IcoSema, Which is a Combination of Insulin Icodec and Semaglutide, Controls Blood Sugar Levels in People With Type 2 Diabetes (T2D), Compared to Daily Insulin Glargine (COMBINE 4) (clinicaltrials.gov) - P3 | N=474 | Active, not recruiting | Sponsor: Novo Nordisk A/S | Recruiting ➔ Active, not recruiting

Enrollment closed • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

IcoSema as an alternative to basal bolus treatment (COMBINE 3) (EASD 2024) - "There is no abstract associated with this presentation."

Metabolic Disorders

Intensification with IcoSema in a GLP-1RA experienced population (COMBINE 2) (EASD 2024) - "There is no abstract associated with this presentation."

Clinical • Metabolic Disorders

Basal insulin intensification by switching to once weekly IcoSema (COMBINE 1) (EASD 2024) - "There is no abstract associated with this presentation."

Metabolic Disorders

IcoSema: unveiling the future of diabetes management from a clinical pharmacology perspective. (PubMed, J Basic Clin Physiol Pharmacol) - "IcoSema, a groundbreaking approach to diabetes management, combines insulin icodec and semaglutide to offer a transformative treatment option...This comprehensive article evaluates the potential of IcoSema from a clinical pharmacology perspective, examining the pharmacokinetics, efficacy, safety, compliance and cost-effectiveness of its individual components, as well as considering comparable combination therapies like iGlarLixi and IDegLira...Ongoing trials investigating IcoSema are expected to provide valuable insights into its efficacy, safety and comparative effectiveness. By addressing concerns such as potential side effects, individual patient response and drug interactions, healthcare providers can optimize treatment outcomes and enhance the management of type 2 diabetes."

Journal • Review • Diabetes • Infectious Disease • Metabolic Disorders • Type 2 Diabetes Mellitus

COMBINE 1: A Research Study to See How Well the New Weekly Medicine IcoSema, Which is a Combination of Insulin Icodec and Semaglutide, Controls Blood Sugar Level in People With Type 2 Diabetes Compared to Weekly Insulin Icodec (clinicaltrials.gov) - P3 | N=1291 | Completed | Sponsor: Novo Nordisk A/S | Active, not recruiting ➔ Completed

Trial completion • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

A Research Study to See How Well New Weekly Medicine IcoSema, Which is a Combination of Insulin Icodec and Semaglutide, Controls Blood Sugar Levels in People With Type 2 Diabetes (T2D), Compared to Daily Insulin Glargine (COMBINE 4) (clinicaltrials.gov) - P3 | N=474 | Recruiting | Sponsor: Novo Nordisk A/S | Not yet recruiting ➔ Recruiting

Enrollment open • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

A Research Study to See How Well New Weekly Medicine IcoSema, Which is a Combination of Insulin Icodec and Semaglutide, Controls Blood Sugar Levels in People With Type 2 Diabetes (T2D), Compared to Daily Insulin Glargine (COMBINE 4) (clinicaltrials.gov) - P3 | N=474 | Not yet recruiting | Sponsor: Novo Nordisk A/S

New P3 trial • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

A Research Study to See How Well the New Weekly Medicine IcoSema, Which is a Combination of Insulin Icodec and Semaglutide, Controls Blood Sugar Level in People With Type 2 Diabetes Compared to Weekly Semaglutide (COMBINE 2) (clinicaltrials.gov) - P3 | N=683 | Completed | Sponsor: Novo Nordisk A/S | Active, not recruiting ➔ Completed

Trial completion • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

COMBINE 3 phase 3a trial successfully completed with once-weekly IcoSema demonstrating non-inferior reduction in HbA1c versus daily basal-bolus treatment (insulin glargine U100 and insulin aspart) in people with type 2 diabetes (Novo Nordisk Press Release) - P3a | N=679 | COMBINE 3 (NCT05013229) | Sponsor: Novo Nordisk A/S | "Novo Nordisk today announced topline results from the COMBINE 3 phase 3a trial of once-weekly IcoSema, a fixed-ratio combination of basal insulin icodec and semaglutide....The trial achieved its primary endpoint of demonstrating non-inferiority in reducing HbA1c at week 52 with once-weekly IcoSema compared with insulin glargine U100 and insulin aspart....From an overall baseline HbA1c of 8.30%, once-weekly IcoSema achieved an estimated reduction in HbA1c of -1.47 percentage points compared with -1.40 percentage points for insulin glargine U100 and insulin aspart (estimated treatment difference: –0.06 percentage points)....COMBINE 3 is the first trial to readout in the phase 3a COMBINE programme, and results from COMBINE 1 and COMBINE 2 will be shared later this year."

P3 data • P3 data: top line • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Novel Alzheimer’s Trials Evaluate Senolytics, Semaglutide, CRISPR, and More (MedPageToday) - "'In 2023, the Alzheimer's drug development pipeline had 187 trials, the highest number on record, according to Jeffrey Cummings...Metformin and semaglutide [Ozempic], effective drugs against type 2 diabetes, are ideal candidates for repurposing to address the metabolic dysfunction in [Alzheimer's disease],' Fillit and co-authors wrote....'We envision a future where multiple treatments address every aspect of this most complex disease,' Carrillo noted. 'And that, once proven, the treatments can be combined in ways that complement and enhance each other to reduce risk, treat effectively, stop the progression, and eventually cure Alzheimer's disease and all other dementia.'"

Media quote

A Research Study to See How Well the New Weekly Medicine IcoSema, Which is a Combination of Insulin Icodec and Semaglutide, Controls Blood Sugar Level in People With Type 2 Diabetes Compared to Insulin Glargine Taken Daily With Insulin Aspart (COMBINE 3) (clinicaltrials.gov) - P3 | N=679 | Completed | Sponsor: Novo Nordisk A/S | Active, not recruiting ➔ Completed

Trial completion • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus