COMBINE 2 is better than one: shaping the future of therapeutics in inadequately controlled type 2 diabetes

Expert Rev Clin Pharmacol. 2025 May;18(5):259-262. doi: 10.1080/17512433.2025.2516784. Epub 2025 Jun 9.

Abstract

During treatment intensification of injectable therapies among persons with type 2 diabetes mellitus (T2DM) without evidence of severe insulin deficiency, a glucagon-like peptide-1 agonist (GLP-1 RA) is preferred to insulin. However, due to its progressive nature, many individuals over the course of disease will ultimately require insulin treatment. The use of fixed-ratio combination of basal insulin and GLP-1 RA represents a practical and convenient method for treatment intensification. It has been shown to be more efficacious in improving glycemic control, compared with GLP-1 RA or basal insulin alone, and similarly effective with lower insulin dose in reducing glycated hemoglobin (HbA1c) levels, along with less weight gain, and a lower risk of hypoglycemia compared with basal/bolus insulin therapy. 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.

Keywords: Glucagon-like peptide-1 agonist; IcoSema; icodec; semaglutide; type 2 diabetes mellitus.

Publication types

  • Review
  • Comparative Study

MeSH terms

  • Blood Glucose / drug effects
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diabetes Mellitus, Type 2* / physiopathology
  • Drug Combinations
  • Drug Therapy, Combination
  • Glucagon-Like Peptide 1
  • Glucagon-Like Peptide-1 Receptor Agonists
  • Glucagon-Like Peptides / administration & dosage
  • Glucagon-Like Peptides / adverse effects
  • Glucagon-Like Peptides / therapeutic use
  • Glycated Hemoglobin / metabolism
  • Humans
  • Hypoglycemia / chemically induced
  • Hypoglycemic Agents* / administration & dosage
  • Hypoglycemic Agents* / adverse effects
  • Hypoglycemic Agents* / pharmacology
  • Hypoglycemic Agents* / therapeutic use
  • Insulin / administration & dosage
  • Insulin / adverse effects

Substances

  • Hypoglycemic Agents
  • Insulin
  • Glucagon-Like Peptides
  • semaglutide
  • Glycated Hemoglobin
  • Drug Combinations
  • Glucagon-Like Peptide-1 Receptor Agonists
  • Blood Glucose
  • hemoglobin A1c protein, human
  • Glucagon-Like Peptide 1