Type 2 diabetes mellitus (T2DM) is characterized by complex pathophysiological mechanisms and progressive disease progression. Combination therapy with drugs of different mechanisms of action has become an important treatment strategy recommended by guidelines both domestically and internationally. Following the successful development of weekly glucagon-like peptide-1 receptor agonist (GLP-1RA) formulations and weekly basal insulin formulations, injectable therapy for T2DM has entered the era of weekly dosing. To further meet clinical treatment needs, the weekly basal insulin/GLP-1RA combination, which integrates the strengths of both agents, has emerged.
In terms of mechanism of action, the combination of basal insulin and GLP-1RA corrects multiple pathophysiological defects in T2DM through complementary mechanisms, exerting effective glucose-lowering effects. Specifically, basal insulin enhances glucose uptake in skeletal muscle, inhibits hepatic glycogenolysis and gluconeogenesis, thereby reducing hepatic glucose output and effectively controlling fasting blood glucose. GLP-1RA exerts pleiotropic effects, including stimulating insulin secretion from pancreatic β-cells, suppressing glucagon secretion from pancreatic α-cells, delaying gastric emptying, and inducing satiety in the central nervous system, thus achieving glucose-lowering and weight-reduction effects. Moreover, the combination reduces the major adverse reactions associated with the use of basal insulin or GLP-1RA alone.
As T2DM progresses, many patients eventually require insulin therapy to achieve and maintain glycemic control despite treatment with oral antidiabetic drugs (OADs) and GLP-1RAs. Previous studies have confirmed the clinical benefits of basal insulin plus GLP-1RA combination therapy. The DUAL series demonstrated that the combination of basal insulin and GLP-1RA (insulin degludec/liraglutide injection) enhances glucose-lowering efficacy, improves HbA1c target attainment rate, and reduces the risk of hypoglycemia and weight gain associated with insulin therapy.
For injectable glucose-lowering medications, the burden of frequent injections is one of the main barriers to timely initiation and treatment adherence. Traditional basal insulin requires daily injections, at least 7 times per week; basal-bolus insulin regimens require two injection pens and 14–28 injections per week, imposing a heavy injection burden. There is a critical clinical need for new regimens that further simplify treatment and reduce injection burden. Fixed-ratio combination products, which integrate two agents into one, have gradually become a new trend in combination therapy and a novel approach for injectable combination therapy.
To address this unmet clinical need, IcoSema, a weekly basal insulin/GLP-1RA combination, was developed. It requires only one injection pen and one injection per week, providing a feasible solution to reduce injection burden.
IcoSema is a fixed-ratio combination of the weekly basal insulin icodec insulin and the weekly GLP-1RA semaglutide, administered once weekly. The formulation contains 700 U icodec insulin and 2 mg semaglutide per mL, with a maximum weekly dose of 350 dose units (i.e., 350 U icodec insulin / 1 mg semaglutide). The glucose-lowering efficacy and safety of icodec insulin and 1 mg semaglutide have been fully validated in their respective Phase 3 clinical trials: the ONWARDS series for icodec insulin and the SUSTAIN series for semaglutide.
The Phase 3a clinical program for IcoSema includes COMBINE 1–3, all global, multicenter, randomized controlled trials. They aim to evaluate the clinical advantages of IcoSema versus monotherapy in T2DM patients uncontrolled on basal insulin (COMBINE 1) and GLP-1RA (COMBINE 2), as well as the efficacy and safety of IcoSema versus basal-bolus insulin therapy in T2DM patients uncontrolled on basal insulin (COMBINE 3). The Phase 3b trial COMBINE 4 evaluates the efficacy and safety of IcoSema versus insulin glargine U100 in T2DM patients uncontrolled on OADs.
To date, COMBINE 1–3 have been completed.
COMBINE 1 enrolled 1,291 T2DM patients with inadequate glycemic control on basal insulin, randomized to once-weekly IcoSema or once-weekly icodec insulin. The results confirmed that IcoSema was superior in HbA1c reduction, body weight change, and hypoglycemia risk. At Week 52, IcoSema reduced HbA1c by 1.55% from baseline and body weight by 3.7 kg, with a significantly lower rate of clinically significant or severe hypoglycemia.
COMBINE 2 enrolled 683 T2DM patients uncontrolled on GLP-1RA, comparing once-weekly IcoSema with once-weekly semaglutide 1.0 mg. IcoSema achieved superior HbA1c reduction (−1.35% from baseline), with similar rates of clinically significant or severe hypoglycemia between groups.
COMBINE 3 enrolled 679 T2DM patients uncontrolled on basal insulin, comparing once-weekly IcoSema with basal-bolus insulin (insulin glargine U100 + insulin aspart). IcoSema reduced HbA1c by 1.47% from baseline, versus 1.40% for basal-bolus therapy, meeting non-inferiority for HbA1c reduction
[Estimated Treatment Difference (ETD): −0.06%, 95%CI: −0.22% to 0.09%, p<0.0001].
IcoSema also showed significantly greater weight loss (−3.56 kg vs. +3.16 kg, p<0.0001), a markedly lower rate of clinically significant or severe hypoglycemia (0.21 events/patient-year vs. 2.23 events/patient-year, p<0.0001), and drastically fewer injections, reducing patient burden.
Diabetes management is long-term and often lifelong. Patient acceptance and adherence strongly influence therapeutic outcomes, driving the continuous pursuit of simpler, more convenient regimens. The arrival of weekly basal insulin/GLP-1RA combinations provides a practical solution to reduce injection burden. Current evidence shows that IcoSema combines efficacy, safety, and simplicity, which will improve patient acceptance and support better diabetes management.
Weekly basal insulin/GLP-1RA combinations have broad clinical prospects, especially for T2DM patients requiring insulin. On the one hand, the combination enhances glucose-lowering efficacy while reducing adverse reactions; GLP-1RA also provides additional benefits such as blood pressure reduction and lipid profile improvement. On the other hand, simpler injectable combination regimens are urgently needed to ease injection burden. The once-weekly basal insulin/GLP-1RA combination is an excellent option, significantly reducing injection frequency, improving treatment adherence, and enhancing quality of life.