In T2DM, weekly insulin icodec did not differ from daily glargine for reducing HbA1c or significant/severe hypoglycemia

An ACP Journal Club commentary pointed out that use of once-weekly insulin for patients with type 2 diabetes will require more cautious dose-titration algorithms and less stringent glycemic targets to avoid hypoglycemia.


A phase 2, manufacturer-funded trial found similar efficacy and safety with once-weekly insulin icodec compared to once-daily insulin glargine U100 in insulin-naive patients with type 2 diabetes and an HbA1c level of 7.0% to 9.5%. The primary end point was the change in HbA1c level from baseline to week 26 (−1.33 percentage points in the icodec group and −1.15 percentage points in the glargine group, to estimated means of 6.69% and 6.87%, respectively). There was no difference in insulin-related key adverse events, and rates of hypersensitivity and injection-site reactions were low in both groups. Insulin icodec is not yet approved by the FDA.

The study was published in the Nov. 26, 2020, New England Journal of Medicine. The following commentary by Tomás P. Griffin, MB, BCh, BAO, MSc, Dip Clin Ed, and Sean F. Dinneen, MD, MSc, was published in the ACP Journal Club section of Annals of Internal Medicine on March 2.

Patients with T2DM are often reluctant to make the transition from tablets to insulin injections. Clinicians too are often reticent to recommend daily insulin therapy until necessary. By reducing the number of injections, insulin icodec would reduce injection burden and potentially increase acceptance of insulin therapy.

Previous studies of weekly vs. daily injections of glucagon-like peptide-1 receptor agonists in T2DM have shown that patients who receive weekly injections adhere better than those who receive daily injections. Better adherence facilitates safe, accurate adjustment of insulin doses. Once-weekly insulin would be particularly suitable for some patients (e.g., those not able to self-administer or with cognitive impairment) but may not be ideal for others who need an insulin regimen that can be adapted to daily changes in routine (e.g., due to exercise or varying levels of stress).

Rosenstock and colleagues found that insulin icodec increased mild hypoglycemic alerts with comparable reductions in HbA1c but did not increase clinically significant hypoglycemia (<54 mg/dL) or severe hypoglycemia. Icodec was expected to have equipotency to glargine, but lower insulin doses of 229 U of icodec vs. 284 U of glargine were required when titrating to the predefined glycemic targets. Despite the apparent difference in potency, the adjustment algorithm in the trial advised modifying the doses of each insulin once weekly by equivalent amounts (e.g., 14 U/wk of icodec vs. 2 U/d of glargine) to target a prebreakfast glucose level of 70 to 108 mg/dL (3.9 to 6.0 mmol/L). This glycemic target is more aggressive than that recommended by the American Diabetes Association (4.4 to 7.2 mmol/L) and may have contributed to the hypoglycemic alerts. More cautious dose-titration algorithms and less stringent glycemic targets should be advised due to the long half-life of icodec and inability to adjust icodec dosing for 7 days if problematic hypoglycemia occurs.

The investigators incorporated “estimands”—a new approach to assist with interpretation of trial results—in their analyses. The choice of comparator used in this trial, however, is problematic and suggests that market considerations rather than trial methodology were at play. Future studies comparing once-weekly insulin icodec with once-daily insulin degludec will be of interest, as degludec is associated with lower rates of nocturnal hypoglycemia compared with once-daily insulin glargine U100. In addition to adjustment of the titration algorithm and treatment targets, it will be interesting to see whether risk for nocturnal hypoglycemia differs between daily insulin degludec and weekly insulin icodec.