Spotlight on weekly insulins

Weekly basal insulins were compared to insulin degludec in multiple recent preapproval trials.

An international phase 3a trial, funded by Novo Nordisk, compared insulin icodec, a once-weekly basal insulin currently under development, to insulin degludec in patients with type 2 diabetes that was inadequately controlled on once- or twice-daily basal insulins. A total of 526 patients were randomized to weekly icodec or daily degludec for 26 weeks. From mean baselines of 8.17% and 8.10%, respectively, their HbA1c levels dropped to 7.20% and 7.42% (estimated treatment difference, −0.22 percentage point [95% CI, −0.37 to −0.08]), demonstrating both noninferiority (P<0.0001) and superiority (P=0.0028) of the novel insulin. Patients on icodec gained 1.40 kg, compared to a 0.30 kg-loss on degludec. Overall rates of combined level 2 (blood glucose <54 mg/dL [2.99 mmol/L]) or level 3 (blood glucose so low that mental or physical functioning is impaired) hypoglycemia were numerically but not statistically higher with icodec (0.73 vs. 0.27 event per patient-year; estimated rate ratio, 1.93 [95% CI, 0.93 to 4.02]). “Notably, this is the first treat-to-target trial comparing two basal insulin analogues showing statistical superiority (in a prespecified analysis) of icodec versus degludec in terms of HbA1c reductions over 26 weeks,” said the study authors. They noted that treatment satisfaction was also higher with the new insulin and that “improved adherence and persistence might be drivers of the HbA1c-lowering efficacy of once-weekly insulin icodec.”

The potential for better adherence with weekly insulin was seconded by a comment that accompanied the study in The Lancet Diabetes & Endocrinology on May 3. “The inconvenience of multiple injections and the accompanying risk of hypoglycaemia and weight gain are major contributors to poor adherence and treatment satisfaction. This can lead to reluctance among both patients and clinicians to intensify therapy, resulting in suboptimal glycaemic control,” it said. The comment called the study's results tantalizing but noted that additional research is necessary, including trials in real-world settings to determine if weekly dosing does improve adherence. “If proven to be effective and safe, the convenience and other benefits to patients are potentially immense,” the comment concluded.

Two other studies, both phase 2 and funded by manufacturer Eli Lilly, compared weekly basal insulin Fc, a fusion protein combining a novel single-chain insulin variant with a human IgG Fc domain, to daily degludec in patients with type 1 or 2 diabetes. The type 2 diabetes trial, published by Diabetes Care on March 21, randomized 278 insulin-naive patients treated with oral medications to either insulin Fc or degludec for 26 weeks and found similar reductions in HbA1c level from baseline (treatment difference between groups, 0.06%; P=0.56). Both groups also had significant reductions in fasting glucose levels and low rates of level 2 hypoglycemia (events per patient year, 0.22 with insulin Fc vs. 0.15 with degludec; P=0.64). Neither group had any severe hypoglycemia. “This study demonstrated the clinical utility and potential of BIF [basal insulin Fc] as a promising once-weekly basal insulin that will reduce the injection burden in insulin-naive patients with [type 2 diabetes],” said the study authors.

The other study, published by Diabetes Care on March 15, included 266 patients with type 1 diabetes, randomized to weekly basal insulin Fc or daily degludec for 26 weeks, titrated to a fasting glucose level of 80 to 100 mg/dL (4.44 to 5.55 mmol/L). The weekly insulin resulted in a statistically significant improvement in HbA1c level compared to degludec (treatment difference, 0.17% [90% CI, 0.01% to 0.32%]; P=0.07). Time in range and rates of level 1 (blood glucose <70 mg/dL [3.88 mmol/L]) or 2 hypoglycemia were similar, but mean fasting glucose level was significantly higher in patients receiving insulin Fc (158.8 mg/dL [8.81 mmol/L] vs. 143.2 mg/dL [7.95 mmol/L]; P=0.003). The study authors noted that patients with type 1 diabetes are “more vulnerable to inadequate basal insulin dosing” than those with type 2 and that the finding of similar glycemic control and hypoglycemia compared with once-daily degludec “suggest that BIF may be effectively used by patients with [type 1 diabetes] and reduce patient burden.” They observed that the increase in fasting glucose level may have been due to underdosing of the new insulin at the start of the trial.