In types 1 and 2 diabetes, weekly basal insulin Fc was noninferior to daily insulin degludec for HbA1c at 26 wk
The arrival of once-weekly insulin will undoubtedly be welcomed by patients and clinicians, but the advantages of fewer shots will have to be weighed against less flexibility in dosing of basal insulin, an ACP Journal Club commentary said.
Two recent studies, both phase 2 and funded by manufacturer Eli Lilly, compared weekly basal insulin Fc (BIF), 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 randomized 278 insulin-naive patients between the two insulins and found that both yielded similar reductions in HbA1c level from baseline. The other trial randomized 266 patients with type 1 diabetes and found a statistically significant improvement in HbA1c level with the weekly insulin compared to degludec.
The two studies were published by Diabetes Care in March and were summarized in the May ACP Diabetes Monthly. The following commentary by Michael J. Lockhart, MD, and Sean F. Dinneen, MD, was published in the ACP Journal Club section of Annals of Internal Medicine on July 4.
More than 100 years after the discovery of insulin in Canada, we now have a plethora of formulations available to prescribe for patients with diabetes. The vast number of options (and the similarity in nomenclature of many currently available insulins) presents challenges to patients and nonspecialist health care professionals, especially during hospitalizations, where insulin prescribing errors are common.
The newest insulins are ultra–long-acting insulins that can be administered once weekly and achieve a virtually flat pharmacodynamic profile due to very slow absorption from the site of subcutaneous injection. Icodec insulin (Novo Nordisk) is currently going through phase 3 clinical trials and will likely be the first once-weekly insulin on the market. BIF (Eli Lilly) is a fusion protein made up of a single chain insulin variant linked to the Fc component of the IgG2 immunoglobulin.
The phase 2 trials by Kazda and colleagues and Bue-Valleskey and colleagues compare BIF with insulin degludec in patients with type 1 diabetes (already receiving basal insulin) and in patients with insulin-naive type 2 diabetes, respectively. In both trials, BIF was administered as a reconstituted powder and dosed in milligrams (vs. IU). Patients randomly assigned to the intervention group were required to attend a clinical center for BIF administration once weekly for the first 12 (of 26) weeks of the trial. Patients had the option of self-administering the once-weekly dose in their homes thereafter and used an algorithm (which was somewhat complex) to guide dose adjustments. A goal of the phase 2 trials with BIF was to establish the potency of the compound and clarify how to dose it in international units (vs. mg) in prefilled pen devices. This is the anticipated method of administration in future phase 3 trials. The difference in HbA1c at 26 weeks seen in the type 1 diabetes trial may have emerged in response to an algorithm for BIF dose adjustment that was too conservative; this will likely be resolved by the time the drug comes to phase 3 trial stage and eventually to the market.
Both patients and clinicians will need to get used to administering what most would consider enormous doses of once-weekly insulin. In the trial of patients with type 1 diabetes, the average daily dose of basal insulin before recruitment was 27 units. This converts to almost 200 units of insulin weekly (for patients receiving BIF) and administration of a loading dose of 600 units at baseline to achieve steady state. There is no mention of a public and patient involvement perspective in either of the 2 trials, but we suspect that this aspect of the new drug would raise concerns for many patients. Doses of this size would normally be associated with harm. In both trials, the rates of adverse events (mainly hypoglycemia) were equivalent to those seen with degludec.
Although the arrival of once-weekly insulin will undoubtedly be welcomed by patients and their health care teams, it remains to be seen how the benefit of fewer injections will be weighed against the limitation of less flexibility in dosing of basal insulin. For active patients and those who frequently adjust their basal insulin, the convenience of a reduced number of injections may not be seen as an absolute reason for changing to a less flexible (in terms of dose adjustment) basal insulin.