57th EASD: Hypoglycemia Risk With A Once-weekly Basal Insulin

Examining the risk for hypoglycemic events with insulin icodec, a novel once-weekly basal insulin analog for patients with type 2 diabetes.

Due to disease progression and uncontrolled glycemic levels, many patients with type 2 diabetes eventually require insulin therapy. However, glycemic control remains poor despite the addition of insulin therapy. Some reasons might include frequent injections, complex dosing, and side effects (weight gain, hypoglycemia), resulting in poor adherence. Even though insulin icodec is in clinical development and trial phases, it can improve adherence and quality of life due to the long half-life (about one week), thus allowing once-weekly administration. However, Dr. Silver noted that due to this drug’s long duration of action, we need to investigate further the side effect profile, more specifically, the risk of hypoglycemia.

Dr. Silver and other researchers conducted a post hoc analysis from two phase II trials to investigate whether once-weekly insulin icodec induces hypoglycemic events of longer duration than once-daily insulin glargine.

The first trial (the titration trial) was a multicenter, multination, randomized, active-controlled, parallel-group, open-label trial that investigated the efficacy and safety of icodec using different once-weekly titration algorithms versus insulin glargine U100 (adjusted by ± 4 units/day) in 205 insulin-naive patients. The three titration algorithms are as follow: titration A – targeted blood glucose of 80 to 130 mg/dL and adjusted by ± 21 units/week; titration B – targeted blood glucose of 80 to 130 mg/dL and adjusted by 28 units/week; titration C – targeted blood glucose of 70 to 106 mg/dL and adjusted by 28 units/week. The second trial (the switch trial) was a multicenter, open-label, randomized, active-controlled, parallel-group, treat-to-target, open-label trial that investigated two approaches for switching to icodec (with or without 100% loading dose) versus once-daily insulin glargine in 154 patients with type 2 diabetes who were receiving daily basal insulin. In both trials, continuous glucose monitoring data collection was utilized, allowing the researchers to evaluate the duration of hypoglycemic episodes. An episode of hypoglycemia was defined as an interstitial glucose level of 3.9 mmol/L (70 mg/dL) for at least 15 minutes during a continuous glucose monitoring interval.

In the results of the titration trial, the median overall hypoglycemic episode duration was 35.0 minutes (IQR 20 to 70 minutes) for titration A, B, and insulin glargine groups. The hypoglycemic episode duration was 39.0 minutes (IQR 24.0 to 70.0 minutes) for titration C. Therefore, the duration of hypoglycemia was similar across all study groups.

In the results of the switch trial, the median overall hypoglycemic episode durations were 40.0 minutes (IQR 20.0 to 80.0 minutes), 40.0 minutes (25.0 to 75.0 minutes), and 35.0 minutes (IQR 20.0 to 60.0 minutes) for insulin icodec with a 100% loading dose, insulin icodec without a loading dose, and insulin glargine, respectively. Hence, the duration of hypoglycemia was similar among the three arms.

The researchers also reported that the median nocturnal hypoglycemic episode duration and the time spent below 3.0 mmol/L (54 mg/dL) were similar among all arms and both trials. Thus, they inferred that regardless of titration algorithm or the use of an initial loading dose with icodec, the length of the hypoglycemic episode was comparative with icodec and with glargine in both insulin-naïve and insulin-experienced patients with type 2 diabetes. Based on current evidence, insulin icodec provides effective glycemic control and is well-tolerated, thus an ideal agent for patients who experience adherence issues with daily basal insulin.

Practice Pearls:

• The results from both studies are similar in both insulin-naive and insulin-experienced patients.
• The duration of the hypoglycemic episodes was similar with both insulin icodec and with insulin glargine.
• Insulin icodec has stable pharmacokinetics and pharmacodynamics properties (half-life of about one week), allowing less frequent injections, and thus more convenient for many patients.

Silver, Robert. “Investigational Once-Weekly Basal Insulin Does Not Increase Hypoglycemic Time in Type 2 Diabetes.” European Association for the Study of Diabetes (EASD) 57th Annual Meeting. September 29, 2021.

Lingvay, Ildiko et al. “A Randomized, Open-Label Comparison of Once-Weekly Insulin Icodec Titration Strategies Versus Once-Daily Insulin Glargine U100.” Diabetes care

Bajaj, Harpreet S et al. “Switching to Once-Weekly Insulin Icodec Versus Once-Daily Insulin Glargine U100 in Type 2 Diabetes Inadequately Controlled on Daily Basal Insulin: Diabetes care

Ding Nguyen, PharmD Candidate, University of South Florida Taneja College of Pharmacy