57th EASD: Pramlintide and Prandial Insulin for Type 1 Diabetes

In managing type 1 diabetes, a single combined formulation of pramlintide and prandial insulin, ADO09, can provide multiple benefits.

Pramlintide is an analog of human amylin approved for the adjunct treatment of type 1 and type 2 diabetes. Pramlintide works by prolonging gastric emptying time, reducing postprandial glucagon secretion, and reducing caloric intake. However, due to its physicochemical incompatibility, pramlintide is not mixable with other prandial insulin, resulting in an additional injection for each administration and lower adherence. Therefore, a novel formulation, called ADO09, of pramlintide and another novel human insulin (A21G) was developed to overcome the drawbacks above and improve clinical outcomes. At the 57th annual meeting of the European Association for the Study of Diabetes (EASD), Dr. Meiffren presented a trial conducted by him and his colleagues, which assessed the safety and efficacy of pre-meal ADO09 with insulin aspart in patients with type 1 diabetes.

The study was a single-center, double-blind, randomized, two-period cross-over trial that included 44 adult participants who have had type 1 diabetes for at least 12 months, have been treated with multiple dosing insulin therapies (MDI) with basal and bolus insulin, HbA1c ≤ 9.0%, and fasting negative c-peptide ≤ 0.30 nmol/L. The study included two parts: part A (28 eligible participants) included participants with a total daily prandial dose ≤ 40 units, and part B (16 eligible participants) included participants with a total daily prandial dose > 40 units. After the 28-day run-in period, to switch and stabilize all participants with insulin degludec for basal insulin, participants were randomized to receive either ADO09 or insulin aspart for 24 days. Then, they went through a washout period of 5 to 7 days before crossing over to the other prandial insulin treatment.

The completion rates were 78.5% and 93.8% in part A and part B, respectively. The mean baseline characteristics were 29% female, 40 years old, 24.5 kg/m2 BMI, 17.7 units basal insulin daily, and 23.2 units prandial insulin daily. The mean baseline characteristics for part B were 6% female, 47 years old, 30.5 kg/m2 BMI, 29.6 units basal insulin daily, and 51.5 units prandial insulin daily.

In the results for part A, ADO09 statistically reduced the total plasma glucose area under the curves (AUC) during the day 24 mixed-meal-tolerance-test by more than 100% in the first 2 hours (p < 0.001). However, the reduction was not statistically different after 4 hours (-39%, p = NS). Additionally, compared to insulin aspart, ADO09 slowed the gastric emptying time (Tmax 2.47 hrs versus 0.50 hrs) and lowered glucagon levels over hours 0 to 2 (AUC 3.19 pmol/h/L versus 11.30 pmol/h/L). ADO09 significantly improved the mean blood glucose over 24 hours with the continuous glucose monitoring over the 3-week outpatient period (-8.2 mg/dL, p < 0.001) and improved the time-in-range of blood glucose level (+51 min, p 0.013).

In the results for part B, ADO09 statistically reduced the incremental plasma glucose AUC during the day 24 MMTT by more than 100% in the first 2 hours (p < 0.001) and by 69% after 4 hours (p = 0.027). Similar to part A, ADO09 slowed the gastric emptying time and lowered the glucagon levels over hours 0 to 2, mean blood glucose over 24 hours, and the time-in-range in part B.

Another benefit of ADO09  was that it reduced body weight compared to insulin aspart (-0.8 kg and p = 0.012 for part A, -1.6 kg, and p – 0.007 for part B). Even though hypoglycemic events were higher with ADO09 (142 versus 115 in part A and 96 versus 79 in part B), no severe hypoglycemia event was reported. Additionally, higher doses of ADO09 did not increase the risk of nocturnal hypoglycemia. More gastrointestinal side effects were reported with ADO09; however, they were mild and consistent with pramlintide’s known side effects profile. The author concluded that ADO09 is well-tolerated and provided multiple benefits (improved glycemic control, a reduced dose of prandial insulin, weight loss…) for patients with type 1 diabetes. Another small trial that compared ADO09 with insulin lispro published earlier this year also showed that ADO09 was well-tolerated and notably reduced postprandial blood glucose in patients with type 1 diabetes. Given current evidence, more studies at a grander scale are needed to validate the clinical application of ADO09.

Practice Pearls:

• ADO09 is a novel therapy for the management of type 1 diabetes.
• ADO09 is well-tolerated and markedly reduced postprandial blood glucose compared with insulin aspart.
• Even though ADO09 is not currently approved in the U.S., current evidence suggests that more extensive trials are needed to validate the efficacy of ADO09 further.

Meiffren, Gregory. “EASD 2021: Investigational Combination of Pramlintide and Prandial Insulin Shows Promise in Type 1 Diabetes” European Association for the Study of Diabetes (EASD) 57th Annual Meeting. September 29, 2021. https://www.easd.org/annual-meeting/easd-2021.html

Andersen, Grit et al. “ADO09, a co-formulation of the amylin analog pramlintide and the insulin analog A21G, lowers postprandial blood glucose versus insulin lispro in type 1 diabetes.” Diabetes, obesity & metabolism

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