General Information

Tresiba (insulin degludec) is a long-acting human insulin analog.

Tresiba is specifically indicated to improve glycemic control in adults with diabetes mellitus. 

Mechanism of Action

The primary activity of insulin, including Tresiba, is regulation of glucose metabolism. Insulin and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin also inhibits lipolysis and proteolysis, and enhances protein synthesis. Tresiba forms multi-hexamers when injected into the subcutaneous tissue resulting in a subcutaneous insulin degludec depot. The protracted time action profile of Tresiba is predominantly due to delayed absorption of insulin degludec from the subcutaneous tissue to the systemic circulation and to a lesser extent due to binding of insulin degludec to circulating albumin.

Side Effects

Adverse effects associated with the use of Tresiba may include, but are not limited to, the following:

• hypoglycemia
• allergic reactions
• injection site reactions
• lipodystrophy
• pruritus
• rash
• edema
• weight gain

Dosing/Administration

Tresiba is supplied as an injection for subcutaneous administration. Inject Tresiba subcutaneously once daily at any time of day into the thigh, upper arm or abdomen. Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy. Individualize and titrate the dose of Tresiba based on the patient’s metabolic needs, blood glucose monitoring results and glycemic control goal. The recommended days between dose increases is three to four days. The recommended doses are as follows:

Starting dose in insulin-naïve patients:

Type 1 diabetes mellitus: The recommended starting dose of Tresiba in insulin-naïve patients with type 1 diabetes is approximately one-third to one-half of the total daily insulin dose. The remainder of the total daily insulin dose should be administered as a short-acting insulin and divided between each daily meal. As a general rule, 0.2 to 0.4 units of insulin per kilogram of body weight can be used to calculate the initial total daily insulin dose in insulin naïve patients with type 1 diabetes. Type 2 diabetes mellitus: The recommended starting dose of Tresiba in insulin-naïve patients with type 2 diabetes mellitus is 10 units once daily.

Starting dose in patients already on insulin therapy:

Type 1 and type 2 diabetes mellitus: Start Tresiba at the same unit dose as the total daily long- or intermediate-acting insulin unit dose. 

Clinical Trial Results

The FDA approval of Tresiba was based on the following trials:

Type 1 Diabetes

Tresiba administered at the same time each day in combination with a rapid-acting insulin analog at mealtimes:

Study A:

The efficacy of Tresiba was evaluated in a 52-week randomized, open-label, multicenter trial in 629 patients with type 1 diabetes mellitus. Patients were randomized to Tresiba once-daily with the evening meal or insulin glargine U-100 once-daily according to the approved labeling. Insulin aspart was administered before each meal in both treatment arms. At week 52, the difference in HbA1c reduction from baseline between Tresiba and insulin glargine U-100 was -0.01 percent with a 95 percent confidence interval of [-0.14 percent; 0.11 percent] and met the prespecified non-inferiority margin (0.4 percent).

Study B:

The efficacy of Tresiba was evaluated in a 26-week randomized, open-label, multicenter trial in 455 patients with type 1 diabetes mellitus. Patients were randomized to Tresiba or insulin detemir once-daily in the evening. After 8 weeks, insulin detemir could be dosed twice-daily. Results: 67.1 percent used insulin detemir once daily at end of trial; 32.9 percent used insulin detemir twice daily at end of trial. Insulin aspart was administered before each meal in both treatment arms. At week 26, the difference in HbA1c reduction from baseline between Tresiba and insulin detemir was -0.09 percent with a 95 percent confidence interval of [-0.23 percent; 0.05 percent] and met the prespecified non-inferiority margin (0.4 percent).

Tresiba administered at the same time each day or at any time each day in combination with a rapid-acting insulin analog at mealtimes:

Study C:

The efficacy of Tresiba was evaluated in a 26-week randomized, open-label, multicenter trial in 493 patients with type 1 diabetes mellitus. Patients were randomized to Tresiba injected once-daily at the same time each day (with the main evening meal), to Tresiba injected once daily at any time each day or to insulin glargine U-100 injected once-daily according to the approved labeling. The any time each day Tresiba arm was designed to simulate a worst-case scenario injection schedule of alternating short and long, once daily, dosing intervals (i.e., alternating intervals of eight to 40 hours between doses). Tresiba in this arm was dosed in the morning on Monday, Wednesday and Friday and in the evening on Tuesday, Thursday, Saturday and Sunday. Insulin aspart was administered before each meal in both treatment arms. At week 26, the difference in HbA1c reduction from baseline between Tresiba administered at alternating times and insulin glargine U-100 was 0.17 percent with a 95 percent confidence interval of [0.04 percent; 0.30 percent] and met the pre-specified non-inferiority margin (0.4 percent).

Type 2 Diabetes

Tresiba administered at the same time each day as an add-on to metformin with or without a dpp-4 inhibitor in insulin naïve patients:

Study D:

The efficacy of Tresiba was evaluated in a 52-week randomized, open-label, multicenter trial that enrolled 1030 insulin naïve patients with type 2 diabetes mellitus inadequately controlled on one or more oral antidiabetic agents (OADs). Patients were randomized to Tresiba once-daily with the evening meal or insulin glargine U-100 once-daily, according to the approved labeling. Metformin alone (82.5 percent) or in combination with a DPP-4 inhibitor (17.5 percent) was used as background therapy in both treatment arms. At week 52, the difference in HbA1c reduction from baseline between Tresiba and insulin glargine U-100 was 0.09 percent with a 95 percent confidence interval of [-0.04 percent; 0.22 percent] and met the prespecified non-inferiority margin (0.4 percent).

Tresiba U-200 administered at the same time each day as an add-on to metformin with or without a DPP-4 inhibitor in insulin-naïve patients:

Study E:

The efficacy of Tresiba U-200 was evaluated in a 26-week randomized, open-label, multicenter trial in 457 insulin naïve patients with type 2 diabetes mellitus inadequately controlled on one or more oral antidiabetic agents (OADs) at baseline. Patients were randomized to Tresiba U-200 once-daily with the evening meal or insulin glargine U-100 once-daily according to the approved labeling. Both treatment arms were receiving metformin alone (84 percent) or in combination with a DPP-4 inhibitor (16 percent) as background therapy. At week 26, the difference in HbA1c reduction from baseline between Tresiba U-200 and insulin glargine U-100 was 0.04 percent with a 95 percent confidence interval of [-0.11 percent; 0.19 percent] and met the pre-specified non-inferiority margin (0.4 percent).

Tresiba administered at the same time each day in insulin-naïve patients as an add-on to one or more of the following oral agents: metformin, sulfonylurea, glinides or alpha-glucosidase inhibitors:

Study F:

The efficacy of Tresiba was evaluated in a 26-week randomized, open-label, multicenter trial in Asia in 435 insulin naïve patients with type 2 diabetes mellitus inadequately controlled on one or more oral antidiabetic agents (OADs) at baseline. Patients were randomized to Tresiba once-daily in the evening or insulin glargine U-100 once-daily according to the approved labeling. Pre-trial oral antidiabetes agents were continued as background therapy except for DPP-4 inhibitors or thiazolidinediones in both treatment arms. At week 26, the difference in HbA1c reduction from baseline between Tresiba and insulin glargine U-100 was 0.11 percent with a 95 percent confidence interval of [-0.03 percent; 0.24 percent] and met the prespecified non-inferiority margin (0.4 percent).

Tresiba administered at the same time each day or any time each day as an addon to one and up to three of the following oral agents: metformin, sulfonylurea or glinides or pioglitazone:

Study G:

The efficacy of Tresiba was evaluated in a 26-week randomized, open-label, multicenter trial in 687 patients with type 2 diabetes mellitus inadequately controlled on basal insulin alone, oral antidiabetic agents (OADs) alone or both basal insulin and OAD. Patients were randomized to Tresiba injected once-daily at the same time each day (with the main evening meal), to Tresiba injected once daily at any time each day or to insulin glargine U-100 injected once-daily according to the approved labeling. The any time each day Tresiba arm was designed to simulate a worst-case scenario injection schedule of alternating short and long, once daily dosing intervals (i.e., alternating intervals of eight to 40 hours between doses). Tresiba in this arm was dosed in the morning on Monday, Wednesday and Friday and in the evening on Tuesday, Thursday, Saturday and Sunday. Up to three of the following oral antidiabetes agents (metformin, sulfonylureas, glinides or thiazolidinediones) were administered as background therapy in both treatment arms. At week 26, the difference in HbA1c reduction from baseline between Tresiba at alternating times and insulin glargine U-100 was 0.04 percent with a 95 percent confidence interval of [-0.12 percent; 0.20 percent]. This comparison met the pre-specified non-inferiority margin (0.4 percent). 

Tresiba administered at the same time each day in combination with a rapid-acting insulin analog at mealtimes:

Study H:

The efficacy of Tresiba was evaluated in a 52-week randomized, open-label, multicenter trial in 992 patients with type 2 diabetes mellitus inadequately controlled on premix insulin, bolus insulin alone, basal insulin alone, oral antidiabetic agents (OADs) alone or any combination thereof. Patients were randomized to Tresiba once-daily with the main evening meal or insulin glargine U-100 once-daily according to the approved labeling. Insulin aspart was administered before each meal in both treatment arms. Up to two of the following oral antidiabetes agents (metformin or pioglitazone) were used as background therapy in both treatment arms. At week 52, the difference in HbA1c reduction from baseline between Tresiba and insulin glargine U-100 was 0.08 percent with a 95 percent confidence interval of [-0.05 percent; 0.21 percent] and met the prespecified non-inferiority margin (0.4 percent).

TRESIBA administered at any time each day as an add-on to one or two of the following oral agents: metformin, sulfonylurea or pioglitazone:

Study I:

The efficacy of Tresiba was evaluated in a 26-week randomized, open-label, multicenter trial in 447 patients with type 2 diabetes mellitus inadequately controlled on one or more oral antidiabetic agent (OADs) at baseline. Patients were randomized to Tresiba once-daily at any time of day or sitagliptin once-daily according to the approved labeling. One or two of the following oral antidiabetes agents (metformin, sulfonylurea or pioglitazone) were also administered in both treatment arms. At the end of 26 weeks, Tresiba provided greater reduction in mean HbA1c compared to sitagliptin (p < 0.001).