Rybelsus

Monotherapy Use of Rybelsus in Patients with Type 2 Diabetes Mellitus

• Approval was based on a 26-week double-blind trial which included 703 adults with type 2 diabetes inadequately controlled with diet and exercise. Patients were randomly assigned to receive Rybelsus 3 mg, 7 mg, or 14 mg once daily or placebo.

• Rybelsus 7 mg and 14 mg as monotherapy significantly reduced hemoglobin A1c to less than 7% after 26 weeks in 69% and 77% of patients, respectively, compared with 31% of patients administered placebo (both P <.001).

• The mean changes from baseline to week 26 were -1.4 kg, -2.3 kg and -3.7 kg in the placebo, Rybelsus 7 mg, and Rybelsus 14 mg arms, respectively. The difference from placebo (95% CI) for Rybelsus 7 mg was -0.9 kg (-1.9, 0.1) and for Rybelsus 14 mg was -2.3 kg (-3.1, -1.5).

Combination Therapy Use of Rybelsus in Patients with Type 2 Diabetes Mellitus

• Approval was based on a 26-week trial which included 822 adults with type 2 diabetes. Patients were randomly assigned to receive Rybelsus 14 mg once daily or empagliflozin 25 mg once daily, in combination with metformin.

• Rybelsus 14 mg once daily significantly reduced hemoglobin A1c to less than 7% after 26 weeks in 67% of patients compared with 40% of patients administered empagliflozin (P <.001).

• The mean changes from baseline to week 26 was -3.8 kg in the Rybelsus arm, and -3.7 kg in the empagliflozin arm. The difference from empagliflozin (95% CI) for Rybelsus was -0.1 kg (-0.7, 0.5).

Combination with Metformin or Metformin with Sulfonylurea

• Approval was based on a 26-week, double-blind trial which included 1864 adults with type 2 diabetes who were currently taking metformin alone or metformin with sulfonylurea. Patients were randomly assigned to receive Rybelsus 3 mg, 7 mg, 14 mg, or sitagliptin 100 mg once daily.

• Rybelsus 7 mg and 14 mg significantly reduced hemoglobin A1c to less than 7% after 26 weeks in 44% and 56% of patients, respectively, compared with 32% of patients administered sitagliptin (both P <.001).

• The mean changes from baseline to week 26 were -2.2 kg, -3.1 kg and -0.6 kg in the Rybelsus 7 mg, 14 mg and sitagliptin 100 mg arms, respectively. The difference from sitagliptin (95% CI) for Rybelsus 7 mg was -1.6 kg  (-2.0, -1.1) and Rybelsus 14 mg was -2.5 kg (-3.0, -2.0).

Combination with Metformin or Metformin with SGLT-2 Inhibitors

• Approval was based on a 26-week, double-blind, double-dummy trial which included 711 adults with type 2 diabetes on metformin alone or metformin with SGLT-2 inhibitors. Patients were randomly assigned to receive Rybelsus 14 mg once daily, liraglutide 1.8 mg subcutaneously once daily or placebo.

• Rybelsus 14 mg once daily significantly reduced hemoglobin A1c to less than 7% after 26 weeks in 68% of patients compared with 62% of patients in the liraglutide arm and 14% of those in the placebo arm (P <.001).

• The mean changes from baseline to week 26 were -0.5 kg, -3.1 kg and -4.4 kg in the placebo, liraglutide 1.8 mg, and Rybelsus 14 mg arms, respectively. The difference from placebo (95% CI) for Rybelsus 14 mg was -3.8 kg (-4.7, -3.0). The difference from liraglutide 1.8 mg for Rybelsus 14 mg was -1.2 (-1.9, -0.6). 

Combination in patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment with Metformin alone, Sulfonylurea alone, Basal Insulin alone, or Metformin in Combination with either Sulfonylurea or Basal Insulin

• Approval was based on a 26-week, double-blind trial which included 324 adults with type 2 diabetes and moderate renal impairment (eGFR_CKD-EPI 30−59 mL/min/1.73 m²). Patients were randomly assigned to receive Rybelsus 14 mg once daily or placebo, in addition to the patient’s stable pre-trial antidiabetic regimen. The insulin dose was reduced by 20% at randomization for patients on basal insulin.

• Rybelsus 14 mg once daily significantly reduced hemoglobin A1c to less than 7% after 26 weeks in 58% of patients compared with 23% of patients in the placebo arm (P <.001).

• The mean changes from baseline to week 26 were -0.9 kg and -3.4 kg in the placebo and Rybelsus 14 mg arms, respectively. The difference from placebo (95% CI) for Rybelsus 14 mg was -2.5 kg (-3.2, -1.8).

Combination with Insulin with or without Metformin

• Approval was based on a 26-week, double-blind trial which included 731 adults with type 2 diabetes inadequately controlled on insulin (basal, basal/bolus or premixed) with or without metformin. Patients were randomly assigned to receive Rybelsus 3 mg, 7 mg, and 14 mg once daily or placebo. All patients reduced their insulin dose by 20% at randomization to reduce the risk of hypoglycemia. Patients were allowed to increase the insulin dose only up to the starting insulin dose prior to randomization. 

• Rybelsus 7 mg and 14 mg once daily significantly reduced hemoglobin A1c to less than 7% after 26 weeks in 43% and 58% of patients, respectively, compared with7% of patients in the placebo arm (both P <.001).

• The mean changes from baseline to week 26 were -0.4 kg, -2.4 kg and -3.7 kg in the placebo, Rybelsus 7 mg, and Rybelsus 14 mg arms, respectively. The difference from placebo (95% CI) for Rybelsus 7 mg was -2.0 kg (-3.0, -1.0), and for Rybelsus 14 mg was -3.3 kg (-4.2, -2.3). 

Cardiovascular Outcomes Trial in Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease

• Approval was based on the multi-center, multi-national, placebo-controlled, double-blind PIONEER 6 trial which included 3183 adults with inadequately controlled type 2 diabetes and atherosclerotic cardiovascular disease. 

• Patients were randomly assigned to receive Rybelsus 14 mg once daily or placebo for a median observation time of 16 months. The primary endpoint, MACE, was the time to first occurrence of a three-part composite outcome which included cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. 

• For the primary analysis, a Cox proportional hazards model was used to test for non-inferiority of Rybelsus 14 mg to placebo for time to first MACE using a risk margin of 1.3. Type-1 error was controlled across multiple tests using a hierarchical testing strategy. Non-inferiority to placebo was established, with a hazard ratio equal to 0.79 (95% CI: 0.57, 1.11) over the median observation time of 16-months. The proportion of patients who experienced at least one MACE was 3.8% (61/1591) for Rybelsus 14 mg and 4.8% (76/1592) for placebo.