Rybelsus (semaglutide): NDA 213182

NDA 213051 was approved with an indication of RYBELSUS as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM).

The estimated hazard ratio for MACE with semaglutide compared to placebo was 0. 79 with a 95% confidence interval of 0.57 to 1.11 (p-value=0.18 for superiority).

The estimated hazard ratio for MACE was 0.79, with a 95% CI of 0.57 to 1.11 (p-value=0.18 for superiority).

The primary analysis for PIONEER 6 was non-inferiority, followed by superiority of Rybelsus vs placebo for time to first occurrence of MACE.

In PIONEER 6, 3183 patients were randomized (1:1) to receive semaglutide 14 mg or placebo.

While PIONEER 6 showed a nominally significant difference in CV death and all-cause death favoring semaglutide vs placebo, these data should not be overinterpreted as the event number was small, the endpoints were not controlled for type 1 error, and these data were not supported by the CVOT with subcutaneous semaglutide, SUSTAIN 6, where no difference was seen for CV- or all-cause death.

The purpose of the study was to demonstrate that oral semaglutide therapy is not associated with an increased risk for major adverse cardiovascular events (MACE).

The difference between treatments in overall number of patients with MACE was primarily attributable to a smaller number of first stroke and CV death with oral semaglutide than with placebo.

However, nominal statistical significance for reduction of all-cause death in study 4221 should not be over interpreted given that type 1 error was not controlled for that endpoint, and because the reduction in risk of all-cause death seen in trial 4221 for RYBELSUS was not mirrored in trial 3744 for OZEMPIC (Table 5).

Hypoglycemia: When RYBELSUS is used with an insulin secretagogue or insulin, consider lowering the dose of the secretagogue or insulin to reduce the risk of hypoglycemia (5.4).

In the pool of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1.

Human relevance of thyroid C-cell tumors in rats is unknown and could not be determined by clinical studies or nonclinical studies [see Boxed Warning and Warnings and Precautions (5.1)].

All patients reduced their insulin dose by 20% at randomization to reduce the risk of hypoglycemia.