Rybelsus and Ozempic tablets results

Overview of Clinical Studies

The effectiveness of OZEMPIC tablets (1.5 mg, 4 mg and 9 mg strengths) [see Dosage and Administration (2.2)] and RYBELSUS (3 mg, 7, mg and 14 mg strengths) [see Dosage and Administration (2.3)] has been established as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus based on adequate and well-controlled studies of RYBELSUS in adult patients with type 2 diabetes mellitus [see Clinical Pharmacology (12.3)] . Below is a display of the efficacy results of the adequate and well-controlled studies of RYBELSUS, referred to below as semaglutide tablets, in adult patients with type 2 diabetes mellitus.

Semaglutide tablets have been studied as monotherapy and in combination with metformin, sulfonylureas, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, insulins, and thiazolidinediones in patients with type 2 diabetes mellitus. The efficacy of semaglutide tablets was compared with placebo, empagliflozin, sitagliptin and liraglutide. Semaglutide tablets have also been studied in patients with type 2 diabetes mellitus with mild and moderate renal impairment.

In patients with type 2 diabetes mellitus, semaglutide tablets produced clinically significant reduction from baseline in HbA 1c compared with placebo.

The efficacy of semaglutide tablets was not impacted by baseline age, sex, race, ethnicity, BMI, body weight, duration of diabetes and degree of renal impairment.

Monotherapy Use of Semaglutide Tablets in Patients with Type 2 Diabetes Mellitus

In a 26-week double-blind trial (Trial 1, NCT02906930), 703 adult patients with type 2 diabetes mellitus inadequately controlled with diet and exercise were randomized to semaglutide tablets 3 mg, semaglutide tablets 7 mg or semaglutide tablets14 mg orally once daily or placebo. Patients had a mean age of 55 years and 51% were men. The mean duration of type 2 diabetes mellitus was 3.5 years, and the mean BMI was 32 kg/m 2 . Overall, 75% were White, 5% were Black or African American and 17% were Asian; 26% identified as Hispanic or Latino ethnicity.

Monotherapy with semaglutide tablets7 mg and semaglutide tablets 14 mg tablets once daily for 26 weeks resulted in a statistically significant reduction in HbA 1c compared with placebo (see Table 4 ).

Table 4. Trial 1 Results at Week 26 in a Monotherapy Trial of Semaglutide Tablets in Adult Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise

a The intent-to-treat population includes all randomized patients. At Week 26, the primary HbA 1c endpoint was missing for 5.6%, 8.6% and 8.6% of patients randomized to placebo, semaglutide tablets 7 mg and semaglutide tablets14 mg, respectively. Missing data were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at Week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 15%, 2% and 1% of patients randomized to placebo, semaglutide tablets 7 mg and semaglutide tablets 14 mg, respectively.

b Estimated using an ANCOVA model based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value and region.

c p<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.

The mean baseline body weight was 88.6 kg, 89 kg and 88.1 kg in the placebo, semaglutide tablets 7 mg, and semaglutide tablets 14 mg arms, respectively. The mean changes from baseline to week 26 were -1.4 kg, -2.3 kg and -3.7 kg in the placebo, semaglutide tablets7 mg and semaglutide tablets 14 mg arms, respectively. The difference from placebo (95% CI) for semaglutide tablets 7 mg was -0.9 kg (-1.9, 0.1) and for semaglutide tablets 14 mg was -2.3 kg (-3.1, -1.5).

Combination Therapy Use of Semaglutide Tablets in Patients with Type 2 Diabetes Mellitus

Combination with Metformin

In a 26-week trial (Trial 2, NCT02863328), 822 adult patients with type 2 mellitus diabetes were randomized to semaglutide tablets 14 mg orally once daily or empagliflozin 25 mg orally once daily, all in combination with metformin. Patients had a mean age of 58 years and 50% were men. The mean duration of type 2 diabetes mellitus was 7.4 years and the mean BMI was 33 kg/m 2 . Overall, 86% were White, 7% were Black or African American and 6% were Asian; 24% identified as Hispanic or Latino ethnicity.

Treatment with semaglutide tablets 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA 1c compared to empagliflozin 25 mg once daily (see Table 5 ).

Table 5. Trial 2 Results at Week 26 in a Trial of Semaglutide Tablets Compared to Empagliflozin in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin

a The intent-to-treat population includes all randomized patients. At Week 26, the primary HbA 1c endpoint was missing for 4.6% and 3.7% of patients randomized to semaglutide tablets 14 mg and empagliflozin 25 mg, respectively. Missing data were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at Week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 1.9% and 1.2% of patients randomized to semaglutide tablets 14 mg and empagliflozin 25 mg, respectively.

b Estimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value and region.

c p<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.

The mean baseline body weight was 91.9 kg and 91.3 kg in the semaglutide tablets 14 mg and empagliflozin 25 mg arms, respectively. The mean changes from baseline to Week 26 were -3.8 kg and -3.7 kg in the semaglutide tablets 14 mg and empagliflozin 25 mg arms, respectively. The difference from empagliflozin (95% CI) for semaglutide tablets 14 mg was -0.1 kg (-0.7, 0.5).

Combination with Metformin or Metformin with Sulfonylurea

In a 26-week, double-blind trial (Trial 3, NCT02607865), 1864 adult patients with type 2 mellitus diabetes on metformin alone or metformin with sulfonylurea were randomized to semaglutide tablets 3 mg, semaglutide tablets 7 mg, semaglutide tablets 14 mg orally once daily or sitagliptin 100 mg once daily. Patients had a mean age of 58 years and 53% were men. The mean duration of type 2 diabetes mellitus was 8.6 years, and the mean BMI was 32 kg/m 2 . Overall, 71% were White, 9% were Black or African American and 13% were Asian; 17% identified as Hispanic or Latino ethnicity.

Treatment with semaglutide tablets 7 mg and semaglutide tablets 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA 1c compared to sitagliptin 100 mg once daily (see Table 6 ).

Table 6. Trial 3 Results at Week 26 in a Trial of Semaglutide Tablets Compared to Sitagliptin 100 mg Once Daily in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin or Metformin with Sulfonylurea

a The intent-to-treat population includes all randomized patients. At Week 26, the primary HbA 1c endpoint was missing for 5.8%, 6.2% and 4.5% of patients randomized to semaglutide tablets 7 mg, semaglutide tablets 14 mg and sitagliptin 100 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at Week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 2.4%, 1.1% and 2.8% of patients randomized to semaglutide tablets 7 mg, semaglutide tablets 14 mg and sitagliptin 100 mg, respectively.

b Estimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication and region.

c p<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.

The mean baseline body weight was 91.3 kg, 91.2 kg and 90.9 kg in the semaglutide tablets 7 mg, semaglutide tablets 14 mg and sitagliptin 100 mg arms, respectively. The mean changes from baseline to Week 26 were -2.2 kg, -3.1 kg and -0.6 kg in the semaglutide tablets 7 mg, semaglutide tablets 14 mg and sitagliptin 100 mg arms, respectively. The difference from sitagliptin (95% CI) for semaglutide tablets 7 mg was -1.6 kg (-2.0, -1.1) and semaglutide tablets 14 mg was -2.5 kg (-3.0, -2.0).

Combination with Metformin or Metformin with SGLT-2 Inhibitors

In a 26-week, double-blind, double-dummy trial (Trial 4, NCT02863419), 711 adult patients with type 2 diabetes mellitus on metformin alone or metformin with SGLT-2 inhibitors were randomized to semaglutide tablets 14 mg orally once daily, liraglutide 1.8 mg subcutaneous injection once daily or placebo. Patients had a mean age of 56 years and 52% were men. The mean duration of type 2 diabetes mellitus was 7.6 years and the mean BMI was 33 kg/m 2 . Overall, 73% were White, 4% were Black or African American and 13% were Asian; 6% identified as Hispanic or Latino ethnicity.

Treatment with semaglutide tablets 14 mg once daily for 26 weeks resulted in statistically significant reductions in HbA 1c compared to placebo. Treatment with semaglutide tablets 14 mg once daily for 26 weeks resulted in non-inferior reductions in HbA 1c compared to liraglutide 1.8 mg (see Table 7 ).

Table 7. Trial 4 Results at Week 26 in a Trial of Semaglutide Tablets Compared to Liraglutide and Placebo in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin or Metformin with SGLT-2i

a The intent-to-treat population includes all randomized patients. At Week 26, the primary HbA 1c endpoint was missing for 5.6%, 4.2% and 2.5% of patients randomized to placebo, liraglutide 1.8 mg and semaglutide tablets 14 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at Week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 7.7%, 3.2% and 3.5% of patients randomized to placebo, liraglutide 1.8 mg and semaglutide tablets 14 mg respectively.

b Estimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication and region.

c p<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.

The mean baseline body weight was 93.2 kg, 95.5 kg and 92.9 kg in the placebo, liraglutide 1.8 mg and semaglutide tablets 14 mg arms, respectively. 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 semaglutide tablets 14 mg arms, respectively. The difference from placebo (95% CI) for semaglutide tablets 14 mg was -3.8 kg (-4.7, -3). The difference from liraglutide 1.8 mg for semaglutide tablets 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

In a 26-week, double-blind trial (Trial 5, NCT02827708), 324 adult patients with moderate renal impairment (eGFR CKD-EPI 30 to 59 mL/min/1.73 m 2 ) were randomized to semaglutide tablets 14 mg orally once daily or placebo once daily. Semaglutide tablets were added to the patient’s stable pre-trial antidiabetic regimen. The insulin dose was reduced by 20% at randomization for patients on basal insulin. Dose reduction of insulin and sulfonylurea was allowed in case of hypoglycemia; up titration of insulin was allowed but not beyond the pre-trial dose.

Patients had a mean age of 70 years and 48% were men. The mean duration of type 2 diabetes mellitus was 14 years and the mean BMI was 32 kg/m 2 . Overall, 96% were White, 4% were Black or African American and 0.3% were Asian; 6.5% identified as Hispanic or Latino ethnicity. 39.5% of patients had an eGFR value of 30 to 44 mL/min/1.73 m 2 .

Treatment with semaglutide tablets 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA 1c from baseline compared to placebo (see Table 8 ).

Table 8. Trial 5 Results at Week 26 in a Trial of Semaglutide Tablets Compared to Placebo in Patients with Moderate Renal Impairment

a The intent-to-treat population includes all randomized patients including patients on rescue medication. At Week 26, the primary HbA 1c endpoint was missing for 3.7% and 5.5% of patients randomized to placebo and semaglutide tablets 14 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at Week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 10% and 4.3% of patients randomized to placebo and semaglutide tablets 14 mg, respectively.

b Estimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication, renal status and region.

c p<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.

The mean baseline body weight was 90.4 kg and 91.3 kg in the placebo and semaglutide tablets 14 mg arms, respectively. The mean changes from baseline to Week 26 were -0.9 kg and -3.4 kg in the placebo and semaglutide tablets 14 mg arms, respectively. The difference from placebo (95% CI) for semaglutide tablets 14 mg was -2.5 kg (-3.2, -1.8).

Combination with Insulin with or without Metformin

In a 26-week double blind trial (Trial 6, NCT03021187), 731 adult patients with type 2 diabetes mellitus inadequately controlled on insulin (basal, basal/bolus or premixed) with or without metformin, were randomized to semaglutide tablets 3 mg, 7 mg and 14 mg orally once daily or placebo once daily. 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.

Patients had a mean age of 61 years and 54% were men. The mean duration of type 2 diabetes mellitus was 15 years and the mean BMI was 31 kg/m 2 . Overall, 51% were White, 7% were Black or African American and 36% were Asian; 13% identified as Hispanic or Latino ethnicity.

Treatment with semaglutide tablets 7 mg and 14 mg once daily for 26 weeks resulted in a statistically significant reduction in HbA 1c from baseline compared to placebo once daily (see Table 9 ).

Table 9. Trial 6 Results at Week 26 in a Trial of Semaglutide Tablets Compared to Placebo in Adult Patients with Type 2 Diabetes Mellitus in Combination with Insulin alone or with Metformin

a The intent-to-treat population includes all randomized patients. At Week 26, the primary HbA 1c endpoint was missing for 4.3%, 4.4% and 4.4% of patients randomized to placebo, semaglutide tablets 7 mg and semaglutide tablets 14 mg, respectively. Missing values were imputed by a pattern mixture model using multiple imputation (MI). Pattern was defined by randomized treatment and treatment status at Week 26. During the trial, additional anti-diabetic medication was initiated as an add on to randomized treatment by 4.9%, 1.1 % and 2.2% of patients randomized to placebo, semaglutide tablets 7 mg and semaglutide tablets 14 mg, respectively.

b Estimated using an ANCOVA based on data irrespectively of discontinuation of trial product or initiation of rescue medication adjusted for baseline value, background medication and region.

c p<0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity.

The mean baseline body weight was 86 kg, 87.1 kg and 84.6 kg in the placebo, semaglutide tablets7 mg and semaglutide tablets 14 mg arms, respectively. The mean changes from baseline to Week 26 were -0.4 kg, -2.4 kg and -3.7 kg in the placebo, semaglutide tablets 7 mg and semaglutide tablets 14 mg arms, respectively. The difference from placebo (95% CI) for semaglutide tablets 7 mg was -2 kg (-3, -1) and for semaglutide tablets 14 mg was -3.3 kg (-4.2, -2.3).

Cardiovascular Outcomes Trial of Semaglutide Tablets in Adult Patients with Type 2 Diabetes Mellitus and High Risk of Having a Cardiovascular Event

Trial 7 (NCT03914326) was a randomized, double-blind, parallel-group, placebo-controlled trial. In this trial, 9,650 patients with type 2 diabetes mellitus and established cardiovascular (CV) disease and/or chronic kidney disease (CKD) (defined as eGFR <60 mL/min/1.73 m 2 ), were randomized to either once daily semaglutide tablets 14 mg or placebo, in addition to standard of care. The primary endpoint, major adverse cardiovascular events (MACE), was the time to first occurrence of a three-part composite outcome which included CV death, non-fatal myocardial infarction (MI) and non-fatal stroke.

Patients eligible to enter the trial were: 50 years of age or older and with established CV disease or CKD. In total, 5,468 patients (56.7%) had established CV disease without CKD, 1,241 (13%) had CKD only, and 2,620 (27%) had both CV disease and CKD. Most patients (97%) were treated with one or more glucose lowering medications at baseline: metformin (76%), insulin (51%), SGLT-2 inhibitor (27%), sulfonylurea (29%), and DPP-4 inhibitor (23%). At baseline, CV disease and risk factors were managed with lipid-lowering medications (89%), platelet-aggregation inhibitors including aspirin (77%), angiotensin converting enzyme inhibitors or angiotensin II receptor blockers (79%), and beta blockers (64%).

The mean age at baseline was 66.1 years, and 71% of the patients were men. Overall, 69% were White, 3% were Black or African American, and 23% were Asian; 14% identified as Hispanic or Latino ethnicity.

The mean duration of diabetes was 15.4 years, the mean BMI was 31.1 kg/m 2 , the mean HbA 1c was 8%, and the mean eGFR was 73.8 mL/min/1.73 m 2 . Concomitant diseases included heart failure (23%), hypertension (91%), previous ischemic stroke (12%), previous MI (40%), and peripheral artery disease (16%). In total, 98.4% patients completed the trial, and the vital status was known at the end of the trial for 99.5%.

Semaglutide tablets significantly reduced the occurrence of MACE. The estimated hazard ratio for time to first MACE was 0.86 (95% CI: 0.77, 0.96) over the median follow-up duration of 49.6 months and 49.4 months for patients randomized to RYBELSUS and placebo, respectively. Refer to Table 10 and Figure 1 . The treatment effect for the primary composite endpoint and its components in Trial 7 are shown in Table 10 .

Table 10. Trial 7 Treatment Effect for MACE and its Components

• Note: Data from the in-trial period based on full analysis set defined as all randomized patients.
• Time from randomization to each endpoint was analyzed using a Cox proportional hazards model with treatment as categorical fixed factor. Subjects without events of interest were censored at the end of their in-trial period. For the primary endpoint the hazard ratio and CI were adjusted for the group sequential design using likelihood ratio ordering. CV death, non-fatal MI and non-fatal stroke are listed descriptively for supportive purpose. CV death includes both CV death and undetermined cause of death.
• N=number of patients; %: percentage of participants in the full analysis set with at least one event; CI: confidence interval

Figure 1: Time to First Occurrence of a MACE in Trial 7

Data from the in-trial period based on full analysis set defined as all randomized patients. Cumulative incidence estimates are based on time from randomization to first EAC-confirmed MACE with non-CV death modeled as competing risk using the Aalen-Johansen estimator. Patients without events of interest were censored at the end of their in-trial observation period. Time from randomization to first MACE was analyzed using a Cox proportional hazards model with treatment as categorical fixed factor. The hazard ratio and confidence interval are adjusted for the group sequential design using the likelihood ratio ordering. HR: Hazard ratio; CI: confidence interval.

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

Trial 8 (NCT02692716) was a multi-center, multi-national, placebo-controlled, double-blind trial. In this trial, 3,183 adult patients with inadequately controlled type 2 diabetes mellitus and atherosclerotic CV disease were randomized to semaglutide tablets 14 mg orally once daily or placebo for a median observation time of 16 months. The trial compared the risk of a MACE between semaglutide tablets 14 mg and placebo when added to current standard of care treatments for diabetes and cardiovascular CV disease. The primary endpoint, MACE, was the time to first occurrence of a three-part composite outcome which included cardiovascular death, non-fatal MI and non-fatal stroke.

Patients eligible to enter the trial were 50 years of age or older and had established, stable, CV, cerebrovascular, peripheral artery disease, CKD or NYHA class II and III heart failure or were 60 years of age or older and had other specified risk factors for CV disease. In total, 1,797 patients (56.5%) had established CV disease without CKD, 354 patients (11.1%) had CKD only, and 544 patients (17.1%) had both CV disease and CKD; 488 patients (15.3%) had CV risk factors without established CV disease or CKD. The mean age at baseline was 66 years and 68% were men. The mean duration of diabetes was 14.9 years and mean BMI was 32 kg/m 2 . Overall, 72% were White, 6% were Black or African American and 20% were Asian; 16% identified as Hispanic or Latino ethnicity. Concomitant diseases of patients in this trial included, but were not limited to, heart failure (12%), history of ischemic stroke (8%) and history of a MI (36%). In total, 99.7% of the patients completed the trial and the vital status was known at the end of the trial for 100%.

For the primary analysis, a Cox proportional hazards model was used to test for non-inferiority of semaglutide tablets 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 semaglutide tablets14 mg and 4.8% (76/1592) for placebo.