CLINICAL PHARMACOLOGY
Mechanism Of Action
Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1. Semaglutide acts as a GLP-1
receptor agonist that selectively binds to and activates the GLP-1 receptor, the target for native GLP-1.
GLP-1 is a physiological hormone that has multiple actions on glucose, mediated by the GLP-1 receptors.
The principal mechanism of protraction resulting in the long half-life of semaglutide is albumin binding, which
results in decreased renal clearance and protection from metabolic degradation. Furthermore, semaglutide is
stabilized against degradation by the DPP-4 enzyme.
Semaglutide reduces blood glucose through a mechanism where it stimulates insulin secretion and lowers
glucagon secretion, both in a glucose-dependent manner. Thus, when blood glucose is high, insulin secretion is
stimulated and glucagon secretion is inhibited. The mechanism of blood glucose lowering also involves a minor
delay in gastric emptying in the early postprandial phase.
Pharmacodynamics
Semaglutide lowers fasting and postprandial blood glucose and reduces body weight. All pharmacodynamic
evaluations were performed after 12 weeks of treatment (including dose escalation) at steady state with
semaglutide 1 mg.
Fasting And Postprandial Glucose
Semaglutide reduces fasting and postprandial glucose concentrations. In patients with type 2 diabetes, treatment
with semaglutide 1 mg resulted in reductions in glucose in terms of absolute change from baseline and relative
reduction compared to placebo of 29 mg/dL (22%) for fasting glucose, 74 mg/dL (36%) for 2 hour postprandial
glucose, and 30 mg/dL (22%) for mean 24 hour glucose concentration (see Figure 1).
Figure 1. Mean 24 hour plasma glucose profiles (standardized meals) in patients with type 2 diabetes
before (baseline) and after 12 weeks of treatment with semaglutide or placebo
Insulin Secretion
Both first-and second-phase insulin secretion are increased in patients with type 2 diabetes treated with
OZEMPIC compared with placebo.
Glucagon Secretion
Semaglutide lowers the fasting and postprandial glucagon concentrations. In patients with type 2 diabetes,
treatment with semaglutide resulted in the following relative reductions in glucagon compared to placebo,
fasting glucagon (8%), postprandial glucagon response (14-15%), and mean 24 hour glucagon concentration
(12%).
Glucose Dependent Insulin And Glucagon Secretion
Semaglutide lowers high blood glucose concentrations by stimulating insulin secretion and lowering glucagon
secretion in a glucose-dependent manner. With semaglutide, the insulin secretion rate in patients with type 2
diabetes was similar to that of healthy subjects (see Figure 2).
Figure 2. Mean insulin secretion rate versus glucose concentration in patients with type 2 diabetes during
graded glucose infusion before (baseline) and after 12 weeks of treatment with semaglutide or placebo
and in untreated healthy subjects
During induced hypoglycemia, semaglutide did not alter the counter regulatory responses of increased glucagon
compared to placebo, and did not impair the decrease of C-peptide in patients with type 2 diabetes.
Gastric Emptying
Semaglutide causes a delay of early postprandial gastric emptying, thereby reducing the rate at which glucose
appears in the circulation postprandially.
Cardiac Electrophysiology (QTc)
The effect of semaglutide on cardiac repolarization was tested in a thorough QTc trial. At a dose 1.5 times the
maximum recommended dose, semaglutide does not prolong QTc intervals to any clinically relevant extent.
Pharmacokinetics
Absorption
Absolute bioavailability of semaglutide is 89%. Maximum concentration of semaglutide is reached 1 to 3 days
post dose.
Similar exposure is achieved with subcutaneous administration of semaglutide in the abdomen, thigh, or upper
arm.
In patients with type 2 diabetes, semaglutide exposure increases in a dose-proportional manner for once-weekly
doses of 0.5 mg and 1 mg. Steady-state exposure is achieved following 4-5 weeks of once-weekly
administration. In patients with type 2 diabetes, the mean population-PK estimated steady-state concentrations
following once weekly subcutaneous administration of 0.5 mg and 1 mg semaglutide were approximately 65.0
ng/mL and 123.0 ng/mL, respectively.
Distribution
The mean apparent volume of distribution of semaglutide following subcutaneous administration in patients
with type 2 diabetes is approximately 12.5 L. Semaglutide is extensively bound to plasma albumin (>99%).
Elimination
The apparent clearance of semaglutide in patients with type 2 diabetes is approximately 0.05 L/h. With an
elimination half-life of approximately 1 week, semaglutide will be present in the circulation for about 5 weeks
after the last dose.
Metabolism
The primary route of elimination for semaglutide is metabolism following proteolytic cleavage of the peptide
backbone and sequential beta-oxidation of the fatty acid sidechain.
Excretion
The primary excretion routes of semaglutide-related material is via the urine and feces. Approximately 3% of
the dose is excreted in the urine as intact semaglutide.
Specific Populations
Based on a population pharmacokinetic analysis, age, sex, race, and ethnicity, and renal impairment do not have
a clinically meaningful effect on the pharmacokinetics of semaglutide. The exposure of semaglutide decreases
with an increase in body weight. However, semaglutide doses of 0.5 mg and 1 mg provide adequate systemic
exposure over the body weight range of 40-198 kg evaluated in the clinical trials. The effects of intrinsic factors
on the pharmacokinetics of semaglutide are shown in Figure 3.
Figure 3. Impact of intrinsic factors on semaglutide exposure
Patients With Renal impairment
Renal impairment does not impact the pharmacokinetics of semaglutide in a
clinically relevant manner. This was shown in a study with a single dose of 0.5 mg semaglutide in patients with
different degrees of renal impairment (mild, moderate, severe, ESRD) compared with subjects with normal
renal function. This was also shown for subjects with both type 2 diabetes and renal impairment based on data
from clinical studies (Figure 3).
Patients With Hepatic impairment
Hepatic impairment does not have any impact on the exposure of
semaglutide. The pharmacokinetics of semaglutide were evaluated in patients with different degrees of hepatic
impairment (mild, moderate, severe) compared with subjects with normal hepatic function in a study with a
single-dose of 0.5 mg semaglutide.
Pediatric Patients
Semaglutide has not been studied in pediatric patients.
Drug Interaction Studies
In vitro studies have shown very low potential for semaglutide to inhibit or induce CYP enzymes, and to inhibit
drug transporters.
The delay of gastric emptying with semaglutide may influence the absorption of concomitantly administered
oral medicinal products. The potential effect of semaglutide on the absorption of co-administered oral
medications was studied in trials at semaglutide 1 mg steady-state exposure.
No clinically relevant drug-drug interaction with semaglutide (Figure 4) was observed based on the evaluated
medications; therefore, no dose adjustment is required when co-administered with semaglutide.
Figure 4. Impact of semaglutide on the exposure of co-administered oral medications
Clinical Studies
Overview Of Clinical Studies
OZEMPIC has been studied as monotherapy and in combination with metformin, metformin and sulfonylureas, metformin and/or thiazolidinedione, and basal insulin in patients with type 2 diabetes mellitus. The efficacy of OZEMPIC was compared with placebo, sitagliptin, exenatide extended-release (ER), and insulin glargine.
Most trials evaluated the use of OZEMPIC 0.5 mg, and 1 mg, with the exception of the trial comparing OZEMPIC and exenatide ER where only the 1 mg dose was studied.
In patients with type 2 diabetes mellitus, OZEMPIC produced clinically relevant reduction from baseline in HbA1c compared with placebo.
The efficacy of OZEMPIC was not impacted by age, gender, race, ethnicity, BMI at baseline, body weight (kg) at baseline, diabetes duration and level of renal function impairment.
Monotherapy Use Of OZEMPIC In Patients With Type 2 Diabetes Mellitus
In a 30-week double-blind trial (NCT02054897), 388 patients with type 2 diabetes mellitus inadequately controlled with diet and exercise were randomized to OZEMPIC 0.5 mg or OZEMPIC 1 mg once weekly or placebo. Patients had a mean age of 54 years and 54% were men. The mean duration of type 2 diabetes was 4.2 years, and the mean BMI was 33 kg/m2. Overall, 64% were White, 8% were Black or African American, and 21% were Asian; 30% identified as Hispanic or Latino ethnicity.
Monotherapy with OZEMPIC 0.5 mg and 1 mg once weekly for 30 weeks resulted in a statistically significant reduction in HbA1c compared with placebo (see Table 3).
Table 3. Results at Week 30 in a Trial of OZEMPIC as Monotherapy in Adult Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise
|
Placebo |
OZEMPIC
0.5 mg |
OZEMPIC
1 mg |
Intent-to-Treat (ITT) Population (N)a |
129 |
128 |
130 |
HbA1c (%) |
Baseline (mean) |
8.0 |
8.1 |
8.1 |
Change at week 30 b |
-0.1 |
-1.4 |
-1.6 |
Difference from sitagliptinb
[95% CI] |
|
-1.2
[-1.5, -0.9]c |
-1.4
[-1.7, -1.1]c |
Patients (%) achieving HbA1c <7% |
28 |
73 |
70 |
FPG (mg/dL) |
Baseline (mean) |
174 |
174 |
179 |
Change at week 30b |
-15 |
-41 |
-44 |
aThe intent-to-treat population includes all randomized and exposed patients. At week 30 the primary HbA1c endpoint was missing for 10%, 7% and 7% of patients and during the trial rescue medication was initiated by 20%, 5% and 4% of patients randomized to placebo, OZEMPIC 0.5 mg and OZEMPIC 1 mg, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts.
bIntent-to-treat analysis using ANCOVA adjusted for baseline value and country.
cp<0.0001 (2-sided) for superiority, adjusted for multiplicity. |
The mean baseline body weight was 89.1 kg, 89.8 kg, 96.9 kg in the placebo, OZEMPIC 0.5 mg, and OZEMPIC 1 mg arms, respectively. The mean changes from baseline to week 30 were -1.2 kg, -3.8 kg and -4.7 kg in the placebo, OZEMPIC 0.5 mg, and OZEMPIC 1 mg arms, respectively. The difference from placebo (95% CI) for OZEMPIC 0.5 mg was -2.6 kg (-3.8, -1.5), and for OZEMPIC 1 mg was -3.5 kg (-4.8, -2.2).
Combination Therapy Use Of OZEMPIC In Patients With Type 2 Diabetes Mellitus
Combination With Metformin And/Or Thiazolidinediones
In a 56-week, double-blind trial (NCT01930188), 1231 patients with type 2 diabetes mellitus were randomized to OZEMPIC 0.5 mg once weekly, OZEMPIC 1 mg once weekly, or sitagliptin 100 mg once daily, all in combination with metformin (94%) and/or thiazolidinediones (6%). Patients had a mean age of 55 years and 51% were men. The mean duration of type 2 diabetes was 6.6 years, and the mean BMI was 32 kg/m2. Overall, 68% were White, 5% were Black or African American, and 25% were Asian; 17% identified as Hispanic or Latino ethnicity.
Treatment with OZEMPIC 0.5 mg and 1 mg once weekly for 56 weeks resulted in a statistically significant reduction in HbA1c compared to sitagliptin (see Table 4 and Figure 5).
Table 4. Results at Week 56 in a Trial of OZEMPIC Compared to Sitagliptin in Adult Patients with Type 2 Diabetes Mellitus In Combination with Metformin and/or Thiazolidinediones
|
OZEMPIC
0.5 mg |
OZEMPIC
1 mg |
Sitagliptin |
Intent-to-Treat (ITT) Population (N)a |
409 |
409 |
407 |
HbA1c (%) |
Baseline (mean) |
8.0 |
8.0 |
8.2 |
Change at week 56 b |
-1.3 |
-1.5 |
-0.7 |
Difference from sitagliptinb
[95% CI] |
-0.6
[-0.7, -0.4]c |
-0.8
[-0.9, -0.6]c |
|
Patients (%) achieving HbA1c <7% |
66 |
73 |
40 |
FPG (mg/dL) |
Baseline (mean) |
168 |
167 |
173 |
Change at week 56b |
-35 |
-43 |
-23 |
aThe intent-to-treat population includes all randomized and exposed patients. At week 56 the primary HbA1c endpoint was missing for 7%, 5% and 6% of patients and during the trial rescue medication was initiated by 5%, 2% and 19% of patients randomized to OZEMPIC 0.5 mg, OZEMPIC 1 mg and sitagliptin, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts.
bIntent-to-treat analysis using ANCOVA adjusted for baseline value and country.
cp<0.0001 (2-sided) for superiority, adjusted for multiplicity. |
The mean baseline body weight was 89.9 kg, 89.2 kg, 89.3 kg in the OZEMPIC 0.5 mg, OZEMPIC 1 mg, and
sitagliptin arms, respectively. The mean changes from baseline to week 56 were -4.2 kg, -5.5 kg, and -1.7 kg for
the OZEMPIC 0.5 mg, OZEMPIC 1 mg, and sitagliptin arms, respectively. The difference from sitagliptin (95%
CI) for OZEMPIC 0.5 mg was -2.5 kg (-3.2, -1.8), and for OZEMPIC 1 mg was -3.8 kg (-4.5, -3.1).
Figure 5. Mean HbA1c (%) over time - baseline to week 56
Combination With Metformin Or Metformin With Sulfonylurea
In a 56-week, open-label trial (NCT01885208), 813 patients with type 2 diabetes mellitus on metformin alone
(49%), metformin with sulfonylurea (45%), or other (6%) were randomized to OZEMPIC 1 mg once weekly or
exenatide 2 mg once weekly. Patients had a mean age of 57 years and 55% were men. The mean duration of
type 2 diabetes was 9 years, and the mean BMI was 34 kg/m2. Overall, 84% were White, 7% were Black or
African American, and 2% were Asian; 24% identified as Hispanic or Latino ethnicity.
Treatment with OZEMPIC 1 mg once weekly for 56 weeks resulted in a statistically significant reduction in
HbA1c compared to exenatide 2 mg once weekly (see Table 5).
Table 5. Results at Week 56 in a Trial of OZEMPIC Compared to Exenatide 2 mg Once Weekly in Adult
Patients with Type 2 Diabetes Mellitus In Combination with Metformin or Metformin with Sulfonylurea
|
OZEMPIC
1 mg |
Exenatide ER
2 mg |
Intent-to-Treat (ITT) Population (N)a |
404 |
405 |
HbA1c (%) |
Baseline (mean) |
8.4 |
8.3 |
Change at week 56 b |
-1.4 |
-0.9 |
Difference from exenatide b
[95% CI] |
-0.5
[-0.7, -0.3]c |
|
Patients (%) achieving HbA1c <7% |
62 |
40 |
FPG (mg/dL) |
Baseline (mean) |
191 |
188 |
Change at week 56 b |
-44 |
-34 |
aThe intent-to-treat population includes all randomized and exposed patients. At week 56 the primary HbA1c endpoint was missing for 9% and 11% of patients and during the trial rescue medication was initiated by 5% and 10% of patients randomized to OZEMPIC 1 mg and exenatide ER 2 mg, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts.
bIntent-to-treat analysis using ANCOVA adjusted for baseline value and country.
cp<0.0001 (2-sided) for superiority, adjusted for multiplicity. |
The mean baseline body weight was 96.2 kg and 95.4 kg in the OZEMPIC 1 mg and exenatide ER arms, respectively. The mean changes from baseline to week 56 were -4.8 kg and -2.0 kg in the OZEMPIC 1 mg and exenatide ER arms, respectively. The difference from exenatide ER (95% CI) for OZEMPIC 1 mg was -2.9 kg (-3.6, -2.1).
Combination With Metformin Or Metformin With Sulfonylurea
In a 30-week, open-label trial (NCT02128932), 1089 patients with type 2 diabetes mellitus were randomized to OZEMPIC 0.5 mg once weekly, OZEMPIC 1 mg once weekly, or insulin glargine once daily on a background of metformin (48%) or metformin and sulfonylurea (51%). Patients had a mean age of 57 years and 53% were men. The mean duration of type 2 diabetes was 8.6 years, and the mean BMI was 33 kg/m2. Overall, 77% were White, 9% were Black or African American, and 11% were Asian; 20% identified as Hispanic or Latino ethnicity.
Patients assigned to insulin glargine had a baseline mean HbA1c of 8.1% and were started on a dose of 10 U once daily. Insulin glargine dose adjustments occurred throughout the trial period based on self-measured fasting plasma glucose before breakfast, targeting 71 to <100 mg/dL. In addition, investigators could titrate insulin glargine at their discretion between study visits. Only 26% of patients had been titrated to goal by the primary endpoint at week 30, at which time the mean daily insulin dose was 29 U per day.
Treatment with OZEMPIC 0.5 mg and 1 mg once weekly for 30 weeks resulted in a statistically significant reduction in HbA1c compared with the insulin glargine titration implemented in this study protocol (see Table 6).
Table 6. Results at Week 30 in a Trial of OZEMPIC Compared to Insulin Glargine in Adult Patients with Type 2 Diabetes Mellitus In Combination with Metformin or Metformin with Sulfonylurea
|
OZEMPIC
0.5 mg |
OZEMPIC
1 mg |
Insulin Glargine |
Intent-to-Treat (ITT) Population (N)a |
362 |
360 |
360 |
HbA1c (%) |
Baseline (mean) |
8.1 |
8.2 |
8.1 |
Change at week 30 b |
-1.2 |
-1.5 |
-0.9 |
Difference from placebo b
[95% CI] |
-0.3
[-0.5, -0.1]c |
-0.6
[-0.8, -0.4]c |
|
Patients (%) achieving HbA1c <7% |
55 |
66 |
40 |
Baseline (mean) |
172 |
179 |
174 |
Change at week 30 b |
-35 |
-46 |
-37 |
aThe intent-to-treat population includes all randomized and exposed patients. At week 30 the primary HbA1c endpoint was missing for 8%, 6% and 6% of patients and during the trial rescue medication was initiated by 4%, 3% and 1% of patients randomized to OZEMPIC 0.5 mg, OZEMPIC 1 mg and insulin glargine, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts.
bIntent-to-treat analysis using ANCOVA adjusted for baseline value, country and stratification factors.
cp<0.0001 (2-sided) for superiority, adjusted for multiplicity. |
The mean baseline body weight was 93.7 kg, 94.0 kg, 92.6 kg in the OZEMPIC 0.5 mg, OZEMPIC 1 mg, and insulin glargine arms, respectively. The mean changes from baseline to week 30 were -3.2 kg, -4.7 kg and 0.9 kg in the OZEMPIC 0.5 mg, OZEMPIC 1 mg, and insulin glargine arms, respectively. The difference from insulin glargine (95% CI) for OZEMPIC 0.5 mg was -4.1 kg (-4.9, -3.3) and for OZEMPIC 1 mg was -5.6 kg (6.4, -4.8).
Combination With Basal Insulin
In a 30-week, double-blind trial (NCT02305381), 397 patients with type 2 diabetes mellitus inadequately controlled with basal insulin, with or without metformin, were randomized to OZEMPIC 0.5 mg once weekly, OZEMPIC 1 mg once weekly, or placebo. Patients with HbA1c ≤ 8.0% at screening reduced their insulin dose by 20% at start of the trial to reduce the risk of hypoglycemia. Patients had a mean age of 59 years and 56% were men. The mean duration of type 2 diabetes was 13 years, and the mean BMI was 32 kg/m2. Overall, 78% were White, 5% were Black or African American, and 17% were Asian; 12% identified as Hispanic or Latino ethnicity.
Treatment with OZEMPIC resulted in a statistically significant reduction in HbA1c after 30 weeks of treatment compared to placebo (see Table 7).
Table 7. Results at Week 30 in a Trial of OZEMPIC in Adult Patients with Type 2 Diabetes Mellitus In Combination with Basal Insulin With or Without Metformin
|
Placebo |
OZEMPIC
0.5 mg |
OZEMPIC
1 mg |
Intent-to-Treat (ITT) Population (N)a |
133 |
132 |
131 |
HbA1c (%) |
Baseline (mean) |
8.4 |
8.4 |
8.3 |
Change at week 30 b |
-0.2 |
-1.3 |
-1.7 |
Difference from placebo b
[95% CI] |
|
-1.1
[-1.4, -0.8]c |
-1.6
[-1.8, -1.3]c |
Patients (%) achieving HbA1c <7% |
13 |
56 |
73 |
Baseline (mean) |
154 |
161 |
153 |
Change at week 30 b |
-8 |
-28 |
-39 |
aThe intent-to-treat population includes all randomized and exposed patients. At week 30 the primary HbA1c endpoint was missing for 7%, 5% and 5% of patients and during the trial rescue medication was initiated by 14%, 2% and 1% of patients randomized to placebo, OZEMPIC 0.5 mg and OZEMPIC 1 mg, respectively. Missing data were imputed using multiple imputation based on retrieved dropouts.
bIntent-to-treat analysis using ANCOVA adjusted for baseline value, country and stratification factors.
cp<0.0001 (2-sided) for superiority, adjusted for multiplicity. |
The mean baseline body weight was 89.9 kg, 92.7 kg, and 92.5 kg in the placebo, OZEMPIC 0.5 mg, and OZEMPIC 1 mg arms, respectively. The mean changes from baseline to week 30 were -1.2 kg, -3.5 kg, and -6.0 kg in the placebo, OZEMPIC 0.5 mg, and OZEMPIC 1 mg arms, respectively. The difference from placebo (95% CI) for OZEMPIC 0.5 mg was -2.2 kg (-3.4, -1.1), and for OZEMPIC 1 mg was -4.7 kg (-5.8, -3.6).
Cardiovascular Outcomes Trial Of OZEMPIC In Patients With Type 2 Diabetes Mellitus
SUSTAIN 6 (NCT01720446) was a 104-week, double-blind trial in which 3,297 patients with type 2 diabetes and high risk of cardiovascular events were randomized to OZEMPIC 0.5 mg once weekly, OZEMPIC 1 mg once weekly, or placebo in addition to standard-of-care. In total, 2,735 (83%) of the patients had a history of cardiovascular disease and 562 (17%) were at high risk but without known cardiovascular disease. The mean age at baseline was 65 years, and 61% were men. The mean duration of diabetes was 13.9 years, and mean BMI was 33 kg/m2. Overall, 83% were White, 7% were Black or African American, and 8% were Asian; 16% identified as Hispanic or Latino ethnicity. Concomitant diseases of patients in this trial included, but were not limited to, heart failure (24%), hypertension (93%), history of ischemic stroke (12%) and history of a myocardial infarction (33%).
In total, 98.0% of the patients completed the trial and the vital status was known at the end of the trial for 99.6%. The primary composite endpoint was the time from randomization to first occurrence of a major adverse cardiovascular event (MACE): cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. The secondary endpoint was time from randomization to first occurrence of an expanded composite cardiovascular outcome, defined as MACE, revascularization (coronary and peripheral), unstable angina requiring hospitalization or hospitalization for heart failure. The total number of primary component MACE endpoints was 254 (108 [6.6%] with OZEMPIC and 146 [8.9%] with placebo). No increased risk for MACE was observed with OZEMPIC.