Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, glucagon-like peptide-1 (GLP-1) analogues, ATC code: A10BJ06

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 in glucose and appetite regulation, and in the cardiovascular system. The glucose and appetite effects are specifically mediated via GLP-1 receptors in the pancreas and the brain.

Semaglutide reduces blood glucose in a glucose dependent manner by stimulating insulin secretion and lowering glucagon secretion when blood glucose is high. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase. During hypoglycaemia, semaglutide diminishes insulin secretion and does not impair glucagon secretion.

Semaglutide reduces body weight and body fat mass through lowered energy intake, involving an overall reduced appetite. In addition, semaglutide reduces the preference for high fat foods.

GLP-1 receptors are also expressed in the heart, vasculature, immune system and kidneys.
Semaglutide had a beneficial effect on plasma lipids, lowered systolic blood pressure and reduced inflammation in clinical studies. In animal studies, semaglutide attenuates the development of atherosclerosis by preventing aortic plaque progression and reducing inflammation in the plaque.

Pharmacodynamic effects
All pharmacodynamic evaluations were performed after 12 weeks of treatment (including dose escalation) at steady state with semaglutide 1 mg once weekly.

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 (mmol/L) and relative reduction compared to placebo (%) for fasting glucose (1.6 mmol/L; 22% reduction), 2 hour postprandial glucose (4.1 mmol/L; 37% reduction), mean 24 hour glucose concentration (1.7 mmol/L; 22% reduction) and postprandial glucose excursions over 3 meals (0.6-1.1 mmol/L) compared with placebo. Semaglutide lowered fasting glucose after the first dose.

Beta-cell function and insulin secretion
Semaglutide improves beta-cell function. Compared to placebo, semaglutide improved first- and second-phase insulin response with a 3– and 2–fold increase, respectively, and increased maximal 

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beta-cell secretory capacity in patients with type 2 diabetes. In addition, semaglutide treatment increased fasting insulin concentrations compared to placebo.

Glucagon secretion
Semaglutide lowers the fasting and postprandial glucagon concentrations. In patients with type 2 diabetes, semaglutide resulted in the following relative reductions in glucagon compared to placebo: fasting glucagon (8–21%), postprandial glucagon response (14–15%) and mean 24 hour glucagon concentration (12%).

Glucose dependent insulin and glucagon secretion
Semaglutide lowered 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 comparable to that of healthy subjects.

During induced hypoglycaemia, semaglutide compared to placebo did not alter the counter regulatory responses of increased glucagon and did not impair the decrease of C-peptide in patients with type 2-diabetes.

Gastric emptying
Semaglutide caused a minor delay of early postprandial gastric emptying, thereby reducing the rate at which glucose appears in the circulation postprandially.

Appetite, energy intake and food choice
Semaglutide compared to placebo lowered the energy intake of 3 consecutive ad libitum meals by 18-35%. This was supported by a semaglutide-induced suppression of appetite in the fasting state as well as postprandially, improved control of eating, less food cravings and a relative lower preference for high fat food.

Fasting and postprandial lipids
Semaglutide compared to placebo lowered fasting triglyceride and very low density lipoproteins (VLDL) cholesterol concentrations by 12% and 21%, respectively. The postprandial triglyceride and VLDL cholesterol response to a high fat meal was reduced by >40%.

Cardiac electrophysiology (QTc)
The effect of semaglutide on cardiac repolarization was tested in a thorough QTc trial. Semaglutide did not prolong QTc intervals at dose levels up to 1.5 mg at steady state.

Clinical efficacy and safety

Both improvement of glycaemic control and reduction of cardiovascular morbidity and mortality are an integral part of the treatment of type 2 diabetes.

The efficacy and safety of semaglutide 0.5 mg and 1 mg once weekly were evaluated in six randomised controlled phase 3a trials that included 7,215 patients with type 2 diabetes mellitus (4,107 treated with semaglutide). Five trials (SUSTAIN 1–5) had the glycaemic efficacy assessment as the primary objective, while one trial (SUSTAIN 6) had cardiovascular outcome as the primary objective.

In addition, a phase 3b trial (SUSTAIN 7) including 1,201 patients was conducted to compare the efficacy and safety of semaglutide 0.5 mg and 1 mg once weekly to dulaglutide 0.75 mg and 1.5 mg once weekly, respectively.
Treatment with semaglutide demonstrated sustained, statistically superior and clinically meaningful reductions in HbA1c and body weight for up to 2 years compared to placebo and active control treatment (sitagliptin, insulin glargine, exenatide ER and dulaglutide).


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The efficacy of semaglutide was not impacted by age, gender, race, ethnicity, BMI at baseline, body weight (kg) at baseline, diabetes duration and level of renal function impairment.

Results target the on-treatment period in all randomised subjects (analyses based on mixed models for repeated measurements or multiple imputation).

In addition, a phase 3b trial (SUSTAIN 11), was conducted to investigate the effect of semaglutide versus insulin aspart, both as add-on to metformin and optimised insulin glargine (U100).

Detailed information is provided below.

SUSTAIN 1 – Monotherapy
In a 30-week double-blind placebo-controlled trial, 388 patients inadequately controlled with diet and exercise, were randomised to semaglutide 0.5 mg or semaglutide 1 mg once weekly or placebo.

Table 2 SUSTAIN 1: Results at week 30
Semaglutide          Semaglutide          Placebo
0.5 mg                1 mg
Intent-to-Treat (ITT) Population (N)                128                  130                129 HbA1c (%)
Baseline (mean)                              8.1                  8.1               8.0 Change from baseline at week 30              -1.5                 -1.6               0 Difference from placebo [95%          -1.4 [-1.7, -1.1]a   -1.5 [-1.8, -1.2]a        - CI]
Patients (%) achieving HbA1c <7%                      74                   72                25 FPG (mmol/L)
Baseline (mean)                              9.7                 9.9               9.7 Change from baseline at week 30              -2.5                -2.3              -0.6 Body weight (kg)
Baseline (mean)                              89.8                 96.9             89.1 Change from baseline at week 30              -3.7                 -4.5             -1.0 Difference from placebo [95%          -2.7 [-3.9, -1.6]a   -3.6 [-4.7, -2.4]a        - CI] a p <0.0001 (2-sided) for superiority

SUSTAIN 2 – Semaglutide vs. sitagliptin both in combination with 1–2 oral antidiabetic medicinal products (metformin and/or thiazolidinediones)
In a 56-week active-controlled double-blind trial, 1,231 patients were randomised to semaglutide 0.5 mg once weekly, semaglutide 1 mg once weekly or sitagliptin 100 mg once daily, all in combination with metformin (94%) and/or thiazolidinediones (6%).

Table 3 SUSTAIN 2: Results at week 56
Semaglutide         Semaglutide         Sitagliptin
0.5 mg               1 mg              100 mg
Intent-to-Treat (ITT) Population (N)                 409                 409                 407 HbA1c (%)
Baseline (mean)                              8.0                  8.0              8.2 Change from baseline at week 56              -1.3                 -1.6             -0.5 Difference from sitagliptin [95%      -0.8 [-0.9, -0.6]a   -1.1 [-1.2, -0.9]a        - CI]
Patients (%) achieving HbA1c <7%                       69                  78                36 FPG (mmol/L)
Baseline (mean)                              9.3                 9.3               9.6 Change from baseline at week 56              -2.1                -2.6              -1.1 

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Body weight (kg)
Baseline (mean)                                                       89.9                                                  89.2                   89.3 Change from baseline at week 56                                       -4.3                                                  -6.1                   -1.9 Difference from sitagliptin [95%                               -2.3 [-3.1, -1.6]a                                    -4.2 [-4.9, -3.5]a              - CI] a p <0.0001 (2-sided) for superiority

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Time since randomisation (week)
Time since randomisation (week)
Semaglutide 0.5 mg    Semaglutide 1 mg                                                                    Semaglutide 0.5 mg    Semaglutide 1 mg Sitagliptin                                                                                               Sitagliptin 
Figure 1 Mean change in HbA1c (%) and body weight (kg) from baseline to week 56 
SUSTAIN 7 – Semaglutide vs. dulaglutide both in combination with metformin In a 40-week, open-label trial, 1,201 patients on metformin were randomised 1:1:1:1 to once weekly semaglutide 0.5 mg, dulaglutide 0.75 mg , semaglutide 1 mg or dulaglutide 1.5 mg, respectively. The trial compared 0.5 mg of semaglutide to 0.75 mg of dulaglutide and 1 mg of semaglutide to 1.5 mg of dulaglutide.

Gastrointestinal disorders were the most frequent adverse events, and occurred in similar proportion of patients receiving semaglutide 0.5 mg (129 patients [43%]), semaglutide 1 mg (133 [44%]), and dulaglutide 1.5 mg (143 [48%]); fewer patients had gastrointestinal disorders with dulaglutide 0.75 mg (100 [33%]).
At week 40, the increase in pulse rate for semaglutide (0.5 mg and 1 mg) and dulaglutide (0.75 mg and 1.5 mg) was 2.4, 4.0, and 1.6, 2.1, beats/min, respectively.

Table 4 SUSTAIN 7: Results at week 40
Semaglutide                                                      Semaglutide                    Dulaglutide           Dulaglutide 0.5 mg                                                          1 mg                         0.75 mg                1.5 mg Intent-to-Treat (ITT)                    301                                                            300                           299                    299 Population(N)
HbA1c (%)
Baseline (mean)                          8.3                                                                     8.2                      8.2                   8.2 Change from baseline at week 40          -1.5                                                                   -1.8                      -1.1                  -1.4 Difference from dulaglutide             -0.4b                                                                   -0.4c                       -                     - [95% CI]                            [-0.6, -0.2]a                                                           [-0.6, -0.3]a Patients (%) achieving HbA1c <7%          68                                                                     79                        52                   67 FPG (mmol/L)
Baseline (mean)                          9.8                                                                           9.8                9.7                   9.6 Change from baseline at week 40          -2.2                                                                          -2.8               -1.9                  -2.2 Body weight (kg)
Baseline (mean)                          96.4                                                                      95.5                  95.6                   93.4 Change from baseline at week 40          -4.6                                                                      -6.5                  -2.3                   -3.0 Difference from dulaglutide             -2.3b                                                                     -3.6c                    -                      - [95% CI]                             [-3.0, -1.5]a                                                             [-4.3, -2.8]a 

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a p <0.0001 (2-sided) for superiority b semaglutide 0.5 mg vs dulaglutide 0.75 mg c semaglutide 1 mg vs dulaglutide 1.5 mg
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Time since randomisation (week)
Time since randomisation (week)
Semaglutide 0.5 mg        Semaglutide 1 mg                                                                       Semaglutide 0.5 mg       Semaglutide 1 mg Dulaglutide 0.75 mg       Dulaglutide 1.5 mg                                                                     Dulaglutide 0.75 mg      Dulaglutide 1.5 mg 
Figure 2 Mean change in HbA1c (%) and body weight (kg) from baseline to week 40 
SUSTAIN 3 – Semaglutide vs. exenatide ER both in combination with metformin or metformin with sulfonylurea
In a 56-week open-label trial, 813 patients on metformin alone (49%), metformin with sulfonylurea (45%) or other (6%) were randomised to semaglutide 1 mg or exenatide ER 2 mg once weekly.


Table 5 SUSTAIN 3: Results at week 56
Semaglutide                                   Exenatide ER
1 mg                                           2 mg
Intent-to-Treat (ITT) Population (N)                                                                  404                                            405 HbA1c (%)
Baseline (mean)                                                                    8.4                                                          8.3 Change from baseline at week 56                                                    -1.5                                                         -0.9 Difference from exenatide [95% CI]                                          -0.6 [-0.8, -0.4]a                                                    - Patients (%) achieving HbA1c <7%                                                             67                                                           40 FPG (mmol/L)
Baseline (mean)                                                                                              10.6                               10.4 Change from baseline at week 56                                                                              -2.8                               -2.0 Body weight (kg)
Baseline (mean)                                                                    96.2                                                         95.4 Change from baseline at week 56                                                    -5.6                                                         -1.9 Difference from exenatide [95% CI]                                          -3.8 [-4.6, -3.0]a                                                    - a p <0.0001 (2-sided) for superiority

SUSTAIN 4 – Semaglutide vs. insulin glargine both in combination with 1–2 oral antidiabetic medicinal products (metformin or metformin and sulfonylurea)
In a 30-week open-label comparator trial 1,089 patients were randomised to semaglutide 0.5 mg once weekly, semaglutide 1 mg once weekly, or insulin glargine once-daily on a background of metformin (48%) or metformin and sulfonylurea (51%).

Table 6 SUSTAIN 4: Results at week 30
Semaglutide                  Semaglutide                  Insulin
0.5 mg                        1 mg                      Glargine
Intent-to-Treat (ITT) Population (N)                                                                                      362                          360                        360 HbA1c (%)
Baseline (mean)                                                                                                     8.1                           8.2                    8.1 

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Change from baseline at week 30                      -1.2                 -1.6                  -0.8 Difference from insulin glargine [95% CI]     -0.4 [-0.5, -0.2]a   -0.8 [-1.0, -0.7]a             - Patients (%) achieving HbA1c <7%                              57                   73                    38 FPG (mmol/L)
Baseline (mean)                                      9.6                  9.9                   9.7 Change from baseline at week 30                      -2.0                 -2.7                  -2.1 Body weight (kg)
Baseline (mean)                                      93.7                 94.0                  92.6 Change from baseline at week 30                      -3.5                 -5.2                  +1.2 Difference from insulin glargine [95% CI]     -4.6 [-5.3, -4.0]a   -6.34 [-7.0, -5.7]a           - a p <0.0001 (2-sided) for superiority

SUSTAIN 5 – Semaglutide vs. placebo both in combination with basal insulin In a 30-week double-blind placebo-controlled trial, 397 patients inadequately controlled with basal insulin with or without metformin were randomised to semaglutide 0.5 mg once weekly, semaglutide 1 mg once weekly or placebo.

Table 7 SUSTAIN 5: Results at week 30
Semaglutide             Semaglutide          Placebo
0.5 mg                   1 mg
Intent-to-Treat (ITT) Population (N)               132                     131                   133 HbA1c (%)
Baseline (mean)                             8.4                    8.3                  8.4 Change from baseline at week 30             -1.4                   -1.8                 -0.1 Difference from placebo [95%         -1.4 [-1.6, -1.1]a     -1.8 [-2.0, -1.5]a            - CI]
Patients (%) achieving HbA1c <7%                     61                     79                   11 FPG (mmol/L)
Baseline (mean)                             8.9                   8.5                   8.6 Change from baseline at week 30             -1.6                  -2.4                  -0.5 Body weight (kg)
Baseline (mean)                             92.7                   92.5                 89.9 Change from baseline at week 30             -3.7                   -6.4                 -1.4 Difference from placebo [95%         -2.3 [-3.3, -1.3]a     -5.1 [-6.1, -4.0]a            - CI] a p <0.0001 (2-sided) for superiority

SUSTAIN 11 - Semaglutide vs. insulin aspart as add-on to insulin glargine + metformin In a 52-week open-label trial, 1748 subjects with inadequately controlled T2D after a 12-week run-in period on insulin glargine and metformin were randomised to 1:1 to receive either semaglutide once- weekly (0.5 mg or 1.0 mg) or insulin aspart three times daily. The included population had a mean diabetes duration of 13.4 years and a mean HbA1c of 8.6%, with a target HbA1c of 6.5-7.5%.

Treatment with semaglutide resulted in reduction in HbA1c at week 52 (-1.5% for semaglutide vs. - 1.2% for insulin aspart).

The number of severe hypoglycaemic episodes in both treatment arms was low (4 episodes with semaglutide vs. 7 episodes with insulin aspart).

Mean baseline body weight decreased with semaglutide (-4.1 kg) and increased with insulin aspart (+2.8 kg) and the estimated treatment difference was -6.99 kg (95%CI -7.41 to -6.57) at week 52.

Combination with sulfonylurea monotherapy


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In SUSTAIN 6 (see subsection “Cardiovascular disease”) 123 patients were on sulfonylurea monotherapy at baseline. HbA1c at baseline was 8.2%, 8.4% and 8.4% for semaglutide 0.5 mg, semaglutide 1 mg, and placebo, respectively. At week 30, the change in HbA1c was -1.6%, -1.5% and 0.1% for semaglutide 0.5 mg, semaglutide 1 mg, and placebo, respectively.

Combination with premix insulin ± 1–2 OADs
In SUSTAIN 6 (see subsection “Cardiovascular disease”) 867 patients were on premix insulin (with or without OAD(s)) at baseline. HbA1c at baseline was 8.8%, 8.9% and 8.9% for semaglutide 0.5 mg, semaglutide 1 mg, and placebo, respectively. At week 30, the change in HbA1c was -1.3%, -1.8% and - 0.4% for semaglutide 0.5 mg, semaglutide 1 mg, and placebo, respectively.

Cardiovascular disease
In a 104-week double-blind trial (SUSTAIN 6), 3,297 patients with type 2 diabetes mellitus at high cardiovascular risk were randomised to either semaglutide 0.5 mg once weekly, semaglutide 1 mg once weekly or corresponding placebo in addition to standard-of-care hereafter followed for 2 years.
In total 98% of the patients completed the trial and the vital status was known at the end of the trial for 99.6% of the patients.

The trial population was distributed by age as: 1,598 patients (48.5%) ≥65 years, 321 (9.7%) ≥75 years, and 20 (0.6%) ≥85 years. There were 2,358 patients with normal or mild renal impairment, 832 with moderate and 107 with severe or end stage renal impairment. There were 61% males, the mean age was 65 years and mean BMI was 33 kg/m2. The mean duration of diabetes was 13.9 years.

The primary endpoint was time from randomisation to first occurrence of a major adverse cardiovascular event (MACE): cardiovascular death, non-fatal myocardial infarction or non-fatal stroke.

The total number of primary component MACE endpoints was 254, including 108 (6.6%) with semaglutide and 146 (8.9%) with placebo. See figure 4 for results on primary and secondary cardiovascular endpoints. Treatment with semaglutide resulted in a 26% risk reduction in the primary composite outcome of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke. The total numbers of cardiovascular deaths, non-fatal myocardial infarctions and non-fatal strokes were 90, 111, and 71, respectively, including 44 (2.7%), 47 (2.9%), and 27 (1.6%), respectively, with semaglutide (figure 4). The risk reduction in the primary composite outcome was mainly driven by decreases in the rate of non-fatal stroke (39%) and non-fatal myocardial infarction (26%) (figure 3).



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Patients with event (%)



HR: 0.74
95% CI 0.58: 0.95
Number of subjects at risk
Semaglutide
Placebo


Time from randomisation (week)
Semaglutide               Placebo


Figure 3 Kaplan-Meier plot of time to first occurrence of the composite outcome: cardiovascular death, non-fatal myocardial infarction or non-fatal stroke (SUSTAIN 6) 
Hazard Ratio     Semaglutide Placebo
(95% CI)          N (%)      N (%)

1648       1649
FAS                                                                                    (100)      (100) 0.74           108        146
Primary endpoint – MACE                                              (0.58- 0.95)      (6.6)      (8.9) Components of MACE
0.98           44         46
Cardiovascular death                                               (0.65-1.48)                  (2.8) (2.7)
0.61           27         44
Non-fatal stroke                                                   (0.38-0.99)       (1.6)      (2.7) 0.74           47         64
Non-fatal myocardial infarction
(0.51-1.08)       (2.9)      (3.9)
Other secondary endpoints
1.05           62         60
All cause death                                                    (0.74-1.50)       (3.8)      (3.6) 

0.2               1                   5
Favours Semaglutide               Favours placebo


Figure 4 Forest plot: analyses of time to first occurrence of the composite outcome, its components and all cause death (SUSTAIN 6)

There were 158 events of new or worsening nephropathy. The hazard ratio [95% CI] for time to nephropathy (new onset of persistent macroalbuminuria, persistent doubling of serum creatinine, need for continuous renal replacement therapy and death due to renal disease) was 0.64 [0.46; 0.88] driven by new onset of persistent macroalbuminuria.

Body weight



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After one year of treatment, a weight loss of ≥5% and ≥10% was achieved for more subjects with semaglutide 0.5 mg (46% and 13%) and 1 mg (52 – 62% and 21 – 24%) compared with the active comparators sitagliptin (18% and 3%) and exenatide ER (17% and 4%).

In the 40-week trial versus dulaglutide a weight loss of ≥5% and ≥10% was achieved for more subjects with semaglutide 0.5 mg (44% and 14%) compared with dulaglutide 0.75 mg (23% and 3%) and semaglutide 1 mg (up to 63% and 27%) compared with dulaglutide 1.5 mg (30% and 8%).

A significant and sustained reduction in body weight from baseline to week 104 was observed with semaglutide 0.5 mg and 1 mg vs placebo 0.5 mg and 1 mg, in addition to standard-of-care (-3.6 kg and -4.9 kg vs -0.7 kg and -0.5 kg , respectively) in SUSTAIN 6.

Blood pressure
Significant reductions in mean systolic blood pressure were observed when semaglutide 0.5 mg (3.5-5.1 mmHg) and 1 mg (5.4–7.3 mmHg) were used in combination with oral antidiabetic medicinal products or basal insulin. For diastolic blood pressure, there were no significant differences between semaglutide and comparators. The observed reductions in systolic blood pressure for semaglutide 1 mg at week 40 were 4.5 mmHg.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Compared to native GLP-1, semaglutide has a prolonged half-life of around 1 week making it suitable for once weekly subcutaneous administration. The principal mechanism of protraction is albumin binding, which results in decreased renal clearance and protection from metabolic degradation.
Furthermore, semaglutide is stabilised against degradation by the DPP-4 enzyme.

Absorption
Maximum concentration was reached 1 to 3 days post dose. Steady state exposure was achieved following 4–5 weeks of once weekly administration. In patients with type 2 diabetes, the mean steady state concentrations following subcutaneous administration of 0.5 mg and 1 mg semaglutide were approximately 16 nmol/L and 30 nmol/L, respectively. Semaglutide exposure increased in a dose proportional manner for doses of 0.5 mg and 1 mg. Similar exposure was achieved with subcutaneous administration of semaglutide in the abdomen, thigh, or upper arm. Absolute bioavailability of subcutaneous semaglutide was 89%.

Distribution
The mean volume of distribution of semaglutide following subcutaneous administration in patients with type 2 diabetes was approximately 12.5 L. Semaglutide was extensively bound to plasma albumin (>99%).

Biotransformation
Prior to excretion, semaglutide is extensively metabolised through proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid sidechain. The enzyme neutral endopeptidase (NEP) is expected to be involved in the metabolism of semaglutide.

Elimination
In a trial with a single subcutaneous dose of radiolabelled semaglutide, it was found that the primary excretion routes of semaglutide-related material were via urine and faeces; approximately 2/3 of semaglutide-related material were excreted in urine and approximately 1/3 in faeces. Approximately 3% of the dose was excreted as intact semaglutide via urine. In patients with type 2 diabetes clearance of semaglutide was 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.

Special population


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Elderly
Age had no effect on the pharmacokinetics of semaglutide based on data from phase 3a studies including patients of 20–86 years of age.

Gender, race and ethnicity
Gender, race (White, Black or African-American, Asian) and ethnicity (Hispanic or Latino, non- Hispanic or -Latino) had no effect on the pharmacokinetics of semaglutide.

Body weight
Body weight has an effect on the exposure of semaglutide. Higher body weight results in lower exposure; a 20% difference in body weight between individuals will result in an approximate 16% difference in exposure. Semaglutide doses of 0.5 mg and 1 mg provide adequate systemic exposure over a body weight range of 40–198 kg.

Renal impairment
Renal impairment did not impact the pharmacokinetics of semaglutide in a clinically relevant manner.
This was shown with a single dose of 0.5 mg semaglutide for patients with different degrees of renal impairment (mild, moderate, severe or patients in dialysis) compared with subjects with normal renal function. This was also shown for subjects with type 2 diabetes and with renal impairment based on data from phase 3a studies, although the experience in patients with end-stage renal disease was limited.

Hepatic impairment
Hepatic impairment did 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 trial with a single-dose of 0.5 mg semaglutide.


Immunogenicity
Development of anti-semaglutide antibodies when treated with semaglutide 1 mg occurred infrequently (see section 4.8) and the response did not appear to influence semaglutide pharmacokinetics.