Ozempic 1 mg solution for injection in pre-filled pen - Summary of Product Characteristics (SmPC) (2023)

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 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.

The efficacy and safety of semaglutide 2 mg once weekly was evaluated in a phase 3b trial (SUSTAIN FORTE) including 961 patients.

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. A phase 3b trial (SUSTAIN 9), was conducted to investigate the efficacy and safety of semaglutide as add-on to SGLT2 inhibitor treatment.

Treatment with semaglutide demonstrated sustained, statistically superior and clinically meaningful reductions in HbA_1c and body weight for up to 2 years compared to placebo and active control treatment (sitagliptin, insulin glargine, exenatide ER and dulaglutide).

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).

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

^ap <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

^ap <0.0001 (2-sided) for superiority

Figure 1 Mean change in HbA_1c (%) 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

^ap <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

Figure 2 Mean change in HbA_1c (%) 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

^ap <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

^ap <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

^ap <0.0001 (2-sided) for superiority

SUSTAIN FORTE – Semaglutide 2 mg vs. semaglutide 1 mg

In a 40-week double-blind trial, 961 patients inadequately controlled with metformin with or without sulfonylurea were randomised to semaglutide 2 mg once weekly or semaglutide 1 mg once weekly.

Treatment with semaglutide 2 mg resulted in a statistically superior reduction in HbA_1c after 40 weeks of treatment compared to semaglutide 1 mg.

Table 8 SUSTAIN FORTE: Results at week 40

^ap<0.001 (2-sided) for superiority

^bp<0.05 (2-sided) for superiority

SUSTAIN 9 – Semaglutide vs. placebo as add-on to SGLT2 inhibitor ± metformin or sulfonylurea

In a 30-week double-blind placebo-controlled trial, 302 patients inadequately controlled with SGLT2 inhibitor with or without metformin or sulfonylurea were randomised to semaglutide 1 mg once weekly or placebo.

Table 9 SUSTAIN 9: Results at week 30

^ap < 0.0001 (2-sided) for superiority, adjusted regarding multiplicity based on hierarchical testing of the HbA_1c value and body weight

Combination with sulfonylurea monotherapy

In SUSTAIN 6 (see subsection “Cardiovascular disease”) 123 patients were on sulfonylurea monotherapy at baseline. HbA_1c 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 HbA_1c 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. HbA_1c 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 HbA_1c 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).

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)

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

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 2 mg and 1 mg at week 40 were 5.3 mmHg and 4.5 mmHg, respectively.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Ozempic in one or more subsets of the paediatric population in type 2 diabetes (see section 4.2 for information on paediatric use).