Semavik®

Pharmacodynamics

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 blood glucose levels

Semaglutide decreases fasting and postprandial glucose concentrations. Compared to placebo, therapy with semaglutide 1 mg in patients with type 2 diabetes mellitus (T2D) resulted in a decrease in glucose concentrations in terms of absolute change from baseline (mmol/L) and relative decrease compared to placebo (%) in terms of: fasting glucose concentrations (1.6 mmol/L; 22 %); glucose concentrations 2 hours after eating (4.1 mmol/L; 37 %); mean daily glucose concentration (1.7 mmol/L; 22 %); and postprandial peak glucose concentrations for 3 meals (0.6–1.1 mmol/L). Semaglutide lowered fasting glucose after the first dose.

Pancreatic beta cell function and insulin secretion

Semaglutide improves pancreatic beta cell function. After intravenous bolus infusion of glucose to patients with T2D, compared to placebo, semaglutide improved the first and second phase insulin release with a 3- and 2-fold increase, respectively, and increased the maximum secretory activity of pancreatic beta cells following an arginine stimulation test. In addition, compared to placebo, therapy with semaglutide increases fasting insulin concentrations.

Glucagon secretion

Semaglutide decreases fasting and postprandial glucagon concentrations. In patients with T2D, semaglutide induces a relative decrease in glucagon concentrations compared to placebo: fasting glucagon concentrations (8–21 %), postprandial glucagon secretion (14–15 %), and mean daily glucagon concentrations (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 T2D patients was comparable to that of healthy volunteers.

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

Body weight and constitution

Greater weight loss was observed with semaglutide compared to other studied comparators (placebo, sitagliptin, extended release exenatide, dulaglutide and insulin glargine) (see Clinical Efficacy and Safety). The body weight loss with semaglutide is mostly due to the fat tissue loss 3 times greater than the muscle tissue loss.

Appetite, energy intake and food choice

Semaglutide compared to placebo lowered the energy intake of three 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

Compared to placebo, semaglutide decreased fasting triglyceride and very low-density lipoprotein (VLDL) cholesterol concentrations by 12 % and 21 %, respectively. In response to a high-fat meal, increased postprandial triglyceride and VLDL cholesterol concentrations were lowered by more than 40 %.

Cardiac electrophysiology (CEP)

The effect of semaglutide on cardiac repolarisation was tested in the CEP study. Semaglutide did not prolong corrected QT intervals at dose levels higher than therapeutic doses (up to 1.5 mg at steady state).

Clinical efficacy and safety

The integral part of T2D therapy is to improve the glycaemic control and decrease the incidence of CV diseases.

The efficacy and safety of semaglutide at 0.5 mg and 1 mg doses were evaluated in six randomised controlled phase 3a trials. Five trials had the glycaemic efficacy assessment as the primary objective, while one trial had cardiovascular outcome as the primary objective. Additionally, two phase 3 trials of semaglutide were conducted in Japanese patients.

In addition, a phase 3b trial 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. Also, a phase 3b trial was conducted to investigate the efficacy and safety of semaglutide as add-on to therapy with sodium glucose cotransporter 2 (SGLT2) inhibitor.

Treatment with semaglutide demonstrated sustained, statistically superior and clinically significant 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).

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

Monotherapy

Semaglutide monotherapy at doses of 0.5 mg and 1 mg once weekly for 30 weeks versus placebo resulted in statistically more significant reductions in HbA1c (-1.5 %, -1.6 % vs. 0 %, respectively), fasting plasma glucose (FPG) (-2.5 mmol/L, -2.3 mmol/L vs. -0.6 mmol/L, respectively), and body weight (-3.7 kg, -4.5 kg vs. -1.0 kg, respectively).

Semaglutide vs. sitagliptin both in combination with 1–2 oral antidiabetic medicinal products (OAD2) (metformin and/or thiazolidinediones)

Therapy with semaglutide 0.5 mg and 1 mg once weekly for 56 weeks versus sitagliptin resulted in sustained and statistically more significant reductions in HbA1c (-1.3 %, -1.6 % vs. -0.5 %, respectively), FPG (-2.1 mmol/L, -2.6 mmol/L vs. -1.1 mmol/L, respectively), and body weight (-4.3 kg, -6.1 kg vs. -1.9 kg, respectively). Therapy with semaglutide 0.5 mg and 1 mg versus sitagliptin significantly decreased systolic BP from 132.6 mmHg at baseline (-5.1 mmHg, -5.6 mmHg vs. -2.3 mmHg, respectively). No changes in diastolic BP were observed.

Semaglutide vs. dulaglutide both in combination with metformin

Therapy with semaglutide 0.5 mg versus dulaglutide 0.75 mg, both once a week for 40 weeks, resulted in sustained and statistically superior reductions in HbA1c (-1.5 % vs. -1.1 %), FPG (-2.2 mmol/L vs. -1.9 mmol/L), and body weight (-4.6 kg vs. -2.3 kg), respectively.

Therapy with semaglutide 1 mg versus dulaglutide 1.5 mg, both once weekly for 40 weeks, resulted in sustained and statistically superior reductions in HbA1c (-1.8 % vs. -1. %), FPG (-2.8 mmol/L vs. -2.2 mmol/L), and body weight (-6.5 kg vs. -3.0 kg), respectively.

Semaglutide versus exenatide ER, both in combination with metformin or metformin and a sulfonylurea derivative

Therapy with semaglutide 1 mg once weekly for 56 weeks versus exenatide ER 2.0 mg resulted in sustained and statistically more significant reductions in HbA1c (-1.5 % vs. -0.9 %), FPG (-2.8 mmol/L vs. -2.0 mmol/L), and body weight (-5.6 kg vs. -1.9 kg), respectively.

Semaglutide versus insulin glargine, both in combination with 1–2 oral antidiabetic medicinal products (metformin monotherapy or metformin and a sulfonylurea derivative)

Therapy with semaglutide at doses of 0.5 mg and 1 mg once weekly versus insulin glargine for 30 weeks resulted in statistically more significant reductions in HbA1c (-1.2 %, -1.6 % vs. -0.8 %, respectively), and body weight (-3.5 kg, -5.2 kg vs. +1.2 kg, respectively).

The reduction in FPG was statistically more significant for semaglutide 1 mg versus insulin glargine (-2.7 mmol/L vs. -2.1 mmol/L). No statistically more significant reduction in FPG was observed for semaglutide 0.5 mg (-2.0 mmol/L vs. -2.1 mmol/L). The proportion of patients who experienced severe or confirmed (<3.1 mmol/L) episodes of hypoglycaemia was lower when using semaglutide 0.5 mg (4.4 %) and semaglutide 1 mg (5.6 %) versus insulin glargine (10.6 %).

More patients achieved HbA1c <7 % without severe or confirmed episodes of hypoglycaemia and without weight gain when using semaglutide 0.5 mg (47 %) and semaglutide 1 mg (64 %) versus insulin glargine (16 %).

Semaglutide vs. placebo both in combination with basal insulin

Therapy with semaglutide at doses of 0.5 mg and 1 mg versus placebo for 30 weeks resulted in statistically more significant reductions in HbA1c (-1.4 %, -1.8 % vs. -0.1 %, respectively), FPG (-1.6 mmol/L, -2.4 mmol/L vs. -0.5 mmol/L, respectively), and body weight (-3.7 kg, -6.4 kg vs. -1.4 kg, respectively). The incidence of severe and confirmed hypoglycaemia episodes did not significantly differ between semaglutide and placebo exposure. The percentage of patients with the HbA1c level ≤8 % at screening who reported on severe or confirmed (<3.1 mmol/L) hypoglycaemic episodes was higher with administration of semaglutide compared to placebo and comparable in patients with the HbA1c level >8 % at screening

Semaglutide versus placebo as an add-on to SGLT2 inhibitor therapy (as monotherapy or in combination with a sulfonylurea derivative or metformin)

Therapy with semaglutide at a dose of 1 mg once a week as an add-on to SGLT2 inhibitor therapy (as monotherapy or in combination with a sulfonylurea derivative or metformin) versus placebo once a week for 30 weeks resulted in statistically significant reductions in HbA1c (-1.5 % vs -0.1 %, respectively), FPG (-2.2 mmol/L vs. 0 mmol/L, respectively), and body weight (-4.7 kg vs. -0.9 kg, respectively).

Combination with sulfonylurea derivative monotherapy

On week 30 of the trial (see Subsection “Assessment of Effect on CVS”) a subset of 123 patients on sulfonylurea derivative monotherapy was evaluated. On week 30, HbA1c decreased by 1.6 % and 1.5 % with semaglutide at doses of 0.5 mg and 1 mg, respectively, and increased by 0.1 % with placebo.

Combination with premix insulin ±1–2 oral antidiabetic medicinal products

On week 30 of the trial (see Subsection “Assessment of Effect on CVS”) a subset of 867 patients on therapy with premixed insulin (with or without 1–2 oral antidiabetic medicinal products) was evaluated. On week 30, HbA1c decreased by 1.3 % and 1.8 % with semaglutide at doses of 0.5 mg and 1 mg, respectively, and increased by 0.4 % with placebo.

Ratio of patients who achieved the target reduction in HbA1c

Up to 79 % of patients achieved the treatment goal to reduce HbA1c by <7 %. The proportion of such patients was significantly higher with semaglutide versus the proportion of patients treated with sitagliptin, exenatide ER, insulin glargine, dulaglutide or placebo.

The proportion of patients achieving HbA1c of less than 7 % without severe or confirmed episodes of hypoglycaemia and without weight gain was significantly higher with semaglutide at doses of 0.5 mg and 1 mg (up to 66 % and 74 %, respectively) versus patients treated with sitagliptin (27 %), exenatide ER (29 %), insulin glargine (16%), dulaglutide 0.75 mg (44 %) and dulaglutide 1.5 mg (58 %).

Body weight

Monotherapy with semaglutide 1 mg or therapy in combination with 1–2 medicinal products resulted in statistically greater body weight loss (loss of up to 6.5 kg) versus therapy with placebo, sitagliptin, exenatide ER, insulin glargine or dulaglutide. The reduction in body weight was sustained for up to 2 years.

After one year of therapy, more patients receiving semaglutide 0.5 mg (46% and 13 %) and 1 mg (up to 62 % and 24 %) achieved ≥5 % and ≥10 % weight loss versus patients on therapy with the active comparators — sitagliptin and exenatide ER (up to 18 % and 4 %).

In the 40-week trial, more patients receiving semaglutide 0.5 mg achieved weight loss of ≥5 % and ≥10 % (44 % and 14 %) versus patients receiving dulaglutide 0.75 mg (23 % and 3 %). More patients receiving semaglutide 1 mg achieved weight loss of ≥5 % and ≥10 % (up to 63 % and 27 %) versus patients receiving dulaglutide 1.5 mg (30 % and 8 %).

In the CV trial, weight loss of ≥5 % and ≥10 % was achieved by more patients receiving semaglutide 0.5 mg (36 % and 13 %) and semaglutide 1 mg (47 % and 20 %) versus patients receiving placebo 0.5 mg (18 % and 6 %) and placebo 1 mg (19 % and 7 %).

FPG and postprandial increase in glucose level

At all three daily meals, semaglutide 0.5 mg and 1 mg demonstrated significant reductions in FPG to 2.8 mmol/L and reduced postprandial increases in glucose level to 1.2 mmol/L (the difference between pre- and post-meal values obtained after three meals) (see Pharmacodynamics section for further details).

Pancreatic beta-cell function and insulin resistance

Therapy with semaglutide 0.5 mg and 1 mg improved pancreatic beta-cell function and reduced insulin resistance, as confirmed by evaluation of homeostatic models of pancreatic beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) (see the Pharmacodynamics section for further details).

Lipids

During the semaglutide trials, improvements in fasting blood lipid profile were observed, predominantly in the group receiving semaglutide 1 mg (see the Pharmacodynamics section for further details).

Assessment of Effect on CVS

A total of 3,297 patients with T2D and high risk of CVD were randomised in 104-week double-blind trial to receive either semaglutide 0.5 mg/1 mg once weekly or placebo 0.5 mg/1 mg as an add-on to the conventional therapy of CVD for the next two years.

Semaglutide therapy resulted in a 26 % reduction in the risk of the primary combined outcome, which included CV death, nonfatal myocardial infarction (MI), and nonfatal stroke. This lower risk was principally driven by a significant decrease in the incidence of nonfatal stroke (39 %) and a nonsignificant decrease in nonfatal MI (26 %) but without significant difference in the rate of CV death.

The risk of coronary or peripheral arterial revascularisation was significantly decreased, while the risk of unstable angina requiring hospitalisation and the risk of hospitalisation due to heart insufficiency were modestly decreased. Microcirculatory disorders included 158 new or worsed cases of nephropathy. The relative risk with respect to time to the onset of nephropathy (new cases of persistent macroalbuminuria, persistent doubling of serum creatinine levels, need for chronic renal replacement therapy, and death due to kidney disease) was 0.64.

Semaglutide 0.5 mg and 1 mg adjunct to the standard cardiovascular therapy significantly decreased and sustained HbA1c from baseline to week 104 (-1.1 % and -1.4versus -0.4% and -0.4 %, respectively).

Blood pressure

There was a significant reduction in mean systolic BP when semaglutide 0.5 mg (3.5–5.1 mmHg) and semaglutide 1 mg (5.4–7.3 mmHg) were used in combination with oral antidiabetic medicinal products or basal insulin. No significant difference in diastolic BP was observed between semaglutide and the comparators.

Semavik®

The pen injector is a prefilled disposable pen injector for multiple injections (“pen injector”) with semaglutide, an antidiabetic drug, glucagon-like peptide-1 (GLP-1) analogue.