LYXUMIA Solution for injection Ref.[8550] Active ingredients: Lixisenatide

Pharmacotherapeutic group: Drugs used in Diabetes, Glucagon-like peptide-1 (GLP-1) analogues
ATC code: A10BJ03

Mechanism of action

Lixisenatide is a selective GLP-1 receptor agonist. The GLP-1 receptor is the target for native GLP-1, an endogenous incretin hormone that potentiates glucose-dependent insulin secretion from the pancreatic beta cells.

Lixisenatide action is mediated via a specific interaction with GLP-1 receptors, leading to an increase in intracellular cyclic adenosine monophosphate (cAMP). Lixisenatide stimulates insulin secretion when blood glucose is increased but not at normoglycaemia, which limits the risk of hypoglycaemia.

In parallel, glucagon secretion is suppressed. In case of hypoglycaemia, the rescue mechanism of glucagon secretion is preserved.

Lixisenatide slows gastric emptying thereby reducing the rate at which meal-derived glucose appears in the circulation.

Pharmacodynamic effects

When administered once daily, lixisenatide improves glycaemic control through the immediate and sustained effects of lowering both post-prandial and fasting glucose concentrations in patients with type 2 diabetes.

This effect on post-prandial glucose was confirmed in a 4-week study versus liraglutide 1.8 mg once a day in combination with metformin. Reduction from baseline in the AUC_0:30-4:30h of plasma glucose after a test-meal was: -12.61 h*mmol/L (-227.25 h*mg/dl) in the lixisenatide group and -4.04 h*mmol/L (-72.83 h*mg/dl) in the liraglutide group. This was also confirmed in an 8-week study versus liraglutide, administered before breakfast, in combination with insulin glargine with or without metformin.

Clinical efficacy and safety

The clinical efficacy and safety of Lyxumia were evaluated in nine randomised double-blind, placebo-controlled clinical studies including 4,508 patients with type 2 diabetes (2,869 patients randomised to lixisenatide, 47.5% men and 52.5% women, and 517 were ≥65 years of age).

Efficacy of Lyxumia was also assessed in two randomised, open-label, active-controlled study (versus exenatide or versus insulin glulisine) and in a meal time study (in total 1,067 patients randomised to lixisenatide).

Efficacy and safety of Lyxumia in patients older than 70 years was addressed in a specifically dedicated placebo-controlled study (176 patients randomised to lixisenatide, including 62 patients ≥75 years of age).

In addition, a double-blind, placebo-controlled cardiovascular outcome study (ELIXA) enrolled 6,068 type 2 diabetes patients with previous acute coronary syndrome (3,034 randomised to lixisenatide, including 198 patients ≥75 years of age and 655 patients with moderate renal impairment).

In the completed Phase III studies, it was observed that approximately 90% of the patients were able to remain on the once daily maintenance dose of 20 mcg Lyxumia at the end of the main 24-week treatment period.

Glycaemic control

Add-on combination therapy with oral antidiabetics

Lyxumia in combination with metformin, a sulphonylurea, pioglitazone or a combination of these agents showed statistically significant reductions in HbA_1c, in fasting plasma glucose and in 2-hour post-prandial glucose after a test-meal compared to placebo at the end of the main 24-week treatment period (tables 2 and 3). The HbA_1c reduction was significant with once-daily administration, whether administered morning or evening.

This effect on HbA_1c was sustained in long term studies for up to 76 weeks.

Add-on treatment to metformin alone

Table 2. Placebo-controlled studies in combination with metformin (24-week results):

In an active-controlled study, Lyxumia once daily showed an HbA_1c reduction of -0.79% compared to -0.96% with exenatide twice daily at the end of the main 24-week treatment period with a mean treatment difference of 0.17% (95% CI: 0.033, 0.297) and a similar percentage of patients achieved an HbA_1c less than 7% in the lixisenatide group (48.5%) and in the exenatide group (49.8%). The incidence of nausea was 24.5% in the lixisenatide group compared to 35.1% in the exenatide twice daily group and the incidence of symptomatic hypoglycaemia with lixisenatide was 2.5% during the 24-week main treatment period compared to 7.9% in the exenatide group.

In a 24-week open-label study, lixisenatide administered before the main meal of the day was non-inferior to lixisenatide administered before breakfast in terms of HbA_1c reduction (LS mean change from baseline: -0.65% versus -0.74%). Similar HbA_1c decreases were observed regardless of which meal was the main meal (breakfast, lunch or dinner). At the end of the study, 43.6% (main meal group) and 42.8% (breakfast group) of patients achieved an HbA_1c less than 7%. Nausea was reported in 14.7% and 15.5% of patients, and symptomatic hypoglycaemia in 5.8% and 2.2% of patients, main meal group and breakfast group, respectively.

Add-on treatment to a sulphonylurea alone or in combination with metformin

Table 3. Placebo-controlled study in combination with a sulphonylurea (24-week results):

Add-on treatment to pioglitazone alone or in combination with metformin

In a clinical study, the addition of lixisenatide to pioglitazone with or without metformin, in patients not adequately controlled with pioglitazone, resulted in an HbA_1c decrease from baseline of 0.90%, compared to a decrease from baseline of 0.34% in the placebo group at the end of the 24-week main treatment period. At the end of the 24-week main treatment period, 52.3% of the lixisenatide patients achieved an HbA_1c less than 7% compared to 26.4% in the placebo group.

During the 24-week main treatment period, nausea was reported in 23.5% in the lixisenatide group compared to 10.6% in the placebo group and symptomatic hypoglycaemia was reported in 3.4% of the lixisenatide patients compared to 1.2% in the placebo group.

Add-on combination therapy with a basal insulin

Lyxumia given with a basal insulin alone, or with a combination of a basal insulin and metformin, or a combination of a basal insulin and a sulphonylurea resulted in statistically significant reductions in HbA_1c and in 2-hour post-prandial glucose after a test-meal compared to placebo.

Table 4. Placebo-controlled studies in combination with a basal insulin (24-week results):

* performed in Asian population

A clinical study was conducted in insulin-naive patients insufficiently controlled on oral antidiabetic agents. This study consisted of a 12-week run-in period with introduction and titration of insulin glargine and of a 24-week treatment period during which patients receive either lixisenatide or placebo in combination with insulin glargine and metformin with or without thiazolidinediones. Insulin glargine was continuously titrated during this period. During the 12-week run-in period, addition and titration of insulin glargine resulted approximately in an HbA_1c decrease of 1%. The addition of lixisenatide led to a significantly greater HbA_1c decrease of 0.71% in the lixisenatide group compared to 0.40% in the placebo group. At the end of the 24-week treatment period, 56.3% of the lixisenatide patients achieved an HbA_1c less than 7% compared to 38.5% in the placebo group.

During the 24-week treatment period, 22.4% lixisenatide patients reported at least one symptomatic hypoglycaemic event compared to 13.5% in the placebo group. The incidence of hypoglycaemia was mainly increased in the lixisenatide group during the first 6 weeks of treatment and thereafter, was similar to the placebo group.

Patients with type 2 diabetes with basal insulin combined with 1-3 oral anti-diabetic agents were enrolled in an open-label randomised study for insulin intensification. After 12-week of optimal insulin glargine titration with or without metformin, inadequately controlled patients were randomised to add single dose of lixisenatide or a single dose (QD) of insulin glulisine (both before the largest meal) or insulin glulisine administered three times a day (TID) for 26 weeks.

The level of HbA_1c reduction was comparable between groups (table 5).

As opposed to both insulin glulisine treatment regimens, lixisenatide reduced body weight (table 5). The rate of symptomatic hypoglycaemic events was lower with lixisenatide (36%) compared to insulin glulisine QD and TID (47% and 52%, respectively).

Table 5. Active-controlled study in combination with basal insulin with or without metformin (26-week results) - (mITT) and safety population:

* p<0.0001

Fasting plasma glucose The reductions in fasting plasma glucose obtained with Lyxumia treatment ranged from 0.42 mmol/L to 1.19 mmol/L (7.6 to 21.4 mg/dl) from baseline at the end of the main 24-week treatment period in placebo-controlled studies.

Post-prandial glucose

Treatment with Lyxumia resulted in reductions in 2-hour post-prandial glucose after a test-meal statistically superior to placebo whatever the background treatment.

The reductions with Lyxumia ranged from 4.51 to 7.96 mmol/L (81.2 to 143.3 mg/dl) from baseline at the end of the main 24-week treatment period across all studies in which post-prandial glucose was measured; 26.2% to 46.8% of patients had a 2-hour post-prandial glucose value below 7.8 mmol/L (140.4 mg/dl). h3. Body weight

Treatment with Lyxumia in combination with metformin and/or a sulphonylurea resulted in a sustained body weight change from baseline in all controlled studies in a range from -1.76 kg to – 2.96 kg at the end of the main 24-week treatment period.

Body weight change from baseline in a range from -0.38 kg to -1.80 kg was also observed in lixisenatide patients receiving stable basal insulin dose, alone or in combination with metformin or a sulphonylurea.

In patients newly started on insulin, body weight remained almost unchanged in the lixisenatide group while an increase was shown in the placebo group.

Body weight reduction was sustained in long term studies up to 76 weeks. The body weight reduction is independent from the occurrence of nausea and vomiting.

Beta cell function

Clinical studies with Lyxumia indicate improved beta-cell function as measured by the homeostasis model assessment for beta-cell function (HOMA-β). Restoration of first phase insulin secretion and improved second phase insulin secretion in response to an intravenous bolus of glucose were demonstrated in patients with type 2 diabetes (n=20) after a single dose of Lyxumia.

Cardiovascular evaluation

No increase in mean heart rate in patients with type 2 diabetes was seen in all placebo controlled phase III studies.

Mean systolic and diastolic blood pressure reductions up to 2.1 mmHg and up to 1.5 mmHg respectively were observed in phase III placebo-controlled studies.

The ELIXA study was a randomized, double-blind, placebo-controlled, multinational study that evaluated cardiovascular (CV) outcomes during treatment with lixisenatide in patients with type 2 diabetes mellitus after a recent Acute Coronary Syndrome.

Overall, 6068 patients were randomized 1:1 to either placebo or lixisenatide 20 mcg (following a starting dose of 10 mcg during the first 2 weeks).

Ninety-six percent of the patients in both treatment groups completed the study in accordance with the protocol and the vital status was known at the end of the study for 99.0% and 98.6% of the patients in the lixisenatide and placebo group, respectively. Median treatment duration was 22.4 months in the lixisenatide group and 23.3 months in the placebo group, and the median duration of study follow-up was 25.8 and 25.7 months, respectively. Mean HbA_1c (±SD) in the lixisenatide and placebo groups was 7.72 (±1.32)% and 7.64 (±1.28)% at baseline and 7.46 (±1.51)% and 7.61 (±1.48)% at 24 months, respectively.

The results of the primary and secondary composite efficacy endpoints, and the results of all the individual components of the composite endpoints are shown in Figure 1.

Figure 1. Forest plot: analyses of each individual cardiovascular event — ITT population:

CV: cardiovascular, MI: myocardial infarction, HF: hospitalization for heart failure, Revasc: coronary revascularization procedure, HR: hazard ratio, CI: confidence interval.

Elderly

People aged ≥70 years

The efficacy and safety of lixisenatide in people aged ≥70 years with type 2 diabetes was evaluated in a double-blind, placebo-controlled study of 24 weeks duration. Frail patients, including patients at risk for malnutrition, patients with recent cardiovascular events and patients with moderate to severe cognitive impairment were excluded. A total of 350 patients were randomized (randomization ratio 1:1). Overall, 37% of the patients were ≥75 years old (N=131) and 31% had moderate renal impairment (N=107). Patients received stable dose(s) of oral antidiabetic drug(s) (OAD) and/or basal insulin as background therapy. Sulfonylureas or glinides were not used with basal insulin as background therapy.

Lixisenatide provided significant improvements in HbA_1c (-0.64% change compared to placebo; 95% CI: -0.810% to -0.464%; p<0.0001), from a mean baseline HbA_1c of 8.0%.

Paediatric population

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