A total of 262 patients were included in the study between November 2015 and December 2016 and followed up by June 2017. Out of them 253 patients came back for the 6-month follow-up visit and 9 patients were lost to follow-up. Thirteen subjects (5% of the enrolled population) had no entries related to the primary endpoint variable. Therefore 249 subjects were included in the efficacy population.
Demographic and Clinical Characteristics of the Study Population
Baseline demographic and clinical characteristics are specified in Table 1. The mean age was 56.2 ± 9.1 years. The majority of patients were between 50 and 65 years old (58.6%). Only 15.3% of the study population was at least 65 years old. The mean BMI was 39.7 ± 4.7 kg/m2. The mean duration of diabetes was 7.3 ± 6.0 years. The mean HbA1c at baseline was 8.8 ± 1.1%. The majority of patients had baseline HbA1c > 8%, with 45.8% between 8% and 9% and 27.7% greater than 9%. The mean FPG at baseline was 10.5 ± 3.1 mmol/l. All 249 patients from the efficacy population had at least one PPG measurement at baseline—after breakfast, after lunch or after dinner, while 32.5% of the patients had all three measurements. The mean from all PPG measurements at baseline was 12.1 ± 3.4 mmol/l.
Table 1 Baseline characteristics of the LIXODAR cohort
Clinical data related to chronic complications of T2D showed a significantly higher proportion of microvascular complications compared to macrovascular complications (Table 1). The most frequent microvascular complication was neuropathy, reported in 49.8% of the patients, while the most frequent macrovascular complication was ischemic heart disease, reported in 12.1% of the patients. Overall the cohort had a high percentage of patients (45.4%) with no complications at all.
All patients from the efficacy population received at least one OAD treatment at baseline (metformin or SU) and 97.6% of the patients received both metformin and SU (Table 1). The most frequently used OAD was metformin in 99.2% of the patients, followed by glimepiride and gliclazide MR in 41.4% and 39.4% of the patients respectively. The OAD usage at baseline and their doses can be found in Supplementary Table 1.
Real-World Effectiveness Outcomes
The proportion of patients achieving target HbA1c < 7% was 39.0% (95% CI 32.9–45.3). The mean HbA1c at visit 2 was 7.5 ± 1.4%. The mean HbA1c change from baseline to the end of the 6-month follow-up period was − 1.3 ± 1.2% (Fig. 1). A post hoc analysis showed that both proportion of patients reaching HbA1c < 7% and mean change in HbA1c depended on the baseline glycaemic control. Fewer patients tended to achieve HbA1c < 7% with the increase of baseline HbA1c, while the mean reduction in HbA1c was greater the worse the baseline glycaemic control was (Figs. 2, 3). Glycaemic response was also stratified by diabetes duration. The HbA1c reduction in the patient population with shorter duration of diabetes (< 10 years) was − 1.4 ± 1.2% while in the population with longer diabetes duration (≥ 10 years) the reduction was − 1.2 ± 1.2%. However this difference was not statistically significant (p = 0.436). Similar results have been observed in regards to the proportion of patients reaching HbA1c < 7%. Numerically more patients reached the target HbA1c at study end in the patient population with shorter duration of diabetes (42.3%) compared to those in the population with longer duration of diabetes (31.1%). However the difference was not statistically significant (p = 0.098).
A total of 245 patients had FPG measurements after 6 months of treatment. The mean FPG at study end was 8.1 ± 3.0 mmol/l. The mean FPG change from baseline was − 2.4 ± 3.2 mmol/l (Fig. 4). Numerically the mean reduction in FPG was most pronounced when lixisenatide was administered before breakfast (− 2.7 ± 3.5 mmol/l) and before lunch (− 2.7 ± 2.6 mmol/l). When lixisenatide was administered before dinner the mean change in FPG from baseline was − 1.6 ± 2.8 mmol/l. However no statistically significant difference was observed (p = 0.124). Univariate analysis also showed no correlation between time of lixisenatide administration and mean change in FPG (p = 0.183). The mean FPG changes from baseline according to the different time of lixisenatide administration (before breakfast, lunch or dinner) are shown in Supplementary Table 2.
Table 2 Hypoglycaemic events
A total of 242 patients had PPG measurements after 6 months of treatment. The mean PPG at study end was 8.9 ± 3.2 mmol/l and the mean change from baseline was − 3.2 ± 3.6 mmol/l (Fig. 5). Numerically the mean reduction in PPG was most pronounced when lixisenatide was administered before breakfast (− 3.6 ± 3.8 mmol/l) and before lunch (− 3.2 ± 2.9 mmol/l). When lixisenatide was administered before dinner the mean change in PPG from baseline was − 2.2 ± 3.3 mmol/l. Statistically significant differences were observed between the before breakfast and before dinner administration subgroups (p = 0.041). There was no statistically significant difference between the before lunch and before dinner subgroups (p = 0.337). Univariate analysis showed no correlation between time of lixisenatide administration and mean change in PPG (p = 0.586). The mean PPG changes from baseline according to the different time of lixisenatide administration (before breakfast, lunch or dinner) are shown in Supplementary Table 3. The mean change from baseline in the different PPG measurements during the day (after breakfast, after lunch and after dinner) are shown in Supplementary Table 4.
The proportion of patients with at least a 0.5% decrease in HbA1c level was 86.7% (95% CI 81.9–90.7). The proportion of patients with at least a 1.0% decrease in HbA1c level was 72.7% (95% CI 66.7–78.1).
The mean individual HbA1c target value specified by the investigators at baseline was 7.2 ± 0.6%. The mean individual FPG target value was 6.7 ± 0.9 mmol/l. Respectively 49.0% (95% CI 42.6–55.4) of the patients reached their individualized HbA1c target and 35.1% (95% CI 29.1–41.4) of the patients achieved their FPG target. The majority of patients (57%) had an individualized HbA1c target set by the investigator at baseline between 7% and 7.5%. Still 27% of the patients had an individualized HbA1c target below 7%, while only 10% and 6% had individualized HbA1c targets between 7.6% and 8%, and more than 8%, respectively. The proportion of patients reaching their individualized HbA1c target at study end according to individualized HbA1c target categories at baseline are shown in Fig. 6. The majority of the patients (85%) had an individualized FPG target set by the investigator below 7.2 mmol/l (in line with ADA/EASD guidelines). Only 14% had individualized FPG target greater than 7.2 mmol/l.
The proportion of patients who have achieved HbA1c < 7% and have had no symptomatic hypoglycaemia and no weight gain for the 6-month treatment period was 36.1% (95% CI 30.2–42.4).
The mean body weight at study end was 104.0 ± 15.6 kg. The mean body weight change from baseline was − 7.2 ± 5.5 kg. The mean BMI at study end was 37.1 ± 4.7 kg/m2. The mean BMI change from baseline was − 2.6 ± 1.9 kg/m2. More than half of the patients managed to achieve at least 5% weight reduction for the 6-month follow-up period, 57.8% (95% CI 51.6–63.8). The proportion of patients with at least 3% reduction was even higher, 83.9% (95% CI 79.0–88.1). The proportion of patients who have achieved HbA1c < 7% with no symptomatic hypoglycaemia and at least 3% weight reduction for the 6-month treatment period was 32.5%. The proportion of patients who have achieved HbA1c < 7% with no symptomatic hypoglycaemia and at least 5% weight reduction for the 6-month treatment period was 26.9%. Weight loss and change in HbA1c were not significantly correlated (Pearson test, p = 0.173).
Hypoglycaemia
There were 29 hypoglycaemic events registered for 16 subjects during the study (Table 2). A total of 21 events in 10 patients were symptomatic, while 8 events in 6 patients were asymptomatic. In one patient two hypoglycaemic events required assistance. There was no event leading to unconsciousness/coma, or seizure, emergency department visit, or fulfilling the definition of a serious AE. The hypoglycaemia incidence was 6.1% (16 patients) for all hypoglycaemic events, 3.82% (10 patients) for symptomatic events and 0.38% (1 patient) for severe events. All patients who reported hypoglycaemic events throughout the 6-month follow-up period were on OAD treatment with metformin and SU.
Adverse Events
There were no AEs reported at baseline in patients who initiated lixisenatide prior to enrolment in the study. During the entire 6-month observational period, four patients from the safety population had reported six non-serious treatment emergent adverse events (two of four patients reported two events each). All AEs were of mild intensity with an outcome of recovered or resolved. One patient had allergic dermatitis (reported twice) possibly related to lixisenatide and leading to treatment discontinuation. One patient had two gastrointestinal AEs, gastritis and gastroesophagitis, possibly related to lixisenatide but the dose was not changed. For the remaining two events, the causality assessment was unrelated to lixisenatide. There was no serious adverse event reported. There were no deaths in the study.
Lixisenatide Treatment
Of the 249 patients included in the efficacy population, 248 (99.6%) had the starting daily dose of 10 µg. The maintenance daily dose was 20 µg for all of the patients. The most frequent daily time of administration was 1 h before breakfast (Table 3). At the 6-month follow-up visit 215 patients (86.3%) continue the therapy with lixisenatide. The daily dose was 20 µg for all of the patients. A total of 34 patients (13.7%) from the efficacy population completed the study treatment period but did not continue treatment with lixisenatide after that. The most frequent reason for lixisenatide discontinuation was the patient decision in 7.2% (18) of the patients. Other reasons, reported in 6.5% (16) of the patients, were mainly related to reimbursement restrictions—either reduction in HbA1c for the 6-month treatment period was ≤ 0.5% and treatment continuation with lixisenatide was not approved by the health fund or patient had to start insulin treatment (at the time of the study combination of GLP- RA and insulin was not reimbursed in Bulgaria). Both patient decision and other reasons were not related to safety/tolerability issues.
Table 3 Lixisenatide daily time of administration