REAL WORLD EFFECTIVENESS OF LIXISENATIDE AND OTHER INTENSIFICATION THERAPY IN THE MANAGEMENT OF TYPE 2 DIABETIC PATIENTS UNCONTROLLED WITH BASAL INSULIN.

Background and objectives: Lixisenatide, a selective short-acting glucagon-like peptide 1–receptor agonist (GLP-1RAs), approved in many countries worldwidefor use with oral glucose-lowering agents with or without basal insulin for the treatment of adults with uncontrolled type 2 diabetes mellitus (T2DM) as an adjunct to diet and exercise. The aim of this study was to assess the effectiveness of basal insulin treatmentregimen intensification with Lixisenatide compared with another injectable drugin patients with T2DM. We also aimed to identify the respective predictive factors for glycemic control. Materials and Methods: This prospective, multi-center, non-controlled observational study included 242 patients with T2DMuncontrolled the effectiveness of Lixisenatide combined with basal on glycemic control in patients with T2DMcompared with basal plus other intensification therapy. placebo-controlled thatadding once-daily lixisenatide for type 2 controlled with initiated and continuously titrated basal and postprandial hyperglycemiaand as an alternative to prandial insulin for patients basal-bolus basal-plus basal-bolusand the reduction in compared with basal-bolus. ahigher of patients basalplus basal-bolus GetGoal-L the efficacy and safety of the once-daily Lixisenatide to established basal insulin therapy alone or together with metformin, in people with type 2 diabetes and elevated HbA1c. Symptomatic hypoglycemia 28% for lixisenatide and 22% for placebo. showed that by HbA1c postprandial hyperglycemia without weight gain in type 2 diabetes with inadequate glycemic control despite stable insulin, lixisenatide to rapid-acting


Materials and Methods:-
We conducted a prospective, multi-center, non-controlled observational study with two parallel arms in Lebanon. The study was initiated in April 2015 and completed in December 2017.Key inclusion criteria were: (1) Patient ≥ 18 yearold; (2) Patients with T2DM who have a basal insulin with or without OAD as part of their current treatmentfor at least six months before the intensification therapy; and Patient who are initiated or have been initiated on intensification therapy of their basal insulin with an injectable for no more than three months because of uncontrolled diabetes according to the physicians judgment.
The patients who met the inclusion criteria were recruited and classified into two groups: patients on basal insulin plus Lixisenatide based intensification (Group 1) and patients on basal insulin plus another intensification therapy (Group 2).This study was conducted over three visitsafter three months of treatment intensification; baseline visit, follow up visit after three months and second follow up visit after six months. Each selected physician recruited an average of 10 to 16 patients who meet the inclusion criteria: 50% of them in group 1 (on Lixisenatide) and 50% in group 2 (on another intensification therapy). This consecutive recruitment limited biases of subject selection.
Patients were assessed according to the glycated hemoglobin (HbA1c) percentage, symptomatic hypoglycemic episodes and weight gain which were recorded throughout the study period.
The main endpoint was the mean difference (MD) in HbA1c, FPG, post-prandial plasma glucose (PPG), and weight from baseline to three months and six months in the two groups.The patient was considered responder (or at target) if the HbA1c was <7% with no symptomatic hypoglycemic episode in the previous three months and no weight gain since the initiation of intensification therapy.
Safety endpoints were the incidence ofadverse events (AEs), including hypoglycemia, weight gain, gastrointestinal side effects, other AEs,andserious AEs. Symptomatichypoglycemia is definedas an event duringwhich typical symptoms of hypoglycemia are associated with a measured plasma glucose concentration of ≤70 mg/dL. Severe hypoglycemia is defined as an event requiring the assistance of another person to actively administer carbohydrates, glucagon, or take other corrective actions. Plasma glucose concentrations may not be available during an event, but neurological recovery following the return of plasma glucose to normal is considered sufficient evidence that the event was induced by low plasma glucose.
Statistical analyses were performed using the statistical software program, SPSS, for Windows version 25.0 (SPSS; Chicago, IL, USA). a).
Categorical variables were presented as frequency and percentage, while the continuous variables according to their distribution; normallydistributed data were presented as mean and standard deviation (SD), while not-normally distributed data were presented as median and range. We used t-testto analyze the normally distributed data of two independent groups, while Mann-Whitney U test was used for skewed data of two independent groups. Analysis of variance (ANOVA) was used for normally distributed data of more than two independent groupswhilekruskal-Wallis test for skewed data of more than two groups. Paired sample t test, Wilcoxon signed-ranks test,andFriedman test were used for paired data. Categorical variables were analyzed using Chi-square test. Multivariate logistic regression analyses were performed to identify the predictive factors for achieving target response defined as achieving HbA1c < 7% with no symptomatic hypoglycemic episode in the previous three months and no weight gain since initiation of intensification therapy. Odds ratio (OR) was presented with its 95% CI Results:-Descriptive Analysis. The current study included 242 patients with T2DM. Of them, a total of 122 patients were included in Lixisenatide combined with basal insulin group (Group 1), and 120 patients were included in other intensification therapy group (Group 2). Table 1showed the demographics and baseline characteristics of included patients. The mean age of patients in group one was 57± 10.3 years, while the mean age of patients in group two was 59.3±9.3 years. The overall mean age for the patients in the two groups was 58.1±9.9 years. The female to male ratio was 41.8% to 58.2% in group one, while in group two was 42.5 % to 57.5%. Most of the included patients were Caucasian, form urban areas, not smoker, and not using alcohol. The mean duration of diabetes was significantly longer in group two than in group one, p=0.002. Furthermore, baseline FPG and PPG were significantly higher in other intensification therapy group (P<0.05), while baseline HbA1c was comparable between the two groups.A significantly higher 1143 number of patients with diabetes-related complications were reported in group two (61.7%), while group one was47.5%, p=0.027. Figure 1 showed the frequency of the most commonly reported diabetes-related complications.Dyslipidemia was the most commonly reported co-morbidity (59.5%), followed by hypertension (51.7%), with no significant difference between the two groups.
A total of 120 patients in group one and 118 patients in group two were on oral diabetic therapy (OAD) in the last six months prior to the intensification therapy. Metformin was the most commonly OAD medication used before and after intensification therapy in both groups, followed by Sulfonylureas as shown in Table 2. Once-daily insulin Glargine was the most commonly basal insulin regimen used in the two groups (82.8% in group one and 85.8% in group two, Table 3). Regarding the intensification therapy at baseline, a total of 122 patients started the addition of Lixisenatide (Group 1) to the basal insulin as once daily dose with a starting dose of 10 mcg in 106 patients (86.9%) and20 mcg in 16 patients (13.1%, although 10 mcg Lixisenatide once daily is the starting dose for 14 daysand 20 mcg Lixisenatide once daily represents the maintenance dose as per Lixisenatide Summary of Product Characteristics). While another 120 patients started other injectable intensification therapy (Group 2) as shown in Table 4.

Efficacy Analysis
We reported a statistically significant reduction in the mean HbA1c, FPG and PPG levels after three and six months of intensification therapy compared with the baseline levels in both groups. The mean HbA1c level in group one was 9.1%(±1.2) at the start of intensification therapy,and it dropped significantly to 7.8% (±0.9) after three months and to 7.3% (±0.8) after six months of intensification therapy (p<0.001). While in the second group, the mean HbA1c level was 9%(±1.3) at the start of intensification therapy and it dropped significantly to 7.7% (±0.9) after three months and to 7.3% (±0.8) after six months of intensification therapy (p<0.001). There were no statistically significant differences between the two groups regarding the % reduction in HbA1c level at three and six months (p=0.704).
Regarding the FPG level, Lixisenatide group showed a significant reduction in FPG level from 165.5 (±50.3)mg/dlat the start of intensification therapy to 129.5 (±31) mg/dl after three months and to 123.9 (±38.1) mg/dl after six months (p<0.001), with no statistical significant differences between the two groups regarding the percent reduction in FPG level at three and six months (p>0.05). Furthermore, the mean PPG level in group one decrease significantly from 217 (±43) mg/dl at the start of intensification therapy to 161.3 (±31.6) mg/dl after three months and to 154.9 (±40.5) mg/dl after six months of intensification therapy(p<0.001), with no statistical significant differences between the two groups regarding the percent reduction in PPG level at three and six months (p>0.05).
In addition, the mean weight in Lixisenatide group was 91.9 (±15.4) kg at the start of intensification therapy and decreased significantly to 89.0 (±14.4) kg after three months, and to 87.9 (±14.1) kg after six months of intensification therapy. (p<0.001), while in the second group, the mean weight was 83.1 (±13.9) kg at the start of intensification therapy and decreased to 82.5 (±12.4) kg after three months, and to 83.0 (±12.4) kg after six months of intensification therapy, with no statistically significant differences after three (p=0.61), and six months (p=0.838). Furthermore, there were statistically significant differences between the two groups regarding the percent of weight reduction at three and six months (p<0.001).
Fourteen patients (12%) in groupone and ten patients (8.4%) in group two achieved the targeted HbA1c < 7% after three months of intensification therapy, with no statistically significant difference between the two groups (p=0.26). While after six months, forty-three patients (36.8%) in group one and 43 patients (36.1%) in group two achieved thetargeted HbA1c < 7%, with no statistically significant difference between the two groups (p=0.92). The targeted HbA1c <7% with no symptomatic hypoglycemic episode after three months of intensification therapy and no weight gain was achieved by 12% of patients in Lixisenatide group compared with 8.4% of patients in the other intensification therapy group (p=0.26), Table 5.
Regarding therespective predictive factors affecting the response to the intensification therapy, the HbA1c and PPG at baseline, regular healthy diet plan, duration of diabetes was significantly associated with the patients' response to intensification therapy as seen in Table 6. While, the multivariate logistic regression analysis showed that baseline HbA1c wasthe only significant predictor for achieving target HbA1c< 7% with no symptomatic hypoglycemic episode in the previous three months and no weight gain since initiation of intensification therapy, Table 7.

Safety Analysis
A total of 42 subjects (32.8%) reported at least one AE in Lixisenatide group compared with 34 subjects (26.2%) in the second group. The most commonly reported AEs in Lixisenatide group were abnormal weight loss (more than 5% weight loss from the weight at baseline) andnausea; compared with abnormal weight loss, hypoglycemia (severe and symptomatic), and abnormal weight gain in group two.Hypoglycemia was reported in 2 patients (1.6%) in Lixisenatide group, and in 9 patients (6.9%) in group two, with a statistically significant difference between the two groups (p=0.033). No serious AEs were reported in Lixisenatide group, while four patients with at least one seriousAE in grouptwo, Table 8.

Discussion:-
Conventional therapy for T2DMfocuses on glycemic control. When patients have failed treatment with OAD therapy and/or basal insulin in combination with or without diet and exercise, an insulin intensification regimen would often be recommended to manage the HbA1c level of a patient [17].
Many patients with T2DMon basal insulin are not properly titrated by fear of increased risk of hypoglycemia. Even after basal insulin has been titrated appropriately, glycemic targets are only achieved in only half of the patients with T2DMin the US [18]or targets of HbA1c level< 7% are not achieved or maintained [19].A systematic review by Esposito et al., of218 clinical trials reported that only 39% of 21615 patients with T2DMtreated with basal insulin achieved HbA1c < 7.0% [20]. Furthermore, few T2DMpatients (7%) reached the glycemic target (HbA1c ≤6.5%) after one year of basal insulin therapy in a primary care database analysis [21].
Endogenous incretin hormones stimulate glucose-dependent insulin secretion that accounts for up to 60% of the insulin secretory response [22]. Adjuvant incretin-based therapy with either a GLP-1 receptor agonist or a DPP-4 inhibitor is found effective for T2DM patients with suboptimal glycemic control, without significantly increasing the risk of hypoglycemia [11]. Many patients with T2DM do not receive intensification therapy although failing to achieve the target glycemic control because insulin intensification regimens with basal insulin have been shown to be associated with increased hypoglycemic events and weight gain [18], [23].
This non-interventional, prospective study assessed treatment intensification effectiveness with Lixisenatide on the optimal glycemic control in uncontrolled T2DM patients with basal insulin with or without OAD. We revealed that Lixisenatide based therapies were significantly effective indecreasing the levels of HbA1c, FPG, and PPG with no significant increase inhypoglycemic events or weightgain. Our results were in line with the previous report comparing efficacy and safety of Lixisenatide versus exenatide (another GLP-1 RAs) in T2DM and revealed that Lixisenatide demonstrated equivalent efficacy but with a lower incidence of symptomatic hypoglycemia and anincidence of gastrointestinal AEs [24]. Moreover, the GetGoal Duo-2 Trialtested Lixisenatide plus basal insulin versus insulin glulisine either as basal-plus or basal-bolus in T2DMand concluded that Lixisenatide as add-on to basal insulinmay become a preferred treatment intensification option, attaining glycemic targets with fewer hypoglycemic events without weight gain compared to basal-plus or basal-bolus in uncontrolled basal insulin-treated T2DM [15].
In the current study, we reported that 12% of patients in Lixisenatide based group and 8.4% in non-lixisenatide based groupachieved the targeted HbA1c < 7%after three months of intensification therapy. While after six months of treatment, 36.8% in Lixisenatide group and 36.1% in non-lixisenatide group achieved thetargeted HbA1c< 7% with no statistical difference between the two groups. Furthermore,we reported a high response rate in Lixisenatide group (12%) compared with the other group (8.4%). Those responders have achieved the targeted HbA1c <7% with no symptomatic hypoglycemic episode after three months of intensification therapy and no weight gain. On the other hand,the numbers of hypoglycemic events reported with Lixisenatide were less than with the other intensification therapies in line with other clinical studies [25]. In addition, patients' body weight has significantly decreased after three months of Lixisenatide intensification therapy. However, it remained unchanged in the other intensification therapy group. Yamada and colleagues reported that there was astatistically significant reduction in the mean body weight in the Lixisenatide compared to Sitagliptin groups (the mean reductions were -0.41 versus +0.39 kg, respectively) [26].

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As regards to the safety, the most commonly experienced AE was abnormal weight loss. This is also in agreement with previous studies. However, no serious AEs were reported in Lixisenatide stratum, while four subjects with at least one serious AE were reported in the other intensification therapy stratum.
The GetGoal-Duo 1randomized, placebo-controlled study showed thatadding once-daily lixisenatide for type 2 diabetes inadequately controlled with newly initiated and continuously titrated basal insulin glargineimproved overall and postprandial hyperglycemiaand deserves consideration as an alternative to prandial insulin for patients not reaching HbA1c goals with recently initiated basal insulin [27]. GetGoal Duo-2 trial tested Lixisenatide plus basal insulin versus insulin glulisine either as basal-plus or basal-bolus and revealed that Lixisenatide plus insulin glargine was non-inferior for HbA1c reduction in comparison with basal-plus and basal-bolusand was statistically superior for the reduction in body weight compared with basal-bolus. Furthermore, symptomatic hypoglycemia occurred in ahigher proportion of patients in the basalplus and basal-bolus arms than in the Lixisenatide group [15]. The GetGoal-L trial examined the efficacy and safety of adding the once-daily Lixisenatide to established basal insulin therapy alone or together with metformin, in people with type 2 diabetes and elevated HbA1c. Symptomatic hypoglycemia was 28% for lixisenatide and 22% for placebo. The study showed that by improving HbA1c and postprandial hyperglycemia without weight gain in type 2 diabetes with inadequate glycemic control despite stable basal insulin, lixisenatide might provide an alternative to rapid-acting insulin or other treatment options[28].
Although our study was observational, selection bias was rare to occurbecause the recruitment had taken place after the decision to intensify the basal insulin therapy. The difference in baseline characteristics between the two groups including diabetes duration, FBG,and body weight may be considered as limitations in our study.
In conclusion, the use of Lixisenatide in combination with basal insulin represented an effective and well-tolerable treatment for patients with T2DM, with improvements in glycemic control, reducing body weight or preventing weight gain, with low risk of hypoglycemia.

Acknowledgments:-
This study was sponsored by Sanofi. The authors thank the study participants, trial staff, and investigators for their participation. Writing assistance was provided by Hussien Ahmed, of RAY-CRO and was funded by Sanofi.  .49 * Never: subject never smoked; ** Former: subject stopped smoking more than 12 months before entry into the registry. *** Current: subject smokes or having smoked within the past 12 months, at least 1 cigarette a day.       Responders = Achieved Target HbA1c < 7 AND no symptomatic hypoglycemic episode in the previous three months; AND no weight gain since initiation of intensification therapy + Never: subject never intake alcohol 1151 ++ Former: subject stopped alcohol more than 12 months before entry into registry. +++ Current:subject intakes alcohol or has intakes alcohol within the past 12 months, at least 1 cup a day.