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Efficacy and safety of lixisenatide in patients with type 2 diabetes and renal impairment

Aims This post hoc assessment evaluated the efficacy and safety of once‐daily, prandial glucagon‐like peptide‐1 receptor agonist lixisenatide in patients with type 2 diabetes (T2D) and normal renal function (estimated glomerular filtration rate ≥90 mL/min), or mild (60‐89 mL/min) or moderate (30‐59 mL/min) renal impairment. Methods Patients from 9 lixisenatide trials in the GetGoal clinical trial programme were categorized by baseline creatinine clearance: normal renal function (lixisenatide n = 2094, placebo n = 1150); renal impairment (mild: lixisenatide n = 637, placebo n = 414; moderate: lixisenatide n = 122, placebo n = 68). Meta‐analyses of placebo‐adjusted mean differences between baseline renal categories were performed for efficacy and safety outcomes. Results HbA1c, 2‐hour postprandial plasma glucose and fasting plasma glucose were comparably reduced in lixisenatide‐treated patients with normal renal function, and mild and moderate renal impairment. The most common adverse events (AEs) in all renal function categories were gastrointestinal (GI), predominantly nausea and vomiting. A 14% higher incidence of GI AEs and a 10% higher incidence of nausea and vomiting were seen with mild impairment vs normal function (P = .003 for both), but no significant differences were observed between the mild and moderate impairment categories (P = .99 and P = .57, respectively), or between the moderate impairment and normal categories (P = .16 and P = .65, respectively). Additionally, the incidence of hypoglycaemia was similar in all categories. Conclusions This study demonstrates that baseline renal status does not affect efficacy outcomes in lixisenatide‐ vs placebo‐treated patients, and that no lixisenatide dose adjustment is required for patients with T2D with mild or moderate renal impairment.


| INTRODUCTION
Type 2 diabetes (T2D) is a progressive life-threatening disease associated with altered glucose homoeostasis. 1 The negative effects of the associated chronic hyperglycaemia may compromise organ and tissue function, including the cardiovascular system, eyes, nerves and kidneys. 2 Because of the systemic nature of the disease, clinical management of T2D is often complex and may be suboptimal, with associated co-morbidities often confounding the issue. 3 Of these comorbid conditions, chronic kidney disease is particularly common in T2D, with about one-quarter of patients aged ≥60 years exhibiting moderate or severe impairment of renal function. 4 A precise definition of the advantages and disadvantages of available therapeutic options in relation to the disease characteristics and comorbidities of the individual patient is needed to select the most appropriate treatment in this setting. In particular, it is essential to understand the pharmacokinetic profile, and specifically the mechanism of excretion, of any drug administered, and to adjust dosing accordingly. 5 The most recent recommendations from the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) suggest that first-line therapy for T2D should be lifestyle modifications and metformin monotherapy. 6 However, further guidance from the ADA states that the use of metformin is contraindicated in individuals with severe renal disease, 7 with recent Food and Drug Administration (FDA) guidance advising that metformin may be used in patients with mild impairment and only in some with moderate impairment. 8 In patients with T2D where first-line metformin monotherapy does not provide sufficient glycaemic control or is not indicated, guidelines recommend the introduction of one of a number of different therapeutic options, including sulphonylureas, sodium-glucose cotransporter-2 (SGLT2) inhibitors, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, basal insulin or glucagon-like peptide-1 receptor agonists (GLP-1 RAs). 6 The extent of clinical experience with these drug classes in patients with renal disease varies, with many of these treatment options contraindicated or not recommended in patients with moderate or severe impairment 9 ; specific concerns have been raised regarding the use of certain sulphonylureas and SGLT2 inhibitors in this population. With regard to GLP-1 RAs, there is a relative lack of data investigating their use in patients with impaired renal function. 10 The evidence to date indicates that exenatide is eliminated by renal mechanisms and should not be given to patients with severe impairment. 10 Further data indicate that the glycaemic efficacy of liraglutide does not appear to be affected by moderate impairment. 11 Elimination of lixisenatide, a once-daily, injectable, prandial GLP-1 RA, is presumed to occur via renal filtration, tubular reabsorption and metabolic catabolism; the resulting metabolites do not appear to stimulate the GLP-1 receptor. 12 Furthermore, clinical evidence suggests that the pharmacokinetic profile of lixisenatide is largely unaffected by mild or moderate renal impairment; however, only limited pharmacokinetic data are available. 10 The efficacy and safety of lixisenatide have been investigated extensively across the GetGoal clinical trial programme, which included patients with T2D with or without renal impairment. [13][14][15][16][17][18][19][20][21][22][23] Overall, these studies have demonstrated that lixisenatide is significantly more effective than placebo at reducing levels of glycated haemoglobin (HbA1c). Moreover, treatment with lixisenatide was associated with significant reductions in postprandial plasma glucose (PPG) and fasting plasma glucose (FPG) compared with placebo.
In order to investigate the potential effects of renal impairment on the efficacy and safety of lixisenatide in patients with T2D, we conducted a post hoc meta-analysis based on trials reported previously from the comprehensive GetGoal clinical trial programme. [13][14][15][16][18][19][20][21][22]

| MATERIALS AND METHODS
This meta-analysis included data from nine GetGoal trials that had been published at the time of the analysis (October 2014). An overview of the designs of these trials, along with their primary results, is presented in Table 1. Five of the trials included assessed lixisenatide as an add-on to oral antidiabetic drugs in patients with T2D over 24 weeks. Three of the trials compared lixisenatide with placebo when added to basal insulin over 24 weeks. One trial assessed lixisenatide as monotherapy over a period of 12 weeks. Furthermore, 2 of the aforementioned trials included in this analysis were conducted in a predominantly Asian population. All trials were approved by the Institutional Review Boards or ethics committees of the participating centres, and were conducted in accordance with the principles of Safety and efficacy data from patients in the selected trials were pooled and stratified by each patient's baseline renal function. This was assessed by estimated glomerular filtration rates (eGFR) using baseline creatinine clearance levels based on the Cockcroft-Gault formula. 24 For the purposes of the present analysis, renal function was categorized as: "normal" (eGFR ≥90 mL/min); "mild renal impairment" (60-89 mL/min); "moderate renal impairment" (30-59 mL/min); or "severe renal impairment" (<30 mL/min), as defined by the ADA. 25 As the included trials had exclusion criteria based on renal function, there was a lack of patients with severe renal impairment in the present analysis. Analyses of safety endpoints included the placebo-adjusted rate of treatment-emergent adverse events (AEs) by system and organ class (SOC) for SOCs identified across all of the renal function subgroups and by higher level term (HLT) for AEs by SOC that were significantly more frequent with lixisenatide.

| Statistical analyses
Analyses of efficacy endpoints were performed using the pooled modified intent-to-treat (mITT) populations from the nine trials, which comprised all randomized participants who received at least one dose of study treatment and had both a baseline and at least one post-baseline assessment for any of the primary or secondary efficacy variables. All of the studies included in the meta-analysis employed the last observation carried forward method. If the end-of-study value was missing for any endpoint, the last available post-baseline value was used. Differences in mean changes from baseline to study end between lixisenatide-and placebo-treated patients (placebo-adjusted changes) were compared for each of the five efficacy endpoints within each renal function category and between categories.
Analyses of safety outcomes were performed using the safety population, which comprised all patients who received at least one dose of study drug. AEs grouped by SOC were analysed using risk differences (placebo-adjusted rates). Comparisons between renal function categories were based on differences in placebo-adjusted rates. Where there were significant differences in the number of AEs between categories, further analyses using all available HLTs or preferred terms were carried out.
To evaluate the differences in assessed efficacy endpoints and safety outcomes across studies, study-level meta-analyses (random effects) were performed using placebo-adjusted changes from baseline or placeboadjusted rates, respectively. Comparisons between renal categories were carried out using effect estimates calculated by study as the difference in placebo-adjusted changes or placebo-adjusted rates between categories.
Effect estimates and their standard errors were entered as generic inverse variances in the Cochrane algorithm RevMan 5.2. Cochran's Q-test and I 2 statistic were used to assess homogeneity between studies.

| Patient demographics and clinical characteristics at baseline
The distribution of patients in the combined safety population by renal function category and a summary of patient characteristics at baseline is given in Table 2.

| Comparisons of changes in efficacy variables from baseline to study end within baseline renal function categories
Of the five efficacy variables evaluated in this analysis, placeboadjusted mean differences in HbA1c, 2-hour PPG and FPG were significantly lower at study end in lixisenatide-than in placebo-treated patients in all three renal function categories (Table 3).
Basal insulin dose data were retrieved from three GetGoal trials (Table S2). In both the normal renal function and the mild impairment categories, end-of-treatment basal insulin dose was significantly lower with lixisenatide than with placebo. However, in the moderate renal impairment category there was no significant difference between lixisenatide and placebo in basal insulin dose.
End-of-treatment body weight was significantly lower compared with baseline in both the normal renal function and the mild impairment categories. Body weight loss was also observed in the moderate renal impairment category, but this did not reach statistical significance.   All data are presented as mean (95% CI).

| Meta-analysis of safety outcomes
Adverse events were analysed using SOCs that were identified across all of the renal function categories. There were 14 SOCs that met this criterion: gastrointestinal (GI) disorders; nervous system disorders; general disorders and administration-site conditions; musculoskeletal and connective tissue disorders; skin and subcutaneous tissues disorders; metabolism and nutrition disorders; psychiatric disorders; cardiac disorders; injury, poisoning and procedural disorders; renal and urinary disorders; eye disorder investigations; respiratory, thoracic and mediastinal disorders; and infections and infestations. There were no significant differences between the normal and mild impairment or between the normal and moderate impairment renal function categories, with the exception of the GI disorders and metabolism and nutrition disorders ( Table 4). The most common AEs in all renal function categories were GI-related, predominantly nausea and vomiting.
There was a lower incidence of any GI disorder AE (SOC), and a lower incidence of nausea and vomiting (HLT), in the normal renal function vs mild renal impairment category (P = .003 for both), but no difference was found for either of these endpoints between the mild and moderate impairment categories (P = .99 and P = .57, respectively), or between the moderate impairment and normal categories (P = .16 and P = .65, respectively). The incidences of any metabolism/ nutrition disorder AE (SOC) and of decreased appetite (HLT) were significantly lower in the normal function vs the mild impairment category (P = .005 and P = .004, respectively). The difference in the incidence of any metabolism/nutrition disorder AE between the mild and moderate renal impairment categories was also significant (P = .03), but no other significant difference between renal function groups was found for either of these safety endpoints (Table 4).
Importantly, with respect to hypoglycaemia, there was no signifi-   Although there was no significant placebo-adjusted difference between the change from baseline in diastolic blood pressure (DBP) in the normal renal function and mild impairment categories (−0.18 mm Hg; 95% CI −1.56, 1.20; P = .80), a significant difference was seen between the mild and moderate renal impairment categories (−5.11 mm Hg; 95% CI −8.93, −1.29; P < .01).

| DISCUSSION
In patients with T2D, good glycaemic control is necessary to prevent  28 Furthermore, although the SGLT2 inhibitors dapagliflozin, canagliflozin and empagliflozin do not increase the risk of hypoglycaemia, there is evidence that they increase the risk of hypovolemic side-effects and that their glycaemic efficacy is diminished in moderate-to-severe renal impairment. 28 In addition, alpha glucosidase inhibitors are not generally recommended for people with renal impairment because of potential accumulation and lack of safety information. 28,29 The ADA/EASD treatment guidelines have designated GLP-1 RAs as a therapeutic option in T2D because of their proven efficacy in improving glycaemic control. 6 Interestingly, preclinical evidence indicates that GLP-1 may play a role in the regulation of renal function, and thus it has been hypothesized that treatment with certain GLP-1 RAs may even aid in improving diabetic nephropathy. 30,31 As clearance of exenatide is via the renal route, it is not recommended in patients with severe impairment. 10 In contrast, despite minor increases in the plasma concentrations of albiglutide and dulaglutide, and increased rates of hypoglycaemia and GI side-effects, 32 the FDA has approved both treatments for use in patients with renal impairment without dose reduction. In Europe, however, their use in patients with severe impairment is not recommended until further data are available. 28  95% CI −37.6, −9.1).
A further consideration regarding the choice of treatment in this patient population is the potential for anti-hyperglycaemic drugs to negatively affect renal function. There are conflicting data available for liraglutide depending on duration of treatment. Evidence from a 26-week study suggests that liraglutide has no effect on renal function 11 ; however, findings from a 1-year study with a small sample size indicate that the drug may elicit a significant reversible decline in GFR, suggestive of a reversible metabolic or haemodynamic effect, without accompanying structural changes in renal physiology. 34 These conflicting results may indicate that there is considerable variation in pharmacodynamic and pharmacokinetic profiles in patients with renal impairment, and that these factors need to be carefully considered prior to initiation of any anti-hyperglycaemic treatment.
This analysis was a post hoc evaluation of multiple trials. One limitation of this approach is that the nine trials included were of varying design, specifically with regard to duration and treatment regimen (i.e. monotherapy or add-on); however, this may also be viewed as a In summary, the clinical management of patients with T2D and impaired renal function can be challenging; however, the results of this analysis support the conclusion that no lixisenatide dose adjustment is required for patients with T2D with mild or moderate renal impairment.