# Abstract

 

## 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. # RESULTS 

## 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](#) . ::::table-wrap

::: caption
Baseline demographics by treatment (safety population)
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Characteristic Placebo Lixisenatide

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( *N* = 1639) ( *N* = 2869)\
*n*(%) *n*(%)\
Sex\
Male 811 (49.5) 1362 (47.5)
Female 828 (50.5) 1507 (52.5)
Age\
\<65 years 1286 (78.5) 2352 (82.0)
≥65 years 353 (21.5) 517 (18.0)
\<75 years 1600 (97.6) 2805 (97.8)
≥75 years 39 (2.4) 64 (2.2)
Race\
White 973 (59.4) 1898 (66.2)
Black 43 (2.6) 73 (2.5)
Asian/Oriental 601 (36.7) 843 (29.4)
Other 22 (1.3) 55 (1.9)
HbA1c [a](#)\
\<8% 744 (45.4) 1277 (44.5)
≥8% 895 (54.6) 1592 (55.5)
Body mass index [b](#)\
\<30 kg/m ^2^ 832 (50.8) 1376 (48.0)
≥30 kg/m ^2^ 807 (49.2) 1493 (52.0)
Renal function category\
Total 1636 2853
NormalCC ≥90 mL/min 1150 (70.3) 2094 (73.4)
Mild impairmentCC 60 to 89 mL/min 414 (25.3) 637 (22.3)
Moderate impairmentCC 30 to 59 mL/min 68 (4.2) 122 (4.3)
Severe impairmentCC \<30 mL/min 4 (0.2) 0 (0.0)

Abbreviations: CC , creatinine clearance; HbA1c , glycated haemoglobin.

Only patients with assessment were included for any particular variable.

Screening.

Baseline.:::: The combined safety population from the nine GetGoal trials included in this analysis comprised 2869 patients who received lixisenatide and 1639 patients who received placebo; the mITT population comprised 2720 patients and 1577 patients who received lixisenatide and placebo, respectively. Within the safety population, 3244 patients were classified as having normal renal function, 1051 patients had a mild renal impairment and 190 patients a moderate renal impairment. No patient had severe renal impairment at baseline in the lixisenatide group. The majority of patients were white and \<65 years old, with approximately half of the patients having HbA1c ≥8% (64 mmol/mol) at baseline (Table [2](#) ). Baseline rates of microalbuminuria, an indicator of diabetic nephropathy, were generally low and similar across all studies and both treatment arms included in the analysis ( *P* = .80 for heterogeneity). 

## 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, placebo‐adjusted 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](#) ). ::::table-wrap
::: caption
Efficacy of lixisenatide compared with placebo by renal function
category ( mITT population)
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Endpoint placebo‐adjusted mean difference Normal Mild impairment Moderate impairment

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CC ≥90 mL/min CC 60‐89 mL/min CC 30‐59 mL/min\
HbA1c (%) −0.52 (−0.65, −0.39) −0.50 (−0.68, −0.31) −0.85 (−1.09, −0.61)
*P*\< .00001 *P*\< .00001 *P*\< .00001
2‐hour PPG (mmol/L) −4.78 (−5.90, −3.66) −5.08 (−6.58, −3.58) −6.81 (−10.81, −2.82)
*P*\< .00001 *P*\< .00001 *P*\< .001
FPG (mmol/L) −0.70 (−0.91, −0.50) −0.48 (−0.74, −0.22) −0.78 (−1.36, −0.20)
*P*\< .00001 *P*\< .001 *P*\< .01
Basal insulin dose (U) −2.53 (−3.84, −1.21) −1.79 (−2.76, −0.83) −0.70 (−2.22, 0.81)
*P*\< .001 *P*\< .001 NS
Weight (kg) −0.64 (−0.93, −0.34) −0.59 (−0.90, −0.28) −0.47 (−1.37, 0.42)
*P*\< .0001 *P*\< .001 NS

Abbreviations: CC , creatinine clearance; FPG , fasting plasma glucose;
HbA1c , glycated haemoglobin; NS , not significant; PPG , postprandial
plasma glucose.

All data are presented as mean (95% CI ).:::: 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. 

## Meta‐analysis of changes in efficacy variables between renal function categories Comparisons of normal vs mild renal function and mild vs moderate renal function were performed to examine the incremental effect of increasing renal impairment on efficacy measures, while the direct comparison of normal vs moderate renal function demonstrates the cumulative effect. When between‐category changes for normal vs mild renal impairment and mild vs moderate renal impairment were assessed across the studies, there was no significant difference in HbA1c reductions at study end for patients with normal renal function vs those with mild renal impairment ( *P* = .58), between patients with mild and moderate renal impairment ( *P* = .36), or between patients with normal and moderate renal impairment ( *P* = .20; Figure [1](#) a). <figure> <p><img src="" /></p> <figcaption>Placebo‐adjusted meta‐analysis of change in A , HbA1c ; B , 2‐hour PPG and C, FPG from baseline to week 24 (week 12 for GetGoal‐Mono ) between renal function categories in patients receiving lixisenatide. Normal renal function: eGFR  ≥90 mL/min; mild impairment: eGFR 60‐89 mL/min; moderate impairment: eGFR 30‐59 mL/min. CI , confidence interval; eGFR , estimated glomerular filtration rate; FPG , fasting plasma glucose; HbA1c , glycated haemoglobin; PPG , postprandial plasma glucose</figcaption> </figure> No difference was observed in placebo‐adjusted change in 2‐hour PPG at week 24 between patients with normal function compared with those with mild renal impairment ( *P* = .72), between patients with mild and moderate renal impairment ( *P* = .59), or between patients with normal function and those with moderate renal impairment ( *P* = .70; Figure [1](#) b). Similarly, the difference in placebo‐adjusted FPG reductions from baseline was not significant for patients with normal renal function vs those with mild renal impairment ( *P* = .12), between patients with mild and moderate renal impairment ( *P* = .37), or between patients with normal function and those with moderate renal impairment ( *P* = .55; Figure [1](#) c). Data for these three subgroup analyses, demonstrating the cumulative effect of increasing renal impairment (i.e. the normal vs moderate renal function comparisons) in each original study population can be seen in Figure [S1](#) . There was no significant placebo‐adjusted difference in insulin dose change from baseline between the normal renal function and the mild impairment categories \[−0.82 U; 95% confidence interval (CI) −2.65, 1.03; *P* = .39\], or between the mild and moderate renal impairment categories (−3.20 U; 95% CI −8.31, 1.92; *P* = .22). Finally, no significant difference was seen in placebo‐adjusted body weight change from baseline between the normal renal function and the mild impairment categories (−0.05 kg; 95% CI −0.47, 0.38; *P* = .82), or between the mild and moderate renal impairment categories (−0.19 kg; 95% CI −1.11, 0.73; *P* = .69). 

## 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. ::::table-wrap
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Placebo‐adjusted meta‐analysis (fixed effect) of selected AE s [a](#)
between renal function categories (safety population)
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Parameter Normal vs mild Mild vs moderate Normal vs moderate

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Estimate *P*‐value Estimate *P*‐value Estimate *P*‐value\
GI disorders (SOC) −0.14 .003 0.00 .99 −0.10 .16
Nausea/vomiting (HLT) −0.1 .003 0.04 .57 −0.03 .65
Metabolism and nutrition disorders (SOC) −0.08 .005 0.15 .03 0.11 .09
Hypoglycaemia (HLT) −0.02 .26 0.04 .53 0.03 .63
Appetite disorders (HLT) −0.03 .009 0.01 .79 −0.03 .47
Decreased appetite (PT) −0.03 .004 0.03 .47 −0.02 .63

Abbreviations: GI , gastrointestinal; HLT , higher level term; PT ,
preferred term; SOC , system and organ class ( MedDRA ).

Fourteen SOC s were identified as common for all three renal impairment
categories. Those showing significant placebo‐adjusted risk differences
are shown here.:::: 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 significant placebo‐adjusted difference in the incidence rate between the normal renal function and the mild impairment categories (−0.02; 95% CI −0.06, 0.02; *P* = .26), between the mild and the moderate renal impairment categories (0.04; 95% CI −0.08, 0.15; *P* = .53), or between the normal renal function and the moderate impairment categories (−0.03; 95% CI −0.08, 0.14). No significant difference was reported for placebo‐adjusted change from baseline in heart rate between the normal renal function and the mild impairment categories \[−1.13 beats per min (bpm); 95% CI −2.54, 0.28; *P* = .12\], or between the mild and moderate renal impairment categories (1.73 bpm; 95% CI −2.72, 6.17; *P* = .45). Similarly, there was no significant placebo‐adjusted difference between the change from baseline in systolic blood pressure (SBP) in the normal renal function and mild impairment categories (−0.99 mm Hg; 95% CI −3.82, 1.84; *P* = .49), or between the mild and moderate renal impairment categories (−7.41 mm Hg; 95% CI −16.30, 1.47; *P* = .10). 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).


Extracted trial result:
Outcome: Nausea (binary)
Intervention: Lixisenatide with moderate impairment
Comparator: Lixisenatide with mild impairment
Intervention group size: 122
Comparator group size: 637
Notes: placebo-adjusted meta-analysis (fixed effect) = 0.04