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

Hanefeld, Markolf; Arteaga, Juan Manuel Sánchez; Leiter, Lawrence A.; Marchesini, Giulio; Nikonova, Elena; Shestakova, Marina Vladimirovna; Stager, William; Gómez‐Huelgas, Ricardo

doi:10.1111/dom.12986

Cited by 18 publications

(13 citation statements)

References 32 publications

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“…Overall, no consistent or clinically relevant pattern of increase or decrease in semaglutide exposure (AUC from time zero to 24 h [AUC 24 ] and maximum concentration [ C max ]) between subjects with varying degrees of renal impairment and normal renal function was observed after 10 consecutive days of once-daily oral administration. This is largely consistent with previous studies that have suggested that impaired renal function has minimal effect on the pharmacokinetics and pharmacodynamics of other GLP-1 receptor agonists [ 23 – 27 ]. Importantly, this trial is also in line with the corresponding study for subcutaneous semaglutide that showed no clinically relevant effect on the pharmacokinetics of semaglutide when administered by subcutaneous injection in 56 subjects [ 15 ].…”

Section: Discussionsupporting

confidence: 92%

Pharmacokinetics, Safety and Tolerability of Oral Semaglutide in Subjects with Renal Impairment

et al. 2018

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BackgroundSemaglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) as a tablet for oral administration. This trial (NCT02014259) investigated the pharmacokinetics, safety and tolerability of oral semaglutide in subjects with and without renal impairment.MethodsSubjects were categorised as having normal renal function (n = 24), mild (n = 12), moderate (n = 12) or severe (n = 12) renal impairment, or end-stage renal disease (ESRD) requiring haemodialysis (n = 11) and received once-daily oral semaglutide (5 mg for 5 days followed by 10 mg for 5 days) in the fasting state, followed by 30 min fasting after dosing. Semaglutide plasma concentrations were measured during dosing and for up to 21 days after the last dose.ResultsSemaglutide exposure (area under the plasma concentration–time curve from time zero to 24 h after the tenth dose and maximum concentration after the tenth dose) did not vary in a consistent pattern across the renal function groups. Similarly, there was no apparent effect of renal impairment on the semaglutide half-life (geometric mean range 152–165 h). Except for one subject in the ESRD group, semaglutide was not detected in urine. Haemodialysis did not affect the pharmacokinetics of semaglutide. Adverse events were in line with those observed for other GLP-1 receptor agonists and no safety concerns were identified.ConclusionThere was no apparent effect of renal impairment or haemodialysis on the pharmacokinetics of oral semaglutide. Based on this trial, renal impairment should not affect dose recommendations for oral semaglutide.

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Section: Discussionsupporting

confidence: 92%

Pharmacokinetics, Safety and Tolerability of Oral Semaglutide in Subjects with Renal Impairment

et al. 2018

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“…The development of liraglutide was delayed because a first wave of phase 2 studies did not sufficiently identify the upper range of effective, but tolerable doses (59,60). A second approach was taken, using initial up-titration to prevent excessive side effects, thus arriving at a substantially higher, but still tolerable dose range (61 Yes (40) Yes (41) No (42) Yes (40) No Yes (minor) Yes (40) Yes (41) Yes (44) Yes (40) Not reported…”

Section: Finding the Optimum Dose For Glp-1 Receptor Agonists In Phasmentioning

confidence: 99%

“…Yes (45) No (27) Dose reduction recommended for mild/ moderate reductions in renal function? (yes/no) No (40) No (41) No (44) No (40)…”

Section: Finding the Optimum Dose For Glp-1 Receptor Agonists In Phasmentioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Are all GLP-1 agonists equal in the treatment of type 2 diabetes?

Nauck

2019

European Journal of Endocrinology

186

193

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GLP-1, a peptide hormone secreted from the gut, stimulating insulin and suppressing glucagon secretion was identified as a parent compound for novel treatments of diabetes, but was degraded (dipeptidyl peptidase-4) and eliminated (mainly by kidneys) too fast (half-life 1–2 min) to be useful as a therapeutic agent. GLP-1 receptor agonist has been used to treat patients with type 2 diabetes since 2007, when exenatide (twice daily) was approved in 2007. Compounds with longer duration of action (once daily, once weekly) and with increasingly better efficacy with respect to glycaemic control and body weight reduction have been developed, and in a recent ADA/EASD consensus statement, were recommended as the first injectable diabetes therapy after failure of oral glucose-lowering medications. Most GLP-1 receptor agonists (lixisenatide q.d., liraglutide q.d., exenatide q.w., dulaglutide q.w., albiglutide q.w., semaglutide q.w., all for s.c. injection, and the first oral preparation, oral semaglutide) have been examined in cardiovascular outcomes studies. Beyond proving their safety in vulnerable patients, most of whom had pre-existing heart disease, liraglutide, semaglutide, albiglutide, and dulaglutide reduced the time to first major adverse cardiovascular events (non-fatal myocardial infarction and stroke, cardiovascular death). Liraglutide, in addition, reduced cardiovascular and all-cause mortality. It is the purpose of the present review to describe clinically important differences, regarding pharmacokinetic behaviour, glucose-lowering potency, effectiveness of reducing body weight and controlling other cardiovascular risk factors, and of the influence of GLP-1 receptor agonist treatment on cardiovascular outcomes in patients either presenting with or without pre-existing cardiovascular disease (atherosclerotic, ischemic or congestive heart failure).

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“…Lixisenatide is eliminated through glomerular filtration, tubular reabsorption, and subsequent metabolic catabolism, and can lead to small increases in exposure with declining renal function . Although only limited data are available, previous clinical evidence suggests that lixisenatide is safe to use in patients with mild (eGFR ≥60 mL/min/1.73 m 2 ) or moderate (eGFR ≥30 to <60 mL/min/1.73 m 2 ) renal impairment; a meta‐analysis of nine lixisenatide trials also showed that clinical outcomes did not differ between the mild or moderate renal impairment categories, and efficacy outcomes were not significantly affected by mild or moderate renal impairment . Therefore, we also performed an analysis in which patients were stratified according to whether they had moderate renal insufficiency (eGFR 30‐59 mL/min/1.73 m 2 , chronic kidney disease [CKD] Stage 3A and B) or had an eGFR >60 mL/min/1.73 m 2 (patients with mild renal insufficiency to normal renal function, CKD Stages 2 and 1, respectively).…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of lixisenatide as add‐on therapy to basal insulin in older adults with type 2 diabetes in the GetGoal‐O Study

Dailey

Dex

Roberts

et al. 2019

Journal of Diabetes

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Background This study compared the efficacy and safety of lixisenatide with placebo as add‐on therapy to basal insulin (BI) in adults aged ≥70 years with type 2 diabetes (T2D), with or without moderate renal insufficiency. Methods This post hoc analysis evaluated data from non‐frail patients with T2D inadequately controlled on BI with or without oral antidiabetic drugs (n = 108), randomized to once‐daily lixisenatide 20 μg or placebo for 24 weeks (GetGoal‐O Study). The primary endpoint was the change in HbA1c from baseline to Week 24. Secondary endpoints included changes from baseline in fasting plasma glucose, 2‐hour postprandial plasma glucose (PPG), average seven‐point self‐monitored plasma glucose (SMPG), area under the curve for SMPG, daily BI dose, body weight, proportion of patients achieving HbA1c > 0.5%, and composite endpoints. Safety outcomes included the incidence of documented symptomatic hypoglycemia (plasma glucose <60 mg/dL) and gastrointestinal treatment‐emergent adverse events (TEAEs). Outcomes were also analyzed by the occurrence of moderate renal insufficiency. Results Compared with placebo, lixisenatide‐treated patients had significantly greater reductions in HbA1c, 2‐hour PPG, average seven‐point SMPG, and body weight. Documented symptomatic hypoglycemia was approximately two‐fold higher in patients treated with placebo than lixisenatide (12.7% vs 5.7%). GI TEAEs occurred more frequently in the lixisenatide‐ than placebo‐treated group (34% vs 9.1%). Moderate renal insufficiency (estimated glomerular filtration rate between ≥30 and <60 mL/min/1.73 m2) did not negatively affect lixisenatide efficacy or safety. A greater proportion of patients treated with lixisenatide than placebo achieved composite endpoints. Conclusions Add‐on therapy with lixisenatide in non‐frail patients aged ≥70 years with T2D uncontrolled with BI is effective, safe, and well tolerated and should be considered in this population.

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

Cited by 18 publications

References 32 publications

Pharmacokinetics, Safety and Tolerability of Oral Semaglutide in Subjects with Renal Impairment

Pharmacokinetics, Safety and Tolerability of Oral Semaglutide in Subjects with Renal Impairment

MANAGEMENT OF ENDOCRINE DISEASE: Are all GLP-1 agonists equal in the treatment of type 2 diabetes?

Efficacy and safety of lixisenatide as add‐on therapy to basal insulin in older adults with type 2 diabetes in the GetGoal‐O Study

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