Lixisenatide (Adlyxin)
Lixisenatide (des-38-proline-exendin-4(1-39)-peptidylpenta-L-lysyl-L-lysinamide)
FDA-approved (2016) once-daily short-acting prandial GLP-1 receptor agonist for type 2 diabetes, marketed as Adlyxin (US, discontinued 2023) and Lyxumia (EU), with particularly strong postprandial glucose lowering via gastric emptying delay (PMID 23423907, PMID 28556176).
Last updated: 2026-03-10
Safety Summary
Nausea is the most common adverse event (25% in clinical trials), with vomiting at 10%, headache at 9%, diarrhea at 8%, and dizziness at 7% (PMID 28556176). In GetGoal-L-Asia, nausea and vomiting were 39.6% and 18.2% versus 4.5% and 1.9% with placebo (PMID 22564709). GI side effects are generally transient, mostly mild-to-moderate, and most frequent during the initial 2-week titration period (PMID 29923298). The 2-step dose increase regimen (10 mcg x14 days, then 20 mcg) reduces nausea rates compared to a 1-step approach (36.4% vs 50.0% at 24 weeks in Japanese patients) (PMID 26342556). When combined with insulin glargine as iGlarLixi, GI side effects are substantially lower than with lixisenatide alone due to gradual titration (9.6% nausea vs 24.0% with lixisenatide alone) (PMID 29923298). Symptomatic hypoglycemia ranged from 0.8% to 42.9% depending largely on background sulfonylurea or insulin use, with severe hypoglycemia below 1.5% (PMID 28556176). The FDA Soliqua label lists hypoglycemia, nausea, diarrhea, and headache among the most common adverse reactions and warns about pancreatitis, kidney injury from volume depletion, and rare anaphylaxis. Anti-drug antibodies developed in 70% of lixisenatide-treated patients at Week 24; in the 2.4% with highest antibody concentrations (>100 nmol/L), an attenuated glycemic response was observed. In the LixiPark Parkinson's disease trial, nausea was reported in 46% and vomiting in 13% of lixisenatide-treated participants (PMID 38598572). Lixisenatide produces a smaller increase in heart rate compared to liraglutide (+3 bpm vs +9 bpm) (PMID 25887358).
Known Side Effects
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Who Should NOT Use This
Anaphylaxis and angioedema have been reported. The FDA label lists serious hypersensitivity as a contraindication.
The FDA Soliqua label lists use during episodes of hypoglycemia as a contraindication.
Rodent carcinogenicity studies showed statistically significant increases in thyroid C-cell adenomas at all doses tested in rats (>=15x human exposure). The Adlyxin standalone label carried a boxed warning for this (PMID 28556176). The current Soliqua label discloses C-cell tumor data in nonclinical toxicology but does not carry a boxed warning.
Acute pancreatitis, including fatal cases, has been observed with GLP-1 receptor agonists. The FDA label recommends discontinuation if pancreatitis is suspected. Notably, liraglutide significantly increased lipase levels by 21 IU/L while lixisenatide did not (PMID 25887358).
The FDA label states Soliqua is not recommended in end-stage renal disease and advises renal monitoring when adverse reactions could cause volume depletion. GI side effects may worsen dehydration and precipitate acute kidney injury.
Animal reproductive studies showed adverse effects. Standard caution for GLP-1 agonists (PMID 28556176).
Increased hypoglycemia risk. Dose reduction of sulfonylurea or insulin may be needed. Symptomatic hypoglycemia ranged up to 42.9% with background SU/insulin (PMID 28556176, PMID 24476092).
Lixisenatide strongly slows gastric emptying (half-time delayed by ~52 min). The FDA label states Soliqua is not recommended in severe gastroparesis.
The FDA label states do not use with other GLP-1 receptor agonists (e.g., semaglutide, liraglutide, dulaglutide, tirzepatide). Class-level contraindication for overlapping mechanism and increased GI adverse event risk.
Talk to Your Doctor
Before considering Lixisenatide (Adlyxin), discuss it with your healthcare provider. Ask about potential interactions with your current medications, whether it is appropriate for your health conditions, and what monitoring may be needed.
Sources: [1-28]
Evidence Assessment
Tier 1 -- FDA-approved (BLA 208471 for Adlyxin, BLA 208673 for Soliqua 100/33) for type 2 diabetes as adjunct to diet and exercise. Supported by the GetGoal Phase 3 program (13 trials, >5,000 patients) and the ELIXA cardiovascular outcomes trial (n=6,068) (PMID 28556176, PMID 26630143). Evidence is strongest for glycemic control in type 2 diabetes and fixed-ratio use with basal insulin (PMID 27650977). For the Parkinson's disease indication, evidence is currently Phase 2 only (PMID 38598572).
1Trial of Lixisenatide in Early Parkinson's DiseaseNCT03439943PMID 38598572
Meissner WG et al. - The New England Journal of Medicine (2024) - RCT (Phase 2, double-blind, placebo-controlled) - 156 (78 per group)
MDS-UPDRS part III scores changed by -0.04 points (lixisenatide) vs +3.04 points (placebo) at 12 months (difference 3.08, 95% CI 0.86-5.30, P=0.007). At 14 months (2-month washout), off-medication scores were 17.7 vs 20.6. Nausea occurred in 46% and vomiting in 13% of lixisenatide group.
Limitations: Small sample size (n=156). Single Phase 2 trial. Gastrointestinal side effects may have unblinded some participants. 2-month washout may be insufficient. Larger, longer confirmatory trials needed. Funded by French Ministry of Health (non-industry).
2Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary SyndromeNCT01147250PMID 26630143
Pfeffer MA et al. - The New England Journal of Medicine (2015) - RCT (Cardiovascular Outcomes Trial, Phase 3b, ELIXA) - 6,068
Lixisenatide demonstrated cardiovascular safety (non-inferiority to placebo; HR 1.02, 95% CI 0.89-1.17 for MACE) in patients with T2DM and recent ACS. Heart failure hospitalization HR 0.96. No excess severe hypoglycemia, pancreatitis, pancreatic neoplasms, or allergic reactions vs placebo. First completed GLP-1 RA CV outcomes trial.
Limitations: Did not demonstrate cardiovascular superiority. All patients had recent ACS (enriched high-risk population). Industry-funded (Sanofi).
3Rationale, design, and baseline characteristics in ELIXANCT01147250PMID 25965710
Bentley-Lewis R et al. - American Heart Journal (2015) - Study design paper - 6,068
ELIXA design paper describing the rationale, study protocol, and baseline characteristics of the 6,068 randomized patients from 49 countries.
Limitations: Design paper only, no outcomes data. See PMID 26630143 for results.
4Efficacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy (GetGoal-Mono)PMID 22432104
Fonseca VA et al. - Diabetes Care (2012) - RCT (Phase 3, double-blind, placebo-controlled) - 361
Over 12 weeks, 1-step and 2-step lixisenatide titration improved HbA1c versus placebo by 0.66% and 0.54%, with 52.2% and 46.5% reaching HbA1c <7.0% versus 26.8% on placebo. Nausea 23%. No severe hypoglycemia.
Limitations: Short placebo-controlled study (12 weeks). No active comparator. Body-weight changes similar across groups. Industry-funded (Sanofi).
5Adding once-daily lixisenatide for type 2 diabetes inadequately controlled with newly initiated and continuously titrated basal insulin glargine (GetGoal-Duo 1)PMID 23564915
Riddle MC et al. - Diabetes Care (2013) - RCT (Phase 3, double-blind, placebo-controlled) - 446
Adding lixisenatide to newly initiated, titrated insulin glargine reduced HbA1c by 0.71% vs 0.40% with placebo, increased HbA1c <7% attainment to 56% vs 39%, lowered 2-h PPG by 3.2 mmol/L vs placebo, reduced body weight by 0.89 kg vs placebo.
Limitations: Industry-funded (Sanofi). Nausea, vomiting, and symptomatic hypoglycemia were more common with lixisenatide.
6Randomized, double-blind, placebo-controlled trial of lixisenatide in Asian patients with T2DM on basal insulin (GetGoal-L-Asia)PMID 22564709
Seino Y et al. - Diabetes, Obesity & Metabolism (2012) - RCT (Phase 3, double-blind, placebo-controlled) - 311
In Asian patients on basal insulin with or without sulfonylurea, lixisenatide improved HbA1c by 0.88% vs placebo, markedly improved PPG. Nausea 39.6%, vomiting 18.2%. No severe hypoglycemia.
Limitations: Regional Asian study. Hypoglycemia rates strongly influenced by concomitant sulfonylurea use. Industry-funded (Sanofi).
7Lixisenatide, a Once-Daily Prandial Glucagon-Like Peptide-1 Receptor Agonist for the Treatment of Adults with Type 2 DiabetesPMID 28556176
Trujillo JM, Goldman J - Pharmacotherapy (2017) - Systematic review - Multiple GetGoal trials reviewed
Comprehensive review of GetGoal program: HbA1c reductions of 0.46-0.99%, 2-h PPG reductions of 55.86-143.43 mg/dL, weight changes -2.96 to +0.3 kg. Symptomatic hypoglycemia 0.8-42.9% (dose/background-dependent), severe hypoglycemia <1.5%. No increased CV risk.
Limitations: Review article, not primary data. Limited long-term safety data beyond 76 weeks.
8A systematic review and meta-analysis of the efficacy of lixisenatide in the treatment of patients with type 2 diabetesPMID 24476092
Schmidt LJ et al. - Diabetes, Obesity & Metabolism (2014) - Systematic review and meta-analysis - 14 RCTs, 6,156 patients
Lixisenatide vs placebo: HbA1c -0.52% (95% CI: -0.64 to -0.39), body weight -0.65 kg (95% CI: -0.94 to -0.37), 2-h PPG -4.58 mmol/L (95% CI: -5.88 to -3.28). More effective at PPG reduction than exenatide and liraglutide but lower HbA1c and weight reduction.
Limitations: Limited head-to-head comparison data at time of publication.
9The effect of subcutaneous Lixisenatide on weight loss in patients with type 2 Diabetes Mellitus: Systematic review and Meta-AnalysisPMID 38490492
Sheng L et al. - Diabetes Research and Clinical Practice (2024) - Systematic review and meta-analysis - 23 articles, 26 RCT arms
Significant reduction in body weight (WMD: -0.97 kg, 95% CI: -1.10 to -0.83, p<0.001) and BMI (WMD: -0.48 kg/m2, 95% CI: -0.67 to -0.29, P<0.001). Greater weight reduction with <19 mcg/day dose (WMD: -1.94 kg) and in patients aged 60+ years (WMD: -1.86 kg).
Limitations: Heterogeneity in study designs, background therapies, and populations.
10Contrasting Effects of Lixisenatide and Liraglutide on Postprandial Glycemic Control, Gastric Emptying, and Safety ParametersPMID 25887358
Meier JJ et al. - Diabetes Care (2015) - RCT (mechanistic, open-label, three-arm) - 142 randomized
Lixisenatide achieved greater postprandial glucose AUC reduction vs liraglutide 1.2 mg (-6.0 h*mmol/L, P<0.001) and 1.8 mg (-4.6 h*mmol/L, P<0.001). Greater gastric emptying delay (P<0.001). Lower 24-h heart rate increase (3 vs 9 bpm, P<0.001). Liraglutide significantly increased lipase levels (+21 IU/L).
Limitations: Open-label. 8-week duration. Small sample size. Industry-funded (Sanofi).
11Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with T2DM on metforminNCT01175473PMID 23368510
Kapitza C et al. - Diabetes, Obesity & Metabolism (2013) - RCT (mechanistic, open-label) - 148 treated
After 28 days, lixisenatide reduced breakfast-test PPG exposure more than liraglutide (-12.6 vs -4.0 h*mmol/L), reduced maximum PPG excursion more (-3.9 vs -1.4 mmol/L), and lowered postprandial glucagon more despite smaller FPG reduction.
Limitations: Short open-label mechanistic study. Not designed for hard clinical outcomes. Industry-funded (Sanofi).
12Mechanisms and clinical efficacy of lixisenatide for the management of type 2 diabetesPMID 23423907
Horowitz M et al. - Advances in Therapy (2013) - Review - N/A (narrative review)
Lixisenatide has ~4-fold higher GLP-1 receptor binding affinity vs native GLP-1. Pronounced gastric emptying delay drives strong PPG lowering. Best suited as add-on to basal insulin due to complementary FPG/PPG coverage.
Limitations: Narrative review, published early in clinical experience.
13LixiLan Proof-of-Concept Randomized TrialPMID 27284114
Rosenstock J et al. - Diabetes Care (2016) - RCT (Phase 3 proof-of-concept) - 323 (161 LixiLan, 162 iGlar)
HbA1c reduced from 8.0% to 6.3% (LixiLan) vs 6.5% (iGlar), demonstrating superiority (difference -0.17%, 95% CI -0.31 to -0.04, P=0.01). 2-h postmeal glucose difference -3.17 mmol/L (P<0.0001). Weight reduced by -1 kg vs +0.5 kg. Low nausea rate (7.5%).
Limitations: Short duration (24 weeks). Industry-funded (Sanofi). Not compared to other intensification strategies.
14LixiLan-L Randomized Trial: iGlarLixi vs insulin glargine in T2DM on basal insulin and metforminPMID 27650977
Aroda VR et al. - Diabetes Care (2016) - RCT (Phase 3) - 736
Once-daily iGlarLixi lowered HbA1c by 1.1% vs 0.6% with insulin glargine alone, achieved HbA1c <7% in 55% vs 30%, reduced body weight by 0.7 kg while glargine alone increased weight by 0.7 kg, with comparable documented symptomatic hypoglycemia.
Limitations: Open-label trial. Industry-funded (Sanofi).
15GetGoal Duo-2 Trial: Lixisenatide Plus Basal Insulin Versus Insulin GlulisinePMID 27222510
Rosenstock J et al. - Diabetes Care (2016) - RCT (Phase 3) - 298 per arm (894 total)
Lixisenatide was noninferior to glulisine once-daily and met coprimary endpoints. HbA1c improved to 7.2% in all arms. Lixisenatide associated with lower symptomatic hypoglycemia and lower body weight vs glulisine groups.
Limitations: Open-label. Industry-funded (Sanofi).
16GetGoal-O: Lixisenatide in Older Patients (>=70 years)PMID 28188240
Meneilly GS et al. - Diabetes Care (2017) - RCT (Phase 3, double-blind, placebo-controlled) - 350
HbA1c reduction -0.57% (lixisenatide) vs +0.06% (placebo, P<0.0001). 2-h PPG reduction -5.12 mmol/L vs -0.07 mmol/L (P<0.0001). Weight loss -1.47 kg vs -0.16 kg (P<0.0001). Safety profile consistent with younger populations.
Limitations: Excluded frail patients and cognitive impairment. 24-week duration. Industry-funded (Sanofi).
17Lixisenatide plus basal insulin: a meta-analysisPMID 25130920
Charbonnel B et al. - Journal of Diabetes and Its Complications (2014) - Meta-analysis - 3 GetGoal trials pooled
Lixisenatide plus basal insulin significantly more effective than basal insulin alone for HbA1c reduction and PPG control. FPG showed no significant difference (complementary mechanism). Increased incidence of hypoglycemia vs basal insulin alone.
Limitations: Pooled 3 trials from same sponsor (Sanofi). Limited to add-on to basal insulin setting.
18Acute Administration of Lixisenatide Diminishes Postprandial Insulin Secretion Associated with Slowing of Gastric EmptyingNCT02308254PMID 35460043
Marathe CS et al. - Diabetes Therapy (2022) - RCT (crossover, double-blind, placebo-controlled) - 30 (15 healthy, 15 T2DM)
Lixisenatide markedly slowed gastric emptying in both healthy subjects (1.45 to 0.60 kcal/min) and T2DM (1.57 to 0.75 kcal/min, both P<0.001). Strong inverse correlation between insulin secretory response and gastric retention in healthy subjects (r=-0.8, P=0.0003).
Limitations: Single-dose study. Small sample size. Acute effects may not fully reflect chronic dosing.
19Postprandial Glucagon Reductions Correlate to Reductions in Postprandial Glucose and HbA1c with LixisenatidePMID 27319011
Ahren B et al. - Diabetes Therapy (2016) - Post hoc analysis of 2 Phase 3 RCTs - GetGoal-M and GetGoal-S pooled
Lixisenatide reduced 2-h postprandial glucagon at Week 24 vs placebo (P<0.00001). Postprandial glucagon change correlated with reductions in postprandial glucose (P<0.00001) and HbA1c (P<0.00001).
Limitations: Post hoc analysis. Industry-funded (Sanofi).
20Lixisenatide Reduces Chylomicron Triacylglycerol by Increased ClearancePMID 30215735
Whyte MB et al. - The Journal of Clinical Endocrinology and Metabolism (2019) - RCT (crossover, double-blind) - 8 obese men with T2DM
Lixisenatide reduced CM-TAG pool size (P=0.046) and CM 13C-oleate AUC (P=0.048) via increased CM-TAG clearance, not decreased production.
Limitations: Very small sample (n=8). Men only. Single-center. Short-term crossover design.
21Effects of Lixisenatide Versus Liraglutide on Esophageal and Gastric FunctionPMID 32647054
Quast DR et al. - Diabetes Care (2020) - RCT (10-week) - 57
Gastric emptying half-time delayed by 52 min with lixisenatide (P=0.0065) vs 25 min with liraglutide (P=0.025). Gastric acidity decreased by -20.7% with GLP-1 RAs (P=0.042). No significant effect on esophageal reflux.
Limitations: Relatively small sample. 10-week duration.
22Low incidence of GI adverse events with iGlarLixi versus lixisenatide alonePMID 29923298
Trujillo JM et al. - Diabetes, Obesity & Metabolism (2018) - Post hoc analysis of Phase 3 RCTs - LixiLan-L and LixiLan-O combined
GI AE rate: 9.6-11.7% (iGlarLixi) vs 27.5% (lixisenatide alone). GI AEs were transient, mostly mild-moderate, occurred mainly during initial titration. Median nausea duration 5-6 days.
Limitations: Post hoc analysis. Industry-funded (Sanofi).
23Long-term safety of lixisenatide in Japanese patients (GetGoal-Mono-Japan)PMID 26342556
Seino Y et al. - Journal of Diabetes and Its Complications (2015) - RCT (76-week, open-label, parallel-group) - 69
2-step dose regimen resulted in less nausea (36.4% vs 50.0%) vs 1-step regimen at 24 weeks. HbA1c, FPG, and body weight reduced at weeks 24 and 76. No severe hypoglycemia.
Limitations: Small sample (n=69). Open-label. Japanese population only. Industry-funded (Sanofi).
24Reduction of postprandial glucose by lixisenatide vs sitagliptin (NEXTAGE Study)NCT02200991PMID 28345162
Yamada Y et al. - Diabetes, Obesity & Metabolism (2017) - RCT (Phase IV, open-label) - 136
Lixisenatide reduced PPG exposure significantly more than sitagliptin: PPG AUC difference -234.0 h*mg/dL (P<0.0001). Maximum PPG excursion: -122.4 vs -46.6 mg/dL (P<0.0001).
Limitations: Open-label. Japanese population. Short duration (29 days primary endpoint). Industry-funded.
25Postprandial renal haemodynamic effect of lixisenatide vs glulisineNCT02276196PMID 28449402
Tonneijck L et al. - Diabetes, Obesity & Metabolism (2017) - RCT (8-week, open-label) - 35
Lixisenatide did not affect postprandial GFR or ERPF vs glulisine. Increased fractional sodium excretion (+0.25%), sustained natriuretic effect. Increased postprandial MAP (+9 mmHg).
Limitations: Small sample (n=35). Open-label. 8-week duration.
26PK, PD and safety of lixisenatide in children and adolescents with T2DMNCT02803918PMID 35411611
Barrientos-Perez M et al. - Pediatric Diabetes (2022) - RCT (Phase 1, ascending dose) - 23 (18 lixisenatide, 5 placebo)
Safety profile consistent with adults in children/adolescents 10-17 years. Most common AEs: vomiting (11.1%) and nausea (11.1%). No symptomatic hypoglycemia.
Limitations: Very small sample (n=23). Phase 1 only. 6-week duration. Industry-funded (Sanofi).
27Lixisenatide: first global approvalPMID 23558600
Elkinson S, Keating GM - Drugs (2013) - Drug approval review - N/A
Lixisenatide is a 44-amino-acid GLP-1 receptor agonist based on exendin-4 with C-terminal hexa-lysine extension and amidation for DPP-4 resistance. First approved in EU (2013).
Limitations: Approval-stage review with limited long-term data.
28Efficacy of lixisenatide across diverse beta-cell function (GetGoal-M and GetGoal-S)PMID 27267268
Yabe D et al. - Journal of Diabetes and Its Complications (2016) - Post hoc analysis of 2 Phase 3 RCTs - 437 lixisenatide-treated patients
Lixisenatide reduced HbA1c (-0.83% to -0.99%) and PPG (-4.3 to -7.9 mmol/L) across all beta-cell function quartiles (all P<0.0001).
Limitations: Post hoc analysis. Industry-funded (Sanofi).