Therapeutics

Liraglutide

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Overview

Name: Liraglutide
Synonyms: Victoza™, Saxenda™
Therapy Type: Other
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2), Parkinson's Disease (Phase 2)
Company: Novo Nordisk A/S
Approved for: Diabetes, weight loss

Background

Liraglutide is an analog of glucagon-like peptide 1. GLP-1 is a hormone that is produced in the gut and activates receptors in the gut, liver, and pancreas to control blood-sugar levels and reduce insulin resistance.

GLP-1 crosses the blood-brain barrier and may improve insulin signaling in the brain (Hölscher, 2018). GLP‐1 was also reported to promote hippocampal synaptic plasticity, cognition, and cell survival (During et al., 2003).    

Diabetes, high blood sugar, and insulin resistance are all associated with dementia. In Alzheimer’s disease, there is evidence for insulin resistance in the brain. Thus, there has been much interest in testing liraglutide and other GLP-1 analogs, such as exendin-4 and semaglutide as potential therapeutics for AD.

Liraglutide has been tested in preclinical AD models. In the APP/PS1 transgenic mouse, liraglutide reduced amyloid deposition, glial activation, and synapse loss, increased neurogenesis, and improved memory  (McClean et al., 2011). Memory reportedly improved regardless of whether liraglutide was given before or after amyloid plaques were established (McClean and Hölscher, 2013; McClean et al., 2015). The same group reported improvements in cerebral blood vessel structure in liraglutide-treated AD mice, resulting in fewer microaneurysms, and less vascular leakage (Kelly et al., 2015). A different group found no effect of liraglutide on amyloid load in the same APP/PS1 model, and one other transgenic model (Hansen et al., 2016). 

Liraglutide reduced tau pathology and cognitive impairment in two different models, APP/PS1/Tau triple transgenic mice and mice with Aβ oligomers infused into the brain (Chen et al., 2017; Qi et al., 2016). In mice expressing mutated human tau, the drug reduced phosphorylation of tau and improved a motor phenotype (Hansen et al., 2016). It lessened tau hyperphosphorylation and Aβ overproduction, and normalized insulin signaling in rats with high blood homocysteine, a risk factor for AD (Zhang et al., 2019).

In nonhuman primates, liraglutide partially restored a loss of insulin receptors and synapses caused by Aβ oligomer infusion into the brain (Batista et al., 2018).

Liraglutide also shows activity in mouse models of Parkinson's disease (Liu et al., 2015; Hansen et al., 2016; Badawi et al., 2017), stroke (He et al., 2020), spinal cord injury (Zhang et al., 2020), and traumatic brain injury (Bader et al., 2019).

A peptide drug, liraglutide is injected once a day using a prefilled disposable pen. Gastrointestinal side effects are common, including nausea, diarrhea, vomiting, decreased appetite, indigestion, and constipation. Liraglutide can cause hypoglycemia and dizziness. In mice and rats, liraglutide caused thyroid tumors, and it should not be taken by people at risk for thyroid cancer.

Findings

A study of liraglutide in 34 people with clinically diagnosed AD began in January 2012 at Aarhus University, Denmark. The primary outcome was change in cerebral amyloid deposition, measured by PiB-PET at baseline and after six months of 1.8 mg liraglutide or placebo per day. Secondary outcomes were the Wechsler Memory Scale-IV for cognition and FDG-PET to measure cerebral glucose metabolism (Egefjord et al., 2012). In the study, amyloid load increased and cognition remained unchanged in both liraglutide and placebo groups. FDG-PET declined in the placebo but not in the liraglutide group (May 2016 news on Gejl et al., 2016). Liraglutide boosted FDG-PET in the AD patients by increasing glucose transfer across the blood-brain barrier, restoring it to the level of healthy controls (Gejl et al., 2017).

In August 2013, a trial at Stanford University examined whether liraglutide affected memory in prediabetes. It enrolled 41 people between 50 and 70 who had elevated blood glucose or impaired glucose tolerance. All were cognitively normal, but expressed subjective memory complaints. Half had a family history of dementia. After 12 weeks of 1.8 mg liraglutide daily or placebo, the investigators detected no change in cognition. They did report an improvement in functional MRI measures of brain connectivity in the default mode network, a system affected in AD (Watson et al., 2019).

Another study of similar size, conducted in Italy, compared memory test scores in people with obesity and pre- or early diabetes who lost weight and improved their metabolic profile while taking liraglutide to test scores of people who achieved equivalent weight loss and metabolic changes with diet and lifestyle changes  only. The liraglutide group significantly improved on a test of short-term memory and a memory composite, compared to the lifestyle change only group (Vadini et al., 2020).

In January 2014, a larger trial in AD started up at Imperial College London. The ELAD study enrolled 204 participants with mild AD dementia but without diabetes for a 12-month course of 1.8 mg liraglutide or placebo per day. The primary outcome is change in FDG-PET. Secondary outcomes include standard clinical and cognitive measures (ADAS-Cog, executive domain scores of the Neuropsychological Test Battery, CDR-SB, and ADCS-ADL), volumetric MRI, as well as changes in PET measures of microglial activation, tau, amyloid, and safety. The protocol is published (Femminella et al., 2019). The trial ended in December 2019. As presented at the 2020 CTAD conference, liraglutide failed on the primary outcome, as no difference in glucose uptake was registered between treatment and placebo groups. Three of five secondary outcomes were improved: the treatment group lost less temporal lobe volume and total brain gray matter volume, and performed better on the ADAS-Exec score, a cognitive outcome that combined the ADAS-Cog and executive domain portions of the NTSB. The CDR-SB and ADCS-ADL were unchanged. The treatment was safe, with fewer serious adverse events in drug versus placebo, and no deaths.

In April 2017, a trial at Cedar-Sinai Medical Center, Los Angeles, began recruiting 63 people with Parkinson’s disease to compare a one-year course of up to 1.8 mg liraglutide daily to placebo. The study is measuring motor, non-motor, and cognitive function, and is set to finish in September 2021. 

In May 2019, a trial at Nanjing University Hospital began comparing liraglutide to the antidiabetic medications dapaglifozin and to acarbose, for their respective effects on cognitive and olfactory function in 87 overweight people whose Type 2 diabetes is poorly controlled with metformin alone. Outcome measures of this 16-week trial include fMRI of odor-induced brain activation, change on the MoCA cognition screen, and an odor detection test. This trial is set to end in February 2021.

Liraglutide is also being evaluated in minor stroke/transient ischemic attack in people with Type 2 diabetes.

For details on liraglutide trials in neurologic indications, see clinicaltrials.gov

Last Updated: 20 Apr 2021

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References

News Citations

  1. Diabetes Drug May Rev Up Brain Metabolism in People with Alzheimer’s

Therapeutics Citations

  1. Dapagliflozin
  2. Semaglutide

Paper Citations

  1. Egefjord L, Gejl M, Møller A, Braendgaard H, Gottrup H, Antropova O, Møller N, Poulsen HE, Gjedde A, Brock B, Rungby J. Effects of liraglutide on neurodegeneration, blood flow and cognition in Alzheimer´s disease - protocol for a controlled, randomized double-blinded trial. Dan Med J. 2012 Oct;59(10):A4519. PubMed.
  2. Gejl M, Gjedde A, Egefjord L, Møller A, Hansen SB, Vang K, Rodell A, Brændgaard H, Gottrup H, Schacht A, Møller N, Brock B, Rungby J. In Alzheimer's Disease, 6-Month Treatment with GLP-1 Analog Prevents Decline of Brain Glucose Metabolism: Randomized, Placebo-Controlled, Double-Blind Clinical Trial. Front Aging Neurosci. 2016;8:108. Epub 2016 May 24 PubMed.
  3. Gejl M, Brock B, Egefjord L, Vang K, Rungby J, Gjedde A. Blood-Brain Glucose Transfer in Alzheimer's disease: Effect of GLP-1 Analog Treatment. Sci Rep. 2017 Dec 13;7(1):17490. PubMed.
  4. Watson KT, Wroolie TE, Tong G, Foland-Ross LC, Frangou S, Singh M, McIntyre RS, Roat-Shumway S, Myoraku A, Reiss AL, Rasgon NL. Neural correlates of liraglutide effects in persons at risk for Alzheimer's disease. Behav Brain Res. 2019 Jan 1;356:271-278. Epub 2018 Aug 9 PubMed.
  5. Vadini F, Simeone PG, Boccatonda A, Guagnano MT, Liani R, Tripaldi R, Di Castelnuovo A, Cipollone F, Consoli A, Santilli F. Liraglutide improves memory in obese patients with prediabetes or early type 2 diabetes: a randomized, controlled study. Int J Obes (Lond). 2020 Jun;44(6):1254-1263. Epub 2020 Jan 21 PubMed.
  6. Femminella GD, Frangou E, Love SB, Busza G, Holmes C, Ritchie C, Lawrence R, McFarlane B, Tadros G, Ridha BH, Bannister C, Walker Z, Archer H, Coulthard E, Underwood BR, Prasanna A, Koranteng P, Karim S, Junaid K, McGuinness B, Nilforooshan R, Macharouthu A, Donaldson A, Thacker S, Russell G, Malik N, Mate V, Knight L, Kshemendran S, Harrison J, Brooks DJ, Passmore AP, Ballard C, Edison P. Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study). Trials. 2019 Apr 3;20(1):191. PubMed. Correction.
  7. Hölscher C. Novel dual GLP-1/GIP receptor agonists show neuroprotective effects in Alzheimer's and Parkinson's disease models. Neuropharmacology. 2018 Jul 1;136(Pt B):251-259. Epub 2018 Jan 31 PubMed.
  8. During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, Bland RJ, Klugmann M, Banks WA, Drucker DJ, Haile CN. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003 Sep;9(9):1173-9. PubMed.
  9. McClean PL, Parthsarathy V, Faivre E, Hölscher C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. J Neurosci. 2011 Apr 27;31(17):6587-94. PubMed.
  10. McClean PL, Hölscher C. Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer's disease. Neuropharmacology. 2013 Aug 21; PubMed.
  11. McClean PL, Jalewa J, Hölscher C. Prophylactic liraglutide treatment prevents amyloid plaque deposition, chronic inflammation and memory impairment in APP/PS1 mice. Behav Brain Res. 2015 Oct 15;293:96-106. Epub 2015 Jul 20 PubMed.
  12. Kelly P, McClean PL, Ackermann M, Konerding MA, Hölscher C, Mitchell CA. Restoration of cerebral and systemic microvascular architecture in APP/PS1 transgenic mice following treatment with Liraglutide™. Microcirculation. 2015 Feb;22(2):133-45. PubMed.
  13. Hansen HH, Fabricius K, Barkholt P, Kongsbak-Wismann P, Schlumberger C, Jelsing J, Terwel D, Termont A, Pyke C, Knudsen LB, Vrang N. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer's Disease. PLoS One. 2016;11(7):e0158205. Epub 2016 Jul 15 PubMed.
  14. Chen S, Sun J, Zhao G, Guo A, Chen Y, Fu R, Deng Y. Liraglutide Improves Water Maze Learning and Memory Performance While Reduces Hyperphosphorylation of Tau and Neurofilaments in APP/PS1/Tau Triple Transgenic Mice. Neurochem Res. 2017 Aug;42(8):2326-2335. Epub 2017 Apr 6 PubMed.
  15. Qi L, Ke L, Liu X, Liao L, Ke S, Liu X, Wang Y, Lin X, Zhou Y, Wu L, Chen Z, Liu L. Subcutaneous administration of liraglutide ameliorates learning and memory impairment by modulating tau hyperphosphorylation via the glycogen synthase kinase-3β pathway in an amyloid β protein induced alzheimer disease mouse model. Eur J Pharmacol. 2016 Jul 15;783:23-32. Epub 2016 Apr 27 PubMed.
  16. Hansen HH, Barkholt P, Fabricius K, Jelsing J, Terwel D, Pyke C, Knudsen LB, Vrang N. The GLP-1 receptor agonist liraglutide reduces pathology-specific tau phosphorylation and improves motor function in a transgenic hTauP301L mouse model of tauopathy. Brain Res. 2016 Mar 1;1634:158-70. Epub 2015 Dec 31 PubMed.
  17. Zhang Y, Xie JZ, Xu XY, Hu J, Xu T, Jin S, Yang SJ, Wang JZ. Liraglutide Ameliorates Hyperhomocysteinemia-Induced Alzheimer-Like Pathology and Memory Deficits in Rats via Multi-molecular Targeting. Neurosci Bull. 2019 Aug;35(4):724-734. Epub 2019 Jan 10 PubMed.
  18. Batista AF, Forny-Germano L, Clarke JR, Lyra E Silva NM, Brito-Moreira J, Boehnke SE, Winterborn A, Coe BC, Lablans A, Vital JF, Marques SA, Martinez AM, Gralle M, Holscher C, Klein WL, Houzel JC, Ferreira ST, Munoz DP, De Felice FG. The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer's disease. J Pathol. 2018 May;245(1):85-100. Epub 2018 Apr 2 PubMed.
  19. Liu W, Jalewa J, Sharma M, Li G, Li L, Hölscher C. Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Neuroscience. 2015 Sep 10;303:42-50. Epub 2015 Jul 2 PubMed.
  20. Hansen HH, Fabricius K, Barkholt P, Mikkelsen JD, Jelsing J, Pyke C, Knudsen LB, Vrang N. Characterization of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in rat partial and full nigral 6-hydroxydopamine lesion models of Parkinson's disease. Brain Res. 2016 Sep 1;1646:354-365. Epub 2016 May 24 PubMed.
  21. Badawi GA, Abd El Fattah MA, Zaki HF, El Sayed MI. Sitagliptin and liraglutide reversed nigrostriatal degeneration of rodent brain in rotenone-induced Parkinson's disease. Inflammopharmacology. 2017 Jun;25(3):369-382. Epub 2017 Mar 4 PubMed.
  22. He W, Wang H, Zhao C, Tian X, Li L, Wang H. Role of liraglutide in brain repair promotion through Sirt1-mediated mitochondrial improvement in stroke. J Cell Physiol. 2020 Mar;235(3):2986-3001. Epub 2019 Sep 18 PubMed.
  23. Zhang D, Yu D, Mei X, Lv G. Liraglutide provides neuroprotection by regulating autophagy through the AMPK-FOXO3 signaling pathway in a spinal contusion injury rat model. Neurosci Lett. 2020 Feb 16;720:134747. Epub 2020 Jan 9 PubMed.
  24. Bader M, Li Y, Tweedie D, Shlobin NA, Bernstein A, Rubovitch V, Tovar-Y-Romo LB, DiMarchi RD, Hoffer BJ, Greig NH, Pick CG. Neuroprotective Effects and Treatment Potential of Incretin Mimetics in a Murine Model of Mild Traumatic Brain Injury. Front Cell Dev Biol. 2019;7:356. Epub 2020 Jan 10 PubMed.

Other Citations

  1. exendin-4

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Muscogiuri G, DeFronzo RA, Gastaldelli A, Holst JJ. Glucagon-like Peptide-1 and the Central/Peripheral Nervous System: Crosstalk in Diabetes. Trends Endocrinol Metab. 2017 Feb;28(2):88-103. Epub 2016 Oct 27 PubMed.
  2. Wiciński M, Socha M, Malinowski B, Wódkiewicz E, Walczak M, Górski K, Słupski M, Pawlak-Osińska K. Liraglutide and its Neuroprotective Properties-Focus on Possible Biochemical Mechanisms in Alzheimer's Disease and Cerebral Ischemic Events. Int J Mol Sci. 2019 Feb 28;20(5) PubMed.
  3. Chow HM, Shi M, Cheng A, Gao Y, Chen G, Song X, So RW, Zhang J, Herrup K. Age-related hyperinsulinemia leads to insulin resistance in neurons and cell-cycle-induced senescence. Nat Neurosci. 2019 Nov;22(11):1806-1819. Epub 2019 Oct 21 PubMed.
  4. Salles GN, Calió ML, Afewerki S, Pacheco-Soares C, Porcionatto M, Hölscher C, Lobo AO. Prolonged Drug-Releasing Fibers Attenuate Alzheimer's Disease-like Pathogenesis. ACS Appl Mater Interfaces. 2018 Oct 31;10(43):36693-36702. Epub 2018 Oct 22 PubMed.
  5. Muscogiuri G, DeFronzo RA, Gastaldelli A, Holst JJ. Glucagon-like Peptide-1 and the Central/Peripheral Nervous System: Crosstalk in Diabetes. Trends Endocrinol Metab. 2017 Feb;28(2):88-103. Epub 2016 Oct 27 PubMed.
  6. Hansen HH, Fabricius K, Barkholt P, Niehoff ML, Morley JE, Jelsing J, Pyke C, Knudsen LB, Farr SA, Vrang N. The GLP-1 Receptor Agonist Liraglutide Improves Memory Function and Increases Hippocampal CA1 Neuronal Numbers in a Senescence-Accelerated Mouse Model of Alzheimer's Disease. J Alzheimers Dis. 2015 Jun 26;46(4):877-88. PubMed.
  7. Long-Smith CM, Manning S, McClean PL, Coakley MF, O'Halloran DJ, Holscher C, O'Neill C. The Diabetes Drug Liraglutide Ameliorates Aberrant Insulin Receptor Localisation and Signalling in Parallel with Decreasing Both Amyloid-β Plaque and Glial Pathology in a Mouse Model of Alzheimer's Disease. Neuromolecular Med. 2012 Sep 21; PubMed.
  8. Parthsarathy V, Hölscher C. Chronic treatment with the GLP1 analogue liraglutide increases cell proliferation and differentiation into neurons in an AD mouse model. PLoS One. 2013;8(3):e58784. PubMed.
  9. Hölscher C. Brain insulin resistance: role in neurodegenerative disease and potential for targeting. Expert Opin Investig Drugs. 2020 Apr;29(4):333-348. Epub 2020 Mar 16 PubMed.
  10. Muscogiuri G, DeFronzo RA, Gastaldelli A, Holst JJ. Glucagon-like Peptide-1 and the Central/Peripheral Nervous System: Crosstalk in Diabetes. Trends Endocrinol Metab. 2017 Feb;28(2):88-103. Epub 2016 Oct 27 PubMed.
  11. Muñoz-Jiménez M, Zaarkti A, García-Arnés JA, García-Casares N. Antidiabetic Drugs in Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review. Dement Geriatr Cogn Disord. 2020;49(5):423-434. Epub 2020 Oct 20 PubMed.
  12. Maskery M, Goulding EM, Gengler S, Melchiorsen JU, Rosenkilde MM, Hölscher C. The Dual GLP-1/GIP Receptor Agonist DA4-JC Shows Superior Protective Properties Compared to the GLP-1 Analogue Liraglutide in the APP/PS1 Mouse Model of Alzheimer's Disease. Am J Alzheimers Dis Other Demen. 2020 Jan-Dec;35:1533317520953041. PubMed.
  13. Kong J, Wan L, Wang Y, Zhang H, Zhang W. Liraglutide Attenuates Aβ42 Generation in APPswe/SH-SY5Y Cells Through the Regulation of Autophagy. Neuropsychiatr Dis Treat. 2020;16:1817-1825. Epub 2020 Jul 27 PubMed.