Therapeutics

Semaglutide

Overview

Name: Semaglutide
Synonyms: Ozempic, Rybelsus
Therapy Type: Other
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3), Parkinson's Disease (Phase 2)
Company: Novo Nordisk A/S
Approved for: Type 2 Diabetes

Background

Semaglutide is a synthetic, long-acting analog of glucagon-like peptide-1, used to treat diabetes. OzempicTM is a once-per-week injection formulation, while RybelsusTM is is a daily pill. RybelsusTM was approved by the U.S. FDA in September 2019 as the first GLP-1 analog that does not need to be injected. It is also approved for use in Japan and the European Union.

GLP-1 is a hormone produced in the gut that activates receptors in the gut, liver, and pancreas to stimulate insulin release, and restore insulin sensitivity (for review, see Knudsen and Lau, 2019). GLP-1 crosses the blood-brain barrier and may improve insulin signaling in the brain (Hölscher, 2018Salameh et al., 2020). GLP‐1 also promotes hippocampal synaptic plasticity, cognition, and cell survival (During et al., 2003). In some people with Alzheimer’s disease, there is evidence for insulin resistance in the brain, providing a rationale for testing semaglutide as a potential therapeutic for AD. Other GLP-1 analogs, for example exendin-4 and liraglutide, are currently in clinical trials for Parkinson’s or Alzheimer’s diseases.

There are few published preclinical studies for semaglutide in Alzheimer’s. A cell-based study implicated the drug in enhanced autophagy and reduced apoptosis (Chang et al., 2020). The drug is reported to be active in rodent models of Parkinson’s (Zhang et al., 2019; Zhang et al., 2018) and stroke (Yang et al., 2019).

Findings

In September 2018, researchers at the University of Oslo registered a Phase 2 trial of semaglutide for Parkinson’s disease. The study aims to enroll 120 newly diagnosed PD patients who will receive 1 mg drug or placebo by weekly injection for two years, followed by an additional two years of open-label administration. As of February 2020, the trial had not begun recruiting.

A Phase 2a trial of semaglutide tablets in 60 people with mild Alzheimer's disease has received funding from the Alzheimer's Association's Part the Cloud program, but is not registered yet.

On December 16, 2020, Novo Nordisk announced it would begin development of semaglutide in people with early Alzheimer’s disease (see press release). Beginning in the first half of 2021, the Phase 3a program will enroll 3,700 people for a planned two-year course of a once-daily 14 mg semaglutide pill or placebo. The company said the decision was based on evaluation of GLP-1 data from preclinical models, real-world studies involving patient registry and insurance claims databases, and post hoc analysis of data from three large cardiovascular outcome trials of semaglutide and liraglutide. That analysis reportedly found a 53 percent reduction in the risk of developing dementia in people with Type 2 diabetes who took either GLP-1 agonist compared to placebo.

In March 2021, the company registered two Phase 3 trials, each enrolling 1,840 people with mild cognitive impairment or mild dementia due to Alzheimer’s disease, confirmed by amyloid PET or CSF Aβ42. The sole primary outcome is change in CDR-SB. Secondary outcomes include other standard cognitive and functional scales, as well as cardiovascular events and stroke. The trials include a one-year extension, and will start in May 2021.

For details on semaglutide trials, see clinicaltrials.gov.

Last Updated: 20 Apr 2021

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References

Therapeutics Citations

  1. Liraglutide

Paper Citations

  1. . The Discovery and Development of Liraglutide and Semaglutide. Front Endocrinol (Lausanne). 2019;10:155. Epub 2019 Apr 12 PubMed.
  2. . 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.
  3. . Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer's and Parkinson's disease therapeutics. Biochem Pharmacol. 2020 Oct;180:114187. Epub 2020 Aug 2 PubMed.
  4. . Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003 Sep;9(9):1173-9. PubMed.
  5. . Semaglutide-mediated protection against Aβ correlated with enhancement of autophagy and inhibition of apotosis. J Clin Neurosci. 2020 Nov;81:234-239. Epub 2020 Oct 14 PubMed.
  6. . Semaglutide is Neuroprotective and Reduces α-Synuclein Levels in the Chronic MPTP Mouse Model of Parkinson's Disease. J Parkinsons Dis. 2019;9(1):157-171. PubMed.
  7. . Neuroprotective effects of the novel GLP-1 long acting analogue semaglutide in the MPTP Parkinson's disease mouse model. Neuropeptides. 2018 Oct;71:70-80. Epub 2018 Jul 11 PubMed.
  8. . The diabetes drug semaglutide reduces infarct size, inflammation, and apoptosis, and normalizes neurogenesis in a rat model of stroke. Neuropharmacology. 2019 Nov 1;158:107748. Epub 2019 Aug 26 PubMed.

Other Citations

  1. exendin-4

External Citations

  1. Phase 2 trial
  2. Part the Cloud program
  3. press release
  4. clinicaltrials.gov

Further Reading

Papers

  1. . Effects of glucagon-like peptide 1 receptor agonists on comorbidities in older patients with diabetes mellitus. Ther Adv Chronic Dis. 2019;10:2040622319862691. Epub 2019 Jul 12 PubMed.
  2. . Diabetes, insulin and new therapeutic strategies for Parkinson's disease: Focus on glucagon-like peptide-1 receptor agonists. Front Neuroendocrinol. 2021 Apr 15;62:100914. PubMed.
  3. . An extended release GLP-1 analogue increases α-synuclein accumulation in a mouse model of prodromal Parkinson's disease. Exp Neurol. 2021 Mar 13;341:113693. PubMed.
  4. . GLP-1 receptor agonists for Parkinson's disease. Cochrane Database Syst Rev. 2020 Jul 23;7:CD012990. PubMed.