Emerging technologies to achieve oral delivery of GLP-1 and GLP-1 analogs for treatment of type 2 diabetes mellitus (T2DM)

Ma, Shengwu; We, Liang; Yang, Hongji; Deng, Shaoping; Jevnikar, Anthony M.

doi:10.24870/cjb.2017-000107

Cited by 12 publications

(14 citation statements)

References 62 publications

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“…An oral GLP‐1RA formulation may improve acceptance and adherence for some patients compared with injectable GLP‐1RAs and may lead to earlier initiation of GLP‐1RA treatment in type 2 diabetes. However, successful delivery of peptides, such as GLP‐1RAs, through the oral route is challenging, because of numerous barriers to absorption, including degradation by gastrointestinal enzymes, pH‐induced conformational changes and limited protein permeability of the intestinal membrane …”

Section: Introductionmentioning

confidence: 99%

“…However, successful delivery of peptides, such as GLP-1RAs, through the oral route is challenging, because of numerous barriers to absorption, including degradation by gastrointestinal enzymes, pHinduced conformational changes and limited protein permeability of the intestinal membrane. 7,8 Semaglutide, a glucagon-like peptide-1 (GLP-1) analogue shown to improve glycaemic control and reduce body weight when administered subcutaneously (s.c.) in patients with type 2 diabetes [9][10][11] and recently approved for use in Europe, 12 Canada, 13 Japan 14 and the United States, 15 is being developed as a once-daily oral tablet formulation. Oral semaglutide is co-formulated with sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC), an absorption enhancer that promotes the absorption of semaglutide across the gastric mucosa via effects on transcellular pathways.…”

Section: Introductionmentioning

confidence: 99%

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Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial

Bain

Mosenzon

Arechavaleta

et al. 2018

Diabetes Obesity Metabolism

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Aims To assess the cardiovascular (CV) safety of oral semaglutide, the first tablet formulation of a glucagon‐like peptide‐1 receptor agonist. Materials and methods PIONEER 6 is a multinational, randomized, placebo‐controlled, double‐blind trial in patients with type 2 diabetes at high risk of CV events (defined as being aged ≥50 years and having established CV disease [CVD] or moderate [stage 3] chronic kidney disease [CKD], or being aged ≥60 years with ≥1 other CV risk factor). Patients were randomized to once‐daily oral semaglutide (up to 14 mg) or placebo added to standard of care. The primary composite endpoint is time to first occurrence of CV death or non‐fatal myocardial infarction or non‐fatal stroke. The primary hypothesis was to exclude an excess in CV risk with oral semaglutide by assessing non‐inferiority versus placebo for the primary endpoint (non‐inferiority margin of 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio). PIONEER 6 is event‐driven, with follow‐up continuing until accrual of at least 122 primary outcome events. There is no pre‐defined minimal duration. Results Overall, 3183 patients have been enrolled (mean age 66.1 years, 31.6% females) in 214 sites across 21 countries. At baseline, the mean duration of diabetes was 14.9 years, mean glycated haemoglobin concentration was 66 mmol/mol (8.2%), and 84.6% of patients had established CVD/moderate CKD. Conclusions PIONEER 6 will provide evidence regarding the CV safety of oral semaglutide in patients with type 2 diabetes and high CV risk.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial

Bain

Mosenzon

Arechavaleta

et al. 2018

Diabetes Obesity Metabolism

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“…Moreover, oral delivery appears to be feasible for Lira due to the relatively large safety window of GLP1 analogs compared to insulin [9]. However, the oral delivery of Lira is still challenging due to low stability along the gastrointestinal (GI) tract and poor intestinal permeability that result in low oral bioavailability [10].…”

Section: Introductionmentioning

confidence: 99%

Encapsulation in Polymeric Nanoparticles Enhances the Enzymatic Stability and the Permeability of the GLP-1 Analog, Liraglutide, Across a Culture Model of Intestinal Permeability

et al. 2019

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The potential of poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) to overcome the intestinal barrier that limits oral liraglutide delivery was evaluated. Liraglutide-loaded PLGA NPs were prepared by the double emulsion solvent evaporation method. In vitro release kinetics and enzymatic degradation studies were conducted, mimicking the gastrointestinal environment. The permeability of liraglutide solution, liraglutide-loaded PLGA NPs, and liraglutide in the presence of the absorption enhancer PN159 peptide was tested on the Caco-2 cell model. Liraglutide release from PLGA NPs showed a biphasic release pattern with a burst effect of less than 15%. The PLGA nanosystem protected the encapsulated liraglutide from the conditions simulating the gastric environment. The permeability of liraglutide encapsulated in PLGA NPs was 1.5-fold higher (24 × 10−6 cm/s) across Caco-2 cells as compared to liraglutide solution. PLGA NPs were as effective at elevating liraglutide penetration as the tight junction-opening PN159 peptide. No morphological changes were seen in the intercellular junctions of Caco-2 cells after treatment with liraglutide-PLGA NPs, confirming the lack of a paracellular component in the transport mechanism. PLGA NPs, by protecting liraglutide from enzyme degradation and enhancing its permeability across intestinal epithelium, hold great potential as carriers for oral GLP-1 analog delivery.

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“…Novo Nordisk finally followed the latter approach (using absorption enhancers) for the development of oral semaglutide. The selected absorption enhancer was a system known as the Eligen TM oral drug delivery system,33 a platform based on the use of synthetic nonacylated amino acid as carriers, via the natural passive transcellular GI transport. Specifically, semaglutide was combined with sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC), which is a small-chain fatty acid that facilitates semaglutide absorption by acting transcellularly on the gastric mucosa through a localized pH increase 34,35…”

Section: Oral Semaglutidementioning

confidence: 99%

<p>The development of an oral GLP-1 receptor agonist for the management of type 2 diabetes: evidence to date</p>

Antza¹,

Nirantharakumar²,

Doundoulakis³

et al. 2019

DDDT

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Glucagon-like peptide 1 receptor agonists (GLP1-RA) are prominent agents in the therapeutics of type 2 diabetes mellitus due to their exemplary efficacy in both preprandial and postprandial glycemia, their safety, low risk of hypoglycemia, their multilevel pathophysiological superiority, weight loss and importantly the observed benefits in cardiovascular disease reduction. Their major drawback is the subcutaneous route of administration, constituting a barrier to adoption and reason for treatment discontinuation. Thus, the development of an oral GLP1-RA agent would promote medication adherence and quality of life, further consolidating its beneficial effects in real-life clinical practice. However, this task is hampered by suboptimal gastrointestinal protein absorption. Yet, the introduction of oral semaglutide, a modified form of semaglutide with the addition of a carrier sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, may have provided a safe and effective way to reach systemic circulation while other molecules are in development. Whether this molecule still has the impressive cardiovascular effects demonstrated with the use of its precursor remains to be explored. However, to date, its efficacy and safety have already been showcased in a randomized trial. More research is warranted in order to further consolidate these findings across different type 2 diabetes mellitus (T2DM) subpopulations, and adequately powered studies with a longer follow-up that would allow the exploration of microvascular and macrovascular complications are needed. Finally, studies comparing oral semaglutide and similar molecules with other currently established antidiabetic agents to evaluate the relative efficacy, the cost-effectiveness and further understand its place in T2DM therapeutic algorithm are needed. This review focuses on the development of oral GLP1-RA agents and summarizes the challenges, milestones and expected benefits associated with a successful introduction.

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Emerging technologies to achieve oral delivery of GLP-1 and GLP-1 analogs for treatment of type 2 diabetes mellitus (T2DM)

Cited by 12 publications

References 62 publications

Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial

Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: Rationale, design and patient baseline characteristics for the PIONEER 6 trial

Encapsulation in Polymeric Nanoparticles Enhances the Enzymatic Stability and the Permeability of the GLP-1 Analog, Liraglutide, Across a Culture Model of Intestinal Permeability

<p>The development of an oral GLP-1 receptor agonist for the management of type 2 diabetes: evidence to date</p>

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