UNASSIGNED: The aim of this review was to provide all the pharmacokinetic data for semaglutide in humans concerning its pharmacokinetics after subcutaneously and oral applications in healthy and diseased populations, to provide recommendations for clinical use.
UNASSIGNED: The PubMed and Embase databases were searched to screen studies associated with the pharmacokinetics of semaglutide. The pharmacokinetic parameters included area under the curve plasma concentrations (AUC), maximal plasma concentration (Cmax), time to Cmax, half-life (t1/2), and clearance. The systematic literature search retrieved 17 articles including data on pharmacokinetic profiles after subcutaneously and oral applications of semaglutide, and at least one of the above pharmacokinetic parameter was reported in all included studies.
UNASSIGNED: Semaglutide has a predictable pharmacokinetic profile with a long t1/2 that allows for once-weekly subcutaneous administration. The AUC and Cmax of both oral and subcutaneous semaglutide increased with dose. Food and various dosing conditions including water volume and dosing schedules can affect the oral semaglutide exposure. There are limited drug-drug interactions and no dosing adjustments in patients with upper gastrointestinal disease, renal impairment or hepatic impairment. Body weight may affect semaglutide exposure, but further studies are needed to confirm this.
UNASSIGNED: This review encompasses all the pharmacokinetic data for subcutaneous and oral semaglutide in both healthy and diseased participants. The existing pharmacokinetic data can assist in developing and evaluating pharmacokinetic models of semaglutide and will help clinicians predict semaglutide dosages. In addition, it can also help optimize future clinical trials.

UNASSIGNED: This study was conducted to investigate the effects of glucagon-like peptide-1 receptor (GLP-1) agonists on the lipid profiles of patients with type 2 diabetes.
UNASSIGNED: We retrieved the data of phase 3 randomized controlled trials on GLP-1 agonists in patients with type 2 diabetes from the PubMed, Embase, and Cochrane library up to 11 February 2024. We extracted % changes in low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol/total cholesterol (T-CHO) and triglycerides levels from baseline. Using Bayesian network meta-analysis, mean differences and 95% credible intervals for lipid changes were estimated as a unit of percentage points (%p) by class.
UNASSIGNED: Twenty-six studies covering 22,290 participants were included. The glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 dual agonist showed significant differences in LDL-C (range of mean differences: -11.61 to -6.77%p), triglycerides (-19.94 to -13.31%p), and T-CHO (-7.94 to -5.09%p) levels compared to placebo, insulin, and sodium-glucose co-transporter 2 (SGLT2) inhibitors. The GLP-1 agonist significantly reduced T-CHO (-5.20%p; -6.39%p) and LDL-C (-4.32%p; -8.17%p) levels compared to placebo and SGLT2 inhibitors, respectively.
UNASSIGNED: The GIP/GLP-1 dual agonist positively affects the lipid profiles of patients with type 2 diabetes. This may contribute to a lower risk of cardiovascular disease in patients with type 2 diabetes.
UNASSIGNED: PROSPERO (CRD42021282668).

BACKGROUND: Alzheimer\'s disease (AD) is a widespread neurological illness in the elderly, which impacted about 50 million people globally in 2020. Type 2 diabetes has been identified as a risk factor. Insulin and incretins are substances that have various impacts on neurodegenerative processes. Preclinical research has shown that GLP-1 receptor agonists decrease neuroinflammation, tau phosphorylation, amyloid deposition, synaptic function, and memory formation. Phase 2 and 3 studies are now occurring in Alzheimer\'s disease populations. In this article, we present a detailed assessment of the therapeutic potential of GLP-1 analogues and DPP4 inhibitors in Alzheimer\'s disease.
OBJECTIVE: This study aimed to gain insight into how GLP-1 analogues and associated antagonists of DPP4 safeguard against AD.
METHODS: This study uses terms from search engines, such as Scopus, PubMed, and Google Scholar, to explore the role, function, and treatment options of the GLP-1 analogue for AD.
RESULTS: The review suggested that GLP-1 analogues may be useful for treating AD because they have been linked to anti-inflammatory, neurotrophic, and neuroprotective characteristics. Throughout this review, we discuss the underlying causes of AD and how GLP signaling functions.
CONCLUSIONS: With a focus on AD, the molecular and pharmacological effects of a few GLP-1/GIP analogs, both synthetic and natural, as well as DPP4 inhibitors, have been mentioned, which are in the preclinical and clinical studies. This has been demonstrated to improve cognitive function in Alzheimer\'s patients.

暂无摘要。

Diabetes Mellitus develops when the body becomes unable to fuel its cells with glucose, which results in the accumulation of sugar excess in the bloodstream. Because it has diverse pathophysiological impacts on the body, diabetes mellitus represents a significant issue of concern in an attempt to find suitable treatment modalities and medications for afflicted diabetic patients. Glucagon-like peptide 1 (GLP-1) plays a pivotal role in the incretin effect, emerging as a prospective treatment for diabetes mellitus and a promising means of regenerating pancreatic cells, whether directly or through its receptor agonists. It has been shown that GLP-1 efficiently increases insulin production, lowers blood sugar levels in patients with type 2 diabetes mellitus, and decreases appetite, craving, and hunger, therefore amplifying the sensation of fullness and satiety. Moreover, since they are all dependent on GLP-1 effect, intricate signaling pathways share some similarities during specific phases, although the pathways continue to exhibit significant divergence engendered by specific reactions and effects in each organ, which encompasses the rationale behind observed differences. This triggers an expanding range of GLP-1 R agonists, creating new unforeseen research and therapeutic application prospects. This review aims to explain the incretin effect, discuss how GLP-1 regulates blood glucose levels, and how it affects different body organs, as well as how it transmits signals, before introducing selenium\'s role in the incretin impact.

Insulin resistance in brain and amyloidogenesis are principal pathological features of diabetes-related cognitive decline and development of Alzheimer\'s disease (AD). A growing body of evidence suggests that maintaining glucose under control in diabetic patients is beneficial for preventing AD development. Dipeptidyl peptidase 4 inhibitors (DDP4is) are a class of novel glucose-lowering medications through increasing insulin excretion and decreasing glucagon levels that have shown neuroprotective potential in recent studies. This review consolidates extant evidence from earlier and new studies investigating the association between DPP4i use, AD, and other cognitive outcomes. Beyond DPP4i\'s benefits in alleviating insulin resistance and glucose-lowering, underlying mechanisms for the potential neuroprotection with DPP4i medications were categorized into the following sections: (Ferrari et al., Physiol Rev, 2021, 101, 1,047-1,081): the benefits of DPP4is on directly ameliorating the burden of β-amyloid plaques and reducing the formation of neurofibrillary tangles; DPP4i increasing the bioactivity of neuroprotective DPP4 substrates including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and stromal-derived factor-1α (SDF-1α) etc.; pleiotropic effects of DPP4is on neuronal cells and intracerebral structure including anti-inflammation, anti-oxidation, and anti-apoptosis. We further revisited recently published epidemiological studies that provided supportive data to compliment preclinical evidence. Given that there remains a lack of completed randomized trials that aim at assessing the effect of DPP4is in preventing AD development and progression, this review is expected to provide a useful insight into DPP4 inhibition as a potential therapeutic target for AD prevention and treatment. The evidence is helpful for informing the rationales of future clinical research and guiding evidence-based clinical practice.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) has become a leading cause of liver disease, affecting 30% of the global population. NAFLD prevalence is particularly high in obese individuals and patients with type 2 diabetes mellitus (T2DM). NAFLD ranges from simple fat deposition in the liver to necroinflammation and fibrosis (non-alcoholic steatohepatitis (NASH)), NASH-cirrhosis, and/or hepatocellular carcinoma. Insulin resistance plays a key role in NAFLD pathogenesis, alongside dysregulation of adipocytes, mitochondrial dysfunction, genetic factors, and changes in gut microbiota. Since insulin resistance is also a major predisposing factor of T2DM, the administration of anti-diabetic drugs for the management of NAFLD seems reasonable.
METHODS: In this review we provide the NAFLD-associated mechanisms of action of some of the most widely used anti-diabetic drugs, namely metformin, pioglitazone, sodium-glucose transport protein-2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor analogs (GLP1 RAs), and dipeptyl-peptidase-4 inhibitors (DPP4i) and present available data regarding their use in patients with NAFLD, with and without T2DM.
RESULTS: Both metformin and DPP4i have shown rather contradictory results, while pioglitazone seems to benefit patients with NASH and is thus the only drug approved for NASH with concomitant significant liver fibrosis by all major liver societies. On the other hand, SGLT2i and GLP1 RAs seem to be beneficiary in patients with NAFLD, showing both remarkable results, with SGLT2i proving to be more efficient in the only head-to-head study so far.
CONCLUSIONS: In patients with NAFLD and diabetes, pioglitazone, GLP1 RAs, and SGLT2i seem to be logical treatment options. Larger studies are needed before these drugs can be recommended for non-diabetic individuals.

Introduction: A growing number of studies have thus far showed the association between type 2 diabetes mellitus (DM) and the intestinal microbiome homoeostasis. As reported, the gut microflora can be significantly different in patients with type 2 DM (T2DM) compared to those in healthy individuals.Methods: The authors collected the relevant articles published until 2022 and these are carefully selected from three scientific databases based on keywords.Discussion: This review highlights research on the anti-diabetic properties of berberine (BBR)-induced glucagon-like peptide-1 (GLP-1), as a glucose-lowering factor and a balance regulator in the microbial flora of the intestines, which plays an important role in adjusting the signalling pathways affecting insulin secretion.Results: Considering the anti-diabetic characteristics of the BBR-induced GLP-1, BBR makes a promising complementary treatment for reducing the clinical symptoms of DM by reducing the hyperglycaemia. Berberin might be a safe and effective drug for T2DM with little or no adverse effects.HighlightsBerberine induces GLP-1 insulin secretion by PLC2 pathway in the intestinalBerberine-induced GLP-1 decreases mitochondrial stress and relocates cytochrome c out of the mitochondria.Berberine induces GLP-1 secretion in the intestine by altering the bacterial profile, thus could possibly lighten diabetes symptomsBerberine-induced SCFA production, SCFA causes GLP-1 secretion from the intestinal L-Cell.Preventing mitochondrial damage, reducing adipose tissue fat, and reducing oxidative stress are thus among the results of BBR-induced GLP-1.The lower costs of BBR, and its limited side effects and higher availability, make it a promising supplementary medicine for DM.

UNASSIGNED: Type 2 diabetes (T2DM) and obesity present significant global health issues, requiring the development of long-lasting and highly effective pharmacotherapies. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) are commonly used for diabetes treatment, their potential for addressing obesity is still being explored.
UNASSIGNED: This review offers a comprehensive overview of recently published patents from January 2020 to July 2023, focusing on modified GLP-1RAs, small molecule GLP-1RAs, GLP-1 R-based multi-agonists, GLP-1RA-based fusion proteins, and combination therapies. The patents discussed pertain to the treatment and prevention of diabetes and obesity. Patent searches were conducted using the PATENTSCOPE database of the World Intellectual Property Organization, using the keywords GLP-1, GLP-1/GIP, GLP-1/GCG, and GLP-1/GCG/GIP.
UNASSIGNED: In recent years, patents have emphasized two main goals for developing GLP-1RAs drugs: oral delivery and improved weight reduction effects. To address the growing demand for improved treatments, researchers have focused their efforts on developing GLP-1 R-based multi-agonists, orally administered GLP-1RAs, and combination therapies utilizing GLP-1RAs. These new approaches offer promising benefits, such as improved effectiveness by targeting multiple pathways and reduced side effects. Additionally, the development of new uses, oral forms, and long-lasting preparations will be crucial in shaping the future market potential of GLP-1 drugs.

Bariatric surgery is the most effective treatment in individuals with obesity to achieve remission of type 2 diabetes. Post-bariatric surgery hypoglycaemia occurs frequently, and management remains suboptimal, because of a poor understanding of the underlying pathophysiology. The glucoregulatory hormone responses to nutrients in individuals with and without post-bariatric surgery hypoglycaemia have not been systematically examined.
The study protocol was prospectively registered with PROSPERO. PubMed, EMBASE, Web of Science and the Cochrane databases were searched for publications between January 1990 and November 2021 using MeSH terms related to post-bariatric surgery hypoglycaemia. Studies were included if they evaluated individuals with post-bariatric surgery hypoglycaemia and included measurements of plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin, C-peptide and/or glucagon concentrations following an ingested nutrient load. Glycated haemoglobin (HbA1c) was also evaluated. A random-effects meta-analysis was performed, and Hedges\' g (standardised mean difference) and 95% confidence intervals were reported for all outcomes where sufficient studies were available. The τ2 estimate and I2 statistic were used as tests for heterogeneity and a funnel plot with the Egger regression-based test was used to evaluate for publication bias.
From 377 identified publications, 12 were included in the analysis. In all 12 studies, the type of bariatric surgery was Roux-en-Y gastric bypass (RYGB). Comparing individuals with and without post-bariatric surgery hypoglycaemia following an ingested nutrient load, the standardised mean difference in peak GLP-1 was 0.57 (95% CI, 0.32, 0.82), peak GIP 0.05 (-0.26, 0.36), peak insulin 0.84 (0.44, 1.23), peak C-peptide 0.69 (0.28, 1.1) and peak glucagon 0.05 (-0.26, 0.36). HbA1c was less in individuals with hypoglycaemia - 0.40 (-0.67, -0.12). There was no evidence of substantial heterogeneity in any outcome except for peak insulin: τ2 = 0.2, I2 = 54.3. No publication bias was evident.
Following RYGB, postprandial peak plasma GLP-1, insulin and C-peptide concentrations are greater in individuals with post-bariatric surgery hypoglycaemia, while HbA1c is less. These observations support the concept that antagonism of GLP-1 would prove beneficial in the management of individuals with hypoglycaemia following RYGB.PROSPERO Registration Number: CRD42021287515.