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Current research and future hope
Published in G. Michael Steelman, Eric C. Westman, Obesity, 2016
Greenway Frank L., R. Smith Steven
Liraglutide is a glucagon-like peptide 1 agonist approved for the treatment of type 2 diabetes at a dose of 1.8 mg per day. Liraglutide at a dose of 3 mg per day is being developed for the treatment of obesity. At the end of 20 weeks, the 3 mg dose of liraglutide gave 6.4 kg more weight loss than placebo and 3.1 kg more weight loss than orlistat (84). The FDA advisory committee considered the approval of liraglutide at the 3 mg dose for the treatment of obesity in September 2014 and recommended its approval by a 14-to-1 majority. The response of the FDA to their recommendation is still pending (85).
Effects of intestinal flora on pharmacokinetics and pharmacodynamics of drugs
Published in Drug Metabolism Reviews, 2023
Amina Džidić-Krivić, Jasna Kusturica, Emina Karahmet Sher, Nejra Selak, Nejra Osmančević, Esma Karahmet Farhat, Farooq Sher
Liraglutide is a second and third line of drugs used in the treatment of patients diagnosed with type 2 diabetes, especially when the control of glycemia was not satisfactory after administration of metformin. Liraglutide acts as a glucagon-like peptide-1 agonist (Shyangdan et al. 2011). Zhao et al. (2018) investigated the potential ability of liraglutide to modulate the composition of bacteria in the gut. 16S ribosomal RNA gene sequencing was used to detect alterations in the gut microbiota. The results showed that liraglutide, through modulation of the structure of the gut microbiota such as an increase in Bacteroidetes and a decrease in Firmicutes, altered glucose and lipid metabolism. Therefore, the authors proved that liraglutide lowers the body weight of the rats who were overweight and the rats who were simultaneously overweight and had diabetes (Zhao et al. 2018). Similarly, Tilg and Moschen (2014) placed great emphasis on the specific member of the microbiota, Akkermansia muciniphila because the decreased levels of this bacteria were described in the gut of patients with diabetes. In addition, when administered to murine, Akkermansia muciniphila expresses antidiabetic effects (Tilg and Moschen 2014).
Diabetes mellitus: an important risk factor for peripheral vascular disease
Published in Expert Review of Cardiovascular Therapy, 2020
Stefanos Giannopoulos, Ehrin J. Armstrong
Previous studies have provided evidence that DM increases the risk for lower-extremity amputation, especially among patients with critical limb ischemia (CLI) [22,23], leading to higher cardiovascular morbidity/mortality rates compared to non-diabetics [13,16]. Patients with DM who undergo amputation due to PAD have a 50-74% 5-year all-cause mortality, which is mainly associated with cardiac and cerebrovascular events [24]. Furthermore, a recent post-hoc analysis from the ‘Exenatide Study of Cardiovascular Event Lowering’ (EXSCEL; ClinicalTrials.gov Identifier: NCT01144338) study, including 2,800 diabetic patients with/without PAD, evaluated the effects of once per week exenatide (glucagon-like peptide 1 agonist) vs placebo [25]. The EXSCEL study demonstrated that patients with DM and PAD had higher rates of all-cause death, lower-extremity amputation and target limb revascularization compared to patients without PAD, over a median follow up of 3.2 years [25]. Moreover, a large retrospective study including almost 62,300 patients from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample, showed that patients with coexistent PAD and DM had higher prevalence of lower-extremity amputation (47%) compared to patients with either DM alone (26%) or PAD alone (26%), indicating that DM and PAD have an additive effect on overall risk [26].
Cathepsin D improves the prediction of undetected diabetes in patients with myocardial infarction
Published in Upsala Journal of Medical Sciences, 2019
Matthijs A. Velders, Fredrik Calais, Nina Dahle, Tove Fall, Emil Hagström, Jerzy Leppert, Christoph Nowak, Åke Tenerz, Johan Ärnlöv, Pär Hedberg
Cathepsin D is an aspartic endopeptidase with the primary biological function of protein degradation in an acidic milieu of lysosomes. It has been studied extensively from the perspective of its role in cancer development and as a suggested tumour marker (14). Furthermore, cathepsin D enzymatic activity induces hydrolytic modification of lipoprotein, including low-density lipoprotein, contributing to the accumulation of modified low-density lipoprotein in arterial intima (15). Higher levels of cathepsin D have been observed in diabetes complicated by diabetic ulcers and retinopathy (16,17). Cathepsin D has also been associated with insulin resistance in two community cohorts, although causality could not be shown with Mendelian randomization (18). Additionally, it has been suggested as a marker of β-cell function (19). Animal models support a role for cathepsin D in lysosomal/autophagic-induced cell death as a major driver of β-cell death and dysfunction in response to glucolipotoxicity in type 2 diabetes. In these models, the glucagon-like peptide 1 agonist exendin-4 was shown to protect β-cells from death by increasing autophagic flux and restoring lysosomal function (20). Clinical studies have shown that the glucagon-like peptide 1 agonist liraglutide as an adjunct to diet and exercise reduces the risk of progression from prediabetes to diabetes in obese patients, with improvement of measures of insulin resistance and β-cell function (2). Additionally, glucagon-like peptide 1 agonists reduce cardiovascular and overall mortality in patients with type 2 DM (3). Whether patients with higher cathepsin D levels have a larger benefit of glucagon-like peptide 1 agonists remains unknown.