Liraglutide

Incretin-Based Weight Loss Pharmacotherapy: Can Resistance Exercise Optimize Changes in Body Composition?[Pubmed:38687506]

Diabetes Care. 2024 Apr 30:dci230100.

This narrative review highlights the degree to which new antiobesity medications based on gut-derived nutrient-stimulated hormones (incretins) cause loss of lean mass, and the importance of resistance exercise to preserve muscle. Glucagon-like peptide 1 receptor agonists (GLP-1RA) induce substantial weight loss in randomized trials, effects that may be enhanced in combination with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists. Liraglutide and semaglutide (GLP-1RA), tirzepatide (GLP-1 and GIP receptor dual agonist), and retatrutide (GLP-1, GIP, and glucagon receptor triple agonist) are peptides with incretin agonist activity that induce approximately 15-24% weight loss in adults with overweight and obesity, alongside beneficial impacts on blood pressure, cholesterol, blood glucose, and insulin. However, these agents also cause rapid and significant loss of lean mass ( approximately 10% or approximately 6 kg), comparable to a decade or more of aging. Maintaining muscle mass and function as humans age is crucial to avoiding sarcopenia and frailty, which are strongly linked to morbidity and mortality. Studies indicate that supervised resistance exercise training interventions with a duration >10 weeks can elicit large increases in lean mass ( approximately 3 kg) and strength ( approximately 25%) in men and women. After a low-calorie diet, combining aerobic exercise with Liraglutide improved weight loss maintenance compared with either alone. Retaining lean mass during incretin therapy could blunt body weight (and fat) regain on cessation of weight loss pharmacotherapy. We propose that tailored resistance exercise training be recommended as an adjunct to incretin therapy to optimize changes in body composition by preserving lean mass while achieving fat loss.

Liraglutide and not lifestyle intervention reduces soluble CD163 after comparable weight loss in obese participants with prediabetes or type 2 diabetes mellitus.[Pubmed:38685051]

Cardiovasc Diabetol. 2024 Apr 29;23(1):146.

BACKGROUND: The GLP-1 receptor agonist Liraglutide is used to treat hyperglycemia in type 2 diabetes but is also known to induce weight loss, preserve the beta cell and reduce cardiovascular risk. The mechanisms underlying these effects are however still not completely known. Herein we explore the effect of Liraglutide on markers of immune cell activity in a population of obese individuals with prediabetes or newly diagnosed type 2 diabetes mellitus. METHOD: Plasma levels of the monocyte/macrophage markers, soluble (s)CD163 and sCD14, the neutrophil markers myeloperoxidase (MPO) and neutrophil gelatinase-associated lipocalin (NGAL),the T-cell markers sCD25 and T-cell immunoglobulin mucin domain-3 (sTIM-3) and the inflammatory marker TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) were measured by enzyme-linked immunosorbent assays in obese individuals with prediabetes or diabetes diagnosed within the last 12 months, prior to and after comparable weight loss achieved with lifestyle changes (n = 20) or Liraglutide treatment (n = 20), and in healthy subjects (n = 13). RESULTS: At baseline, plasma levels of the macrophage marker sCD163, and the inflammatory marker LIGHT were higher in cases as compared to controls. Plasma levels of sCD14, NGAL, sTIM-3 and sCD25 did not differ at baseline between patients and controls. After weight reduction following lifestyle intervention or Liraglutide treatment, sCD163 decreased significantly in the Liraglutide group vs. lifestyle (between-group difference p = 0.023, adjusted for visceral adipose tissue and triglycerides basal values). MPO and LIGHT decreased significantly only in the Liraglutide group (between group difference not significant). Plasma levels of MPO and in particular sCD163 correlated with markers of metabolic dysfunction and inflammation. After weight loss, only sCD163 showed a trend for decreased levels during OGTT, both in the whole cohort as in those of Liraglutide vs lifestyle group. CONCLUSION: Weight loss following treatment with Liraglutide was associated with reduced circulating levels of sCD163 when compared to the same extent of weight loss after lifestyle changes. This might contribute to reduced cardiometabolic risk in individuals receiving treatment with Liraglutide.

Advancements in pharmacological treatment of NAFLD/MASLD: a focus on metabolic and liver-targeted interventions.[Pubmed:38681750]

Gastroenterol Rep (Oxf). 2024 Apr 26;12:goae029.

In the present narrative review, we have summarized evidence on the pharmacological treatment of non-alcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD). We start by reviewing the epidemiology of the condition and its close association with obesity and type 2 diabetes. We then discuss how randomized-controlled trials are performed following guidance from regulatory agencies, including differences and similarities between requirements of the US Food and Drug Administration and the European Medicine Agency. Difficulties and hurdles related to limitations of liver biopsy, a large number of screening failures in recruiting patients, as well as unpredictable response rates in the placebo group are evaluated. Finally, we recapitulate the strategies employed for potential drug treatments of this orphan condition. The first is to repurpose drugs that originally targeted T2DM and/or obesity, such as pioglitazone, glucagon-like peptide 1 receptor agonists (Liraglutide and semaglutide), multi-agonists (tirzepatide and retatrutide), and sodium-glucose transporter 2 inhibitors. The second is to develop drugs specifically targeting NAFLD/MASLD. Among those, we focused on resmetirom, fibroblast growth factor 21 analogs, and lanifibranor, as they are currently in Phase 3 of their clinical trial development. While many failures have characterized the field of pharmacological treatment of NAFLD/MASLD in the past, it is likely that approval of the first treatments is near. As occurs in many chronic conditions, combination therapy might lead to better outcomes. In the case of non-alcoholic steatohepatitis, we speculate that drugs treating underlying metabolic co-morbidities might play a bigger role in the earlier stages of disease, while liver-targeting molecules will become vital in patients with more advanced disease in terms of inflammation and fibrosis.

Health Technology Assessment: Evaluation of 7 Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Type 2 Diabetes Mellitus.[Pubmed:38680477]

Risk Manag Healthc Policy. 2024 Apr 23;17:1053-1067.

PURPOSE: This study provides a reference for healthcare organizations in the selection and rational use of glucagon-like peptide-1 receptor agonists (GLP-1RAs), based on the Rapid Guide for Drug Evaluation and Selection in Chinese Medical Institutions (Second Edition). METHODS: According to the Rapid Guide for Drug Evaluation and Selection in Chinese Medical Institutions (Second Edition) released in 2023, relevant databases such as PubMed, Cochrane, and Embase, drug labels, and clinical guidelines were searched for drug information. We systematically evaluated 7 GLP-1RAs marketed in China for safety, efficacy, economy, pharmacological properties, and other attributes using a percentage scoring method. RESULTS: The final assessment result scores from highest to lowest were semaglutide (71.5 points), dulaglutide (68.9 points), Liraglutide (68.7 points), exenatide (62.5 points), lixisenatide (59.9 points), polyethylene glycol loxenatide (55.9 points), and benaglutide (45.1 points). CONCLUSION: When a healthcare organization introduces GLP-1RAs to their hospital, they can refer to the assessment results and use the top three recommended medications: semaglutide, dulaglutide, and Liraglutide.

Glucagon-like peptide-1 class drugs show clear protective effects in Parkinson's and Alzheimer's disease clinical trials: A revolution in the making?[Pubmed:38677445]

Neuropharmacology. 2024 Apr 25;253:109952.

Parkinson's disease (PD) is a complex syndrome for which there is no disease-modifying treatment on the market. However, a group of drugs from the Glucagon-like peptide-1 (GLP-1) class have shown impressive improvements in clinical phase II trials. Exendin-4 (Bydureon), Liraglutide (Victoza, Saxenda) and Lixisenatide (Adlyxin), drugs that are on the market as treatments for diabetes, have shown clear effects in improving motor activity in patients with PD in phase II clinical trials. In addition, Liraglutide has shown improvement in cognition and brain shrinkage in a phase II trial in patients with Alzheimer disease (AD). Two phase III trials testing the GLP-1 drug semaglutide (Wegovy, Ozempic, Rybelsus) are ongoing. This perspective article will summarize the clinical results obtained so far in this novel research area. We are at a crossroads where GLP-1 class drugs are emerging as a new treatment strategy for PD and for AD. Newer drugs that have been designed to enter the brain easier are being developed already show improved effects in preclinical studies compared with the older GLP-1 class drugs that had been developed to treat diabetes. The future looks bright for new treatments for AD and PD.

Development of Syringaldehyde as an Agonist of the GLP-1 Receptor to Alleviate Diabetic Disorders in Animal Models.[Pubmed:38675498]

Pharmaceuticals (Basel). 2024 Apr 22;17(4):538.

The phenolic aldehyde syringaldehyde (SA) has been shown to have an antihyperglycemic effect in diabetic rats due to increased glucose utilization and insulin sensitivity. To understand the direct effect of SA on the GLP-1 receptor, STZ-induced diabetic rats were used. The levels of pro-inflammatory cytokines, liver enzymes, and renal function were measured using specific ELISA kits. The mechanisms of SA effects were investigated using CHO-K1 cells, pancreatic Min-6 cells, and cardiomyocyte H9c2 cells. The results indicated that the antihyperglycemic effect of SA in diabetic rats was abolished by blocking the GLP-1 receptor with an antagonist. SA has a direct effect on the GLP-1 receptor when using CHO-K1 cells transfected with the exogenous GLP-1 receptor gene. In addition, SA stimulated insulin production in Min-6 cells by activating GLP-1 receptors. SA caused a dose-dependent rise in GLP-1 receptor mRNA levels in cardiac H9c2 cells. These in vitro results support the notion that SA has a direct effect on the GLP-1 receptor. Otherwise, SA inhibited the increase of pro-inflammatory cytokines, including interleukins and tumor TNF-alpha, in type 1 diabetic rats in a dose-dependent manner. Moreover, as with Liraglutide, SA reduced plasma lipid profiles, including total cholesterol and triglyceride, in mixed diet-induced type 2 diabetic rats. Intriguingly, chronic treatment with SA (as with Liraglutide) reversed the functions of both the liver and the kidney in these diabetic rats. SA displayed less efficiency in reducing body weight and food consumption compared to Liraglutide. In conclusion, SA effectively activates GLP-1 receptors, resulting in a reduction in diabetic-related complications in rats. Therefore, it is beneficial to develop SA as a chemical agonist for clinical applications in the future.

Efficacy and safety of liraglutide in patients with patients with an ileal pouch-anal anastomosis and chronic high bowel frequency: A placebo-controlled, crossover, proof of concept study.[Pubmed:38668926]

Am J Gastroenterol. 2024 Apr 12.

INTRODUCTION: After colectomy with ileo-anal pouch anastomosis (IPAA), many patients develop high bowel frequency (BF) refractory to antimotility agents despite normal IPAA morphology. Low circulating levels of glucagon-like protein-1 (GLP-1), a modulator of gastroduodenal motility, have been reported after colectomy. METHODS: Double-blind crossover study of 8 IPAA patients with refractory high BF treated with daily administration of the GLP-1 receptor agonist (GLP-1-RA) Liraglutide or placebo. RESULTS: Liraglutide, but not placebo, reduced daily BF by more than 35% (P<0.03). DISCUSSION: Larger randomized controlled studies are warranted to delineate the treatment potential of GLP-1RA's in IPAA patients suffering from non-inflammatory high BF.

No effect of liraglutide on high density lipoprotein apolipoprotein AI kinetics in patients with type 2 diabetes.[Pubmed:38653365]

Diabetes Metab. 2024 Apr 21;50(3):101535.

AIM: The catabolism of high density lipoprotein (HDL) apolipoprotein AI (apoAI) is accelerated in patients with type 2 diabetes (T2D), related to hypertriglyceridemia, insulin resistance and low plasma adiponectin levels. Since Liraglutide is likely to partly correct these abnormalities, we hypothesized that it might have a beneficial effect on HDL apoAI kinetics in patients with T2D. METHODS: An in vivo kinetic study of HDL apoAI was performed in 10 patients with T2D before and after 6 months of treatment with 1.2 mg/day of Liraglutide, using a bolus of l-[1-(13)C]leucine followed by a 16-hour constant infusion. RESULTS: Liraglutide reduced BMI (34.9 +/- 4.7 vs 36.6 +/- 4.9 kg/m(2), P = 0.012), HbA1c (7.1 +/- 1.1 vs 9.6 +/- 2.6%, P = 0.003), HOMA-IR (5.5 +/- 1.9 vs 11.6 +/- 11.2, P = 0.003), fasting triglycerides (1.76 +/- 0.37 vs 2.48 +/- 0.69 mmol/l, P < 0.001) and triglycerides during kinetics (2.34 +/- 0.81 vs 2.66 +/- 0.65 mmol/l, P = 0.053). Plasma HDL cholesterol and adiponectin concentrations were unchanged (respectively 0.97 +/- 0.26 vs 0.97 +/- 0.19 mmol/l, P = 1; 3169 +/- 1561 vs 2618 +/- 1651 microg/l, P = 0.160), similar to triglyceride content in HDL (5.13 +/- 1.73 vs 5.39 +/- 1.07%, P = 0.386). Liraglutide modified neither HDL apoAI fractional catabolic rate (0.35 +/- 0.11 vs 0.38 +/- 0.11 pool/day, P = 0.375), nor its production rate (0.44 +/- 0.13 vs 0.49 +/- 0.15 g/l/day, P = 0.375), nor its plasma concentration (1.26 +/- 0.19 vs 1.29 +/- 0.14 g/l, P = 0.386). CONCLUSION: Six months of treatment with 1.2 mg/day of Liraglutide had no effect on the kinetics of HDL apoAI in patients with T2D. The lack of decrease in triglyceride content in HDL related to an only moderate decrease in triglyceridemia, probably greatly explains these results. Insufficient improvement of insulin sensitivity and adiponectinemia may also be implied.

Erratum. Liraglutide and Exercise Synergistically Attenuate Vascular Inflammation and Enhance Metabolic Insulin Action in Early Diet-Induced Obesity. Diabetes 2023;72:918-931.[Pubmed:38652481]

Diabetes. 2024 Apr 23:db24er07a.

In the article cited above, Fig. 7G mistakenly featured the same images as Fig. 7E due to an error during manuscript preparation. The corresponding graphs and associated data interpretation were not affected, and the conclusions remain unchanged. The correct image for Fig. 7G appears below. The authors apologize for the error. The online version of the article (https://doi.org/10.2337/db22-0745) has been updated with the correct image.

A Retrospective Analysis of Liraglutide (GLP-1 Agonist) Use in a Chinchilla (Chinchilla lanigera) Model of Auditory Blast Injury.[Pubmed:38649263]

Comp Med. 2024 Apr 22.

Chinchillas are a relatively novel research model compared with other rodent species. They require special considerations when it comes to their husbandry and daily care. Chinchillas tend to be shy animals that are well adapted to masking clinical signs of illness. These characteristics can make them a difficult species to maintain in a research setting. The authors' institution has maintained chinchillas and established standardized daily animal care procedures for them. Chinchillas are most commonly used for auditory research. They are often used to study the mechanism of different induced auditory conditions or injuries as well as exploration for potential alleviating treatments. Often, tested therapeutics have demonstrated potentially beneficial effects but have not been applied in the specific condition or injury of interest. The development of new applications for therapeutics can lead to groundbreaking discoveries, but testing of new therapeutic applications is often initially performed in an animal model without knowing how the therapeutic will behave in the species. During testing, unexpected adverse events may manifest that require more focused monitoring and supportive care. This scenario occurred when adverse effects were observed in a chinchilla blast-injury model after receiving an acylated glucagon-like peptide-1 (GLP-1) receptor agonist. The study involved evaluation of this therapeutic over an extended amount of time after inducing a controlled pressurized blast-injury followed by multiple repeated hearing tests under anesthesia. Chinchillas enrolled in the study exhibited several clinical signs including weight loss, lethargy, labored breathing, neurologic abnormalities, decreased appetite or decreased fecal output, and otitis. Five primary abnormalities were reported on pathology: aspiration pneumonia, hepatic steatosis, right ventricular dilation, pancreatitis, and tubulointerstitial nephritis. Initially abnormal clinical signs, early mortality rates, and pathology were attributed to multiple anesthetic events. However, a retrospective analysis evaluating the association of different study variable exposures in a stratified comparison demonstrated that the early mortality rates were actually associated with the therapeutic drug given for the first time in this species. In this study, we describe the detailed findings of the retrospective analysis and explore different strategies that can be incorporated to maintain good animal welfare and decrease early animal loss.

Lifestyle Interventions in a Patient Identified as Super-Super Obese With a Body Mass Index of 90.5.[Pubmed:38646420]

J Med Cases. 2024 Apr;15(2-3):55-59.

Obesity is a growing global health concern. Saudi Arabia is experiencing a higher prevalence of obesity compared to the globe. This case report focuses on a 38-year-old female with a body mass index (BMI) of 90.5 kg/m(2), prediabetes, and obstructive sleep apnea who successfully underwent a lifestyle modification process resulting in remarkable weight loss. The patient's past unsuccessful attempts at weight loss had left her with a reluctance to try again initially. A multidisciplinary team collaborated to develop a management plan starting with an intensive lifestyle intervention. Lifestyle was assessed, then a structured personalized lifestyle intervention based on a plant-based diet and a gradual increase in physical activity was implemented. Over 6 months, the patient succeeded in losing 23 kg, a percent weight loss of 11.9%. An additional 5 kg was lost when Liraglutide "Saxenda" was added. This case report represents the effectiveness of intensive lifestyle interventions in patients with super-super obesity for weight loss and long-term health improvement. Additional research is required to determine if the positive outcomes seen in treating a single patient can be applied to a larger population with super-super obesity. This brings up the question of whether pharmacotherapy or surgical interventions should be the primary approaches for addressing these cases, considering that surgical interventions usually involve lifestyle changes. What we already know about such cases: patients with super-super obesity often require interventions such as surgery or medication to aid in weight reduction, as they typically do not respond to lifestyle interventions alone. What this case report adds to existing knowledge: the use of lifestyle interventions proved effective in such cases as super-super obesity and delayed the need for surgical intervention even without weight reduction medications.

Time to unshackle the medical treatment of obesity in the NHS.[Pubmed:38643826]

Clin Med (Lond). 2024 Apr 19:100206.

Obesity affects 1 in 4 people in the United Kingdom and costs the National Health Service (NHS) approximately pound6.5 billion annually. The glucagon-like peptide-1 (GLP-1) receptor analogues, such as once-daily subcutaneous Liraglutide 3.0 mg (Saxenda(R)) and once-weekly subcutaneous Semaglutide 2.4 mg (Wegovy(R)), were approved by the National Institute of Clinical Excellence (NICE) as a treatment for obesity and funded by the NHS for 2 years. Our local data shows that Saxenda is effective at reducing bodyweight and glycaemia in people with obesity and diabetes however, the supply issues of GLP-1 receptor analogues has contributed to the unavailability of Saxenda and Wegovy in our service. Our patients are devastated that they cannot access NICE-approved GLP-1 receptor analogues for obesity. The 2-year GLP-1 receptor analogue treatment limit for obesity alongside a lack of funded NHS services and supply issues represent barriers to treatment for people living with obesity who have clear medical indications.

Effect of liraglutide in different abdominal fat layers measured by ultrasound. The importance of perirenal fat reduction.[Pubmed:38643760]

Obes Facts. 2024 Apr 20.

INTRODUCTION: Ultrasonography in patients with Obesity allows us to measure different layers of abdominal fat (Superficial subcutaneous, Deep subcutaneous, Preperitoneal, Omental and Perirenal), not assessable by DEXA or CT scan. Omental and Perirenal fat depots are considered predictors of metabolic complications. Liraglutide is particularly effective in reducing weight in patients with insulin-resistance, but its direct impact on each abdominal fat layer is unknown. METHODS: We measured, at the L4 level, all 5 abdominal fat depots in 860 patients with obesity (72.8% women. Mean age 56.6+/-1.5 years. BMI 34.4+/-4.7 kg/m2. Body fat 47+/-2%. Abdominal circumference 105.8+/-3 cm), before and after 6 months of Liraglutide treatment. Laboratory tests for glucose, insulin and lipid profile were routinely done. T-student was used to compare intra-individual differences. RESULTS: Weight loss was 7.5+/-2.8 Kg (7.96% from baseline), with no differences by sex/age/BMI. Greater loss was observed in patients with higher dosages and NAFLD. All US-measured fat layers showed a significant reduction (p<0.05) at 6th months. Preperitoneal fat showed a -26+/-5.5% reduction and 46% of the patients went below Metabolic syndrome (MS) risk cut-off values. Omental fat was reduced by -17.8+/-5% (67% of the patients below MS risk) and perirenal fat by -22.4+/-4.4% (56% of the patients below MS). Both Omental and Perirenal fat reduction correlated with total and LDL cholesterol. Higher Perirenal fat reduction (-28%) was seen among patients with obesity and hypertension. Perirenal fat also correlated with blood pressure reduction. CONCLUSION: Liraglutide induces greater fat loss in the layers involved with Metabolic syndrome. However, the maximal reduction is seen at perirenal fat, which has been recently related with Hypertension and could play an important role in modulating kidney's expansion and intraglomerular pressure. US is a reproducible clinical tool to assess pathologic fat depots in patients living with Obesity.