Medical Weight Loss

Co-morbidities Related to Obesity

Overweight and obese persons are at risk of a number of medical conditions which can lead to further morbidity and mortality. A study by BMC public health provides an estimate of the incidence of each co-morbidity related to obesity and overweight using a meta-analysis.

Guh, D. P., Zhang, W., Bansback, N., Amarsi, Z., Birmingham, C. L., & Anis, A. H. (2009). The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC public health, 9, 88. https://doi.org/10.1186/1471-2458-9-88 (https://pubmed.ncbi.nlm.nih.gov/19320986/)

Endocrinology and Obesity

Guidelines by the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) recognize that obesity is a complex, adiposity-based chronic disease, where management targets both weight-related complications and adiposity to improve overall health and quality of life.

Garvey, W. T., Mechanick, J. I., Brett, E. M., Garber, A. J., Hurley, D. L., Jastreboff, A. M., Nadolsky, K., Pessah-Pollack, R., Plodkowski, R., & American Association of Clinical Endocrinologists and American College of Endocrinology. (2016). American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocrine Practice, 22(Suppl 3), 1–203. https://doi.org/10.4158/EP161365.GL

(https://www.sciencedirect.com/science/article/pii/S1530891X20446300)

Pharmacotherapy and Obesity

Weight loss can sometimes lead to physiological adaptations that promote weight regain. As a result, lifestyle treatment alone typically produces only modest weight loss that is difficult to sustain. This study by The Lancet Diabetes & Endocrinology explores pharmacotherapy as an accepted adjunct to lifestyle for weight loss.

Progress and challenges in anti-obesity pharmacotherapy. (2018). The Lancet Diabetes & Endocrinology, 6(3), 237–248. https://doi.org/10.1016/S2213-8587(17)30236-X (https://www.sciencedirect.com/science/article/abs/pii/S221385871730236X)

Semaglutide and Weight Loss

Once-Weekly Semaglutide in Adults with Overweight or Obesity

Obesity is a global health challenge with few pharmacologic options. A trial by The New England Journal of Medicine explores whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention.

Wilding, J. P. H., Batterham, R. L., Calanna, S., Davies, M., Van Gaal, L. F., Lingvay, I., McGowan, B. M., Rosenstock, J., Tran, M. T. D., Wadden, T. A., Wharton, S., Yokote, K., Zeuthen, N., & Kushner, R. F. (2021) Once-weekly semaglutide in adults with overweight or obesity. The New England Journal of Medicine. https://doi.org/10.1056/NEJMoa2032183

Safety of Semaglutide

A review in Frontiers in Endocrinology discusses the occurrence of adverse events associated with semaglutide and highlights potential underlying mechanisms. This review also discusses whether effects are specific for semaglutide or a class effect.

Smits, M. M., & Van Raalte, D. H. (2021). Safety of Semaglutide. Frontiers in endocrinology, 12, 645563. https://doi.org/10.3389/fendo.2021.645563

Semaglutide as a promising antiobesity drug

Semaglutide was recently evaluated in Obesity Reviews as an antiobesity drug in a phase II dose-finding trial. The magnitude of semaglutide-induced weight loss in this study exceeded the criteria of both the EMA and FDA for antiobesity drugs, and there were no safety concerns, indicating the eligibility of once daily sc semaglutide as a future antiobesity drug.

Christou, G. A., Katsiki, N., Blundell, J., Fruhbeck, G., & Kiortsis, D. N. (2019). Semaglutide as a promising antiobesity drug. Obesity reviews : an official journal of the International Association for the Study of Obesity, 20(6), 805–815. https://doi.org/10.1111/obr.12839

Ozempic (semaglutide) injection prescribing information, revised.

Highlights and full prescribing information from the Food and Drug Administration (FDA) to prescribe OZEMPIC® safely and effectively.

Food and Drug Administration. (2020, January). Ozempic (semaglutide) injection prescribing information (Revised ed.). https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209637s003lbl.pdf

Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial

This trial by Lancet evaluates the efficacy and safety of the glucagon-like peptide-1 (GLP-1) analogue semaglutide in comparison with liraglutide and a placebo in promoting weight loss.

O'Neil, P. M., Birkenfeld, A. L., McGowan, B., Mosenzon, O., Pedersen, S. D., Wharton, S., Carson, C. G., Jepsen, C. H., Kabisch, M., & Wilding, J. P. H. (2018). Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet (London, England), 392(10148), 637–649. https://doi.org/10.1016/S0140-6736(18)31773-2

Semaglutide 2.4 mg for the Treatment of Obesity: Key Elements of the STEP Trials 1 to 5

The obesity epidemic is a public health concern, warranting further research into pharmacological treatments for weight management (WM) as an adjunct to lifestyle interventions. The Semaglutide Treatment Effect in People with obesity (STEP) program aims to investigate the effect of semaglutide versus placebo on weight loss, safety, and tolerability in adults with obesity or overweight.

Kushner, R. F., Calanna, S., Davies, M., Dicker, D., Garvey, W. T., Goldman, B., Lingvay, I., Thomsen, M., Wadden, T. A., Wharton, S., Wilding, J. P. H., & Rubino, D. (2020). Semaglutide 2.4 mg for the Treatment of Obesity: Key Elements of the STEP Trials 1 to 5. Obesity (Silver Spring, Md.), 28(6), 1050–1061. https://doi.org/10.1002/oby.22794

Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity

A trial by Diabetes, obesity & metabolism investigates the mechanism of action for body weight loss with semaglutide.

Blundell, J., Finlayson, G., Axelsen, M., Flint, A., Gibbons, C., Kvist, T., & Hjerpsted, J. B. (2017). Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes, obesity & metabolism, 19(9), 1242–1251. https://doi.org/10.1111/dom.12932

Semaglutide lowers body weight in rodents via distributed neural pathways

A study in JCI insight explores how semaglutide modulated food preference, reduced food intake, and caused weight loss without decreasing energy expenditure.

Gabery, S., Salinas, C. G., Paulsen, S. J., Ahnfelt-Rønne, J., Alanentalo, T., Baquero, A. F., Buckley, S. T., Farkas, E., Fekete, C., Frederiksen, K. S., Helms, H. C. C., Jeppesen, J. F., John, L. M., Pyke, C., Nøhr, J., Lu, T. T., Polex-Wolf, J., Prevot, V., Raun, K., Simonsen, L., … Hogendorf, W. F. J. (2020). Semaglutide lowers body weight in rodents via distributed neural pathways. JCI insight, 5(6), e133429. https://doi.org/10.1172/jci.insight.133429

Tirzepatide and Weight Loss

Tirzepatide for Patients With Type 2 Diabetes

In an issue of JAMA, Dahl et al presents the findings of the SURPASS-5 clinical trial that compared 3 doses of tirzepatide vs placebo in the treatment of patients with type 2 diabetes within an insulin glargine titration protocol.

Chipkin, S. R. (2022). Tirzepatide for patients with type 2 diabetes. JAMA, 327(6), 529–530. https://jamanetwork.com/journals/jama/fullarticle/2788799

Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction

Tirzepatide is an acylated peptide engineered to activate the GIP and GLP-1 receptors, key mediators of insulin secretion that are also expressed in regions of the brain that regulate food intake. Five clinical trials in type 2-diabetic subjects (SURPASS 1–5) have shown that tirzepatide at 5–15 mg per week reduces both HbA_1c (1.24 to 2.58%) and body weight (5.4–11.7 kg) by amounts unprecedented for a single agent.

Nauck, M.A., D‘Alessio, D.A. Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. Cardiovasc Diabetol 21, 169 (2022). https://doi.org/10.1186/s12933-022-01604-7; https://cardiab.biomedcentral.com/articles/10.1186/s12933-022-01604-7

GLP-1

Glucose-dependent insulinotropic polypeptide (Gastric Inhibitory Polypeptide; GIP)

Glucose-dependent insulinotropic polypeptide (GIP; gastric inhibitory polypeptide) is a 42 amino acid hormone that is produced by enteroendocrine K-cells and released into the circulation in response to nutrient stimulation. Both GIP and glucagon-like peptide-1 (GLP-1) stimulate insulin secretion in a glucose-dependent manner and are thus classified as incretins. This review explores the significant interest in potential clinical applications for GIP analogs and both agonists and antagonists have been developed for preclinical studies.

McIntosh, C. H., Widenmaier, S., & Kim, S. J. (2009). Glucose-dependent insulinotropic polypeptide (Gastric Inhibitory Polypeptide; GIP). Vitamins and hormones, 80, 409–471. https://doi.org/10.1016/S0083-6729(08)00615-8 (https://pubmed.ncbi.nlm.nih.gov/19251046/)

GLP-1a: Going beyond Traditional Use

Glucagon-like peptide-1 (GLP-1) is a human incretin hormone derived from the proglucagon molecule. GLP-1 receptor agonists are frequently used to treat type 2 diabetes mellitus and obesity. However, the hormone affects the liver, pancreas, brain, fat cells, heart, and gastrointestinal tract. A study in the International journal of molecular sciences performs a systematic review on the use of GLP-1 other than in treating diabetes.

Laurindo, L. F., Barbalho, S. M., Guiguer, E. L., da Silva Soares de Souza, M., de Souza, G. A., Fidalgo, T. M., Araújo, A. C., de Souza Gonzaga, H. F., de Bortoli Teixeira, D., de Oliveira Silva Ullmann, T., Sloan, K. P., & Sloan, L. A. (2022). GLP-1a: Going beyond Traditional Use. International journal of molecular sciences, 23(2), 739. https://doi.org/10.3390/ijms23020739 (https://pmc.ncbi.nlm.nih.gov/articles/PMC8775408/)

Glucagon-Like Peptide-1 Receptor Agonists and Dual Glucose-Dependent Insulinotropic Polypeptide/Glucagon-Like Peptide-1 Receptor Agonists in the Treatment of Obesity/Metabolic Syndrome, Prediabetes/Diabetes and Non-Alcoholic Fatty Liver Disease-Current Evidence

A review in the Journal of cardiovascular pharmacology and therapeutic highlighta the main pathophysiological mechanisms and risk factors (RFs), that could be controlled by GLP-1 and dual GIP/GLP-1 RAs independently or through synergism or differences in their mode of action. It also addresses the evidence on the use of GLP-1 and dual GIP/GLP-1 RAs in the treatment of obesity, MetS and its related conditions (prediabetes, T2DM and NAFLD/NASH).

Muzurović, E. M., Volčanšek, Š., Tomšić, K. Z., Janež, A., Mikhailidis, D. P., Rizzo, M., & Mantzoros, C. S. (2022). Glucagon-Like Peptide-1 Receptor Agonists and Dual Glucose-Dependent Insulinotropic Polypeptide/Glucagon-Like Peptide-1 Receptor Agonists in the Treatment of Obesity/Metabolic Syndrome, Prediabetes/Diabetes and Non-Alcoholic Fatty Liver Disease-Current Evidence. Journal of cardiovascular pharmacology and therapeutics, 27, 10742484221146371. https://doi.org/10.1177/10742484221146371 (https://pubmed.ncbi.nlm.nih.gov/36546652/)

Effects of Glucagon-like peptide 1 (GLP-1) analogs in the hippocampus

GLP-1 enhances learning and memory in the hippocampus, promotes neurogenesis, decreases inflammation and apoptosis, modulates reward behavior, and reduces food intake. Its pharmacokinetics have been improved to enhance the peptide's half-life, enhancing exposure and time of action. The GLP-1 agonists are successfully in clinical use for the treatment of type-2 diabetes, obesity, and clinical evaluation for the treatment of neurodegenerative diseases.

Diz-Chaves, Y., Herrera-Pérez, S., González-Matías, L. C., & Mallo, F. (2022). Effects of Glucagon-like peptide 1 (GLP-1) analogs in the hippocampus. Vitamins and hormones, 118, 457–478. https://doi.org/10.1016/bs.vh.2021.12.005 (https://pubmed.ncbi.nlm.nih.gov/35180937/)

Glucagon-like peptide-1 (GLP-1) receptor agonists and neuroinflammation: Implications for neurodegenerative disease treatment

A review in Pharmacological research discusses incretin signaling, neuroinflammatory pathways, and the intersections between neuroinflammation, brain IR, and neurodegenerative diseases, with a focus on AD and PD.

Kopp, K. O., Glotfelty, E. J., Li, Y., & Greig, N. H. (2022). Glucagon-like peptide-1 (GLP-1) receptor agonists and neuroinflammation: Implications for neurodegenerative disease treatment. c, 186, 106550. https://doi.org/10.1016/j.phrs.2022.106550 (https://pubmed.ncbi.nlm.nih.gov/36372278/)

Glucagon-like Peptide-1 Receptor-based Therapeutics for Metabolic Liver Disease

An article in Endocrine reviews discusses evolving concepts of GLP-1 action that improve liver health and highlight evidence that links sustained GLP-1R activation in distinct cell types to control of hepatic glucose and lipid metabolism, and reduction of experimental and clinical nonalcoholic steatohepatitis (NASH).

Yabut, J. M., & Drucker, D. J. (2023). Glucagon-like Peptide-1 Receptor-based Therapeutics for Metabolic Liver Disease. Endocrine reviews, 44(1), 14–32. https://doi.org/10.1210/endrev/bnac018 (https://pubmed.ncbi.nlm.nih.gov/35907261/)

Therapeutic Potential of Semaglutide, a Newer GLP-1 Receptor Agonist, in Abating Obesity, Non-Alcoholic Steatohepatitis and Neurodegenerative diseases: A Narrative Review

This review discusses Semaglutide's use to improve insulin resistance, insulin signalling pathway, and reduce body weight which are responsible for prevention or progression of NASH and neurodegenerative diseases.

Mahapatra, M. K., Karuppasamy, M., & Sahoo, B. M. (2022). Therapeutic Potential of Semaglutide, a Newer GLP-1 Receptor Agonist, in Abating Obesity, Non-Alcoholic Steatohepatitis and Neurodegenerative diseases: A Narrative Review. Pharmaceutical research, 39(6), 1233–1248. https://doi.org/10.1007/s11095-022-03302-1 (https://pubmed.ncbi.nlm.nih.gov/35650449/)