Liraglutide in obesity

Liraglutide is a human glucagon-like peptide 1 (GLP1) analog that is used for the control of type 2 diabetes and also for weight reduction in patients who are overweight, obese and also for those who have obesity and type II diabetes simultaneously (diabesity). What changes are the doses of the drug for each pathology (1).

Weight loss with liraglutide depends on the dose, the higher the dose the greater the effect (up to 3.0 mg once a day) and its action is mediated by a reduction in appetite and energy intake rather than by an increase in energy expenditure generated by the drug. (2)

How does liraglutide work?

Its mechanism of action to improve diabetes is to increase insulin secretion and, simultaneously, to inhibit glucagon secretion (among other mechanisms), but both are dependent on the patient’s blood glucose (sugar) levels, i.e., the higher the blood glucose level, the greater its normalizing effect. (1) Also, due to its slowing effect on gastric emptying, it allows a slower absorption of glucose at intestinal level, thus avoiding hyperglycemia and insulin peaks.

Its action on weight loss is achieved by its appetite inhibitory action at brain level, due to its satiating effect by slowing down gastric emptying (1) and it is even more effective when associated with physical exercise (3).

Another mechanism that could explain weight loss, according to studies in mice (not in humans), is the production of internal heat (thermogenesis) from brown fat (4).

How is liraglutide administered?

It is administered subcutaneously in weekly progressive daily doses.

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It has also been observed that its use in obese patients without diabetes, following the use of a low-calorie diet (LCD) of between 800-1200kcal/day, achieves better maintenance of the weight lost by the diet (previously performed) than if it were not used. Some 81.4% of those using liraglutide maintained the initial ≧ 5% weight loss achieved with the diet, compared with those receiving placebo: 48.9% (P

Does it cause side effects?

The prevalence of side effects of the drug (liraglutide), such as hypoglycemia (low blood sugar) should not be underestimated. In obese patients with type 2 diabetes, using Liraglutide as the only drug, it is 2-15%, in diabetics the combination of liraglutide with sulfonylureas (oral hypoglycemic) reaches 28%; and in non-diabetics it is 2%. (4)

We also know that in the SCALE study the greatest average weight loss achieved was -8.4+-7kg after 56 weeks (1 year) of treatment (vs. placebo which was +2.8 + – 6.5kg) and the average decrease in BMI was 3.0 Kg/m2. (6) Furthermore, 80.3% of the patients treated with liraglutide and with an incidence of adverse effects greater than 5% presented some type of adverse effect (3). Only a very small group of patients had serious adverse effects: acute pancreatitis (0.2%), acute cholecystitis (0.5%) (6).

In obese patients the most frequent side effects with the use of liraglutide were nausea (40.2%), diarrhea (21%), constipation (20%), vomiting (16%) (6). Constipation is usually transient in most cases.

There are currently insufficient data to confirm the association of liraglutide use with the development of pancreatitis and pancreatic cancer, although its use is not recommended in patients with such a history, as well as in those with a personal or family history of medullary thyroid carcinoma, multiple endocrine neoplasia (MEN-2), pregnant women. Liraglutide should be used with caution in patients with thyroid disease and a history of previous pancreatitis.(7)

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Its use is not recommended in patients over 75 years of age due to lack of therapeutic experience in this age group. Neither in patients with renal insufficiency with a glomerular filtration rate lower than 30 cc/min (chronic renal insufficiency Grade IV or V). Its safety and efficacy have not been proven in children under 12 years of age (7).

Can liraglutide be combined with the ketogenic diet?

On the other hand, we must say that there are currently no published studies combining the use of liraglutide with the very low calorie ketogenic diet (VLCKD). Possibly because their association could increase the risk of hypoglycemia, due to the inhibition of glucagon production by the drug (this hormone is key during ketosis since it allows maintaining blood glucose levels at normal and stable values during ketosis).

Currently, the use of liraglutide is contraindicated during the ketogenic steps of the Pronokal Method (500-800kcal/day) for the same reason. Furthermore, we know that during ketosis carbohydrate intake levels are greatly reduced (no more than 50g/day), so we can deduce that these beneficial incretin effects (hormonal effect produced in the intestine in response to food intake) of the drug could be minimal in ketosis, although there are no studies to support this to date.

Bibliographic reference

(1) Michael A. Nauck, PhD, Johan Jendle, PhD. “GLP-1 receptor agonists: a key element in current diabetes management.” Medscape 8/22/2014

http://img.medscape.com/images/828/898/828898_reprint_spa.pdf

(2) J van Can J, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WHM. “Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults”. Int. J. Obes (Lond) 2014; 38: 784 – 793. https://pubmed.ncbi.nlm.nih.gov/23999198/

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(3) Lundgren JR, Janus C, Jensen SBK, et al. “Healthy weight loss maintenance with exercise, liraglutide, or both combined”. N Engl J Med 2021; 384:1719-1730.

(4) Beiroa D, Imbernon M, Gallego R, et al. “GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK”. Diabetes 2014; 63:3346-3358.

https://pubmed.ncbi.nlm.nih.gov/24917578/

(5) Wadden TA, Hollander P, Klein S, Niswender K, Woo V, Hale PM, et. al. “Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study”. Int J Obes (Lond). 2013 Nov; 37(11):1443-51.

(6) Xavier Pi-Sunyer, M.D.,Arne Astrup, M.D., D.M.Sc., Ken Fujioka, M.D., Frank Greenway, M.D., Alfredo Halpern, M.D., Michel Krempf, M.D., Ph.D., David C.W. Lau, M.D., Ph.D., Carel W. le Roux, F.R.C.P., Ph.D., Rafael Violante Ortiz, M.D., Christine Bjørn Jensen, M.D., Ph.D., and John P.H. Wilding, D.M. for the SCALE Obesity and Prediabetes NN8022-1839 Study Group. “A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management”. N Engl J Med 2015; 373:11-22. DOI: 10.1056/NEJMoa1411892.

https://www.nejm.org/doi/full/10.1056/nejmoa1411892

(7) Spanish Agency for Medicines and Health Products. “FICHA TECNICA SAXENDA 6 MG/ML SOLUCION INYECTABLE EN PLUMA PRECARGADA”. March 23, 2015.

https://www.ema.europa.eu/en/documents/product-information/saxenda-epar-product-information_es.pdf. http://www.ema.europa.eu