Metabolic Manipulators

Introduction:

The pathways of metabolism are evident to be complex and interlinked [1]. Therefore, any kind of changes within this pathway might lead to the development of intricate disorders and eventually causes an imbalance of the homeostasis and metabolism of the physiological system. This is the exclusive reason behind the significance of the metabolic pathways within the clinical analysis and treatment management [1]. Researchers have developed varied strategies to manipulate the pathways of metabolism with the aid of high throughput techniques such as manipulation of the gene expression, gene therapy or boosting up the metabolic system through supplementation such as weight loss via the consumption of caffeine, through physical activities such as through aerobic training, and with the aid of modified patterns of diet regime [2]. Moreover, in certain situations, the biochemical analysis of the cell’s by-products, blood, and urine investigation helps to detect the progressive stages of varied maladies, failure of organs, doping/drug cheating case investigation in the field of forensic studies [2].

Overview:

For the present assignment the metabolic manipulator, liraglutide is chosen because it acts as an agonist of the glucagon-like peptide-1 receptor (GLP-1) and is also being referred to as “incretin mimetics” [3]. The compound works with the mechanism of enhancement of the discharge of insulin from the organ pancreas, and in turn also diminishes the excess release of the glucagon in the plasma which eventually results in the postponement of empty of the gastric cavity, and suppression of appetite along with tachycardia [3, 4]. It was evident from the past scientific communications that along with the recommended diet and exercise, liraglutide resulted in about 4 to 6 kg of loss in weight and patients also reported that a minimum of 5 to 10% of loss in weight in comparison to the placebo [3, 5]. However, past research investigations also revealed about the contraindications of the compound such as the gastrointestinal discomfort, enhanced risk of pancreatitis along with nausea and vomiting that occurred during the initial phase of the course of treatment [6]. Comparative studies also revealed that the weight-loss accomplished with the utilization of liraglutide was found to be greater than compounds like lorcaserin or orlistat and it is lower than the compound phentermine/topiramate [7]. Moreover, recent research investigations have also demonstrated that liraglutide within the dosage value of 1.8mg had beneficial cardiovascular effects when trial outcomes were evaluated within a large sample population [8]. It should also be noted that there are certain barriers to its usage in the real clinic setting as the first-line treatment management such as the adverse gastrointestinal problems, excessive cost, and the application of the drug via injection [4].

Research:

The drug is marketed in the name of Victoza® and Saxenda® [4]. The weight loss effect is due to the effect of GLP-1 and the half-life of it in the circulating form is lower than 2 minutes as the enzymes neutral endopeptidases (NEP) and dipeptidyl peptidase‐IV (DPP‐IV) degrades GLP-1 rapidly [4]. The biochemical pathways involve the increment of the cyclic AMP that stimulates the glucose dependant discharge of hormone insulin, along with the inhibition of the glucose dependant release of glucagon, which eventually results in the postponement of empty of the gastric cavity, and suppression of appetite along with tachycardia [6]. Following the subcutaneous injection of liraglutide, the peak absorption happens within 11 hours and the bioavailability is 55%. The drug is highly bonded with protein substance (98%) and it has a large fatty acid chain and a huge volume of distribution [4, 6]. The compound is prescribed to patients of type 2 diabetes and normal healthy individuals with a half-life of 13 hours and therefore its administration is restricted to one time daily. The compound does not interfere with the cytochrome P450 system and its elimination occurs via the kidneys and the liver in the form of small peptides [4].

Fig1: Effects of the compound liraglutide along with the adverse reactivities [4]

Diagnosis:

The diseased states that might result as a consequence of the treatment with liraglutide are the gastrointestinal discomfort, nausea, vomiting, and the heightened risk of pancreatitis [4]. It must be noted that animal model study had revealed that with the utilization of liraglutide, there occurs an enhanced risk of death of the embryo or fetal abnormalities along with HbA1c > 7 that causes in 20-25% risk of birth anomalies [6].

Treatment

In case of gastrointestinal discomfort caused by liraglutide, the compound should be administered as per the NICE guidelines with the introductory dosage value of 0.6mg on daily basis. Thereafter, a minimum period of 1 week, the dose of the compound could be increased to 1.2mg. It can be also stated that depending on the clinical response and the summary of the product characteristics, the dosage of liraglutide could be enhanced to 1.8mg [9]. Investigations conducted by varied authors there is a significant loss in body weight of 76.1% versus placebo 29.6% (P-value < 0.001); 73% versus placebo 28% (P value ≤ 0.001); 50.5% versus placebo 21.8% (P-value < 0.0001) with the dosage value of liraglutide lying in between 1.2 mg to 3mg in comparison to placebo effect [7, 10, 11]. There is no requirement of dosage alteration among the patients with renal impairment, though studies are needed upon end-stage renal disease patients and caution should be exercised before prescribing it to the population having hepatic impairment [6].

Policy:

According to the NICE policy or guidelines for the administration of liraglutide, it can be prescribed at a dosage value of 1.2 mg routinely along with metformin and sulfonylurea or thiazolidinedione for the treatment of patients with type 2 diabetes [9]. As per the policy of the FDA, the manipulator can be used as an adjunct to a low-calorie diet, and enhanced exercise for the persistent management of weight having an initial body mass index (BMI) of a minimum of 27 kg/m² (overweight) and 30kg/m² (obese) along with one co-morbid condition that is related to weight. The recommended dosage value of the marketed manipulator named Saxenda® is 3mg. However, if the patient cannot tolerate increased dosage then delaying the escalation of dosage has to be practiced for a minimum period of 1 week [12].

Conclusion:

The assignment detailed about the following sections of the metabolic manipulator, liraglutide such as the overview, research, diagnosis, treatment, and policies.

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References:

1. Lutsenko S. Human copper homeostasis: a network of interconnected pathways. Current opinion in chemical biology. 2010 Apr 1;14(2):211-7.
2. Koene S, Smeitink J. Metabolic manipulators: a well founded strategy to combat mitochondrial dysfunction. Journal of inherited metabolic disease. 2011 Apr 1;34(2):315-25.
3. Moreira GV, Azevedo FF, Ribeiro LM, Santos A, Guadagnini D, Gama P, Liberti EA, Saad MJ, Carvalho CR. Liraglutide modulates gut microbiota and reduces NAFLD in obese mice. The Journal of nutritional biochemistry. 2018 Dec 1;62:143-54.
4. Mehta A, Marso SP, Neeland IJ. Liraglutide for weight management: a critical review of the evidence. Obesity science & practice. 2017 Mar;3(1):3-14.
5. Wettergren A, Schjoldager B, Mortensen PE, Myhre J, Christiansen J, Holst JJ. Truncated GLP-1 (proglucagon 78–107-amide) inhibits gastric and pancreatic functions in man. Digestive diseases and sciences. 1993 Apr 1;38(4):665-73.
6. Liraglutide (Source: https://go.drugbank.com/drugs/DB06655) (Accessed on 13.10.2020)
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8. Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, Hu FB, Hubbard VS, Jakicic JM, Kushner RF, Loria CM. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014 Jun 24;129(25 Suppl 2):S139-40.
9. National Institute for Health and Clinical Excellence. Final appraisal determination: Liraglutide for the treatment of type 2 diabetes mellitus.
10. Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjøth TV, Andreasen AH, Jensen CB, DeFronzo RA. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. Jama. 2015 Aug 18;314(7):687-99.
11. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, Lau DC, Le Roux CW, Violante Ortiz R, Jensen CB, Wilding JP. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. New England Journal of Medicine. 2015 Jul 2;373(1):11-22.
12. Mullard A. 2017 FDA drug approvals. (Source: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/206321Orig1s004.pdf) (Accessed on 13.10.2020)
13. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, Lau DC, Le Roux CW, Violante Ortiz R, Jensen CB, Wilding JP. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. New England Journal of Medicine. 2015 Jul 2;373(1):11-22.