GIP and GLP-1 analogues mimic the action of these hormones, known as incretins, which are physiologically produced by cells of the stomach, duodenum, and intestine.
Their secretion is stimulated by the passage of food through the gastrointestinal tract, mainly via mechanical and nutritional stimuli.
GLP-1: What It Is and How It Works
GLP-1 (Glucagon-Like Peptide-1) is a hormone produced mainly by L cells of the intestinal mucosa, but also by alpha cells of the pancreatic islets and by specific neurons of the nucleus tractus solitarius in the central nervous system.
It is essential for normal glucose tolerance and exerts its effects by binding to a specific GLP-1 receptor.
Main Actions of GLP-1
• Stimulates insulin secretion in a glucose-dependent manner (only when blood glucose levels are elevated)
• Inhibits pancreatic glucagon secretion
• Reduces the risk of hypoglycemia
• Slows gastric and intestinal emptying
• Increases the feeling of satiety
• Acts on appetite-control centers in the brain
GLP-1 is released after every meal and becomes active only in the presence of an increase in blood glucose related to carbohydrate intake.
For this reason, these drugs cannot be considered “anti-hunger” medications: the effect on hunger is only secondary to the drug’s mechanism of action and therefore cannot be equated with anorectic drugs such as amphetamines previously available on the market.
Cardiovascular Effects of GLP-1
Over the past ten years, numerous studies have shown that GLP-1 exerts protective effects on the cardiovascular system, contributing to a reduced risk of:
• Myocardial infarction
• Heart failure
• Stroke
These effects are also mediated by a direct action on perivascular fat, the adipose tissue surrounding blood vessels.
GLP-1, Hunger, and Appetite Control
GLP-1 acts directly on hunger and satiety centers located in the central nervous system. Of these centers:
• Only one is located in the cerebral cortex (voluntary control)
• Two are located in subcortical areas, regulated mainly by biochemical and hormonal signals
This means that approximately two-thirds of hunger control does not depend on willpower, but rather on signals produced by adipocytes, particularly from visceral adipose tissue.
The Physiological Limitation of GLP-1
The main limitation of endogenous GLP-1 is that, after its release, it is rapidly degraded by the enzyme DPP-4 (Dipeptidyl Peptidase-4).
For this reason, GLP-1 receptor agonists have been developed: molecules structurally similar to GLP-1 but resistant to degradation by DPP-4.
Some of these drugs are bound to molecules that slow subcutaneous absorption, thereby prolonging their duration of action.
GIP: A Complementary Incretin
GIP (Glucose-dependent Insulinotropic Peptide) is produced mainly in the duodenum and plays a fundamental role in stimulating postprandial insulin secretion, likely even more pronounced than that of GLP-1.
Main Differences Between GIP and GLP-1
• Greater effect of GIP on insulin secretion
• Improved peripheral insulin sensitivity
• Lesser effects on:
o Glucagon secretion
o Body weight reduction
• Does not induce nausea; may have antiemetic effects
GLP-1 and GIP Medications Available in Italy
1. Liraglutide (Saxenda®)
• Active ingredient: Liraglutide
• Manufacturer: Novo Nordisk
• Administration: Daily subcutaneous injection
2. Semaglutide (Wegovy® – Ozempic® – Rybelsus®)
• Wegovy®: formulation specifically indicated for obesity
• Administration: Weekly (Wegovy®)
The STEP clinical trials demonstrated a weight loss of 15–18% compared with placebo.
Indications:
• Adults
• Adolescents >12 years with obesity (BMI >95th percentile and weight >60 kg)
Additional benefits:
• Reduction in blood pressure
• Improvement in lipid profile
• Benefits for hepatic steatosis and renal function
• Specific indication for the control of food compulsivity
Indicative price: €220–294, depending on dosage.
3. Tirzepatide (Mounjaro®)
• Dual GLP-1/GIP agonist
• Administration: Weekly
• Recently available in Italy
Benefits:
• Significant weight loss
• Improved glycemic control
• Reduction of hepatic steatosis
• Cardiovascular and renal benefits
Indicative price: €346–485–623, depending on dosage.
Additional Benefits of GLP-1 Agonists
Beyond weight loss, these drugs provide numerous systemic advantages:
• Reduction in cardiovascular risk
(22% reduction in cardiovascular mortality)
• Hepatic benefits
reduction of steatosis and prevention of NASH
• Renal protection
• Overall metabolic improvement
• Reduction in all-cause mortality
up to 57% (SELECT Study), including a reduction in:
o Colorectal cancer
o Breast cancer
The Future: Triple Agonists
The new frontier of research is represented by triple GLP-1/GIP/glucagon agonists (Retatrutide), which combine:
• The metabolic efficacy of GLP-1/GIP
• The potent weight-loss effect of GLP-1/glucagon
Preliminary results show:
• Glycemic control comparable to dual agonists
• Greater weight loss
• Greater reduction of hepatic steatosis
• Possible protective effects against cognitive decline
These molecules could pave the way for new therapeutic indications beyond obesity and diabetes.
References
1. Müller TD, Finan B, Bloom SR, D’Alessio D.
Glucagon-like peptide 1 (GLP-1). Molecular Metabolism. 2019;30:72–130. doi:10.1016/j.molmet.2019.09.010.
2. Giorgino F.
Type 2 diabetes therapy: GLP-1 analogues are smart drugs. Why? 2020.
3. Nauck MA, Meier JJ.
GIP and GLP-1: stepsiblings rather than monozygotic twins within the incretin family. Diabetes. 2019;68(5):897–900. doi:10.2337/dbi18-0006.
4. Samms RJ, Coghlan MP, Sloop KW.
How may GIP enhance the therapeutic efficacy of GLP-1? Trends in Endocrinology & Metabolism. 2020;31(6):410–421. doi:10.1016/j.tem.2020.02.006.
5. Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, et al.; SELECT Trial Investigators.
Semaglutide and cardiovascular outcomes in obesity without diabetes. New England Journal of Medicine. 2023;389(24):2221–2232. doi:10.1056/NEJMoa2307563. PMID: 37952131.
