As sales of weight-loss drugs skyrocket, concerns persist over GLP-1 agonists, drugs introduced as anti-diabetics that have since become wildly popular for their weight-loss effects.
1. Semaglutide-based drugs
Drugs containing the active ingredient semaglutide , including the now acclaimed OZEMPIC , have become a viral phenomenon, pushing such medicines onto the list of scarce, almost unobtainable medicines.
This increasing scarcity is attributed to its high popularity, fueled by a widespread rush to find a miracle weight loss remedy.
Originally conceived as an antidiabetic drug, semaglutide has shown surprising effects on body weight reduction.
2. Weight loss VS slimming
It is crucial to emphasize that when we talk about "weight loss", we are referring to a change that involves various compartments of the body, and not exclusively to the decline in fat mass that characterizes weight loss.
In fact, weight loss represents the reduction in weight resulting exclusively from fat mass, while weight loss is a broader and more nonspecific term, indicating a decrease in weight coming from any body compartment.
This type of weight loss often includes loss of muscle mass, which can lead to a decrease in quality of life, a reduction in calorie expenditure, and an increased risk of developing disease.
For this reason, this situation is defined as “wasting” and not weight loss .
This article will not dwell on the cost-effectiveness analysis of the drug, as it takes time to formulate an opinion based on the evidence of long-term trials.
The main goal is instead to highlight the collective frenzy that, losing sight of reason, seeks a quick solution for weight loss in a medicine, even when it is only a few kilograms, neglecting the possible side effects.
3. Slimming drugs: a conscious choice?
A reflection on sustainability and awareness of such choices therefore becomes essential, considering the context of a society often inclined to embrace immediate solutions without fully evaluating the possible risks associated.
For years we have been dedicated to spreading new knowledge about REAL foods, made with non-genetically modified raw materials.
These foods allow our enzyme system to break them down during digestion without forcing it to produce excessive amounts of DPP-4 (dipeptidyl peptidase-4), an enzyme that breaks down protein parts that are still too complex and also regulates the degradation of specific hormones, including GIP and GLP1. The latter are essential in regulating several bodily processes, including the management of blood glucose.
The obvious solution should be to choose to consume only REAL foods, compatible with our organism, this would avoid the organism having to produce an excess of DPP-4 and, consequently, dysregulate blood sugar levels due to a decrease in GIP and GLP1 over time.
This solution appears clear, simple and, above all, free of risks and side effects, unlike the option of using drugs that chemically try to mimic GLP1, reflecting a mechanistic and stylized approach to the problem.
It is plausible to assume that the introduction of an active ingredient designed to mimic GLP1 may not optimally replicate its function, potentially generating systemic problems involving the immune system.
Furthermore, since the body maintains a delicate balance between GIP and GLP1, the exclusive introduction of an active substance that mimics GLP1 could disturb this delicate balance, with the risk of causing serious side effects.
While we wait for more in-depth answers, we encourage everyone to adopt the first approach to weight loss: eliminate foods made with genetically modified raw materials from your diet and favor REAL FOODS.
Insights into slimming drugs
With a worrying increase in the prevalence of type 2 diabetes (T2D) and its associated complications, the need for appropriate treatment strategies for this devastating disease has never been greater.
However, in addition to studying the potential beneficial effects of new hypoglycemic agents, regulatory bodies and clinicians are increasingly focusing their attention on long-term safety aspects.
One of the new classes of antihyperglycemic drugs that is receiving particular attention with regard to safety are the glucagon-like peptide-1 receptor agonists ( GLP-1RAs ).
These new drugs are designed to mimic the action of the incretin hormone GLP-1, a gut-derived hormone that is a potent stimulator of insulin and suppresses glucagon secretion.
In combination with their inhibitory effects on gastric evacuation and hepatic gluconeogenesis, GLP-1RAs effectively reduce glucose levels.
GIP is a 4,984 kDa molecule, produced by K cells in the duodenum, jejunum, and ileum, released upon ingestion of a mixed meal, especially if rich in carbohydrates and lipids.
The main biological activities include:
- inhibition of gastric acid secretion;
- stimulation of insulin secretion;
- insulin-like activity on adipose tissue (Figure 1).
GLP-1 is a molecule of approximately 4,200 kDa, produced by L cells of the distal small intestine and colon.
Several agents are now available after the first one gained commercial approval in 2005. Within the class of GLP-1RAs, there are notable differences in drug structure, efficacy, dosage range, and even adverse effects .
However, in general, a decrease in HbA1c of 1–1.5% is observed, as well as beneficial effects on body weight, blood pressure and lipid profile. However, partly due to the widespread presence of GLP-1 receptors, several adverse effects have been observed, including pancreatitis, pancreatic cancer and thyroid cancer, which were initially reported as safety concerns .
The most recently approved GLP-1RA is semaglutide .
This agent is somewhat special among GLP-1RAs as it is the only drug available as both a subcutaneous injection (similar to all other GLP-1RAs) and an oral formulation. Additionally, with years of development after the first GLP-1RA was marketed, registration studies with semaglutide were able to focus on any known safety risks of this class of drugs .
In this review, we will look in detail at the safety aspects of this drug.
Semaglutide
Semaglutide was developed based on the broad body of research that underpinned the development of liraglutide.
Compared to liraglutide, which is administered once daily, semaglutide has an even longer half-life, allowing for once-weekly administration .
While this represents a significant improvement over once- or twice-daily subcutaneous administration, the route of administration may be a barrier for some potential users.
An absorption enhancer (sodium N-<8-(2-hydroxybenzoyl) aminocaproate> or SNAC) has been discovered, which, when co-administered with semaglutide, has been shown to provide therapeutic levels of semaglutide.
SNAC helps protect semaglutide from proteolytic degradation in the stomach and facilitates its absorption across the gastric mucosa through transient effects on transcellular pathways.
At equivalent exposure levels, similar glycemic and weight responses were observed with semaglutide administered orally and subcutaneously.
Semaglutide Side Effects
Semantically, the on-target effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) are those that lead to a reduction in glucose levels.
Any other effects can be considered as pleiotropic, off-target or, in the case of unwanted actions, adverse effects as shown in (Figure 1).
Many of the common (adverse) effects are shared between the different GLP-1RAs, however, some differences do occur.
In the case of semaglutide, one might expect a different side effect profile for the oral formulation versus the subcutaneous formulation.
Besides the obvious fact that the tablets do not induce injection site reactions, it could be suggested that higher portal levels cause more gastrointestinal disturbances.
Additionally, at the maximum oral dosage, plasma levels are lower than at the maximum subcutaneous dose (20 mg oral produces plasma levels of approximately 25 nM, 1 mg subcutaneous produces plasma levels of approximately 45 nM).
The active ingredient “Semaglutide” present in all drugs similar to OZEMPIC is generating a heated debate among experts, especially regarding side effects.
The polarization of opinions highlights a significant disparity of views among industry experts regarding critical cost/benefit analysis.
Possible side effects include: risk of hypoglycemia, gastrointestinal discomfort, increased risk of pancreatitis and pancreatic cancer, thyroid cancer, gallstones, effects on the cardiovascular system, acute renal failure, risk of diabetic retinopathy, and allergies/reactions at the injection site .
Discussion on weight loss drugs
For all new drugs, it is necessary to establish a comprehensive safety profile, with particular emphasis on cardiovascular safety.
While safety within the Phase 3 program is sufficient for marketing authorization, it is the post-marketing phase that is most significant, where rare or less rare adverse events and any other potential safety risks are identified , given the increasing controversy regarding potential conflicts of interest, where the pharmaceutical companies themselves are responsible for both the organization and execution of Phase 3.
The same FDA document requires post-marketing trials to demonstrate that the new agent does not increase cardiovascular risk by more than 30% compared to placebo, if pre-marketing studies have not already demonstrated this.
Conclusion
Over the years, the use of GLP-1 receptor agonists has initially been associated with several adverse events, most of which have since been largely nuanced or refuted.
As one of the newer agents in the class, the safety of semaglutide – both in the subcutaneous and oral formulations – has been examined in Phase 3 programs and cardiovascular trials.
Compared with placebo and active comparator, semaglutide mainly induces mild and transient gastrointestinal disturbances and increases the risk of gallstones.
However, no significant safety concerns have emerged to date, although no definitive conclusions can be drawn for pancreatic cancer, thyroid cancer and complications of DRP.
Comparing the beneficial effects of these drugs on glucose metabolism, blood pressure, body weight, and cardiovascular (and potentially also renal) endpoints, at this time, it would appear that these agents present an overall favorable risk/benefit profile for the treatment of patients with type 2 diabetes.
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- Front Endocrinol (Lausanne). 2021; 12:645563.
- Published online 2021 Jul 7. doi: 10.3389/fendo.2021.645563
