Treating type 2 diabetes mellitus with GLP-1 RAs
The treatment of type 2 diabetes mellitus has changed profoundly in recent years. The aim of therapy, in fact, is no longer limited to lowering blood glucose levels, but also includes body weight management and cardiovascular and renal protection.
In this context, GLP-1 receptor agonists, also referred to by the abbreviation GLP-1 RAs, have taken on an increasingly important role. Medicines such as semaglutide, liraglutide, dulaglutide and exenatide can improve glycaemic control and promote weight loss, with a generally low risk of hypoglycaemia.
Let us therefore take a closer look at how they work, when they are used and what role nutritional support can play during treatment.
What are GLP-1 RAs and what role do they play in type 2 diabetes mellitus?
To understand why these medicines have become so important, we need to start with their mechanism of action. GLP-1 RAs act on several processes involved in controlling blood glucose, appetite and digestion.
GLP-1 is a hormone produced by the intestine after food intake. It helps regulate blood glucose by stimulating insulin secretion when glucose levels rise. At the same time, it reduces glucagon production, slows gastric emptying and contributes to feelings of satiety. The main GLP-1 agonists reproduce these effects for longer than the natural hormone. The result is improved blood glucose control both when fasting and after meals.
Current guidelines consider these therapies to be among the main treatment options for type 2 diabetes, particularly in the presence of obesity, cardiovascular disease or chronic kidney disease. Depending on the patient’s condition, they can also be introduced without waiting for prolonged disease progression or the failure of numerous previous treatments.1
The main GLP-1 RAs used in the treatment of type 2 diabetes
The molecules belonging to this class share the same therapeutic objective, but differ in duration of action, method of administration and effectiveness in controlling blood glucose and body weight. The choice therefore depends on the person’s clinical profile and individual needs.
Semaglutide, liraglutide, dulaglutide and exenatide
GLP-1 RA medicines are not all the same. Liraglutide is administered once daily, while dulaglutide and injectable semaglutide are generally administered once weekly. Exenatide is available in formulations with different dosing frequencies.
Once-weekly administration can simplify treatment management and encourage adherence. In any case, the choice must take into account the patient’s clinical condition, tolerability and preferences.
Tirzepatide is also among the new medicines for the treatment of obesity and diabetes. This molecule is not a selective GLP-1 RA, because it acts simultaneously on the GIP and GLP-1 receptors. It is therefore more accurate to describe it as a dual incretin agonist.
The benefits of GLP-1 RAs for glycaemic control
The main objective of GLP-1 RAs in type 2 diabetes remains the improvement of glycaemic control. However, their mechanism also makes it possible to act on body weight, without generally exposing the patient to the same risk of hypoglycaemia associated with some traditional therapies.
Reduction in HbA1c and improvement in blood glucose levels
Glycated haemoglobin, or HbA1c, provides an indication of average blood glucose levels over the previous months. GLP-1 RAs can produce clinically significant reductions in this parameter, including in patients who do not achieve their target with metformin alone.
Effectiveness varies according to the molecule, dose and starting situation. For this reason, the HbA1c value should be interpreted alongside age, duration of the disease and the presence of other clinical conditions.
Low risk of hypoglycaemia compared with other therapies
The action of GLP-1 RAs on insulin secretion depends on the presence of glucose. When they are used alone or with medicines that do not cause hypoglycaemia, the risk of an excessive reduction in blood glucose is therefore generally low.
The situation changes when they are combined with insulin or sulphonylureas. In these patients, the doctor may consider adjusting the doses to reduce the risk of hypoglycaemic episodes.2
Effectiveness in patients with diabetes and obesity
Many people with type 2 diabetes are also overweight or have obesity. In these cases, the reduction in appetite and calorie intake can promote weight loss that may also be beneficial for metabolic control.
Weight loss, however, should also be assessed from the point of view of body composition. A rapid reduction in food intake can also affect lean mass, particularly when the patient consumes too little protein and leads a sedentary lifestyle. For this reason, diet and exercise remain an integral part of treatment.
Cardiovascular and renal benefits of GLP-1 RAs
The effectiveness of these medicines is not limited to blood glucose control. Some molecules have also demonstrated benefits in terms of cardiovascular risk and the progression of kidney damage, aspects that are particularly important in patients with long-standing diabetes or associated conditions.
Reduction in major cardiovascular events
Some GLP-1 RAs have been shown to reduce the risk of major adverse cardiovascular events, referred to by the acronym MACE, in patients with type 2 diabetes and established cardiovascular disease or high cardiovascular risk.
The evidence mainly concerns events such as heart attack, stroke and cardiovascular mortality. However, the benefit should not automatically be attributed to every molecule: when choosing a medicine, it is important to verify which outcomes have been demonstrated in clinical trials.3
Effects on blood pressure, albuminuria and kidney function
Treatment can also have favourable effects on certain factors related to renal and cardiovascular health, such as weight, blood pressure and urinary albumin excretion.
In patients with chronic kidney disease, GLP-1 RAs with documented benefits may help slow the progression of kidney damage. SGLT-2 inhibitors nevertheless retain a particularly important role in kidney protection and the prevention of heart failure.
Impact on mortality and heart failure
Data on mortality and hospitalisation for heart failure are not consistent across the entire class. GLP-1 RAs are particularly relevant for atherosclerotic cardiovascular risk, while SGLT-2 inhibitors are often preferred when heart failure is the predominant clinical concern.
The choice may also include combining the two classes when the doctor considers their benefits to be complementary.
Tolerability and nutritional support during treatment
As with any pharmacological treatment, GLP-1 RAs can also cause side effects. In this case, the problems mainly affect the gastrointestinal system and can influence appetite, energy levels and the ability to maintain an adequate diet.
Gastrointestinal symptoms, reduced appetite and fatigue
Nausea, feelings of fullness, diarrhoea and constipation are among the most common effects. They often tend to appear during the early stages of treatment or following a dose increase.
If symptoms are persistent or severe, it is necessary to consult a doctor. A food supplement does not replace clinical assessment and should not be used to continue a poorly tolerated treatment independently.
Within a supervised treatment pathway, there are some food supplements that can provide important support for gastrointestinal wellbeing and energy metabolism during periods characterised by reduced appetite and fatigue.
Weight loss and protection of muscle mass
The weight reduction associated with GLP-1 RAs can also involve lean mass. Adequate protein intake and resistance exercise are therefore important for supporting muscle function during treatment.
When the diet is unable to meet nutritional requirements, a healthcare professional may consider targeted nutritional support. In this context, the EuStabil, formulated with Berberine, Artichoke, Butyrate, and FOS, can be introduced to help maintain muscle mass as nutritional support following GLP-1 receptor agonist therapy, helping to prevent the rebound effect that may occur upon discontinuing treatment.
What role can food supplements play?
Food supplements can support the treatment pathway when reduced food intake makes it more difficult to achieve an adequate nutrient intake. However, their use should be personalised and assessed in relation to kidney function, other treatments being taken and the patient’s nutritional status.
Cor.Con. International approaches supplementation as part of a broader pathway. Supplements for the metabolic system can complement lifestyle measures and professional advice, without replacing prescribed medicines.
When to use GLP-1 RAs in type 2 diabetes
There is no single point at which a GLP-1 RA should be introduced. The decision depends on the level of glycaemic control, associated conditions and the goals agreed with the patient.
Patients with inadequate glycaemic control
GLP-1 RAs may be considered when diet, physical activity and the treatment already being used do not allow the patient to achieve the HbA1c target established by the doctor.
The choice does not depend solely on exceeding the 7% threshold. Glycaemic targets should in fact be personalised according to age, duration of the disease and risk of hypoglycaemia.
Diabetes associated with obesity or high cardiovascular risk
These medicines may be particularly suitable when diabetes is associated with obesity, cardiovascular disease or a high risk of developing events such as heart attack and stroke.
In the presence of chronic kidney disease or heart failure, the doctor should also assess the use of other drug classes, such as SGLT-2 inhibitors.
Personalising treatment according to the patient’s profile
The choice takes into account the method of administration, gastrointestinal tolerability, kidney function and the patient’s ability to follow the treatment correctly.
Personal preferences and access to the medicine are also part of the assessment. Reimbursement by the National Health Service depends on the authorised indications and the criteria set out in the applicable provisions.
GLP-1 RAs in combination with other antidiabetic therapies
In most cases, GLP-1 RAs are introduced as part of an existing treatment regimen. The possible combinations vary according to the medicines being used and the glycaemic, cardiovascular and renal goals.
Combination with metformin
Metformin can be continued when it is effective and well tolerated. Combining it with a GLP-1 RA often makes it possible to intensify glycaemic control without significantly increasing the risk of hypoglycaemia.
Combination with insulin
Combining a GLP-1 RA with insulin can also be useful. In this case, the GLP-1 RA can improve glycaemic control and limit weight gain, while the insulin dose should be reassessed by the doctor.
Combination with SGLT-2 inhibitors
In patients with cardiovascular or renal risk, combination with an SGLT-2 inhibitor may be considered. The two classes act through different mechanisms and may offer complementary benefits.
GLP-1 RAs and DPP-4 inhibitors, on the other hand, are not generally combined because they act on the same incretin system and the additional benefit is limited.1
Treatment continuity and management after discontinuation
Treatment with GLP-1 RAs may continue over the long term and should not be stopped without a clinical assessment. The period following discontinuation requires attention to both glycaemic control and weight management.
Why GLP-1 RAs should not be stopped independently
In people with diabetes, discontinuation can lead to a worsening of blood glucose control. Appetite and thoughts about food may also increase again, with possible regain of the weight lost.
Discontinuation should therefore be planned with the doctor, who can reassess the treatment and advise how blood glucose levels should be monitored during the transition.
Diet and metabolic support during the maintenance phase
Diet, physical activity and metabolic monitoring become particularly important after reducing or stopping the medicine. Available studies show that weight regain is common, although its extent varies from person to person.
Scientific evidence and future prospects
Knowledge of GLP-1 RAs continues to evolve. In addition to assessing the effectiveness of molecules already available, research is investigating new formulations and therapies capable of acting simultaneously on multiple metabolic pathways.
Clinical trials and meta-analyses on GLP-1 RAs
Clinical trials have documented benefits for HbA1c control, body weight and, for some molecules, cardiovascular and renal risk. Meta-analyses also make it possible to compare the results obtained with different medicines and identify the groups of patients who may benefit most from them.
However, it remains necessary to distinguish the benefits demonstrated for individual molecules from effects attributed to the class as a whole.
Precision medicine and the future of type 2 diabetes treatment
The direction is towards precision medicine: choosing treatment according to the glycaemic profile, body weight, cardiovascular and renal risk, and the individual characteristics of the person.
We can therefore say that there is no single GLP-1 RA suitable for everyone. Rather, there is a treatment pathway to be built over time, in which medicines, diet, physical activity and any supplementation must be carefully coordinated.
References
- https://diabetesjournals.org/care/article/49/Supplement_1/S183/163934/9-Pharmacologic-Approaches-to-Glycemic-Treatment ↩︎
- https://diabetesjournals.org/care/article/49/Supplement_1/S183/163934/9-Pharmacologic-Approaches-to-Glycemic-Treatment ↩︎
- https://diabetesjournals.org/care/article/49/Supplement_1/S216/163933/10-Cardiovascular-Disease-and-Risk-Management ↩︎