New Developments in Treating Type 2 Diabetes and Obesity: Oral Weight-Loss Medications

The treatment of type 2 diabetes and obesity has changed significantly in recent years. In particular, GLP-1-based medications have shown that hormonal regulatory pathways can be specifically influenced. While injectable formulations have been the primary focus so far, a new development is increasingly coming to the fore: oral weight-loss medications.

We show why these active substances are being intensively researched, how tablets differ from weight-loss injections, and what significance this development may have for the treatment of metabolic diseases.

Weight-Loss 2.0? Why Are Weight-Loss Medications Being Developed as Tablets?

The GLP-1 receptor agonists currently in use are predominantly administered subcutaneously. While this is feasible for many patients, it often requires a certain degree of effort. Especially in long-term therapies, however, a “practical” dosage form plays a crucial role in real-world adherence, as also reflected in findings from the World Health Organization (WHO, 2003).

Why Are Tablets Pharmacologically Challenging?

GLP-1-based substances belong to the group of peptide hormones. These are normally rapidly broken down in the digestive tract and only reach the bloodstream in very small amounts.

For oral administration to be possible at all, several conditions must be met:

·       protection against enzymatic degradation in the gastrointestinal tract

·       sufficient absorption through the mucosa

·       stable active substance concentration in the blood

Oral semaglutide uses an absorption enhancer that enables uptake in the stomach (FDA, 2019).

GLP-1-Based Substances: Differences Between Pills and Injections

Any initial euphoria needs to be tempered at this point. Because oral GLP-1 medications differ from injectable preparations in several respects:

·       daily intake instead of weekly injection

·       lower bioavailability

·    stricter administration requirements

Another drawback: these differences also affect clinical efficacy. Studies show that oral GLP-1 preparations achieve a significant improvement in blood glucose levels, but the effects on body weight are less pronounced than with injectable GLP-1 receptor agonists (Pratley et al., 2019).

What Does This Mean for the Treatment of Obesity?

Currently available oral formulations are used primarily for blood glucose regulation. In the context of obesity, they are — if at all — prescribed only on the basis of individual medical decisions outside their approved indications (off-label use).

Pronounced effects on body weight — such as those seen with injectable formulations — have not yet been achieved to the same extent due to the lower bioavailability of oral formulations. Therefore, tablets should currently be regarded as a complementary option that cannot (yet) replace the effects of injectable treatments, particularly in cases of significant obesity (Pratley et al., 2019. Although the reference cited here dates from 2019, the situation has not changed significantly).

GLP-1-Based Substances: The Limits of What Is Currently Possible

In addition to these aspects, the following limitations remain — and overcoming them will be crucial for the long-term evaluation of new treatment approaches for diabetes and obesity:

·       the underlying causes of obesity are not directly addressed

·       the effect depends on continuous use

·       after discontinuation, weight regain may occur — as already observed with injectable preparations

Conclusion: Oral GLP-1 Medications Represent Progress — Their Full Potential Is Yet Unclear

Oral GLP-1 medications demonstrate that hormonal therapies may become easier to integrate into everyday life in the future. However, at present — particularly with regard to weight reduction — they do not match the efficacy of injectable preparations.

Whether this will change through new active substances and improved technologies is the subject of ongoing research — and will likely determine the future role of these medications in the treatment of metabolic diseases.

FAQ – Frequently Asked Questions About Oral GLP-1 Medications

1. What role do different dosages play in oral vs injectable GLP-1 medications?

Oral preparations must be dosed significantly higher because a large proportion of the active substance is lost in the digestive tract. Even so, they usually do not achieve the same plasma levels as injections. This is a key reason for the differing efficacy.

2. Why is the effect of GLP-1 tablets less consistent than that of injections?

Absorption in the stomach is susceptible to individual variation and external influences. As a result, active substance levels may fluctuate more, whereas injections provide a more stable and controllable effect.

3. Why is further development of the molecular structure crucial for the success of oral therapies?

Current limitations are not primarily due to the mechanism of action, but to absorption. Progress is therefore expected mainly from new molecular structures that are more stable and can be absorbed more efficiently.

Regardless of the dosage form, the mechanisms of action of all GLP-1 medications remain the same: they act on the same receptors and influence appetite, gastric emptying and metabolism.

4. What are the requirements for taking oral GLP-1 medications?

Administration must follow strictly defined conditions to ensure adequate absorption. This usually includes taking the medication on an empty stomach, at least 30 minutes before the first meal, with only a small amount of water and without taking other medications at the same time. Food or drink should only be consumed afterwards (FDA, 2019).

5. What are the risks if instructions for taking oral preparations are not followed?

Absorption of the active substance may be significantly reduced or fail entirely. This leads to insufficient plasma levels, which markedly reduces efficacy. The challenge is that reduced effectiveness is not immediately noticeable to patients, meaning the therapy may appear to be followed correctly while not working optimally.

Further information on the treatment of obesity and diabetes can be found in the respective volumes of our “Medizinskandale” series, as well as in the volumes of our “Codex Humanus.” The fifth volume has just been published. Feel free to visit our online shop. Our blog articles also provide additional details on these and many other topics.

Sources:

·       World Health Organization (2003): “Adherence to Long-Term Therapies: Evidence for Action,” Sabaté, E. (ed.).

·       U.S. Food and Drug Administration (2019): “Rybelsus (semaglutide) tablets – Prescribing Information.”

·       Pratley, R. et al. (2019): “Oral Semaglutide versus Subcutaneous Liraglutide and Placebo in Type 2 Diabetes,” The Lancet.