How to treat type 2 diabetes, or have you ever thought about examining a poisonous lizard's saliva?

The previous article summarized the discovery of incretins and other hormones produced in the gut and involved in glucose homeostasis. It also noted that in patients with type 2 diabetes (DM2) and obesity, the incretin effect is greatly reduced or absent, in part due to an impaired postprandial response of the incretin GLP-1, which contributes significantly to glycemic control.

Why has it taken so long to capitalize on scientific discoveries and change the approach the approach in treating DM2?

The stumbling block was the short period of activity of incretins due to their rapid deactivation by the serine protease DPP-4 (dipeptidyl peptidase IV).

The search for a solution to this problem went in several directions.

Gliptins 

If peptide hormones are so briefly active, shouldn't we block the DPP-4 enzyme that turns them into an inactive form? Thought - found. In 2006 it was possible to synthesize a stable form of a blocker of this enzyme called sitagliptin

The names of drugs that block DPP-4 have the suffix ☛ gliptin.

• sitagliptin (Januvia®)
• saxagliptin (Onglyza®)
• vildagliptin (Galvus®)
• linagliptin (Trajenta®)

The advantage of these drugs is the possibility of using the tablet form. The drugs differ in the rate of reabsorption in the GI tract and the half-life of elimination.

Linagliptin does not require correction in renal dysfunction, unlike the others.

Vildagliptin is not recommended in case of hepatic dysfunction.

There are reports about development of marked skin allergic reactions to Saxagliptin and Vildagliptin as well as joint pain while on Saxagliptin > Linagliptin / Vildagliptin.

After three months of taking gliptins, HbA1C decreases on average by 0.5-0.8%. This reduction is rather modest, comparable to the effect of gliflozins (SGLT2 inhibitors).

The effect of gliptins on glycemic control is lower in comparison with GLP-1 receptor agonist drugs, which will be discussed later.

It is necessary to take into account the fact that this enzyme does not limit its influence only to incretins, it participates in a variety of biological reactions. In particular, DPP-4 is involved in the degradation of cytokines and regulatory peptides containing alanine and proline, such as neuropeptide Y, somatoliberin and peptide YY. DPP-4 has been implicated in T-cell co-stimulation and activation.

Perhaps this circumstance explains possible infections of urinary tract and lungs against the background of gliptin administration.

In general, we do not know what effects long-term use of these drugs may lead to.

Gliptins have little or no effect on the weight of patients with DM2. They rarely cause nausea and do not inhibit gastric motility. The risk of hypoglycemia is minimal unless they are combined with drugs that cause it (insulin, sulfonylurea derivatives). This makes them particularly attractive in the treatment of elderly patients in whom metformin monotherapy has been exhausted.

Gliptins reduce inflammatory markers and improve endothelial function, both as a result of increased levels of incretins and by a mechanism independent of GLP-1. However, there are as yet no unequivocal results on the reduction in cardiovascular mortality resulting from treatment with these drugs.

Gliptins are more expensive than metformin and sulfonylurea derivatives.

GLP-1 agonists

Another direction in the search was an attempt to find substances similar to GLP-1 but more resistant to DPP-4 degradation. This discovery was led to some extent by chance multiplied by curiosity.

Meet the star - large gila monster lizard, a resident of the Arizona desert.

In early 90's John Eng and Jean-Pierre Raufman, studying the poisonous saliva of this lizard, discovered a new peptide hormone of the glucagon family, which caused an enlargement of the pancreas in experimental animals. It was named exendin-4.

Interest in the peptide increased even more when it was discovered that the lizard could go without food for almost a whole year, eating only for a short period of time in the spring. At the same time it was enough to eat only a few rabbits to last until the next hunting season. The lizard was able to keep its glucose levels constant while hibernating without compromising its health.

A striking similarity was found between exendin-4 and GLP-1 ( 53% ), an incretin produced in human GI L-cells. Both peptides bind to and activate the G-protein coupled receptor for GLP-1 on the surface of pancreatic β-cells. In doing so, they exhibited similar affinity and binding strength characteristics, leading to glucose-dependent insulin secretion. However, the half-life of the proteins differed: a few minutes for GLP-1 versus several hours for exendin-4. Something in the protein structure of the latter made it much more resistant to the destructive action of DPP-4.

A synthetic version of exendin-4 was registered under the name exenatide (Byetta ®) and approved by the FDA for the treatment of DM2 in 2005. Currently (end 2024), this drug is only available in a prolonged form called Bydureon BCise® , which is administered subcutaneously at a dose of 2 mg once a week. The drug reduces HbA1C to a lesser extent compared to Ozempic®. Prolonged administration of Bydureon BCise® leads to some weight loss (about 5%).

Side effects during therapy with exenatide are similar to those that occur during therapy with other GLP-1 receptor agonists. Allergic reactions have also been noted.

The drug currently occupies an insignificant segment on the market. The launch of the original drug Byetta®, which had to be administered twice a day, was stopped due to low sales.

Analogs based on the human GLP-1

Research on lizard venom inspired Novo Nordisk to create GLP-1 receptor agonists based on recombinant DNA technology. Their names have the suffix ☛ (glu)tide

There are injectable forms of shorter-acting medications that require daily administration. These include:

• Liraglutide (Victoza®, Saxenda®)
• Lixisenatide (Lyxumia®)

The first attempts led to the development of short-acting drugs like Liraglutide with the brand name Victoza® (2010), which not only glucose-dependently stimulated insulin formation but also led to greater weight loss compared with Byetta® (about 10%). However, this drug had to be administered subcutaneously once daily. Therefore, the search focused on creating a long-acting form, which, in addition to everything else, could affect the CNS neurons that have receptors for GLP-1. And, as a consequence, influence human eating behavior. The result was the creation of recombinant semaglutide, which has 94% similarity to human GLP-1. It exists on the market in a form for weekly subcutaneous administration: Ozempic®(2017) and Wegovy® (2021), and as an oral form of Rybelsus®.

These drugs are expensive , price depends on the dosering;

The drugs are FDA-approved and have sufficient safety. In addition to improving glycemic control, they also lead to weight loss (Wegovy® effect above Ozempic®).

The drugs with prolonged action also include dulaglutide (2014), but its T 1/2 is 5 days, which is somewhat shorter than semaglutide.

§ How can we increase T 1/2 of GLP-1 agonists?

Extended effect of s.c. semaglutide is provided due to two structural modifications. The first consists in its high affinity to albumin. It reduces the rate of renal excretion. The other consists in imparting resistance to DPP-4 deactivation.

§ How does the outcome of therapy with short-acting drugs differ from long-acting drugs?

Short-acting drugs primarily reduce post-prandial glucose levels by inhibiting gastric emptying, in addition to enhancing insulin secretion.

Long-acting GLP-1R preparations reduce fasting glucose levels by stimulating insulin secretion and reducing glucagon levels during a prolonged period of action. They have less effect on post-prandial glucose level due to possible tachyphylactic effect on gastric motility.

Current data show that success in achieving better glycemic control depends on the duration of peptide activity. This has been shown by comparing the results of the short-acting(twice-daily) and long-acting (once-weekly) forms of exenatide. In turn semaglutide was found to be more effective compared to long-acting exenatide.

§ Why is oral semagludide (Rybelsus®) not digested in the intestine?

Oral semaglutide was made possible by a combination peptide so called "absorption enhancer" (SNAC). A 0.6% reduction in HbA1c was observed with the tablet form 3 mg/day. (PIONEER 3 trial 78-weeks).

For the 7 mg/day and 14 mg/day doses, HbA1c reductions were 1% and 1.3%, respectively, over 26 weeks of follow-up.

Weight reductions were -1.2 kg, -2.2 kg, and -3.1 kg with oral semaglutide (3 mg / 7 mg / 14 mg).

The results with the 7 mg and 14 mg daily doses were better than with gliptin therapy. Side effects of oral semaglutide were nausea and diarrhea. As with the injectable form, there was no increased risk of pancreatitis compared with placebo.

§ Do small molecul (non-peptide) oral GLP-1 receptor agonists already exist?

Yes. This alternative approach offers a promising option. Orforglipron tablets shoed good weight loss results with a satisfactory safety profile. While another oral GLP-1 non-peptide analog Danuglipron (Pfizer) caused severe nausea, vomiting and pain that required patients to discontinue treatment. The delivery of non-peptide forms is potentially less expensive than recombinant peptides.

§ It may seem that GLP-1R analogs, although superior to gliptins and gliflozins, are not the "silver bullet" in the treatment of DM2 and obesity. Is this the case?

These drugs currently show promise as second-line agents after metformin therapy for DM2 has become inadequate in DM2. They not only improve glycemic control but also reduce weight, and show beneficial effects on cardiovascular and renal function. However, not everything is as rosy as we would like. These drugs have side effects, some of which are due to their mechanism of action. The most common side effects are nausea and constipation, which in rare may require medical attention. In some cases, gastroparesis may occur. Improving glycemic control requires slightly lower doses than those that effectively reduce weight, and weight loss is a priority in the treatment of DM2. However, the higher the dose, the greater the risk of these complaints and, consequently, of discontinuation of therapy.

The answer to this challenge was the idea of combining GLP-1R agonists with a GIP-1 receptor agonist and/or with glucagon receptor agonists (GCGR). This is how duo-, and triple-combinations of GLP-1 receptor agonists came about.

* - approximately ( depends on dose)

** - see more retatrutide, not FDA approved.

Duo-therapy:

§ Why add a GIP-R analog to GLP-1R agonists?

As we already know, the GIP incretin is produced in the K-cells of the upper intestine and helps to coordinate the α- and β-cells of the pancreas. The effect on β-cells is similar to that of GLP-1, but differs with respect to glucagon production by α-cells. GIP increases glucagon secretion, making GIP monotherapy inappropriate for the treatment of DM2. However, the addition of a GIP-R receptor analog to a GLP-1R analog can achieve the desired effect of glycemic control and weight loss while reducing GLP-1R-induced GI side effects.

Duo-therapy:

§ Why include a synthetic glucagon receptor analog in combination with GLP-1R agonists, given the properties of glucagon to cause hyperglycemia?

To answer this question, let us make a lyrical digression. As already mentioned, glucagon release from pancreatic alpha cells is normally inhibited by hyperglycemia, insulin, GLP-1 and somatostatin. Receptors for glucagon (G-protein coupled) are found on many cells, but are particularly abundant in liver, kidney (descending loop of Henle and distal tubules), heart, and adipose tissue. The interaction of glucagon with the receptor on renal cells activates sodiumuresis and increases glomerular filtration. Glucagon can even stimulate pancreatic β-cells to insulin secretion, although to a much lesser extent than insulin due to weak binding to GLP-1 receptor. Interaction of glucagon with the receptor on hepatocytes leads to increased bile formation, increased glucose levels by the mechanism of glycogenolysis and by activation of glyco-neo-genesis. There is also destruction of fats in the course of lipolysis, leading to the formation of ketones. Even proteins are thrown into the furnace! This is how glucagon tries to release resources to supply our body with the necessary fuel.

Relative hyperglucagonemia is seen in both type 1 and type 2 diabetes mellitus. It is thought to play a role in the pathogenesis of both conditions. There is a search for ways to pharmacologically block its action. Although such drugs have already been developed, unfortunately they cause numerous side effects and require further research.

Combining the glucagon receptor analog (GCGR) with GLP-1R analogs allows us to take advantage of glucagon's property of burning "fuel", increasing energy expenditure, but controlling hyperglycemia with GLP-1. Also an important property of glucagon is its suppression of hunger. This distinguishes it from other substances that increase energy intake, such as thyroxine and amphetamines. They stimulate appetite at the same time, which makes them of little appeal in obesity.

§ What is used in duo-combination drug cotadutide?

The hormone used is not pure glucagon, but a synthetic analog of the hormone oxyntomodulin, which is composed of glucagon and an octopeptide tail IP-1 It is the product of the aforementioned pre-pro-glucagon gene, which triggers its script in the L-cells of the small intestine.

The receptors for oxyntomodulin are not yet known, but it has been successful in activating both the glucagon receptor and the GLP-1 receptor. Oxyntomodulin has been used successfully in clinical trials of obese people, reducing appetite, increasing energy expenditure, while not impairing glucose tolerance. Adding an oxyntomodulin analog to GLP-1 reduces the risk of side effects that cause patients to discontinue GLP-1R therapy. And GLP-1R, by increasing insulin formation, suppresses gluconeogenesis induced by glucagon.

Perhaps this solution will help some specific categories of patients with DM2 and obesity complicated by non-alcoholic hepatic steatosis, which may develop into cirrhosis.

Cotadutide has been shown to be successful in hepatic steatosis. This is due not only to weight loss (at the expense of fat) with extrahepatic release of fatty acids from the liver, but also by de novo suppression of hepatic lipogenesis by activating glucagon receptors.

Triple-therapy: involves utilizing the synergistic beneficial properties of all the above-mentioned approaches.

It turned out to be a very long article. Who read it to the end, well done! It was not intended to reflect all the details of therapy, contraindications and side effects of treatment with GLP-1R analogs. It also omitted discussion of the duration of therapy with these drugs. Inquisitive readers can find it all on the internet themselves. But I hope that these notes will help guide you through the general outlines of therapy for the end of 2024.