Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder, primarily characterized by a decrease in insulin secretion and typically accompanied by insulin resistance. When untreated, T2DM is leading to an inevitable long-term complication. However, the novel treatment of T2DM like for example Glucagon-like Peptide-1 receptor agonists (GLP-1 RAs) give new perspectives for the patients to achieve a better glycemic control and additional metabolic improvements. Pharmacogenetics is a field in pharmacotherapy, which investigates the individual response to the medical treatment, according to polymorphic variations in the receptors of the drugs. This review aims to summarize current scientific evidence on the pharmacogenetics of the GLP-1 RA /liraglutide/ and the possible implementation in the treatment of T2D.

GLP1RA, pharmacogenetics, precision medicine, T2DM

More than 400 million people throughout the world are suffering from diabetes and more than 90% are diagnosed with T2DM (Saeedi et al. 2019). Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder, primarily characterized by a decrease in insulin secretion and characterized by the inability of the body to carry out the typical role of the insulin, accompanied by insulin resistance. When untreated, T2DM is leading to multiple vascular complications, resulting in blindness, kidney failure, heart attacks, stroke and lower-limb amputation and can result in lower life expectancy by 5–10 years (Rathmann and Bongaerts 2021).

During the last decade, some new drug groups have been added in the American and European guidelines for diabetes treatment. These include the classes of dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) and sodium-glucose linked transporter-2 (SGLT-2) inhibitors (Miller et al. 2000).

The GLP-1 receptor agonist are glucose-lowering medicatireceptor agonistsns, approved of treatment of diabetes. The American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD), American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) recommend GLP-1RAs as a class of agents that improve the glycemic control and lower the risk of cardiovascular complications in patients with T2DM (van Schaik et al. 2020).

Pharmacogenetics is a part of the pharmacology, focused on the variation in human genome and how it influences the individual response of treatment, efficacy, and toxicity. Moreover, the difference in genetics modulates the mechanism action of the drugs and changes the approach in which these patients are treated.

The aim of this article is to review the mechanism of action and clinical profile of GLP-1RAs regarding the individual polymorphisms in the receptors of GLP1RA.

T2DM is a chronic metabolic disease characterized with insulin resistance and progressively reduced insulin secretion, which leads to impaired glucose utilization, dyslipidemia and hyperinsulinemia and progressive pancreatic beta cell dysfunction (Petersen and Shulman 2018). The etiology of T2D is known to have a significant genetic component, confirmed by family based studies (Ali 2013). The development of genotyping technologies and statistical tools combined with computational software have achieved a remarkable progress in the research of genetic associations in recent years (Daly and Hovorka 2021). Since the first genome-wide association study (GWAS) for T2DM identified novel susceptibility loci in 2007, more than 100 T2DM susceptibility loci have been discovered (Marullo et al. 2014; Caparrotta et al. 2021).

Over the last decade there has been an excessive development of antidiabetic agents. One of the main strategies aimed to improve the outcome of the therapy might be an individualized approach which is facilitated by pharmacogenetic studies. Establishing the mechanism of drug-gene interactions may give an attractive perspective for treatment in the clinical practice—stratifying the patient groups, decision-making on the therapeutic approach, reducing the rates of side effects and thereby improving the outcome of T2D. All these take part of the so-called precision medicine.

It was well known that an oral food intake leads to a greater insulin response compared to the intravenous glucose application (Nicolaidis and Rowland 1976). This response is provoked by the effect of incretins. These are peptides that are secreted in the small intestine. Some of them are Glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 (Nauck and Meier 2018). They are produced by the K cells and L cells in the distal ileum and colon and influence the b-cells in the pancreas through connecting with GLP-1 and GIP receptors (Nauck et al. 2021). This connection activates b-cells, which leads to a glucose-dependent insulin secretion (Fig. 1). More than a half of the insulin secretion is in response to the secretion of incretins from the gastrointestinal tract (Vilsboll and Holst 2004). However, only GLP-1 exerts further glucose lowering actions via slowing gastric emptying and inhibition of glucagon secretion (Maselli and Camilleri 2021).

Figure 1. 

Via mTOR-dependent HIF-1 alfa activation, GLP-1R signaling impacts glucose metabolism in beta cells. When GLP-1 binds with its receptor GLP-1R (G-protein receptor), adenylyl cyclase (AC) is activated. The cyclic ATP is increased, which promotes the mTOR pathway in beta cells, HIF-1 alfa upregulates the transcription of glycolic genes. The increased glycolic enzymes lead to elevated glycolytic flux and capacity, these increase the ATP and results in GSIS (glucose stimulated insulin secretion).

The half-life of the autonomic incretins is limited and their effects are decreased in patients with T2D (Holst 2019). Additionally, there is a pancreatic resistance to the effects of GLP-1 regarding the insulin secretion, resulting in decreased the secretion of GLP-1 by L cells (Lim et al. 2009). All these processes lead to developing a glucose intolerance (Akerstrom et al. 2022). The impaired incretin effect of GLP-1 occurs early in the natural history of T2DM, which makes the replacement therapy with GLP-1 agonists a logical choice to improve the insulin response in patients with T2DM (Meloni et al. 2013).

The GLP-1RA are designed to imitate GLP-1 activity, but to resist the quick metabolic degradation (Hinnen 2017). Nowadays, there are several GLP-1RA used in clinical practice with subcutaneous and oral formulations. GLP-1RA are considered as safe antidiabetic drugs, which have a positive impact on reducing the cardiovascular complications and as a second line therapy when metformin is insufficient or inappropriate (Trujillo et al. 2015).

It is nowadays estimated that some subtypes of GLP1RA have shown cardioprotective benefits (Ravassa et al. 2012). These are long-acting liraglutide and semaglutide. Moreover, several studies have shown a positive role of GLP1Rs in treatment of fatty liver disease, which also has an impact on glucose homeostasis (Mantovani et al. 2021). The positive effect of liraglutide, a short acting GLP-1RA, was reported in patients with NASH in Western countries (LEAN study) and Japanese studies (LEAN-J study) (Zhu et al. 2021). Semaglutide, a novel GLP-1 RA, is the newest and most popular labeled drug for diabetes (Andreadis et al. 2018). To investigate the effect of semaglutide on NASH, a phase 2 RDBPCT comparing the efficacy and safety of three different doses of once-daily subcutaneous semaglutide versus placebo in 372 participants with NASH is now ongoing Newsome et al. 2021).

The mechanism of action of GLP-1-receptor agonists

Glucagon-like peptide 1 is a peptide hormone secreted by the small intestine (Muller et al. 2019). It increases insulin secretion and decreases glucagon secretion from the pancreas in a glucose-dependent manner (Nadkarni et al. 2014). GLP-1 RAs act in reducing glucose levels and weight by increasing glucose-dependent insulin secretion and decreasing glucagon secretion. They also delay gastric emptying and increase satiety (MacDonald et al. 2002). Moreover, GLP-1 RA are highly efficacious weight loss drugs (Aroda 2018). Most of the GLP-1 RA agents are applied as subcutaneous (SC) injections, but there are also oral forms (Cho et al. 2013). The adverse effects differ between specific agents, the main adverse effects with the GLP-1 RA class are gastrointestinal (GI) related (nausea, vomiting, and diarrhea). In Europe there are five approved for use exenatide, liraglutide, albiglutide, lixisenatide, dulaglutide and semaglutide (Fig. 2) (Trujillo et al. 2015).

Figure 2. 

Mechanisms of action of GLP-1RA.

Pharmacogenetics of GLP1RA

Pharmacogenetics explores the role of human genome in the effect of the treatment with pharmacological agents (Fig. 3) (Imamovic Kadric et al. 2021). According to a large cohort study, rs10305492 variant in the GLP1R gene is associated with a lower risk of heart disease, lower fasting glucose and reduced T2D risk (Scott et al. 2016). Several other studies explored the pharmacogenetics of GLP-1RA (Table 2).

Figure 3. 

Representation of genetic variants affecting pharmacokinetics and pharmacodynamics of GLP-1 Ras. PG: plasma glucose; BMI: body mass index; HbA1C: glycemic hemoglobin, PI/I: proinsulin/insulin ratio.

Table 2.

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Genetic variations, which affect the response to GLP-1 RAs.

Study	Drug	Gene	Location	SNPs	Amino-acid change	Impact
Yu M et al. (2019)	Exenatide	GLP-1	6p21	rs3765467C > T; rs10305420C > T	Missense Variant-Impair.	A 0.4% reduction in HbA1C and a 1.27 kg less weight loss
Lin et al. 2015	Exenatide	GLP-1	6p21	rs3765467C >T; rs761386C > T	Missense Variant-Impair. Intron variant	Effect on plasma glucose levels
Chedid et al. (2018)	Exenatide Liraglutide	GLP-1	6p21	rs3765467C > T; rs10305492	Missense variants-Impair receptor function	Impaired β cell secretion of insulin and β cell viability
Guan et al. (2022)	Exenatide Liraglutide	GLP-1	6p21	rs3765467C > T	Missense variants-Impair receptor function	Larger reduction of HbA1C
Long et al. (2022)	Liraglutide	GLP-1	6p21	rs3765467C>T. rs2254336 A > T	Missense Variant-Impair receptor function; Intron variant	Associated with gastrointestinal adverse reaction

For example, a study with 285 overweight Chinese patients with T2D, genotyped for the two common variants rs3765467 C>T and rs10305420 (C>T; p. Pro7Leu), was examining the effects of exenatide after 6 months of treatment, the results showed that the minor allele of rs10305420 was associated with a decreased reduction in body weight and HbA1c, which means that this variant is a potentially good pharmacogenetic marker especially in overweight diabetic patients (Yu et al. 2019).

A GWAS identified a variant rs57922 (C/C genotype) linked to a higher GLP-1 secretion and cardio-vascular benefits from intensive hypoglycemic treatment (Hayes 2013).

Another study was conducted with 36 patients with uncontrolled T2D, who were treated with exenatide for 3 days after 6 days of subcutaneous insulin infusions. The authors found a significant change in the levels of the plasma glucose during the treatment with exenatide associated with the variants rs3765467 C>T and rs761386 C>T. However, after multivariate analysis the data became insignificant (Lin et al. 2015). In a similar study with 90 overweight patients with T2D, treated with liraglutide for 14 weeks, was concluded that patients carrying variant A allele of rs6923761 had greater reductions in BMI (−0.59±2.5 kg/m2 vs. −1.69±3.9 kg/m2; p<0.05), weight (−2.78±2.8 kg vs. −4.52±4.6 kg; p<0.05) and fat mass (−0.59±2.5 kg vs. −1.69±3.9 kg; p<0.05) after liraglutide treatment (de Luis et al. 2015). Moreover, another study with 60 obese patients, has examined the effect of liraglutide and exenatide on the gastric emptying and weight loss. The result after 5 weeks of treatment with liraglutide 3 mg/daily and exenatide 10 mkgr/daily for the period of 30 days was that patients carrying the A allele of rs6923761 had a decrease in gastric emptying after treatment with either liraglutide or exenatide (117.9±27.5 minutes and 128.9±38.3 minutes, respectively) compared to the GG carriers (95.8±30.4 minutes and 61.4±21.4 minutes, respectively) (p = 0.11). The genotypes did not affect weight loss (Chedid et al. 2018).

Additionally, according to a study examining the effect of incretins’ therapy in a total of 176 subjects (mean age 50.9 ± 12.7 years, 111 men), treated for 12 weeks with either exenatide (20 μg/day) or liraglutide (1.2 mg/day), the reduction in HbA1c levels was more significant in subjects carrying the rs3765467 GG genotype vs. GA + AA genotypes (1.7% ± 2.4% vs. 0.8% ± 1.8%; P = 0.002). Moreover, the target of 7.0% for the HbA1c was more significant in subjects carrying the rs3765467 GG genotype vs. GA + AA genotypes (50.9% vs. 23.8%; P = 0.002). Gastrointestinal adverse reactions did not differ significantly among different genotypes. They concluded that GLP1R rs3765467 polymorphism is associated with therapeutic response to GLP1RAs in Chinese T2DM patients. HbA1c reduction was larger in subjects with the GG genotype (Long et al. 2022).

In their study Long et al. described the effect of rs3765467 and rs2254336 in the GLP-1 R gene on adverse reactions in the gastrointestinal system in patients with T2DM treated with liraglutide. According to the study, the females are more susceptible to gastrointestinal adverse reactions compared to males. Furthermore, this adverse effect was associated with the T allele of rs2254336 and the A allele of rs3765467 respectively (Pearson et al. 2019).

Another study is genome-wide pharmacogenomic study of GLP-1 receptor agonists conducted with 4571 adults from different nations (3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and 47% of all participants were women.

According to a recent studies and practical guidelines when the therapy is started early and patients are well-controlled, the rate of the late diabetes complications is decreased. Nowadays with the progression of technologies, increased information and digitalization, the rate of mortality and morbidity associated with type 2 diabetes is significantly reduced (Davies et al. 2022). It is not fully estimated whether genetic information can be constantly implicated in the prevention and treatment of diabetes. This is still the beginning of the usage of genetic information for stratification individuals for their individual response to the treatment. This information needs to be considered together with the clinical status for everyone along to their disease progression path. The increasing availability and decreasing cost of human genetic analysis can be implicated in clinical medicine and used for diagnostic and therapeutic recommendations in different fields beyond the diabetology (Gonzaga-Jauregui et al. 2012). Algorithms incorporating predictive genetic variation and biomarkers for drug response and complications, validated by clinical trials, should enhance our ability to transform diabetes care (Dennis 2020).

A precision medicine approach requires attention to the gaps in our current knowledge base, which include the clinical guideline for a treatment in adolescents, the elderly, and during pregnancy. The available outcomes data for recommending type 2 diabetes therapy that is directed at primary prevention of macrovascular complications in young, healthier individuals are insufficient (Davies et al. 2022).

Nevertheless, given the staggering numbers of patients with type 2 diabetes, critical evaluation of the cost versus benefit of the use of genomics, biomarkers, new technologies, and specific medications will be needed to support recommendations for clinical use in specific populations. Given the tremendous progress made over the past decade, it is reasonable to predict greater adoption of precision medicine approaches in the type 2 diabetes clinic in the years to come (Gloyn and Drucker 2018).

T2D is a pandemic disease rapidly spreading all over the world. According to the prognosis the number of people suffering from diabetes has been expected to rise from 366 to 522 million by 2030. The major factor, contributing to this is that it goes undiagnosed in many individuals. More than 183 million individuals have been still undiagnosed with diabetes worldwide. The current therapeutic approaches for the treatment of diabetes include various drug categories according to the overall state of the patients. GLP-1 receptor agonists are one of the second-line oral anti-diabetic drugs prescribed by clinicians and administrated as a therapy for overweight and obese patients. They influence both insulin secretion and glucagon-suppression.

Pharmacogenetic studies are focusing on T2DM therapies. Unravelling the pharmacogenetics of T2DM is an approach towards individualized therapy. Although the research in the field of pharmacogenetics/ pharmacogenomic in T2DM is not still a part of the clinical practice, the genetic basis of personalized medicine is growing with solid evidence indicating its importance in future clinical practice.