Clinical Potential of Glucagon-like Peptide-1 Analogs in the Management of Diabesity : Journal of Diabetology

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Review Article

Clinical Potential of Glucagon-like Peptide-1 Analogs in the Management of Diabesity

Sharma, Nidhi; Singh, Shreya

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Journal of Diabetology 14(1):p 1-13, Jan–Mar 2023. | DOI: 10.4103/jod.jod_102_22
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Abstract

Obesity and cardiovascular complications are the two pandemic which plays a crucial role in the pathophysiology of type 2 diabetes mellitus. Loss of weight and increased cardiovascular risk are becoming the hurdles for the diabetic population. The tremendous hike in the rate of obesity is one of the main reasons for the increased cases of diabetes mellitus and hence, obesity becomes a high-risk factor for diabetes. Glucagon-like peptide-1 (GLP-1) agonists were initially developed for the treatment of diabetes mellitus but was found to be effective not only for the glycemic control but also for the weight loss. Hence this review article aims to assess the clinical efficacy of GLP-1 agonists in the management of weight loss, and also discusses the detailed insights of FDA approved drugs used in weight management, and discuss the mechanisms by which GLP-1 agonist, used in weight loss therapy. It also discusses the role of dual co-agonist in the treatment of obesity. This literature survey has been done by searching term “GLP-1 agonist, diabetes, obesity, novel drug targets” in the PubMed, Scopus, Embase, and web of science databases. Then, the search is further narrowed by including the articles having recent updates only and then further it is narrowed by excluding the animal studies and including only the clinical studies. This article is purely based on the published clinical data obtained from various clinical trials. Based on the previous studies and clinical trials, it has been observed that GLP-1 agonists such as liraglutide and semaglutide are more efficacious drug than other approved drugs in weight management therapy and have advantage of improving the blood glucose profile and reduces the cardiovascular risk also. It is also found that dual gastric inhibitory polypeptide (GIP)/GLP-1 agonists is regarded as the more effective in treating obesity than the GLP-1 agonist alone.

HIGHLIGHTS

  • This review discusses the safety and efficacy of liraglutide in the treatment of diabesity.
  • How obesity and diabetes are interlinked with each other.
  • Rationale of glucagon-like peptide-1 agonist in weight loss therapy.
  • Detailed insights of US Food and Drug Administration (FDA)-approved drugs used in weight management.
  • Novel drug targets for weight management.

INTRODUCTION

Obesity is a complex and relapsing disorder[1,2] of excessive fat[3] and due to its increased prevalence,[4] it is considered a global pandemic[5,6] that is responsible for increased comorbidities and reduced life span.[7] Obesity and comorbidities are the major threats to type 2 diabetes mellitus (T2DM).[8] Loss of body weight and increased cardiovascular risk are the two major obstacles that a diabetic population is facing,[9,10,11] in view of the fact that important classes of the hypoglycemic agents, such as insulin, sulfonylureas, and thiazolidinediones,[12,13] tend to increase the bodyweight with the potential to counteract the favorable effects of glycemic control on cardiovascular disease (CVD) risk.[14] In this view, glucagon-like peptide-1 (GLP-1) agonists would be considered as the preferred drug for the diabetic population who are having comorbidities, as an adjunct to lifestyle interventions[15] and metformin, by showing an additional benefit of weight loss.[16] GLP-1 agonists aid in glucose homeostasis by enhancing the after-meal insulin secretion and decreasing the glucagon release in a glucose-dependent manner.[17] Hence, the GLP-1 agonist acts as a substitute for naturally releasing insulin hormone as it mimics the actions of incretin hormone that augments the secretion of insulin from pancreatic β-cells of Islets of Langerhans.[18,19] In addition to this, GLP-1 agonist plays a crucial role in the management of weight loss by reducing the appetite and increasing the feeling of fullness.[20,21]

Relationship between obesity and type 2 diabetes mellitus

Obesity is defined as an abnormal or excessive accumulation of fat that can impair health.[22] It occurs when a person’s body mass index (BMI) is greater than or equal to 30 kg/m2.[23] It is one of the most important risk factors for T2DM. T2DM is a metabolic disorder that occurs due to insulin resistance,[24] which is mediated by predisposing genetic factors and obesity.[25,26] There is an inverse relationship between the BMI and diagnostic age of T2DM.[27] This clearly depicts that obesity induces T2DM and insulin resistance,[28] but the mechanism behind this remains unclear. But this proves a strong relationship between the development of T2DM and obesity.[29]

Pathophysiology of diabetes and its correlation with obesity

The pathophysiology of diabetes is a complex process that is associated with the levels of insulin within the body, and the ability of body to use that insulin.[30] There are broadly two types of diabetes: one is type 1 diabetes, in which there is completely absence of insulin in the body and the other is T2DM, in which peripheral tissues resist insulin to show its effects.[31]

Pathogenesis of this disease is associated with abnormality in feedback loops between secretion and action of insulin which ultimately causes abnormal levels of glucose in the blood that will lead to the occurrence of diabetes mellitus.[32] In the case of improper functioning of β-cells of the pancreas, the levels of insulin secretion are diminished, which limit the capacity of the body to maintain the levels of glucose in the bloodstream. On the contrary, insulin resistance causes the increased production of glucose in the liver and reduced the uptake of glucose in liver, muscles, and adipose tissue.[33] Both processes play a significant role in the pathogenesis and development of diabetes mellitus [Figure 1]. However, hyperglycemia is augmented, if both of the contributing factors, that is, abnormal functioning of β-cells and insulin resistance, are present and will lead to the development of T2DM.[34,35]

F1-1
Figure 1:
Showing the pathophysiology of diabetes mellitus and obesity and their correlation with each other

In obesity, there is excessive fat deposition around the abdominal area that acts as a major contributor to systemic inflammation. This obesity-induced inflammation occurs due to the action of inflammatory cytokines and reactive oxygen species, leading to the destruction of β cell or the production of insulin resistance and hence plays a significant role in the development of prediabetes or T2DM. Hence, diabetes and obesity are interconnected with each other and obesity is the major risk factor for the development of T2DM.[35]

CLINICAL PHARMACOLOGY OF GLUCAGON-LIKE PEPTIDE-1 AGONIST

GLP-1 agonists are considered as second-line agents in the treatment of diabetes mellitus.[36] They act via numerous mechanisms in glycemic control and also help in metabolic effects.[37] They enhance the secretion of insulin from the β-cells of islets of Langerhans and decrease the secretion of glucagon from α-cells of islets of Langerhans.[38] They bind with the GLP-1 receptor and mimic its action also. Furthermore, it delays gastric emptying within the intestine and enhances the feeling of fullness or saturation.[39]

Liraglutide, a GLP-1 agonist, was approved in 2010 by US Food and Drug Administration (FDA) for the treatment of diabetes and is sold under the brand name “Victoza” and another marketed product of liraglutide was approved in 2014 for the management of weight loss and is sold under the brand name “Saxenda.”[40,41,42,43] It achieves glycemic control by regulating the blood glucose and weight loss via gastroparesis.[19,44] It secretes the insulin in a glucose-dependent manner and hence also lowers the risk of hypoglycemia.[45] Given its extra added advantage of having very little fear of hypoglycemia and weight gain tendency, it might be a preferable drug in the management of weight loss therapy in people with or without T2DM.[46,47]

Liraglutide reduces cardiovascular risk and is therefore considered a potential drug in the treatment of diabetes mellitus in patients with or without cardiovascular risk.[48] It can also be indicated as an adjuvant in the treatment of people with stable CVD.[49]

Pharmacokinetic profile of liraglutide, a glucagon-like peptide-1 agonist

Liraglutide is an acylated analog of GLP-1,[50] having 97% amino-acid sequence similarity with the native GLP-1.[51] It is the first approved analog of GLP-1 that produces the sustained release effect and due to its pharmacokinetic profile, it is best suitable for once-daily dosing with half-life of approximately 13 h.[52,53] It is released slowly from the injection site and also reduces the elimination rate which leads to metabolic stabilization and decreased renal filtration.[54] Drug exposure is largely independent of the injection site as well as age, race, and ethnicity. It is widely used for the treatment of T2DM, and administered by subcutaneous injection once daily.[18,55]

There is continuous improvement in the pharmacokinetic profile of GLP-1 agonist, starting from the native molecule with t1/2 of 2–3 min to the development of exenatide, twice daily, then to liraglutide once daily and even the semaglutide once weakly formulation, it highlights the advancement in the pharmaceutical field.

Mechanism of action of glucagon-like peptide-1 agonist in weight loss management

In addition to the action on pancreatic and gastric receptors, GLP-1 acts on the brain’s subcortical areas to produce satiety. The subcortical areas of the brain such as the brainstem and the hypothalamus are responsible for the control of energy homeostasis, which receive peripheral, neural, and hormonal signals about nutritional state and adiposity.[56] The arcuate nucleus (ARC) of the hypothalamus has an important role in the regulation of food consumption and energy homeostasis. Neurons of the paraventricular and ARC of the hypothalamus were altered by GLP-1, hence weakened orexigenic signals and decreased craving for food.[57] Hence, GLP-1 is a gut-derived hormone capable of improving the glucose tolerance and reducing the glucose levels by promoting the secretion of insulin through cyclic adenosine monophosphate (cAMP)-signaling pathway.[58,59,60] GLP-1 is an endogenous incretin hormone that slows down gastrointestinal emptying, enhances post-cibal satiety, and decreases food craving and food consumption by interfering with the central nervous system.[61] These actions contribute to the feeling of fullness, which helps in weight management and this makes GLP-1 a crucial target for the treatment of obesity and its associated metabolic disease[62,63,64] and liraglutide, one of the GLP-1 analog has shown promising effect in the treatment of diabesity, that is, combination of diabetes and obesity [Figure 2].

F2-1
Figure 2:
The flow diagram representing the rationale of GLP-1 RAs in improving glycemic levels and in weight management. The figure depicts that GLP-1 RA binds with GLP-1 R in arcuate (ARC) nucleus of hypothalamus of brain, which leads to the stimulation of proopiomelanocortin (POMC) or cocaine- and amphetamine-regulated transcript (CART) and inhibition of neuropeptide Y (NPY) and agouti-related peptide (AgRP). This eventually results in reduced hunger, energy intake, and craving for food and increased satiety, respectively

Clinical effectiveness of glucagon-like peptide-1 analogs in the management of diabesity

Several clinical trials documents the clinical effectiveness of GLP-1 analogs in the management of weight loss and they are outlined below.[65,66,67,68,69,70] SUSTAIN 1 reported that Semaglutide could be a potential target in the management of weight loss as it improves HbA1c levels and significantly reduces body weight in comparison to placebo in type 2 diabetic patient.[71] SUSTAIN 3 reported that the semaglutide 1 mg is more superior drug than exatenide 2 mg in improving the glycemic profile and reducing the weight and it was also observed that it has better safety profile in comparison to exatenide.[72] SUSTAIN 7 reported the superiority of semaglutide over dulaglutide in improving glycemic profile and significant weight reduction, and thus enables it to achieve clinically significant glycemic target and weight loss with a similar safety profile.[73] SUSTAIN 10 documents the superiority of semaglutide over liraglutide in reducing body weight and HbA1c levels and had a similar safety profile except for higher rates of GI-side effects in comparison to liraglutide.[74] PIONEER4 reported the noninferiority of oral semaglutide over subcutaneous liraglutide and superiority over placebo in reducing HbA1c levels, and superiority over liraglutide and placebo in reducing body weight but had similar safety profile.[75] STEP-8 strongly proves the superiority of semaglutide over other injectable GLP-1 agonists and it edges out liraglutide from weight reduction. Rubino et al.[76] suggested that once-weekly semaglutide 2.4 mg as an adjunct to lifestyle modification might be a better option than once-daily liraglutide 3.0 mg in weight reduction, but not in improving glycemic control.

On the contrary, a recent cohort study confirms that regardless of maximal dose, that is, 3 mg s.c. daily, liraglutide, even at submaximal or well-tolerated doses, induces significant weight loss and these effects can be potentiated by the addition of Metformin to liraglutide.[77]

On the basis of the series of clinical studies, it has been confirmed that liraglutide 3.0 mg once daily[78] and semaglutide 2.4 mg once weekly[68,79,80] have been established for the weight loss therapy with great clinical success, and it has also been observed that semaglutide is comparatively superior to liraglutide in terms of achieving significant weight loss of more than 10%.[76,81,82] More recently, these GLP-1 analogs have been combined with gastric inhibitory polypeptide (GIP)[77,83,84,85,86] or glucagon,[87,88] and they could be a novel drug target for the treatment of diabesity [Figure 3].

F3-1
Figure 3:
Pathogenesis involved in the management of diabesity

US Food and Drug Administration (FDA)-approved weight lowering drugs

Obesity is a chronic disease with multiple comorbidities, and hence it requires individualized treatment and a positive attitude of the patient toward a healthy lifestyle is essential. The goal of its treatment is to achieve significant weight loss and maintained it as well in the long term, and to improve life expectancy and quality of life. But if the goals are not achieved with lifestyle modification, then pharmacological treatment is recommended.

Antiobesity drugs are used to enhance weight loss and reduce the cardiometabolic risks achieved by lifestyle modification alone. But due to their severe toxic effects, the withdrawal of various antiobesity drugs from the market and the discontinuation of clinical studies led to skepticism concerning their role in the treatment of obesity.[37,89,90] GLP-1 RA is the first option to be added for its treatment but if it does not produce the favorable effects or there is poor tolerance or if it is contraindicated then it can be replaced by an orlistat 120 mg or a combination of naltrexone 32 mg with bupropion 360 mg and norepinephrine extended-release. In this view, FDA has approved five drugs [Table 1]: orlistat,[91] phenteramine-topiramate,[92] naltrexone-bupropion,[93] liraglutide, and semaglutide for the long-term management of obesity [Figure 4]. Setmelanotide is the sixth FDA-approved drug for its management,[94,95] but it is limited to patients having one of three specific rare genetic disorders and their diagnosis must be confirmed by genetic testing.

T1-1
Table 1:
Detailed overview of FDA-approved drugs for the weight management
F4-1
Figure 4:
Site of action of FDA-approved antiobesity drug

Emerging novel targets for diabesity

  1. Dual GIP/GLP-1 receptor co-agonist: Gastrointestinal hormones play a significant role in the treatment of diabesity. Incretin-based preparation with GIP or GLP-1 gives a new insight into reducing the blood glucose level, body weight, and lipid metabolism.[96] It has been observed that, GIP, an incretin was not producing favorable results in controlling diabetes mellitus. However, it produces significant effects on insulin and glucagon secretion. But GIP when combined with GLP-1 produces a stronger effect than that observed with GLP-1 alone. Hence, the development of dual GIP/GLP-1 receptor co-agonists is thought to be a potential target in the treatment of diabesity. Tirzepatide, GIP/GLP-1 receptor co-agonist, is the first highly effective peptide in reducing body weight and it also produces potential effects in the treatment of obesity in non-diabetic patients. Jastrebof et al.[95] reported reductions of 15%–20.9% of baseline body weight with 5–15 mg tirzepatide per week. The reported adverse effects were again nausea, vomiting, diarrhea, and constipation. On the basis of the calculation of available clinical data, it has been reported approximately 2 kg of weight loss for a reduction in 1.0% glycated hemoglobin (HbA1c) via glucosuria.[97,98] Tirzepatide has also shown potential effects in reducing intrahepatic triglyceride levels in T2DM,[99] and thus offers a novel treatment options for fatty liver disease.[100] On the basis of previous clinical trial data, it is employed as a once-weekly injected compound that produces significant glycemic control and weight reduction, and these effects are likely to change the underlying pathophysiology of the disease and is associated with diabetic remission.[101,102,103] On the basis of the results of SURPASS CVOT trial, it has been considered a potential antiatherosclerotic agent that also produces beneficial cardiovascular effects.[104,105] On the basis of the previous clinical data, tirzepatide might be the emerging target in the treatment of diabesity and its associated disease.
  2. GLP-1/histone deacetylase-6 (HDAC-6) inhibitors: A recent study also experimentally concluded that GLP-1 agonists when taken along with HDAC-6 inhibitors, an anti-cancer drug[106] improves the blood glucose profile and produces significant weight loss in comparison to alone GLP-1 agonists as they potentiate the effect of a GLP-1 agonist. The result of this study suggests that HDAC-6 inhibitor (MS-275) can synergizes the effect of GLP-1 drugs and is hence more effective in normalizing blood glucose and in reducing weight. Hence, this combination can serve as a potential drug target in the treatment of obesity.

Surgical interventions: A permanent cure for obesity

In a conference of the American National Institute of Health, it has been reported that bariatric surgery is recommended for patients with BMI greater than 40 kg/m2 or greater than 35 kg/m2 with associated comorbidities. The bariatric procedures are broadly classified as (i) restrictive surgery, the surgery, in which, the size of the stomach is shrunk, thereby slowing down of digestion. The aim of this surgery was to make you less eat and hence you will lose your weight more. (ii) Malabsorptive/restrictive surgery, the surgery, in which, size of the stomach is reduced along with removal/ bypass of part of the gastrointestinal tract, which makes it difficult for the body to absorb calories. (iii) Implantation of an electrical device, the newest technique, in which there is instant weight loss occurs due to the interruption of nerve signals between the brain and the stomach. Currently, the International Federation for the Surgery of OBESITY AND METABOLIC DISORDERS recommended five standard surgical interventions which do weight loss by the aforementioned procedures, and have been approved for the treatment of obesity, and are summarized as follows:

  1. Laparoscopic adjustable gastric banding: This invasive, fast, and reversible procedure can be done by an adjustable silicone band. The silicone band is placed around the upper portion of the stomach that results in constriction of stomach and hence reduces the food intake which ultimately leads to the feeling of fullness with lesser food. This procedure results in significant weight loss and also improves the glycemic profile. It is FDA-approved procedure used in the treatment of obesity. The benefit of this surgery is that food is digested as usual in this procedure without its malabsorption but the drawback of the surgery is that, after the surgery, the patient needs to strictly follow only liquid diet.[107]
  2. Laparoscopic sleeve gastrectomy: This procedure can be performed by removing 75% of the stomach, which results in the stomach acquiring the shape of a sleeve that can accommodate less food and hence results in weight loss. This surgery is used for superobese patients whose BMI is more than 40. It is a permanent or irreversible procedure as while removing the portion of stomach, ghrelin hormone also known as the huger hormone get also reduced which reduces the hunger this hormone plays a crucial role in the metabolism of blood sugar and hence useful in the management of diabetes. The benefit of this surgery is that it does not require any implantation nor it de-route the process of digestion but the drawback is that as it is an irreversible procedure so the risk of long-term nutrient deficiencies will be there.[108]
  3. Laparoscopic Roux-En-Y gastric bypass: This procedure is helpful in achieving long-term weight loss benefits along with improvement in obesity-associated comorbidities and hence regarded as the gold standard in bariatric surgery. In this surgery, a small pouch is created within the stomach that is connected directly to the small intestine that leads to gastric bypass. This surgery thus bypasses most of the stomach and a small part of the small intestine. This surgery is performed when obesity poses serious health problems and diet and exercise are not benefiting the obese person.[109]
  4. Biliopancreatic diversion with duodenal switch: This is an uncommon procedure that consists of two major steps, in the first step, sleeve gastrectomy is done by removing approximately 80% of the stomach, and in the next step, gastric bypass is performed and thus dietary intake and absorption of nutrients get reduced. This procedure is very effective but is recommended only when BMI is more than 50 due to its severe risks such as malnutrition and vitamin deficiency.[110]
  5. Laparoscopic mini-gastric bypass: This is a short and reversible bypass surgery that requires general anesthesia. In this surgery, multiple incisions are made in the abdomen and through one of the incision, a laparoscope is inserted to visualize the internal organs. This procedure also consists of two steps, in the first step, size of stomach is constricted by converting it into the long slender pouch by stapling and in the next step, bypass is created from that new stomach pouch and leads to the formation of omega loop, a loop that enables food to bypass the lower part of stomach, duodenum and few part of the small intestine. After that, the incision is closed by suture. The advantage of this procedure is that it is reversible in nature due to its simplicity and also helpful in resolving obesity-related comorbidities but the drawback is that, it leads to more nutritional deficiencies.[110]

DISCUSSION

The primary goal of obesity treatment is clinically significant weight loss with long-term fat mass reduction. Diet and lifestyle changes usually lead to a weight loss of 5%–7%, which is regained slowly. Bariatric surgery is the most effective approach in the treatment of obesity, showing significant weight loss, but it is rarely used due to its drawbacks such as irreversibility, surgical complications, and postoperative side effects. To date, there is a gap in the treatment of obesity and there is a need for novel treatments that can achieve significant weight loss and deliver significant health benefits. In this view, GLP-1 agonists, an FDA-approved class,, can be used for weight loss therapy and could significantly fill this gap in diabetic or non-diabetic patients. The mechanism and clinical efficacy of GLP-1 agonists in the treatment of weight loss have been previously discussed. On the basis of the previous studies, it has been reported that, among GLP-1 analogs, liraglutide and semaglutide are considered safe and efficacious drugs in the management of weight loss and improvement the weight-related complications. In addition to this, the development of dual GIP/GLP-1 receptor co-agonists can also play a crucial role in filling this gap and might be an emerging target for improving glycemic control, reducing body weight, and improving cardiovascular health. The development of multiple agonists, such as dual or triple agonists, will be inspired by the clinical success of dual GIP/GLP-1 agonists. Hence, novel or emerging multiple agonists shows promising effects in the treatment of diabesity.

CONCLUSION

As previously discussed, obesity is a complex relapsing disorder characterized by excessive body mass and a risk factor for diabetes. Owing to its increased ubiquity and bad impact on quality of life, novel strategies are required, as it is deteriorating our economy too. Therefore, this literature review has been done to assess the clinical potentials of GLP-1 agonists in weight loss therapy in diabetic or nondiabetic patients. This literature review has provided detailed insights into GLP-1 analogs in terms of their pharmacodynamics and pharmacokinetic profile, and their rationale in weight management therapy. On the basis of our literature survey, we can conclude that, liraglutide and semaglutide are the most preferred, safest, and most effective GLP-1 agonists for weight management along with good glycemic control and have the additional benefit of reducing cardiovascular risk too. Due to their good safety profile and minimum contraindication, they are considered as an attractive option in the management of diabesity.

This review article also discusses the novel drug targets in the management of weight loss and it has been concluded that GLP-1 RA in combination with GIP would be a more effective option in treating obesity and its associated risk factors.

In terms of surgical interventions, it has been concluded that Laparoscopic Roux-En-Y gastric bypass surgery is considered as the gold standard in bariatric surgery.

Financial support and sponsorship

Not applicable.

Conflicts of interest

There are no conflicts of interest.

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Keywords:

Cardiovascular risk; GLP-1 agonist; obesity; type 2 diabetes mellitus; weight loss

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