New Developments in Pharmacological Treatment of Obesity and Type 2 Diabetes—Beyond and within GLP-1 Receptor Agonists

Guidelines for the management of obesity and type 2 diabetes (T2DM) emphasize the importance of lifestyle changes, including a reduced-calorie diet and increased physical activity. However, for many people, these changes can be difficult to maintain over the long term. Medication options are already available to treat obesity, which can help reduce appetite and/or reduce caloric intake. Incretin-based peptides exert their effect through G-protein-coupled receptors, the receptors for glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), and glucagon peptide hormones are important regulators of insulin secretion and energy metabolism. Understanding the role of intercellular signaling pathways and inflammatory processes is essential for the development of effective pharmacological agents in obesity. GLP-1 receptor agonists have been successfully used, but it is assumed that their effectiveness may be limited by desensitization and downregulation of the target receptor. A growing number of new agents acting on incretin hormones are becoming available for everyday clinical practice, including oral GLP-1 receptor agonists, the dual GLP-1/GIP receptor agonist tirzepatide, and other dual and triple GLP-1/GIP/glucagon receptor agonists, which may show further significant therapeutic potential. This narrative review summarizes the therapeutic effects of different incretin hormones and presents future prospects in the treatment of T2DM and obesity.

White adipose tissue possesses highly complex functions, with its primary role lying in energy storage. The function of white adipose tissue is often impaired in obese and diabetic individuals, resulting in adipocyte hypertrophy, pathological fat accumulation, and ectopic fat deposition, which can lead to the development of metabolic and cardiovascular diseases. Obesity is associated with increased insulin secretion, leading to insulin resistance and ultimately beta-cell failure, thereby promoting the development of T2DM [ 10 ]. Numerous inflammatory mediators are produced in adipose tissue, significantly contributing to the development of chronic inflammatory conditions [ 11 ] ( Figure 2 ). One of the main characteristics in white adipose tissue is an increase in the number of macrophages, which also participate in the development of insulin resistance [ 12 ]. Among obese individuals, it is possible for the phenotype of macrophages to change, indicating the dominance of proinflammatory M1-polarized macrophages over M2 macrophages involved in anti-inflammatory and reparative mechanisms. This suggests a change in the innate immune system in obesity [ 13 ]. Due to chronic inflammation, the secretion profile of adipokines in white adipose tissue also shifts, increasing the production of proinflammatory factors such as tumor necrosis factor-alpha (TNFα), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and leptin, while decreasing the secretion of anti-inflammatory interleukin-10 (IL-10) and adiponectin. M1-polarized macrophages enhance the development of abnormal lipid profiles and insulin resistance, regardless of the inflammatory mediators in adipose tissue. Ultimately, persistent inflammation occurs in dysfunctional adipose tissue due to hypoxia, fibrosis, and mitochondrial dysfunction, leading to systemic inflammation, progression of atherosclerosis, and the development of T2DM and cardiovascular diseases [ 14 ]. Obesity and associated insulin resistance are accompanied by increased oxidative stress in endothelial cells, during which the production of reactive oxygen species (ROS) surpasses the capacity of antioxidant factors to balance them. As a result, signaling pathways are modified, and the lipid, protein, and DNA content of cells is damaged. The superoxide anion, with high reactivity, binds and inactivates the physiological function of endothelial nitric oxide synthase (eNOS), leading to the production of peroxynitrite instead of NO. Peroxynitrite is a potent oxidizing agent that can cause lipid peroxidation, protein tyrosine nitration, DNA damage, and cell death. Additionally, peroxynitrite oxidizes tetrahydrobiopterin, an essential cofactor for eNOS, rendering it biologically inactive and unable to catalyze endothelial NO synthesis [ 15 ]. Consequently, eNOS catalyzes the production of further superoxide radicals instead of NO. Beyond other intracellular signaling and metabolic changes, the inactivation of eNOS is a key factor in the relationship between oxidative stress and pathological functional changes in the endothelium. In diabetes, chronic hyperglycemia, acute fluctuations in blood glucose levels, and insulin resistance all contribute to increased oxidative stress and, therefore, to the development of endothelial dysfunction [ 16 ]. GLP-1 receptor agonists may potentially reduce inflammation and oxidative stress in adipose tissue by affecting the expression of cytokines, chemokines, and macrophage infiltration, with prolonged GLP-1 action potentially alleviating obesity-related adipose tissue inflammation while enhancing the expression of anti-inflammatory genes [ 17 , 18 ] ( Figure 2 ).

Glucose-dependent insulinotropic polypeptide (GIP) is produced from K cells in the mucosa of the small intestine and exerts its effects through a receptor coupled to a G protein. The glucose-dependent insulin-releasing effect of GIP, like GLP-1, is impaired in T2DM, but combining them may further improve beta-cell function and insulin secretion [ 50 ] ( Figure 4 ). Similar to GLP-1, GIP also inhibits beta-cell apoptosis in the pancreas, thereby improving its survival during T2DM progression [ 51 ]. GIP also stimulates bone formation by inhibiting osteoclast apoptosis [ 52 ]. The precise effects of GIP on lipid metabolism are currently unclear; some studies suggest it may increase lipid uptake in adipose tissue and decrease lipolysis [ 53 , 54 ], while others suggest GIP may have lipolytic activity, as adipose tissue from transgenic mice overexpressing GIP has been found to be resistant to high-fat feeding [ 55 , 56 ]. It is hypothesized that by enhancing lipid-buffering capacity and insulin sensitivity in white adipose tissue postprandially, GIP may prevent ectopic fat deposition between tissues and muscles [ 57 ]. Activation of GIP receptors improved blood glucose levels in obese mouse models without altering body weight or fat tissue quantity [ 58 ], and activation of GIP receptors in the hypothalamus reduced food intake as well [ 59 ]. Whole-genome association studies have shown associations between different activity levels of human GIP receptor variants and the degree of obesity [ 60 ]. The anti-inflammatory effect of GIP on atherosclerosis is not clear from preclinical studies; therefore, the role of GIP in the atherosclerosis process seems to be controversial at the moment. In cell cultures, the administration of GIP may exert both anti-atherogenic effects (increased nitric oxide and adiponectin concentration, decreased endothelin-1 levels, reduced oxidative stress, decreased migration and proliferation of fibroblast cells) and pro-atherogenic effects (decreased adiponectin levels, increased endothelin-1 and osteopontin levels) [ 61 ]. In another study, high-dose administration of GIP reduced macrophage translocation into the vessel wall, thereby reducing foam cell formation, decreasing matrix metallopeptidase-9 activity and interleukin-6 secretion, and ultimately reducing the size of atherosclerotic plaques [ 62 ]. In summary, besides effectively reducing blood sugar levels, GIP analog treatment has also been shown to affect food intake and weight loss, especially when combined with GLP-1 receptor agonists. However, the detailed effects of GIP on lipid metabolism, atherosclerosis, metabolic activity of adipose tissue, and energy expenditure are still unclear.

The GLP-1 receptor agonist liraglutide at a high dose (administered as a single daily injection of 3 mg subcutaneously) has been approved as an adjunctive medication for weight loss achieved through a low-calorie diet and physical activity in adults with obesity or overweight-related comorbidities, as well as for the treatment of obese children and adolescents aged 12 years or older [ 70 ]. Previous large randomized clinical trials have demonstrated that a 3 mg dose of liraglutide can result in an average weight loss of 5.6 kg over nearly one year in overweight or obese individuals without diabetes [ 71 ]. The results achieved with high-dose liraglutide have encouraged further development of peptide therapies for the management of obesity and overweight. Recent significant clinical trials evaluating the efficacy of weight loss are summarized in Figure 5 and Figure 6 . The STEP clinical trials collectively provide valuable information about semaglutide’s safety, efficacy, and impact on weight loss and cardiovascular outcomes in various patient populations. The STEP trials have evaluated the effects of once-weekly subcutaneous administration of the GLP-1 receptor agonist semaglutide at a dose of 2.4 mg [ 72 ] ( Figure 5 ). Generally, approximately 15% weight loss was observed in overweight and obese, non-diabetic adults across various treatment periods, lasting up to 2 years (from STEP-1 to STEP-6, STEP-8) [ 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ]. Similar efficacy was achieved with once-weekly subcutaneous injections of 2.4 mg semaglutide in the STEP Teens trial among adolescents aged 12–18 years [ 80 ], as well as with high-dose oral administration of 50 mg semaglutide in overweight and obese, non-diabetic adults (OASIS-1) [ 81 ] ( Figure 6 ). In the STEP-2 trial, a smaller but significant 9.6% weight loss was observed with weekly subcutaneous administration of 2.4 mg semaglutide in obese patients with T2DM [ 73 ]. In the 52-week STEP-HFpEF study, besides significant weight reduction in obese patients with heart failure with preserved ejection fraction treated with once-weekly subcutaneous 2.4 mg semaglutide, a decrease in heart failure symptoms (fatigue, dyspnea, and edema) and improvement in physical performance were observed [ 82 ]. In the SELECT trial, over an average of 40 weeks of follow-up, a 20% reduction in the occurrence of the three-point composite cardiovascular endpoint (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) was found in overweight and obese, non-diabetic adults with once-weekly subcutaneous semaglutide (2.4 mg) [ 83 ]. In clinical trials with high-dose semaglutide, nausea and vomiting were the most common side effects, which were associated with delayed gastric emptying and occurred in approximately 40% of participants in the studies. These side effects were generally mild to moderate in severity and resolved after 1–3 months of treatment, leading to treatment discontinuation in less than 5% of cases. Initial gastrointestinal side effects were observed in approximately 80% of participants taking high-dose oral semaglutide (50 mg once daily), but like with subcutaneous weekly 2.4 mg semaglutide, their severity decreased over time [ 81 ]. Currently, high-dose subcutaneous semaglutide (2.4 mg once weekly) is approved in the United States and Europe for the treatment of obesity and overweight as an adjunct to a calorie-restricted diet and increased physical activity. Further data are needed for regulatory approval as part of the ongoing OASIS trial program evaluation. The design of the SURMOUNT clinical trials of experiments with the dual GLP-1 and GIP receptor agonist tirzepatide bears many similarities to the STEP program ( Figure 6 ). The SURMOUNT trials have demonstrated tirzepatide glucose-lowering efficacy, weight loss efficacy, and cardiovascular safety in various patient populations. In the SURMOUNT-1 and -3 studies, tirzepatide administered at a high dose of 15 mg subcutaneously once weekly resulted in approximately a 20% reduction in body weight in overweight and obese, non-diabetic adults, even after up to 2 years of treatment [ 84 , 85 ]. Weight loss was slightly lower, at 14.7%, in overweight and obese patients with T2DM in the SURMOUNT-2 study [ 86 ]. To minimize gastrointestinal side effects, the tirzepatide dose was gradually increased in all SURMOUNT clinical trials, starting at 2.5 mg and escalating by 2.5 mg every 4 weeks until reaching the maintenance dose required. Initial gastrointestinal side effects were reported by approximately 30% of participants, which were generally mild to moderate in severity and significantly diminished during sustained treatment achieved through dose titration, resulting in a discontinuation rate of less than 8% [ 87 ]. Several large, randomized clinical trials are currently underway in the SURMOUNT program, aiming to determine the effectiveness of tirzepatide in promoting weight loss in overweight and obese chi

Glucagon alters lipid metabolism and energy expenditure favorably while also reducing appetite and food intake, making it an attractive option for the treatment of T2DM and obesity, especially when combined with the insulinotropic effects of GLP-1. The first monomolecular glucagon receptor/GLP-1 receptor co-agonist was discovered in 2009, and its weekly administration significantly improved carbohydrate metabolism and reduced weight in obese mice fed a high-calorie diet during preclinical studies [ 97 ]. In recent years, two glucagon receptor/GLP-1 receptor co-agonists underwent phase II clinical trials in human experiments, namely, SAR425899 and cotadutide [ 98 , 99 ]. Further development of SAR425899 was eventually halted during human trials. Cotadutide effectively lowered blood sugar levels and reduced weight in obese individuals and T2DM patients, increased insulin secretion, delayed gastric emptying, with the most common side effects being gastrointestinal symptoms (nausea and vomiting), which were dose-dependent [ 99 , 100 ]. A multicenter study evaluated the effects of subcutaneously administered cotadutide in 834 participants in daily doses of 100 μg, 200 μg, and 300 μg compared with placebo and 1.8 mg liraglutide daily [ 101 ]. The study lasted for 54 weeks and assessed liver abnormalities and metabolic parameters in overweight and obese T2DM patients. Every dose of cotadutide and liraglutide significantly reduced HbA1c levels compared to placebo (change in HbA1c—cotadutide 100 μg: −1.03%; 200 μg: −1.16%; 300 μg: −1.19%, liraglutide 1.8 mg: −1.17%); however, there was no significant difference in HbA1c reduction between cotadutide and liraglutide. The highest dose of cotadutide resulted in a significantly greater reduction in weight compared to liraglutide and placebo (change in weight—cotadutide 100 μg: −3.7 kg; 200 μg: −3.22 kg; 300 μg: −5.02 kg, liraglutide 1.8 mg: −3.33 kg). Higher doses of cotadutide also showed more significant improvement in liver enzyme levels and parameters indicative of liver fibrosis compared to liraglutide [ 101 ]. Based on the favorable results, the effects of cotadutide are primarily planned to be extended towards the treatment of MAFLD. A comparison of the HbA1c and weight-reducing effects of cotadutide with various doses of dulaglutide, liraglutide, and semaglutide currently in clinical use is shown in Figure 3 [ 102 ].

Orforglipron is an orally administered, non-peptide GLP-1 receptor agonist that can be taken once daily. However, it binds differently to the GLP-1 receptor compared to native GLP-1, thereby inducing G-protein activation rather than beta-arrestin recruitment [ 107 ]. It is being investigated for the treatment of obesity and T2DM and could represent a competitive alternative to oral semaglutide, as its less burdensome administration does not require fasting. In T2DM patients, the average change in HbA1c was −2.1% with a dose of 45 mg of orforglipron (compared to dulaglutide and placebo), and nearly half of the participants achieved more than a 10% reduction in body weight in a 26-week phase 2 trial [ 108 ]. In obese, non-diabetic individuals, orforglipron administration for 36 weeks in a phase 2 trial, ranging from 12 mg to 45 mg doses, resulted in dose-dependent weight loss of up to 14.7%, accompanied by improvements in cardiometabolic risk factors [ 109 ] ( Figure 6 ). Danuglipron is another orally administered, non-peptide GLP-1 receptor agonist oriented towards G-protein [ 110 ]. In a phase 2 study in T2DM patients over 16 weeks, the highest dose of danuglipron administered twice daily (120 mg) resulted in an average HbA1c reduction of 1.2%, with an average weight loss of 4.2 kg [ 111 ]. A recently completed phase 2 trial in obese and non-diabetic individuals revealed, according to a press release, that danuglipron at doses ranging from 40 to 200 mg twice daily resulted in a 11.7% weight loss after 32 weeks of treatment compared to placebo. However, the rate of discontinuation due to adverse events (gastrointestinal side effects) exceeded 50% in each dosage group compared to placebo [ 112 ]. Several potential formulations for obesity treatment are currently undergoing clinical trials. The triple GLP-1/GIP/glucagon receptor agonist retatrutide (administered once weekly as 12 mg subcutaneous injections) achieved a 24% weight loss in a 48-week study involving overweight and obese individuals [ 113 ]. Several unimolecular dual or triple agonist proteins are also currently being studied, including those based on the action of the oxyntomodulin hormone, such as survodutide, pemvidutide, and mazdutide, which show promising weight-reducing effects [ 114 ]. The dual GLP-1/glucagon receptor agonist cotadutide and the triple GLP-1/GIP/glucagon receptor agonist efpeglenatide are being studied for the treatment of MAFLD [ 101 ]. The appetite-suppressing effect of pancreatic peptide YY (peptide tyrosine tyrosine) is well known, and initial clinical studies are underway with long-acting YY peptide analogs as monotherapy and in combination with GLP-1 receptor agonists for obesity treatment [ 115 ]. The amylin analog pramlintide, used in the United States as a prandial adjunct to insulin therapy, delays gastric emptying, improves postprandial blood sugar levels, and reduces weight [ 116 ]. A long-acting amylin analog similar to pramlintide, cagrilintide, administered parenterally once weekly at the highest dose of 4.5 mg, induced a significant 10.8% weight loss [ 117 ] ( Figure 6 ). According to results from a recently published 32-week phase 2 trial, combined therapy with weekly parenteral administration of 2.4 mg cagrilintide and 2.4 mg semaglutide (CagriSema) reduced body weight by an average of 15.6% and HbA1c by an average of 2.2% in patients with T2DM compared to baseline [ 118 ] ( Figure 7 ). Phase 3 trials with CagriSema combination therapy, part of the REDEFINE program, are evaluating its efficacy in weight loss and cardiovascular safety in patients with T2DM and overweight/obese, non-diabetic individuals [ 119 ]. The completion of the trials is expected in 2026 and 2027. Clinical trials have recently been initiated for obesity treatment with other long-acting amylin analogs and a dual amylin/calcitonin receptor agonist [ 120 , 121 ]. Further investigations are underway regarding protein-based approaches relying on other hormonal effects for effective weight loss; however, it currently appears that the potential clinical benefits of these are moderate. The appetite-suppressing effect of leptin analogs rapidly diminishes with the development of leptin resistance; thus, the use of metreleptin is limited to cases of congenital or acquired leptin deficiency [ 122 ]. Direct activation of the melanocortin-4 receptor in the hypothalamus with melanocortin-4 receptor agonist setmelanotide resulted in significant weight loss in small clinical studies conducted in severely obese individuals with pro-opiomelanocortin deficiency or other rare congenital conditions affecting the melanocortin-4 signaling pathway [ 123 ]. While inhibition of the appetite-stimulating (orexigenic) hormone ghrelin may seem an attractive therapeutic target, studies targeting ghrelin receptor inhibition have not reported sufficient efficacy to encourage further clinical development [ 124 ].

Obesity represents a serious public health issue, characterized as a chronic inflammatory condition closely associated with insulin resistance, T2DM, and an increased risk of cardiovascular diseases. Pharmacological treatment for obesity has seen dynamic development in recent years, with ongoing research focusing on the long-term clinical efficacy and safety of the employed formulations. These studies will further elucidate their role in the management of obesity and its related complications in the coming years. Long-acting GLP-1 receptor agonists are widely applicable in the treatment of T2DM, known not only for their favorable effects on glycemic control and weight but also for significantly reducing the risk of cardiovascular diseases associated with atherosclerosis. GLP-1 receptor agonists have proven effective in the treatment of obesity and MAFLD alongside T2DM. Moreover, an increasing number of new and innovative formulations based on the mechanism of action of incretin hormones are becoming available for everyday clinical practice, including oral GLP-1 receptor agonists, the dual GLP-1/GIP receptor agonist tirzepatide, and other dual and triple GLP-1/GIP/glucagon receptor agonists, which may demonstrate further significant therapeutic potential. The dual GLP-1/GIP receptor agonist tirzepatide has already received approval in the United States and Europe, with the introduction of other dual receptor agonists expected soon. These novel agents may open further possibilities for future diabetes therapies in a personalized manner. For dual and triple GLP-1/GIP/glucagon receptor agonist formulations, as with efficacy, it is also warranted to assess safety through cardiovascular outcome trials.