Glucagon-like peptide-1 receptor agonists in type 2 diabetes: Evidence for disease modification and therapeutic switching

Abstract

The discovery of the incretin system and the subsequent development of pharmacotherapeutic agents to manipulate incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, as well as glucagon, with various drugs, have revolutionised the management of type 2 diabetes mellitus (T2DM) in the 21^st century. The first few drug molecules in this group were the GLP-1 receptor agonists (GLP-1RA), which have been used for treating patients with T2DM in the past 2 decades, and newer molecules, including incretin polyagonists, are being added to the growing list of incretin-based drugs in recent years. Generally, these newer molecules possess longer biological half-lives and dosing intervals, better weight loss potentials, higher efficacy in glycemic control and possibly improved disease-modifying properties such as a higher chance for T2DM remission and better cardiometabolic outcomes. Therefore, newer incretin-based medications are currently preferred by many diabetologists and switching from older molecules to the newer ones is not uncommon in day-to-day clinical practice. However, outside the remit of randomised controlled trial settings, there is only limited evidence emerging from real-world data. A study by Kassem et al published in the World Journal of Diabetes provides us with robust evidence from a large real-world study of 18047 patients with T2DM from Israel on the benefits of switching from an old GLP-1RA to a newer agent, with a remarkable improvement in glycemic control. With the most up-to-date evidence, we update the rationale for switching GLP-1RA molecules in managing T2DM with a detailed review of the therapeutic benefits, including the anticipated cardiometabolic outcomes and cost benefit analysis from such switching in this editorial.

Key Words: Glucagon-like peptide-1 receptor agonists; Incretin polyagonists; Type 2 diabetes mellitus; Switching glucagon-like peptide-1 receptor agonist; Glycemic control

Core Tip: Pharmacological manipulation of the incretin system has revolutionised the management of type 2 diabetes mellitus (T2DM) in the 21^st century. The first few drug molecules in this group were the glucagon-like peptide-1 receptor agonists (GLP-1RA), which have been used for treating patients with T2DM in the past 2 decades. Newer molecules, including incretin polyagonists, with longer half-lives and dosing intervals, and better cardiometabolic outcomes, are being added recently. A study by Kassem et al published in the World Journal of Diabetes provides us with robust evidence from a large real-world study from Israel on the benefits of switching from an old GLP-1RA to a newer agent, the theme of this editorial.

This editorial refers to “Glucagon-like peptide 1 receptor agonists switching patterns in type two diabetes: A retrospective real-world study” by Kassem et al, 2025; https://dx.doi.org/10.4239/wjd.v16.i11.112999.

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INTRODUCTION

The incretin system represents an enteroendocrine mechanism through which nutrient exposure in the gut triggers hormonal and neural signals regulating insulin secretion, feeding behavior, and gastrointestinal motility. Its discovery marked a major milestone in understanding gut-pancreas cross-talk in glucose homeostasis and metabolic regulation[1-3]. This understanding paved the way for therapeutic modulation of the incretin axis as a pharmacological strategy in the management of type 2 diabetes mellitus (T2DM) and adiposity-related diseases over the past two decades[4].

Chronic low-grade inflammation and oxidative stress constitute central drivers of insulin resistance, β-cell dysfunction, and adipose-tissue metabolic impairment in diabesity. Pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-6, NLRP3 inflammasome activation, and excess reactive oxygen species promote impaired insulin signaling, mitochondrial dysfunction, and worsening glucolipotoxicity[5]. Preclinical studies have demonstrated improvement in inflammatory markers and other biochemical parameters with antioxidant therapy in diabetic animal models[6,7]. These upstream inflammatory and oxidative pathways provide an important biological context for understanding the pleiotropic effects of glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs). They attenuate inflammatory signaling, reduce oxidative stress, and improve mitochondrial efficiency in addition to their direct glycaemic benefits, underscoring the mechanistic pathways that contribute to their emerging role as disease-modifying therapies[8].

GLP-1 became the first clinically exploited incretin, leading to the development of GLP-1RAs with progressive improvements in stability, potency, and metabolic efficacy. In practice, attenuation of response to older agents has led clinicians to adopt intra-class switching to newer molecules or incretin co-agonists to enhance glycaemic and weight reduction outcomes. In this context, Kassem et al[9] recently published a study in World Journal of Diabetes, reported real-world data from 18047 patients with T2DM demonstrating significant metabolic gains following such GLP-1RA switching. This editorial reviews the current evidence on the metabolic, cardiovascular, and organ-protective benefits of GLP-1RAs and newer incretin-based therapies.

GLP-1RAS IN DIABESITY

The journey from the isolation of the GLP-1 gene in anglerfish islet cells by Richard Goodman in 1979 to the synthesis of more stable GLP-1RA has proven to be a pivotal one in the management of diabetes and obesity. GLP-1 is an incretin predominantly secreted by the small intestinal L-cells, alpha cells in the pancreatic islet and the neurons of the nucleus tractus solitarius[10]. It exerts its physiological actions by binding to GLP-1 receptors, acting via the protein kinase A pathway on a wide array of target tissues. It has a pivotal role in glucose control by stimulating glucose-dependent insulin secretion, suppressing glucagon secretion, and attenuating postprandial glucose surge due to delay in gastric emptying, in addition to its β-cell protective actions. It also decreases appetite by its central and peripheral actions, playing a pivotal role in energy balance.

GLP-1RAs are synthetic formulations mimicking the actions of endogenous GLP-1, with the newer molecules designed to have greater enzymatic stability, longer half-lives and enhanced metabolic potency. These paved the way for multi-receptor co-activation strategies designed to amplify metabolic benefits, improved glycaemia, greater weight loss, and potential cardiovascular and hepatic protection, leading to the development of dual agonists like tirzepatide [GLP-1/glucose-dependent insulinotropic polypeptide (GIP)] and triple agonists (GLP-1/GIP/glucagon). In this context, we summarize the key metabolic and organ-protective effects of GLP-1RAs and related molecules.

Effect on blood glucose and body weight

GLP-1RAs, as a class effect, have demonstrated impressive glucose-lowering and body weight reducing potential, with glycated hemoglobin (HbA1c) reductions ranging from approximately 0.8% to 1.9%, and body weight changes ranging from -1.14 kg to -6.9 kg[11]. Both the antihyperglycemic and weight loss efficacy seem to be a function of the half-lives of the molecule and the receptor breadth covered by the molecules.

The earliest GLP-1RAs were short-acting formulations such as exenatide and lixisenatide, which exert their principal metabolic action through delayed gastric emptying and attenuation of post-prandial glucose excursions. However, these effects are transient and contribute relatively little to the overall 24-hour glycaemic exposure. Their limited influence on nocturnal and fasting glucose levels, coupled with minimal engagement of central satiety pathways, likely accounts for the modest reductions in both HbA1c and body weight observed with these agents[12]. In contrast, long-acting GLP-1Ras developed through molecular modification of exendin-4 (e.g., once-weekly exenatide) or human GLP-1 analogues (e.g., liraglutide, albiglutide, dulaglutide, and semaglutide) possess extended elimination half-lives that allow less frequent dosing. These agents achieve sustained receptor activation, resulting in more robust suppression of fasting plasma glucose and enhanced signaling in central appetite-regulating centers, thereby producing greater and more durable improvements in glycaemic control and weight reduction[12,13].

In a recent meta-analysis, Yao et al[14] demonstrated that the next-generation dual and multi-agonists achieved the most pronounced HbA1c reductions in T2DM patients: -2.17% with tirzepatide, -2.09% with mazdutide, -1.8% with cagrilintide + semaglutide (CagriSema), and -1.49% with orforglipron. Among conventional GLP-1RAs, longer-acting formulations such as semaglutide (-1.4%), dulaglutide (-1.09%), liraglutide (-1.04%), albiglutide (-1.01%), and PEGylated exenatide (-0.97%) produced greater glucose-lowering effects than short-acting agents like exenatide (-0.81%) and lixisenatide (-0.61%)[14].

Similarly, the authors also reported the highest body weight reduction with newer molecules like CagriSema (-14.03 kg), tirzepatide (-8.47 kg), retatrutide (-7.87 kg), orforglipron (-4.88 kg), followed by semaglutide (-3.13 kg) and liraglutide (-1.33 kg). Dulaglutide, PEGylated exenatide, and short-acting GLP-1RAs (exenatide, lixisenatide) were not associated with a significant reduction in body weight[14]. Additionally, the disease-modifying potential of GLP-1RA was demonstrated in the metanalysis by Yanto et al[15], in which treatment with GLP-1RA in overweight or obese individuals with prediabetes was associated with a higher likelihood of regression to normoglycaemia and a lower risk of progression to overt T2DM. Figure 1 shows the GLP-1RA and polyagonists available for management of diabesity.

Figure 1 Glucagon-like peptide-1 receptor agonists and polyagonists. GLP-1: Glucagon-like peptide-1; GIP: Glucose-dependent insulinotropic polypeptide.

Effect on β-cell survival

GLP-1RAs also hold great promise as potential disease-modifying agents in diabesity. GLP-1RAs activate the phosphatidylinositol 3-kinase/protein kinase B pathway, which has a role in β-cell survival and proliferation[16]. GLP-1 activation also mitigates the endoplasmic reticulum (ER) stress by activating the protein kinase A pathway, promoting β-cell survival[17]. Studies of GLP-1RAs in murine models have revealed improved β-cell function and survival secondary to amelioration of oxidative and ER stress[18,19]. Although large human trials with dedicated β-cell mass endpoints are lacking, clinical and ex vivo human islet studies demonstrate that GLP-1RAs reduce glucolipotoxicity-induced β-cell apoptosis and enhance glucose-stimulated insulin and C-peptide secretion, thereby supporting more durable glycaemic control over time[20-22]. These mechanisms provide the biological foundation for the durable glycaemic efficacy seen in long-term incretin therapy.

Effect on adipose tissue biology

GLP-1RAs also exert meaningful effects on adipose tissue distribution and quality, targeting a core abnormality in diabesity. In a study by Akoumianakis et al[23], treatment was associated with significant reductions in visceral adipose tissue, epicardial fat, hepatic fat infiltration, subcutaneous adipose tissue, and overall total adipose tissue. Similarly, Xie et al[24] demonstrated that GLP-1RA therapy reduced insulin resistance indices alongside decreases in both visceral and subcutaneous fat depots, indicating improvements in adipose tissue function as well as quantity. In individuals with obesity and non-alcoholic fatty liver disease, GLP-1RAs have additionally been shown to improve hepatic steatosis and lower fibrosis-4 scores, supporting their role in adipose tissue remodeling and mitigating the metabolic and hepatic consequences of diabesity[24].

Effect on cardiovascular disease

Cardiovascular disease (CVD) remains the major cause of morbidity and mortality in T2DM. GLP-1RAs exert anti-atherogenic effects through multiple convergent mechanisms, including improvements in endothelial function, reductions in vascular inflammation and oxidative stress, and favorable modulation of lipid handling and visceral adiposity[25]. These cardioprotective actions are biologically distinct from, and additive to, their effects on glycaemia and weight, thus underscoring their role as holistic metabolic therapies[26].

These mechanistic insights have translated into cardiovascular benefits in large cardiovascular outcomes trials with several GLP-1RAs. All the GLP-1RAs have undergone cardiovascular outcome trials (CVOT) as per the United States Food and Drug Administration guidance for newer antihyperglycemic agents. The pertinent findings from the GLP-1RA CVOTs have been summarized in Table 1.

Table 1 Summary of findings from the cardiovascular outcome trials with glucagon-like peptide-1 receptor agonists[16,27-29,52-54].

	EXSCEL[27]	ELIXA[28]	LEADER[29]	REWIND[30]	HARMONY[31]	SUSTAIN-6[32]	PIONEER-6[33]
Intervention	Exenatide once weekly subcutaneous vs placebo	Once-daily subcutaneous lixisenatide vs placebo	Once daily subcutaneous liraglutide vs placebo	Weekly subcutaneous dulaglutide vs placebo	Weekly subcutaneous albiglutide vs placebo	Once-weekly subcutaneous semaglutide vs placebo	Once-daily oral semaglutide vs placebo
Population (n)	14752	6068	9340	9901	9463	3297	3183
Established CV disease (%)	73.1	100	81.3	31.5	100	83	84.7
Follow-up period (years), (median IQR)	3.2 (2.2 to 4.4)	2.1	3.8	5.4	1.6 (1.3 to 2)	2.1	1.3
Mean/median HbA1c at baseline (%)	8	7.6	8.7	7.2	8.7	8.7	8.2
Mean difference in HbA1c (%), (95%CI)	-0.53 (-0.57 to -0.50)	-0.27 (-0.31 to -0.22)	-0.40 (-0.45 to -0.34)	-0.61 (-0.65 to -0.58)	-0.52 (-0.58 to -0.45)	-0.7 (-0.80 to -0.52) for a 0.5 mg/week dose-1 (-1.19 to -0.91) for a 1 mg/week dose	-0.7% (-0.42 to -1.26)
Mean difference in body weight (kg), (95%CI)	-1.27 (-1.4 to -1.13)	-0.7 (-0.9 to -0.5)	-2.3 (-2.5 to -2)	-1.46 (-1.67 to -1.25)	-0.83 (-1.06 to -0.6)	-2.9 (-3.47 to -2.28) for a 0.5 mg/week dose-4.3 (-4.94 to -3.75) for a 1 mg/week dose	-3.4 (-4.2 to -2.3)
Mean difference in systolic blood pressure (mmHg), (95%CI)	Not reported	−0.8 (-1.3 to -0.3)	-1.2 (-1.9 to 0.5)	-1·70 (-1.33 to -2.07)	–0.67 (-1.40 to 0.06)	-1.3 (P = 0.10) for 0.5 mg/week dose, -2.6 (P < 0.001) in 1.0 mg/week dose	-2.6 (-3.7 to -1.5)
Primary outcome, HR (95%CI)	3P-MACE, 0.91 (0.83 to 1.0) P < 0.001 for noninferiority, P = 0.06 for superiority	4P-MACE, 1.02 (0.89 to 1.17) P = 0.81	3P-MACE, 0.87 (0.78 to 0.97), P = 0.01 for superiority1	3P-MACE, 0.88 (0.79 to 0.99), P = 0.026 for superiority1	3P-MACE, 0.78 (0.68 to 0.90), P = 0.0006 for superiority1	3P-MACE, 0.74 (0.58 to 0.95), P = 0.02 for superiority1	3P-MACE, 0.79 (0.57 to 1.11)
Key secondary outcomes
CV death, HR (95%CI)	0.88 (0.76 to 1.02)	0.98 (0.78 to 1.22)	0.78 (0.66 to 0.93), P = 0.0071	0.91 (0.78 to 1.06)	0.93 (0.73 to 1.19)	0.98 (0.65 to 1.48)	0.49 (0.27 to 0.92)
All-cause mortality, HR (95%CI)	0.86 (0.77 to 0.97)	0.94 (0.78 to 1.13)	0.85 (0.74 to 0.97), P = 0.021	0.90 (0.80 to 1.01)	0.95 (0.79 to 1.16)	1.05 (0.74 to 1.50)	0.51 (0.31 to 0.84)
Non-fatal myocardial infarction, HR (95%CI)	0.97 (0.85 to 1.10)	1.03 (0.87 to 1.22), P = 0.71	0.86 (0.73 to 1.00), P = 0.0461	0.96 (0.79 to 1.15)	0.75 (0.61 to 0.90), P = 0.0031	0.74 (0.51 to 1.08)	1.18 (0.73 to 1.90)
Non-fatal stroke, HR (95%CI)	0.85 (0.70 to 1.03)	1.12 (0.79 to 1.58)	0.86 (0.71 to 1.06)	0.76 (0.62 to 0.94), P = 0.011	0.86 (0.66 to 1.14)	0.61 (0.38 to 0.99), P = 0.041	0.74 (0.35 to 1.57)
Hospitalization for HF, HR (95%CI)	0.94 (0.78 to 1.13)	0.96 (0.75 to 1.23)	0.87 (0.73 to 1.05)	0.93 (0.77 to 1.12)	0.85 (0.64 to 1.11)	1.11 (0.77 to 1.61)	0.86 (0.48 to 1.55)
Adverse effects	No clinically relevant between-group differences	Leading to discontinuation (11.4% vs 7.2%, P < 0.001). GI events (4.9% vs 1.2%), P < 0.0011	GI events were more frequent in the liraglutide group than in the placebo group. Acute gallstone disease (3.1% vs 1.9%), P < 0.0011. Pancreatic carcinoma (0.3% vs 0.1%), P = 0.061	GI events (47.4% vs 34.1%), P < 0.00011	Injection site reactions (2% vs 1%)	Retinopathy complications 1.76 (1.11 to 2.78), P = 0.021. GI disorders are more common in the semaglutide arms vs the placebo	Treatment discontinuation and GI events were more common in the semaglutide than the placebo group

¹Significant outcomes.

New or worsening nephropathy persistent macroalbuminuria, persistent doubling of the serum creatinine level and a creatinine clearance of less than 45 mL per minute per 1.73 m² of body-surface area (according to the modification of diet in renal disease criteria), or the need for continuous renal-replacement therapy. Retinopathy complications vitreous hemorrhage, onset of diabetes-related blindness, and the need for treatment with an intravitreal agent or retinal photocoagulation. CV: Cardiovascular; HR: Hazard ratio; HbA1c: Glycated hemoglobin; CI: Confidence interval; HF: Heart failure; IQR: Interquartile range; GI: Gastrointestinal; 3P-MACE: 3-point major adverse cardiovascular event; 4P-MACE: 4-point major adverse cardiovascular event.

A significant cardiovascular benefit concerning 3-point major adverse cardiovascular event (MACE) outcomes was demonstrable in the CVOTs of liraglutide, dulaglutide and subcutaneous semaglutide, whereas cardiovascular neutrality was seen with exenatide, lixisenatide and oral semaglutide[27-33]. The data for individual cardiovascular outcomes are more heterogenous, with a significant reduction in non-fatal myocardial infarction (MI) demonstrable with liraglutide and albiglutide, a reduction in non-fatal stroke seen with dulaglutide and subcutaneous semaglutide, and a reduction in all-cause and cardiovascular mortality noted in the liraglutide CVOT.

In a recent meta-analysis incorporating the results of 24 randomized controlled trials (RCTs) evaluating cardiovascular outcomes of GLP-1RA vs placebo in diabetic and non-diabetic obese individuals, Hosseinpour et al[26] reported a significant reduction in MACE, cardiovascular death, MI, stroke and hospitalization for heart failure. The mortality and MACE benefits were similar irrespective of diabetic status, whereas the reduction in MI and hospitalization for heart failure was statistically significant only in the non-diabetic group. Rivera et al[34] also had similar findings in their meta-analysis, with significant reductions seen with MACE, all-cause mortality, cardiovascular mortality, fatal and non-fatal stroke and coronary revascularization with use of GLP-1RAs. These benefits were consistent irrespective of gender, diabetes status, history of CVD, body mass index and estimated glomerular filtration rate (eGFR)[34].

Effect on renal outcomes

Beyond cardiovascular benefits, GLP-1RAs also exert clinically meaningful renal protection. In prespecified secondary analyses of LEADER, SUSTAIN-6, and REWIND, GLP-1RAs consistently reduced new-onset persistent macroalbuminuria and slowed eGFR decline vs placebo[29,30,32]. These findings were recently reinforced by the FLOW trial with dedicated renal outcomes, in which semaglutide significantly reduced the risk of kidney disease progression and major renal outcomes, leading to early trial termination for efficacy[35]. The nephroprotective effects of GLP-1RAs are postulated to result from improved glycaemic control, reduced intraglomerular pressure, and attenuation of renal inflammation and oxidative stress, underscoring their role as comprehensive cardiorenal-metabolic modifiers.

Taken together, these data establish GLP-1RAs as true disease-modifying therapies in diabesity, offering integrated protection across metabolic, cardiovascular, renal, and hepatic domains. However, not all agents within the class deliver equivalent potency or durability of effect. The advent of longer-acting and multi-receptor agonists has prompted clinicians to explore strategic switching as a means of sustaining glycaemic control and weight reduction over time. In patients with diabesity and related comorbidities already on GLP-1RA therapy, the focus is now shifting towards individualized, evidence-driven optimization, where the choice of agent is guided by comparative efficacy, targeted clinical outcomes, tolerability, patient preference, and affordability.

GLP-1RA SWITCHING: RATIONALE AND REAL-WORLD EVIDENCE

Although GLP-1RAs have demonstrated consistent metabolic, cardiovascular, and renal protection, variability in individual response is common in clinical practice. Over time, some patients experience attenuation of glycaemic or weight-lowering benefits, reflecting progressive β-cell dysfunction, attenuation of gastric-emptying-inhibitory effects with use of longer-acting GLP-1RAs or chronic exposure to short-acting GLP-1RAs, suboptimal adherence, or differences in pharmacokinetic and receptor-binding characteristics among agents[14,16,36-38]. Structural diversity within the class-exendin-4 based vs human GLP-1 analogues translates to differing metabolic potency and cardiovascular outcomes (Table 1). These mechanistic and pharmacological distinctions underpin the emerging clinical practice of intra-class switching as a means of restoring or sustaining metabolic efficacy before escalating to insulin or combination injectable therapy.

Real-world evidence

The recent nationwide retrospective study by Kassem et al[9], published in the World Journal of Diabetes, represents the most comprehensive real-world assessment of GLP-1RA switching to date. Conducted using a large Israeli national database encompassing 70654 adults with T2DM over 12 years (2009-2021), it provides invaluable insight into real-world switching trends, efficacy, and tolerability. Approximately 18047 patients (25.5%) underwent intra-class switching during the study period, reflecting the rapid evolution of incretin pharmacotherapy and the trend to transition from short-acting to long-acting formulations. Among the 13970 patients with paired HbA1c data, mean HbA1c decreased from 8.5% ± 1.6% to 7.6% ± 1.4% (P < 0.001) after the switch, with 78% of participants achieving measurable improvement. Kassem et al[9] observed the greatest benefit when switching from daily to weekly regimens, likely reflecting higher efficacy, improved adherence, and greater convenience of once-weekly formulations.

The physiological reasons underpinning the higher glycemic efficacy and weight loss of long-acting GLP-1RA and multi-agonist molecules individually have been explored in the previous section and demonstrated in several meta-analyses[14,39]. The feasibility and benefits of intra-class switching to the newer generation molecules, on the other hand, have gained traction from the results of several RCTs. Switching from daily exenatide to liraglutide resulted in additional HbA1c lowering in the LEAD-6 trial[40]. With newer agents, the results are even more compelling. The EXPERT trial demonstrated that switching from any prior GLP-1RA to semaglutide 1 mg produced further mean reductions of 0.7 % in HbA1c and approximately 3 kg in body weight after six months[41]. The SWITCH-SEMA-1 study confirmed comparable improvements when transitioning from liraglutide or dulaglutide to semaglutide 1 mg, with maintained tolerability and minimal gastrointestinal adverse effects[42]. Collectively, these data affirm that intra-class optimization within the GLP-1RAs can recapture therapeutic efficacy, as also reflected in the findings by Kassem et al[9]. The authors also note that the temporal rise in switching frequency has paralleled the wider commercial availability of longer-acting GLP-1RAs.

However, clinical use of any new agent also comes with the caveat of anticipating the adverse effects and effectively managing them. The gastrointestinal adverse effects seen with these agents seem to be a class effect, with some nuances. In comparative analyses, Ma et al[43] observed that treatment discontinuation due to adverse events occurred most frequently with the short-acting agent exenatide and with higher-dose long-acting formulations, namely liraglutide 3.0 mg and semaglutide 2.4 mg. These findings suggest that intolerance-driven discontinuation is most pronounced either with short-acting GLP-1RAs or when higher doses of potent, long-acting agents are employed. Hence, while the choice of agent is majorly dictated by efficacy data, careful dose titration and patient education need to be underscored to optimize adherence.

The frequency of dosing remains the other major factor that determines real-world prescription trends. In the systematic review by Claxton et al[44], compliance with treatment was observed to be inversely proportional to the number of doses. These trends have been noted in GLP-1RA use, where higher adherence and persistence rates were seen with weekly GLP-1RA formulations as compared to daily formulations[45,46].

Taken together, this pattern of switching from daily to weekly GLP-1RAs suggests that clinicians increasingly recognize switching as a therapeutic optimization step, rather than as a marker of treatment failure. The observed improvements in glycaemic control without an accompanying increase in adverse events underscore the feasibility and safety of such a strategy in real-world settings. Clinical prompts for considering a switch include suboptimal HbA1c control, the need for further weight reduction, the emergence of higher cardiovascular risk, or suboptimal adherence to the current regimen. It would be pragmatic to also take into consideration other real-world barriers to GLP-1RA use. These include cost constraints, limited insurance coverage, gastrointestinal intolerance and dosing frequency burdens, leading to the generally high discontinuation rates (37%-81% at one year) observed with GLP-1RA use[47]. These factors must be considered when evaluating switching strategies, as optimization of therapy requires alignment of clinical efficacy with patient-specific affordability, tolerability, and the likelihood of adherence to therapy.

Although limited by its retrospective design, variable HbA1c follow-up, and lack of weight or adherence data, the findings of the study by Kassem et al[9] remain robust. Even without stratification by comorbidity or organ-risk profile, the magnitude and consistency of benefit underscore the clinical relevance of GLP-1RA switching in everyday diabetes management. It bridges the gap between controlled-trial efficacy and real-world effectiveness, providing external validation for therapeutic sequencing within the incretin class. Future prospective studies with composite metabolic and organ-protection endpoints are needed to delineate the optimal timing and predictors of benefit from switching.

From a health-economic standpoint, switching to potent once-weekly GLP-1RAs is supported by cost-effectiveness models. Weekly semaglutide 1 mg was found to be more cost-effective than daily liraglutide, despite being priced higher in the United Kingdom, due to improved quality-adjusted life years and lower lifetime costs due to cardiovascular and renal outcome benefits[48,49]. Although acquisition costs remain high in resource-limited settings, selective switching guided by adherence potential, cardiovascular risk, and affordability can optimize both efficacy and value. Figure 2 shows the rationale for switching GLP-1RAs.

Figure 2 The rationale for switching glucagon-like peptide-1 receptor agonists. GLP-1: Glucagon-like peptide-1; HbA1c: Glycated hemoglobin.

Future perspectives

The next evolution in incretin therapy will likely shift from intra-class GLP-1RA switching to the sequential use of multi-agonists targeting complementary pathways, such as GIP and glucagon receptors. Beyond GLP-1–specific actions, incretin multi-agonists demonstrate synergistic metabolic mechanisms that broaden their therapeutic potential. GIP receptor activation enhances insulin secretion, improves adipocyte insulin sensitivity, and amplifies central satiety signaling[50]. Additionally, the GIP-receptors have also been identified in oligodendrocytes in the median eminence that regulate the access of peripheral satiety signals to the arcuate nucleus. Hence, GIP agonism may potentiate the anorexigenic effect of GLP-1RA by increasing its access to the anorexigenic neuronal population in the mediobasal hypothalamus[51]. Additionally, preclinical models have demonstrated that GIP receptor agonism attenuates the nausea and emesis associated with GLP-1RA use[52].

Together, the dual engagement of GLP-1 and GIP receptors can lead to greater improvements in metabolic end-points with potentially fewer adverse effects than observed with GLP-1 monotherapy, supporting the rationale for therapeutic escalation or switching to polyagonists in appropriate patients. In the SURPASS-SWITCH trial, patients with T2DM on dulaglutide who switched to tirzepatide achieved greater HbA1c and weight reductions than those who continued or escalated dulaglutide, supporting a “switch-rather-than-up-titrate” approach[53]. Jabbour et al[54] reported additional glycaemic and weight benefits within the first 12 weeks of treatment when transitioning from prior GLP-1RA therapy (liraglutide/dulaglutide/semaglutide) to tirzepatide, with acceptable tolerability.

Beyond dual agonism, triple-receptor molecules such as retatrutide (GLP-1/GIP/glucagon agonist) have demonstrated profound, dose-dependent glycemic (HbA1c reduction up to -2.02% at 24 weeks) and weight loss efficacy (up to 16.9% at 24 weeks) in a phase 2 trial in T2DM patients, outperforming placebo and dulaglutide[55]. Likewise, CagriSema produced greater weight loss (-15.6%) than semaglutide (05.1%) or cagrilintide (-8.1%), while HbA1c reduction (-2.2%) was similar to semaglutide (-1.8%) and superior to cagrilintide (-0.9%) with comparable adverse effects[56]. Future research must define sequencing algorithms clarifying when to switch within the GLP-1RA class vs when to move to dual or triple agonists and identify predictors of response to guide individualized therapy.

CONCLUSION

From their origins as gut-derived peptides to their evolution as comprehensive metabolic modulators, GLP-1RAs have transformed diabesity management. Their actions extend beyond glycaemia to include β-cell preservation, weight regulation, and multi-organ protection, redefining them as disease-modifying therapies rather than mere glucose-lowering agents. The findings of Kassem et al[9] exemplify the clinical consolidation of incretin therapy showing that intra-class switching can sustain and often enhance metabolic control. This reflects a shift from static prescribing to dynamic incretin optimization, aligned with precision medicine principles, where molecule selection is guided by potency, tolerability, adherence, and cost-effectiveness. Future care algorithms will likely formalize sequencing strategies incorporating dual and triple agonists, guided by metabolic responsiveness and cardiovascular risk. The choice and timing of incretin therapy should be individualized to delay insulin dependence, optimize cardiorenal outcomes, and ensure simplicity and sustainability in diabetes care.