100 Years Of Weight Loss Drugs Timeline

Before delving into the timeline of GLP-1 agonists, it's essential to understand how they work. In this blog, we'll explore the onset of action of GLP-1s and provide insights into what you can anticipate when starting this treatment. We ensure that patients stay on track with their prescriptions by identifying potential drop-off points in real-time. Learn why leading life science companies partner with Nimble to generate revenue across millions of high-intent patients. Effortless online ordering that keeps your patients happy and healthy. In hindlimb-unloading rats, exenatide improves bone mass by promoting osteogenic differentiation of bone marrow stem cells . Similar neuroprotective effects have been reported in various PD rodent models treated with GLP-1R agonists , , , , , . Overexpression of mutant HTT impairs insulin signaling and stimulates neuronal apoptosis in human SK-N-MC neuronal cells . Emerging data mostly acquired from the CVOT’s conducted for the various GLP-1 receptor agonists now available, also suggest that they may offer renoprotection . This class of drugs are frequently used by diabetologists for their strong glucose-lowering effects, beneficial safety profile as well as for their cardiovascular protection as described below. Second, over a decade ago, market access was granted to the first glucagon-like peptide (GLP-1) receptor agonist. The prevalence of people living with type 2 diabetes (T2D) has increased to over 450 million worldwide and is expected to increase further in the next decades . These include mitigation of hyperglycemia, overweight and insulin resistance, systemic and glomerular hypertension, dyslipidemia, sodium retention, inflammation and renal hypoxia. While side effects can be challenging, you can take a proactive approach through lifestyle adjustments, proper hydration, and thoughtful dietary choices. In this guide, we’ll cover nine common side effects and provide clear, practical tips to help you manage each one with confidence. However, as your body adjusts, certain side effects may arise, particularly gastrointestinal symptoms like nausea and vomiting. Research shows that GLP-1 medications can be effective tools for improving blood sugar control and supporting weight management.

• GLP-1RAs and Osteoblasts Osteoblasts arise through the differentiation of mesenchymal stem cells and play a crucial role in the process of bone formation.
• Change in weight over 26 weeks was −1.30 kg, +0.2 kg, −1.07 kg, and +1.24 kg for dulaglutide 1.5 mg, dulaglutide 0.75 mg, exenatide, and placebo, respectively.
• GLP-1 helps regulate blood sugar levels by stimulating the release of insulin, suppressing glucagon secretion (which raises blood sugar levels), and slowing the rate at which the stomach empties, leading to a feeling of fullness and reduced appetite.69 In addition to its use in diabetes management, GLP-1RA has also shown potential in other areas of research.
• Consistent with this role of Irs2, increased expression of Irs2 in β-cells improves insulin secretion in obese mice and protects against STZ-induced β-cell destruction (as reviewed in ).
• Obesity specialists know how to taper up the dose over time to manage some of these side effects.
• In a double blind placebo controlled study, 12 week treatment with liraglutide in patients at risk for AD did not show cognitive differences between the study cohorts .
• While substantial evidence supports a role of Pdx1 in the negative regulation of Gcg expression, Pdx1 immunoreactivity has also been demonstrated in some Gcg expressing L-cells .

GLP-1 receptor agonists have been studied in combination with several of the oral antidiabetic agents. Table 6 shows the various renal and hepatic adjustments necessary for GLP-1 receptor agonists and outlines considerations that need to be taken with individual agents. Albiglutide once weekly was studied in a phase 3 trial compared to sitagliptin in patients with renal impairment and was found to be superior with similar tolerability. Liraglutide is not eliminated renally , and mild renal impairment has not demonstrated a significant effect on its efficacy or safety, although there have been case reports of acute kidney injury with use of liraglutide in patients with moderate to severe renal impairment . Similar conclusions have been reached by analysis of the GLP-1 bound receptor conformation using cryo-electron microscopy and by analyzing the crystal structure of GLP-1R bound to truncated peptide agonist . Based on this model, a negative allosteric modulator binds and deactivates GLP-1R through binding between the cleft of the GLP-1R helices VI and VII, thereby pushing helix VI to an inactive state that prevents association of the receptor with the G protein . A model for ligand-induced receptor conformation has also been proposed based on comparative molecular simulations using GLP-1R bound to positive and negative allosteric modulators . A two-domain model has emerged and suggests that GLP-1 binds via its α-helical and C-terminal motifs to the N-terminal ECD of GLP-1R followed by the activation of GLP-1R through binding of the N-terminal residues of GLP-1 with the transmembrane helices and extracellular loops of the receptor 401,421,422. By definition, short-acting GLP-1 RAs (exenatide b.i.d. and lixisenatide) are characterized by short-lived peaks in plasma drug concentrations following each injection, with intermittent periods of near-zero concentrations. Since the parent compound of GLP-1 RAs, GLP-1, has a very short elimination half-life that precluded its clinical use outside settings characterized by continuous administration, compounds/preparations with longer intervals between injections have been developed over time (Table 1). Figure 3 depicts the visual appearance and some essential properties as well as the authors’ evaluation of their ease of use of all available pen injection devices for GLP-1 RAs (free and fixed-dose combinations). The dulaglutide pen injection device has received attention because of its single-use design and the needle, which is never visible throughout the injection procedure. In rats, liraglutide- but not exendin-4-induced inhibition of gastric emptying is markedly diminished after 14 wk of treatment . Several studies in mice 465,467,685,774 and humans , , , , have failed to detect changes in energy expenditure following chronic or acute peripheral treatment with different GLP-1R agonists. Consistent with these data, central administration of the GLP-1R agonists liraglutide and exendin-4 increases energy expenditure and BAT thermogenesis through mechanisms that include AMPK signaling in the mediobasal hypothalamus . These data suggest that that GLP-1's effects on renal function might be transient and vanish upon more chronic treatment. Studies using a stabilized radiolabeled (Ser8)GLP-1 revealed rapid uptake into the brain after intravenous (i.v.) administration without self-inhibition when challenged with increased doses of unlabeled (Ser8)GLP-1 or upon inhibition of brain GLP-1 influx upon pretreatment with exendin (9–39). In 1902, Ernest Bayliss and William Starling identified a substance that is produced in and secreted from the epithelial cells of the duodenum in response to the contact of these cells with acidic chyme . Two glucagon-related peptides were subsequently identified in the rat 47,48, hamster , bovine , and human proglucagon sequence. By using a method that allows the prediction of a protein sequence through decoding of recombinant cDNA clones, at the beginning of the 1980s Joel Habener established that a different glucagon-related peptide is encoded within the anglerfish preproglucagon cDNA , , . Thus, it appeared that proglucagon undergoes a tissue-specific, differential processing leading to the formation of glicentin and oxyntomodulin in the gut and to glucagon plus the N-terminal fragment of glicentin in the pancreas 34,43 (Figure 1). In 1982, a smaller intestinal form was identified as a 37-amino acid peptide containing the full 29-amino acid sequence of glucagon with 8 additional amino acids on its C-terminal end , the same as found in the C-terminus of glicentin. Importantly, current guidelines prioritize the use of GLP-1 RAs with demonstrated CV benefit (dulaglutide, liraglutide, and injectable semaglutide) in patients with atherosclerotic CV disease (ASCVD) and ASCVD risk, independent of baseline A1C. The long-acting agents tend to produce more significant weight loss compared with the short-acting agents, with semaglutide once again taking the lead on the greatest weight reduction. Within the outcomes reported through the DTR-QoL survey, patients had significantly less anxiety and dissatisfaction with 7 mg ETD 6.03, 95% CI 0.76–11.30 and 14 mg ETD 7.21, 95% CI 1.91–12.51 oral semaglutide compared with dulaglutide.26 The SUSTAIN-3, 7, and 10 trials examined patient satisfaction through the DTSQ.21–23 In the SUSTAIN-3 trial, treatment satisfaction was higher with semaglutide than exenatide ER (p p p p p p In the PIONEER-4 trial, at 52 weeks, there was no difference in treatment satisfaction between liraglutide and oral semaglutide in regards to their DTSQ scores.24 The PIONEER-9 trial utilized the Diabetes Therapy-Related QOL (DTR-QOL) questionnaire to assess patient satisfaction. PIONEER-10 reported similar high rates of AEs, starting with 77% of patients in the 3 mg semaglutide group, increasing to 80% in the 7 mg group, and 85% in the 14 mg group; this was compared with 82% of patients using dulaglutide.26 Serious AEs were less linear, reported in nine patients (7%), four patients (3%), seven patients (5%) and one patient (2%), respectively. Complications of diabetic retinopathy were rare but more commonly seen in patients who received injectable semaglutide vs placebo (3.0% vs 1.8%) in SUSTAIN-6.7 This findins has been attributed to the rapid reduction in blood glucose in a patient population at higher risk for retinopathy complications, which has been observed with insulin therapy when poorly controlled hyperglycemia is rapidly rectified. Professional society guidelines now recommend GLP-1RA therapy for cardiovascular risk mitigation in patients with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD) or multiple ASCVD risk factors, independent of glucose control or background antihyperglycemic therapy (other diabetes medications being used). To date, randomized clinical trials of albiglutide, dulaglutide, liraglutide, and injectable semaglutide have reported favorable cardiovascular outcomes. Beyond improvement of glucose control and weight reduction, GLP-1 RAs have been shown over large randomised clinical trials (RCTs) to significantly reduce major adverse cardiovascular events in diabetic patients, particularly among individuals with atherosclerotic disease or those considered to be at high-risk of cardiovascular disease.3 Both lixisenatide and liraglutide lowered hemoglobin A1C significantly from baseline (liraglutide −0.51% vs lixisenatide −0.32%; p41]. Patients treated with the lower dose of albiglutide experienced a significantly lower incidence of gastrointestinal complaints (p37]. Administered as a 0.75 mg injection, the dose can be escalated to 1.5 mg once weekly to achieve glycemic targets. Similar to exenatide once weekly, albiglutide is not appropriate as a first-line agent for therapy . Treatment of type-2 diabetic patients with a combination of the DPP-4 inhibitor sitagliptin and liraglutide showed no greater efficacy on glucose control relative to treatment with liraglutide alone, potentially because of GLP-1R saturation by the liraglutide monotherapy . The combination of GLP-1R analogs with basal insulin has yielded promising effects to accelerate metabolic and glycemic outcomes in patients with type-2 diabetes , , . Higher doses of GLP-1R agonists can achieve clinically relevant weight loss, and greater increases in dose levels, in theory, can drive more weight-lowering efficacy. The weight loss induced by liraglutide at 3 mg is typically in the range of ∼5–10% after 52 wk of treatment of non-diabetic obese patients . After injection, exenatide levels can be measured for approximately 10 hours, although peak levels are achieved at 2.1 hours after injection. The usefulness of endogenous incretin hormones in glucose homeostasis is limited by rapid degradation by the DPP-4 enzyme, resulting in a half-life of GLP-1 of approximately 2 minutes . Interestingly, the secretion of GLP-1 and gastric-inhibitory peptide (GIP), another incretin hormone, had no bearing on each other . While the American Diabetes Association recommends metformin as first-line therapy due to its efficacy in reducing hemoglobin A1C, widespread availability, safety, and tolerability, a single agent is often not sufficient to bring a patient’s blood glucose level to meet the target . The most common adverse effects seen with GLP-1 therapy include nausea, vomiting, and injection-site reactions. Not all rodent studies report elevated BP in response to GLP-1R agonism, but dose could be a discriminatory factor. Collectively, these data suggest that acute GLP-1 effects on HR and BP in normal animals may involve signaling via both, the sympathetic and parasympathetic nervous systems. However, while the hypertensive effect of GLP-1 is not abolished by inhibition of β-adrenergic signaling , exendin-4 induction of HR is blocked by the β-adrenergic receptor antagonist propranolol , and exendin-4 fails to affect HR in adrenalectomized rats (as reviewed in ). However, in rats, GLP-1 elevation of BP is preserved upon pretreatment with reserpine, propanolol or phentolamine, thus indicating that the hypertensive effect of GLP-1 does not exclusively depend on catecholamine signaling . Accordingly, in the isolated perfused rat pancreas, GLP-1 fails to stimulate insulin release at glucose concentrations 6.6 mM 82,480. This process, generally referred to as calcium-induced calcium release (CICR) (Figure 5) 489,, , , ensures that the insulinotropic action of GLP-1 is highly dependent on the ambient glucose concentration. The subsequent Ca2+ influx promotes exocytosis of the insulin granules and acute secretion of insulin into the circulation. Exogenous GLP-1 administration may restore blood glucose regulation to near normal levels in patients with T2DM whose incretin effect is reduced . Impaired incretin effect in T2DM could be due to impaired incretin hormone secretion (incretin hormone deficiency) and/or defective insulinotropic action of the incretin hormones (incretin hormone resistance). Their effects are progressively amplified from the beginning of a meal in response to increase in plasma glucose concentrations. The incretin hormones may be responsible for up to 70% of postprandial insulin secretion. Therefore, the ideal agent to treat type 2 diabetes would have favorable effects on weight, blood pressure, and lipids . In the AWARD-6 study, 290 patients were randomized to receive dulaglutide 1.5 mg once weekly along with 300 patients who received liraglutide 1.8 mg daily for a treatment duration of 26 weeks. Therapeutic concentrations are achieved faster with dulaglutide compared to other once-weekly GLP-1 receptor agonists, within 1–3 days , while steady state concentrations occur within 2–4 weeks after administration of the once-weekly injection . Patients with type 2 diabetes were randomized to receive either albiglutide 30 mg once weekly, which could be escalated to a dose of 50 mg once weekly after 6 weeks, or liraglutide 0.6 mg daily, titrated to the goal dose of 1.8 mg daily after 2 weeks. Since insulin must be titrated slowly as part of the dose-finding process, the GLP-1 RA component of these fixed-dose combinations is titrated slowly as well. In studies comparing basal insulin and GLP-1 RAs alone and in combination with each other, the combination achieved the lowest HbA1c or highest HbA1c reduction and a body weight transformation in between GLP-1 RA alone (lowest) and insulin alone (highest) . When a GLP-1 RA is added to (basal) insulin, the combination is as effective as an intensified (basal bolus) insulin regime in terms of HbA1c control, but with a much lower risk of hypoglycemia and weight gain . It should only be used in patients needing a combination of two injectable treatments, especially considering the costs of such a combination.

• In addition to GLP-1 RAs, SGLT-2 inhibitors are another class of glucose-lowering medications that have proven beneficial CV effects, especially regarding the prevention of heart failure complications (Figure 6 110,111).
• GLP-1's improvement of learning and memory can be blocked by pretreatment with exendin (9–39), and is absent in mice deficient for the GLP-1 receptor .
• In this review, the mechanism of action of GLP-1 receptor agonists on glucose metabolism and on the kidney are discussed as well as the (pre)clinical data that currently are suggestive of renoprotection, and potentially involved pathways.
• In fact, the peptide acts as a weak GLP-1R antagonist, clearly counteracting the biological effects of GLP-1 (7-36amide) in vitro .
• GLP-1 can stimulate pancreatic β-cells to release insulin.236,237 Insulin not only directly lowers blood glucose levels but also further inhibits glucagon secretion from α-cells through a feedback mechanism.238 The high concentration of insulin in the local pancreatic environment creates a negative feedback effect, reducing the amount of glucagon secreted by α-cells.234 Additionally, GLP-1 can reduce blood glucose production by delaying gastric emptying and decreasing appetite, which also contributes to overall blood glucose control.239,240 In summary, GLP-1 lowers blood glucose levels and inhibits glucagon secretion through direct action on α-cells, promotion of insulin secretion, and regulation of gastrointestinal activity.241
• In these mice scattered GLP-1R expression was detected in cardiomyocytes of the atrium but not in the ventricles, and widespread expression was detected in smooth muscle cells of coronary vessels .

By week 36, this weight loss effect was even more pronounced, increasing from 9.4% to 14.7%, while the placebo group saw a reduction of only 2.3%. It was the world’s first PEGylated long-acting GLP-1RA.123 PEG-loxenatide is used for blood glucose control in adult patients with T2DM. CagriSema is composed of the GLP-1 RA semaglutide and the long-acting insulin analog cagrilintide, and can be administered subcutaneously once a week.117 Semaglutide is a long-acting GLP-1RA agent used once weekly to improve glycemic control in patients with T2DM.115 Compared with the structure of human GLP-1(7-37), the amino acid sequence of semaglutide contains diaminoisobutyric acid at position 8, arginine at position 34, and acylated lysine at position 26.31 Semaglutide has a longer aliphatic chain and increased hydrophobicity, but its hydrophilicity is greatly enhanced by PEG modification of the short chain. Lixisenatide was developed by Sanofi to treat T2DM.64,93 Structurally, lixisenatide is based on the exenatide structure but lacks proline at position 38, and six lysines are linked after serine at position 39.94 The six lysine residues increase the rigidity of the molecule’s structure, thus allowing its drug properties to be improved.78 These changes stabilize its structure, prevent protein degradation of the molecule in the circulation, and increase the circulation time enough to ensure once-daily injection (compared with exenatide, which is injected two or three times daily). The clinical trial programme of GLP-1 RAs licensed or under regulatory approval in one or more South Asian countries is presented in Table 10. As the proposed consensus on GLP-1 RAs is based on a pragmatic review of clinical evidence and insights from experts across South Asia, pragmatic review relies on detailed and thorough analysis of clinical evidence to draw inferences. AACE/ACE guidelines strive for stringent HbA1c targets (≤ 6.5%) compared to American Diabetes Association–European Association for the Study of Diabetes (ADA/EASD) guidelines which aim for an HbA1c target of 7% . All the guidelines listed in Table 9 recommend GLP-1 RAs as a part of dual or triple therapy in combination with OAD drugs with or without insulin in accordance with the respective algorithm 55, 59, 60, 62–64. The usefulness of GLP-1 analogues in glycaemic control with low risk of hypoglycaemia and body weight reduction has been taken into consideration in all the guidelines listed in Table 9. This is one important reason for testing higher doses, for example, dulaglutide , to seek approval for more effective, higher doses of GLP-1 RAs for those who tolerate them. The quantitative differences in body weight reduction typically achieved with different GLP-1 RAs critically depend on the respective doses selected in phase 2 studies. Liraglutide (at doses somewhat higher than used to treat diabetes mellitus) is also approved for pharmacological obesity therapy 64,65. Nevertheless, a recent systematic Cochrane Database review declared the evidence of improved motor impairment in GLP-1 RA-treated patients with Parkinson's disease as “low certainty” . Parkinson's disease is another neurodegenerative disease for which GLP-1 RAs are being explored as treatment options 221,228. In Alzheimer's disease, the most prevalent form of dementia, animal studies have shown the positive effects of GLP-1 RAs on cognitive impairment 222,223. Systematic studies elucidating the mechanisms of a potential non-response to GLP-1 RA treatment (such as genetics or lifestyle issues) remain lacking. Real-world studies analyzing existing databases documenting medication use and clinical outcomes may help in this respect, but no such analysis seems to be currently available. The effect was neutral with exenatide LAR (Exenatide Study of Cardiovascular Event Lowering Trial; EXSCEL) and lixisenatide (Evaluation of LIXisenatide in Acute coronary syndrome; ELIXA) . Several cardiovascular outcome trials (CVOTs) have been conducted or are being conducted to elucidate CV safety of GLP-1 RAs in patients. Evidence also suggests that these drugs may have beneficial effects on endothelial function, coronary ischaemia and heart failure . Keep glucose tablets, juice, or other quick sugar sources handy in case your blood sugar drops. We advise starting slowly, beginning with a low dose and increasing it gradually. We recommend the following to help you manage the side effects listed above. Recognizing these potential side effects can help you manage them effectively. Conjugates of particular antisense oligonucleotides to a GLP-1 analog enhanced the productive uptake of the oligonucleotide in GLP-1R expressing cells to elicit selective and effective gene silencing in vitro and in vivo with limited off-target accumulation of the oligonucleotide. GLP-1/antisense conjugates have been developed to bypass a refractory nature of pancreatic β-cells to the uptake of antisense oligonucleotides while harnessing the untapped potential of these oligonucleotides to repress the expression of pathological intracellular targets . The aim is to alter the cellular physiology of these specific cell subtypes by the action of the effector molecule while simultaneously capitalizing on the therapeutic benefits of the GLP-1 targeting molecule. This product was approved for the treatment of T2DM; it has a half-life of 11 minutes and requires 3 injections per day.78 Dulaglutide was approved by the FDA in 2014 for the treatment of T2DM.112 Dulaglutide is a once-weekly long-acting GLP-1RA. Tanzeum was discontinued by GlaxoSmithKline (GSK) in 2017, primarily due to economic factors.110,111 Despite GSK’s attempts to gain a competitive edge through low pricing, Tanzeum failed to achieve sufficient market acceptance.106 In 2017, Tanzeum was removed from the preferred drug list of leading pharmacy benefit manager (PBM) company Express Scripts and was replaced by Eli Lilly’s Trulicity, highlighting Tanzeum’s weak market presence.106,108 Moreover, this decision was part of a broad strategic reform led by GSK’s new CEO Emma Walmsley.106 This reform aimed to refocus the company’s efforts on areas with higher revenue potential, such as respiratory and HIV treatments, as well as oncology and immunology.108 Additionally, Tanzeum struggled to establish a significant market share in the competitive GLP-1RA market, which was another reason GSK decided to withdraw the drug globally.108 In addition, fixed-ratio combination has the advantage of a less complex treatment regimen, with only one injection per day. As discussed earlier, many guidelines across the world recommend GLP-1 RAs along with insulin. This also helps patients who depend on caregivers for injections. Due to their glucose-lowering efficacy as well as other beneficial effects on blood pressure, body weight and lipid metabolism, they have taken a central place in the management of hyperglycemia in people with T2D. GLP-1 was discovered to be one of the key hormones to underlie the so-called incretin effect, i.e. an augmented insulin response to an oral glucose load compared with intravenous (IV) glucose administration. As a drug class, the GLP-1 receptor agonists possess properties that could translate to improved renal energetics including its effects on substrate metabolism. If you're considering using semaglutide for weight loss, it's important to consult a healthcare provider. The action of GLP-1(7-36) on δ cells may be more indirect, such as through the influence on hormones secreted by β and α cells (insulin and glucagon), which indirectly affects δ cell somatostatin secretion. The PI3K/Akt pathway enhances glucose sensitivity in β cells, promoting insulin secretion. As a result, GLP-1(9–36) reduces the number of granules available for exocytosis in α-cells, thereby decreasing the release of glucagon.241 This mechanism decreases intracellular Ca2+ concentration, thereby inhibiting glucagon secretion.241 Additionally, GLP-1(9–36) can effectively inhibit glucagon secretion induced by β-adrenergic stimulation, amino acids, and membrane depolarization, indicating its inhibitory effect under various stimulatory conditions.241 In α-cells of patients with T2DM, the ability of GLP-1(9–36) to inhibit glucagon secretion is lost. The results showed that during the 16-week treatment period, patients who received the highest dosage (120 mg twice daily) of danuglipron experienced an average reduction in HbA1c of 1.16 percentage points and a weight loss of 4.17 kilograms. In a 26-week study, orforglipron demonstrated a significant dose-dependent effect on weight loss, with weight reduction ranging from 8.6% to 12.6% across various dosages, compared to only 2.0% in the placebo group. In combination with post-prandial effects of GLP-1 RAs (through decelerating gastric emptying, stimulating insulin, or suppressing glucagon secretion ), this provides excellent chances to achieve the target ranges for fasting, post-prandial, and overall (HbA1c) glycemic control. The combination of (basal) insulin with a GLP-1 RA is a highly effective treatment even for advanced stages of type 2 diabetes. It was surprising that when meta-analyzing studies directly comparing insulin treatment (mainly basal insulin combined with oral agents) with any of the GLP-1 receptor agonists, there was, at most, a minor difference in glycemic effectiveness 44,45. At this early stage or later, single (mostly metformin) or combination therapy with oral glucose-lowering agents is recommended until injectable therapy with more effective drugs (insulin or GLP-1 receptor agonists) becomes necessary. Most weight loss will typically occur within the first 4 to 5 months. In the ever-evolving landscape of weight-loss medications, semaglutide has emerged as a groundbreaking option. If your weight loss goals are not met, an obesity specialist can help determine which weight loss surgery is right for you. If you are obese and want to lose weight, it’s best to work with an obesity specialist who can tailor your treatment to your needs. GLP-1s may also be prescribed after weight loss surgery if weight returns.

7. Gastrointestinal and other adverse events

Peak plasma concentrations may determine the time when nausea and vomiting are observed with GLP-1 RA treatment. Arrows indicate the time from injection (or oral administration in the case of oral semaglutide) to peak plasma concentrations (Cmax) for GLP-1 RAs (Tmax). To account for the relatively low bioavailability of semaglutide when absorbed through the gastrointestinal tract, oral semaglutide needs to be administered daily. Semaglutide is another compound with a structure generally similar to liraglutide (GLP-1 with a free fatty acid side chain) but with a much longer half-life, apparently mediated by even tighter coupling to albumin. Other approaches followed the strategy to couple (modified) GLP-1 to large proteins such as an immunoglobulin Fc fragment (dulaglutide or efpeglenatide) or albumin (albiglutide). The reduction in fasting plasma glucose was systematically more pronounced with long-acting compounds. For short-acting GLP-1 RAs, delayed gastric emptying is the main mechanism for post-meal reductions in plasma glucose rises . A comparison of the reported coefficients of variation for reducing HbA1c and body weight is displayed in panel E. A linear regression analysis relating reductions in fasting plasma glucose to reductions in HbA1c is shown in panel D. After the pen needle is attached and the appropriate dose is dialed on the pen, the needle should be inserted into the skin at an appropriate site. Table 1 details the dose frequency, starting dose, and dose titration of currently available GLP-1RAs with proven favorable cardiovascular outcomes. Society recommendations and guidelines support the concurrent use of GLP-1RAs and SGLT2 inhibitors when needed for adequate glycemic control, but data on whether such combinations may yield incremental cardiovascular advantages are lackingthusfar.15,16,21 Given distinct mechanisms of action, nonoverlapping adverse effect profiles, and unique target cardiovascular effects, incremental advantages may be anticipated with concurrent use, which is reasonable in the absence of prohibitive polypharmacy or cost. Despite lifestyle modification and pharmacotherapy, patients may require further medication escalation to achieve glycemic targets. For patients with HF with reduced EF, SGLT2 inhibitors should be prescribed preferentially over GLP-1RAs. The GetGoal-X trial compared the efficacy and safety of lixisenatide with exenatide twice daily in patients with uncontrolled T2D on metformin.17 The mean change in A1C was −0.79% in the lixisenatide group compared with −0.96% in the exenatide twice daily group, which met predefined criteria for non-inferiority (95% CI 0.033–0.297). Change in weight over 26 weeks was −1.30 kg, +0.2 kg, −1.07 kg, and +1.24 kg for dulaglutide 1.5 mg, dulaglutide 0.75 mg, exenatide, and placebo, respectively. A1C, hemoglobin A1C; AG, α-glucosidase inhibitor; BID, twice daily; BMI, body mass index; kg, kilogram; GLP-1 RA, glucagon-like peptide-1 receptor agonists; QD, once daily; QW, once weekly; SU, sulfonylurea; TZD, thiazolidinedione.

Obtaining GLP-1 Medications

The use of GLP-1 RAs may be limited by the adverse effects (mostly GI and injection-site related), need for subcutaneous administration (except with the new oral semaglutide formulation), and cost. Within the once-weekly agents, dulaglutide, which offers less steps and no reconstitution or needle attachments requirements, may be favored by patients. A crossover study between the dulaglutide pen and semaglutide pen in 310 participants showed that more participants preferred the dulaglutide pen than the semaglutide pen (84.2% versus 12.3%, p versus 6.8%, p 33 The AWARD-6 utilized a European quality-of-life five dimensions visual analog scale, which did not demonstrate any statistical differences between the dulaglutide and liraglutide groups.20 Preclinical proof of concept of enhanced body weight lowering relative to GLP-1 mono-therapy without impaired glycemic control was first demonstrated by two independent research efforts. With a single molecule approach, the ratio of activities of the constituents, however, will be fixed, whereas individual combination therapies present the potential benefit of being titratable to allow more optimal ratio between doses of the agonists. However, adverse gastrointestinal effects generally preclude the use of higher doses, even with adjusted uptitration dosing algorithms 734,877. In the PIONEER-4 trial, at 52 weeks, there was no difference in treatment satisfaction between liraglutide and oral semaglutide in regards to their DTSQ scores.24 The PIONEER-9 trial utilized the Diabetes Therapy-Related QOL (DTR-QOL) questionnaire to assess patient satisfaction. Similar to the PIONEER-4 trial, the PIONEER-9 trial determined that there was no difference in treatment satisfaction, anxiety/dissatisfaction, and burden on daily and social activities between oral semaglutide and liraglutide at 52 weeks.25 The PIONEER-10 trial examined patient satisfaction using the DTR-QoL as well. The DURATION-1 trial comparing exenatide twice daily with exenatide once weekly demonstrated significant DTSQ treatment satisfaction changes at 30 weeks with willingness to continue current treatment and perceived hypoglycemia frequency, both favoring the once weekly formulation.30 Patients using exenatide once weekly reported a significant increase in treatment satisfaction from baseline compared with exenatide twice daily, despite similar adherence rates (98%) between the two groups.30 The authors theorized this may be due to reduced frequency of injections. In the LEAD-6 trial, patient-reported outcomes, using the Diabetes Treatment and Satisfaction Questionnaire (DTSQ), were significantly higher with liraglutide compared with exenatide twice daily.29 Specific items from the DTSQ scale that showed significant differences between the two groups included convenience, flexibility, recommend the therapy, and continue therapy. GLP-1/gastrin fusions hold potential to re-granulate diseased islets and improve islet cell health in rodents genetically prone to develop diabetes . Thus, engineering GLP-1-based multi-agonists that are hybridized sequences is likely restricted to similarly structured hormones. Similar preclinical benefits of a triple-acting GLP-1R, GIPR, and GCGR peptide have been observed in high-fat fed mice . In a separate analysis, lixisenatide reduced incident macroalbuminuria, while adjustments for baseline characteristics such as age, blood pressure and eGFR, as well as on trial HbA1c, blood pressure and weight, did not significantly attenuate the association . Correction for small differences in glycemic control during the trial diminished significance indicating some glucose-dependency . In ELIXA, the effects of lixisenatide versus placebo in 6,026 people with T2D and a recent acute coronary event were investigated. The primary outcomes of these trials were 3-point major adverse cardiovascular event (3-MACE) and the studies have together provided a wealth of data that, amongst others, have changed clinical guidelines. Based on the US FDA industry guidance issued in 2008, all new glucose-lowering agents were required to perform a large-sized placebo-controlled cardiovascular outcome/safety trial, usually conducted in people with T2D with pre-existent or at high-risk of developing CVD. Summarizing adverse event reporting from clinical trials examining GLP-1 RAs discloses subtle differences in the risk of these side effects depending on the short- (worse) vs long-acting nature (better) background medication (worse in combination with metformin or insulin) that are also related to the individual compound/preparation . Since these symptoms can occur in fasting subjects, they are probably not related to the effects of GLP-1 RA treatment on gastrointestinal functions (e.g., deceleration of gastric emptying) but instead are caused by direct interactions with CNS GLP-1 receptors (Figure 6) most likely located in the brain stem (area postrema). Impaired glucose tolerance often improves while subjects receive this type of treatment, most likely explained by the glucose-lowering properties of GLP-1 RAs 65,86. Doses of up to 4.5 mg per week (vs a maximum of 1.5 mg for type 2 diabetes) are being explored for dulaglutide . In the first 24 to 48 hours, many patients notice subtle changes in appetite and satiety. After your first injection, the medication enters your bloodstream and starts binding to GLP-1 receptors in multiple tissues, including the pancreas, gastrointestinal tract, and brain. This guide provides evidence-based information on what happens after your first dose. Understanding the typical timeline and side effects helps you prepare for this adjustment period and recognize when medical attention may be needed. Track meals, weight, and symptoms. Injection teaching can be performed in 5 to 10 minutes but may be abbreviated for dulaglutide, given its built-in pen, and for patients who are already familiar with subcutaneous medications (such as insulin). Robust clinical benefits, including decreased mortality, were observed with dapagliflozin in the DAPA-HF (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) trial, regardless of type 2 diabetes status.44 For patients with overweight or obesity status, GLP-1RAs may be preferred over SGLT2 inhibitors for adjunctive weight loss. In general, GLP-1RAs are contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 (Box), although these concerns are based exclusively on observations in rodent models with uncertain human clinical relevance, as reflected in US product labeling. The crude OR between the GLP1-RA exposed group and the reference group with diabetes was 1.37 (95% CI, 0.36 to 5.23), and the adjusted OR was 0.99 (95% CI, 0.22 to 4.42). In the sensitivity analysis, the rates of major birth defects, when all major anomalies irrespective of aetiology were included, were 3.1% in the GLP1-RA exposed group and 4.2% in the reference group with diabetes. In comparison with the overweight/obese reference group, which had a rate of major birth defects of 3.9%, the adjusted OR was 0.54 (95% CI, 0.11 to 2.75). Psychiatric conditions were more frequently reported in the overweight/obese reference group. Hypertension and dyslipidaemia were more frequently reported in the GLP1-RA exposed and in the reference group with diabetes. CAMP activates PKA, which phosphorylates the β2 subunit of the L-type VDC channels and potentially the Kir6.2 and SUR1 subunits of the KATP channels . In summary, there is substantial evidence indicating that cAMP is an important second messenger driving the acute insulinotropic effect of GLP-1. While GLP-1 enhances proinsulin expression 82,372,373,463,464, there are no differences in pancreatic insulin expression in GLP-1R KO mice . Although the incretin effect is diminished in GLP-1R KO mice, these mice have normal body weight and food intake on regular chow diets , , . Moreover, GLP-1R has not yet been identified on human myocardial cells, negating any direct effects of GLP-1RAs on myocardial cells.470 GLP-1 by inhibiting the chemoreception in carotid body cell activity to adjust the new mechanism of sympathetic nerve excitability, and points out that GLP-1 agonists can inhibit the origin of the carotid body around chemical reflection to lighten the sympathetic nerve excitability, which is expected to improve the sympathetic activity of the patients with high blood pressure, reduce blood pressure levels First, GLP-1RAs have been shown to inhibit the expression and release of proinflammatory cytokines, such as IL-6 and TNF-α, thereby inhibiting the overall inflammatory response.461 GLP-1RAs can suppress the activation of nuclear factor-kappa B (NF-κB), a key transcription factor involved in the regulation of inflammatory processes.462 Inhibition of the NF-κB signaling pathway leads to the decreased production of inflammatory mediators, including adhesion molecules and chemokines, which are crucial for the recruitment of immune cells to sites of inflammation.463 In addition, liraglutide can delay the formation of AS by inducing cell cycle arrest in vascular smooth muscle cells through the AMPK pathway.5 GLP-1RAs have diverse effects, including alleviating neuroinflammation and pain in OA, reducing food intake and improving body weight, protecting peripheral nerves, maintaining astrocyte function and metabolic homeostasis, and showing potential therapeutic benefits in AD and PD. However, the administration of semaglutide appeared to block this process, potentially leading to a diminished alcohol-induced reward and punishment response within the body.433 Remarkably, compared with untreated rats, treated rats exhibited a significant reduction in alcohol intake, which was reduced by half.433 These findings highlight the potential therapeutic efficacy of semaglutide in mitigating alcohol consumption.434 We demonstrated that GLP-1 enhances physical endurance by inducing skeletal muscle remodeling, which may be mediated by GLP-1R/AMPK signaling.389 Overall, GLP-1 secretion is induced by exercise. GLP-1RAs in Enhancing Exercise Endurance Studies indicate that acute exercise and short-term endurance training significantly increase GLP-1 secretion in mice. In addition, treatment with the long-acting GLP-1RA duraglutide restored muscle mass and function in DBA/2J-mdx mice.379 In a study examining the effects of GLP-1RA on osteoporosis induced by ovariectomy in aged rats, administering exendin-4 for 16 weeks prevented deterioration of the trabecular microarchitecture and increased bone strength. GLP-1RAs and Osteoblasts Osteoblasts arise through the differentiation of mesenchymal stem cells and play a crucial role in the process of bone formation. “In many cases, patients with scheduled procedures should continue taking the drug. “As anesthesiologists, we are committed to considering all factors to ensure patients get the best and safest care whenever anesthesia care is required,” said ASA President Donald E. Arnold, M.D., FACHE, FASA. In rare cases, surgery should be delayed in patients whose risk is expected to decrease. The guidance notes the team can minimize the risk of delayed stomach emptying by having the patient follow a liquid-only diet for 24 hours before surgery, adjusting the anesthesia plan to minimize aspiration risk and using point-of-care ultrasound right before the procedure to assess stomach contents in patients at highest risk. Infusion of liraglutide inhibits eating in rats by directly activating hypothalamic Pomc/Cart neurons in the ARC, without activating GLP-1-producing neurons in the hindbrain, and independent of GLP-1R signaling in vagal afferents, the area postrema (AP) and the PVN . When administered s.c., liraglutide fails to inhibit eating in mice possessing a CNS-specific deletion of GLP-1R . Central GLP-1R appear to be necessary for the anorectic effect of peripherally administered GLP-1R agonists in rodents , , . Peripheral administration of GLP-1 analogs decreases body weight via suppression of food intake , , ,665,685. Nausea may also occur because GLP-1 receptors impact the central nervous system (CNS). These include how GLP-1s work in the body, differences between types of GLP-1 medications, and individual characteristics. Patients can significantly reduce their impact with simple strategies, allowing for continued treatment and better outcomes. In some cases, these digestive issues can cause patients to temporarily or entirely stop the medications. Gastrointestinal (GI) or digestive side effects are the most common hurdle for many users, with 40 to 70 percent experiencing symptoms at some level.

• However, in general, these medications start to exert their effects relatively quickly after administration.
• They are classified as short-acting or postprandial GLP-1 receptor agonists due to their glucose-lowering effects in the postprandial state .
• The weight loss induced by the combination compared to the single agents appeared to be additive, but HbA1c reduction was less than additive.
• As a GLP-1 drug, semaglutide mimics the action of the natural GLP-1 gastrointestinal hormone.
• The strongest risk factor for CVD and mortality in T2D is diabetic kidney disease (DKD) and DKD has been proposed to account for the majority of CVD risk observed in people with diabetes.
• BCompared to control (placebo, sitagliptin, exenatide, liraglutide and glargine)
• GLP-1s, commonly called ‘weight loss injections,’ can help you lose weight, but how they fit into your weight loss treatment plan is best decided by a weight loss specialist.

Underlining the role of cAMP in the insulinotropic effect of GLP-1, enhanced cAMP hydrolysis through overexpression of the cyclic nucleotide phosphodiesterase 3B (PDE3B) diminishes GLP-1-induced insulin secretion . In β-cells, binding of GLP-1 to its receptor leads to activation of adenylate cyclase (AC) and subsequently to an increase in cAMP (Figure 5) . When chronically fed a high-fat diet (HFD), GLP-1R KO mice are paradoxically leaner than their wild-type controls yet are more glucose intolerant . The insulinotropic efficacy of these biased-signaling molecules was inversely correlated to the receptor internalization; i.e. insulin release was greatest using molecules that retain GLP-1R at the cell surface . Nevertheless, GLP-1 RA therapy with a background of oral glucose-lowering medications may fail to achieve glycemic targets as well. Similar conclusions were derived from specifically assessing 4 head-to-head clinical trials comparing short- and long-acting GLP-1 RAs (depicted in Nauck and Meier 2019 ). Efficacy regarding reductions in fasting plasma glucose and HbA1c were highly correlated (Figure 4D), underscoring the importance of controlling fasting plasma glucose to achieve acceptable overall glycemic control based on commonly recommended target ranges.

• CAlso available as a treatment-initiation pack containing both doses of multi-dose prefilled pens
• Currently, most GLP-1RAs are based on proteins or peptides, meaning they are large molecules typically administered via injection.37 Small molecule GLP-1RAs are chemically synthesized, and compared to protein-based drugs, they generally have smaller molecular sizes.171 The development of small molecule GLP-1RAs aims to overcome some of the limitations of traditional protein or peptide-based GLP-1RAs, such as the need for injection.
• The primary endpoint was the number of treatment-emergent adverse events (AEs) over 57 weeks.
• In the phase 2 study of type-2 diabetic patients, Tirzepatide produced a profound reduction in body weight and improved HbA1c levels, both of which were superior relative to effects of Dulaglutide in the active comparator arm , thus demonstrating the translation of the preclinical observations.
• After your first injection, the medication enters your bloodstream and starts binding to GLP-1 receptors in multiple tissues, including the pancreas, gastrointestinal tract, and brain.
• Phase two and three trials are now required to demonstrate that they do not increase cardiovascular risk in comparison to existing therapies, especially when used in patients with advanced age or declining renal function .
• It should be noted, however, that estimated eGFR may be biased in this population where severe weight loss may be accompanied by muscle mass loss, making eGFR that was often reported less reliable.
• For instance, changes in the composition of this phospholipid layer have been observed by researchers, along with their detrimental effects on the bones and joints of individuals with OA.394 Surprisingly, GLP-1RAs can influence the phospholipid structure and cytokines surrounding joints, leading to beneficial transformations that safeguard joints and even facilitate partial repair of any existing damage.395 (Fig. 4).
• Glucagon-like peptide-1 (GLP-1) receptor agonists offer a unique and innovative treatment advancement to the management of type 2 diabetes mellitus.

Dulaglutide

Another trial in non-diabetes patients with Alzheimer's disease found that 6 months of liraglutide treatment prevented a further decline in brain glucose uptake (assessed by positron emission tomography), but did not change cognitive function tests . In a clinical trial of patients with prediabetes and type 2 diabetes, memory function improved after 4 months of liraglutide administration . Effects of GLP-1 or GLP-1 RAs on residual insulin secretion , glucagon suppression 190,191, gastric emptying delay , and plasma glucose 192,193 in type 1 diabetic subjects were described starting in the early stages of GLP-1 discovery. Of note, over a six-month treatment period, 26.2% of dulaglutide and 48.4% of once-weekly exenatide patients discontinued treatment, and in a direct comparison of dulaglutide and liraglutide, the respective discontinuation rates were 28.0% and 35.6% . For each variable, the results were significantly better for long-acting compounds (liraglutide, once-weekly exenatide, dulaglutide, and semaglutide based on 6 studies) compared to short-acting compounds (exenatide b.i.d. and lixisenatide based on 8 studies).

Pharmacologic profiles, safety, and efficacy of approved agents

Of note, patients with NYHA IV heart failure were excluded from the CVOTs with GLP-1 RAs, such that no firm conclusions could be drawn regarding these patients. However, a meta-analysis pooling results from all individual trials provided some insight that CV events can generally be prevented by GLP-1 RA treatment . Hence, the results are, from a clinical perspective, quite heterogeneous and suggest that some GLP-1 RAs are more suitable to prevent CV events than others. Figure 7A displays hazard ratios (active treatment vs placebo) for MACE and their 95% confidence intervals for all published CV outcome trials with GLP-1 RAs. (B) Results of a published meta-analysis analyzing various cardiovascular endpoints across all of the clinical trials shown in panel A. When orally administered, glutamine also increases circulating GLP-1 and insulin in lean, obese and type-2 diabetic individuals . Protein and amino acid stimulation of GLP-1 secretion has been demonstrated in murine primary colonic L-cell cultures 260,302, in GLUTag cells 256,259, in human NCI-H716 cells 251,303 and in the isolated perfused rat ileum or colon 250,304 as well as in vivo in mice , rats 256,306, and humans 307,308. A receptor-independent stimulation of GLP-1 release from GLUTag cells has been reported for oleic acid, which stimulates GLP-1 release by uncoupling oxidative phosphorylation and, hence, indirectly stimulating glycolysis with the resulting activation of the mechanism alluded to above . But without the drugs in your system, you will likely have an increased appetite that may cause you to eat more and regain some of the weight you lost. Stopping the medication should not cause any type of adverse withdrawal symptoms. Most people have missed a dose of prescription medication at some point. Remember that GLP-1 therapy is typically considered a long-term treatment approach. The gradual approach helps minimize side effects while allowing your body to adjust to the medication's effects on appetite, digestion, and metabolism. These medications work by mimicking the glucagon-like peptide-1 (GLP-1) hormone, which helps control blood sugar levels and promotes weight loss. Typically, the initial effects of GLP-1 agonists on blood sugar control become apparent within the first week of treatment. These medications stimulate insulin secretion from the pancreas while inhibiting the release of glucagon, leading to lower blood sugar levels. Of note, albiglutide does not require renal elimination or any dose adjustments for renal impairment . In 2009, the FDA approved revisions to the drug label for exenatide to include information on post-marketing reports of altered kidney function . Exenatide is eliminated by renal mechanisms, and it is not recommended for use in patients with severe renal impairment or end-stage renal disease . Both GLP-1RAs and SGLT2 inhibitors are costly, compared with older classes of antihyperglycemic medications. Because GLP-1RAs delay gastric emptying, caution should be used in prescribing these agents to patients with gastroparesis, chronic nausea, or previous gastric surgical procedure. Concurrent use should be considered among eligible patients in the absence of prohibitive polypharmacy or cost. Specifically, SGLT2 inhibitors are currently contraindicated in patients with a preinitiation eGFR less than 30 mL/min/1.73 m2; patients with established ASCVD and an eGFR below this threshold may be good candidates for GLP-1RA therapy. However, although metformin use was reported in 65% to 80% of patients in the completed GLP-1RA cardiovascular outcomes trials,6–12 background metformin use was not required in any of the trials. The symptoms in patients are severe and often accompanied by functional impairments, especially in the obese population. GLP-1RAs have been shown to reduce the levels of systemic inflammatory markers.457,458 Importantly, the effective management of inflammation is widely acknowledged to play a crucial role in the prevention of cardiovascular diseases.459,460 The anti-inflammatory effects of GLP-1RAs contribute to the attenuation of atherosclerotic plaque lesion development through various mechanisms. One study suggested that GLP-1RAs exert direct endothelial protective effects by activating the GLP-1R-dependent AMPK/Akt/eNOS pathway. GLP-1RAs have been shown to exert beneficial effects on the maintenance of endothelial integrity. Semaglutide, a diabetes drug, can also reduce alcohol consumption by modulating the brain’s reward and punishment systems Liraglutide stimulation of cardiac ANP secretion is PKA independent but mediated by Epac2 in a cAMP and PLC-dependent manner . GLP-1R agonists acutely stimulate natriuresis in rodents and may also do so in humans, lowering BP, potentially also via reduction of the ECFV 641,642,660,661. Notably, in healthy human volunteers, acute administration of GLP-1, GLP-1 (9-36amide), or exenatide did not affect blood flow in the mesenteric or renal arteries, excluding splanchnic vasodilatation as a potential mechanism underlying the chronic hypotensive effect of GLP-1 . This was inspired by prior GIP (glucose-dependent insulinotropic polypeptide) research, highlighting that besides GIP, other substances in the intestine also stimulate insulin secretion. From the discovery of the GLP-1 fragment GLP-1(7-37) to the development of more stable and long-acting GLP-1 analogs, these milestones represent significant breakthroughs in the medical field.11,12 For instance, the success of exenatide has not only spurred the development of potent GLP-1 analogs such as liraglutide and semaglutide but also unveiled the vast potential of GLP-1RAs in treating various systemic diseases. Additionally, this paper explores the potential applications of GLP-1 receptor agonists (GLP-1RAs) in fields such as neuroprotection, anti-infection measures, the reduction of various types of inflammation, and the enhancement of cardiovascular function. The glucagon-like peptide-1 (GLP-1) receptor, known as GLP-1R, is a vital component of the G protein-coupled receptor (GPCR) family and is found primarily on the surfaces of various cell types within the human body. As GLP-1 RA therapy initiation is largely influenced by clinical requisites of patients, it is imperative that a pragmatic review of current evidence be integrated and applied in the context of an individualised patient-centred approach. Treatment of rats with the nonspecific muscarinic receptor antagonist atropine or with the M1 selective antagonist pirenzipine, but not treatment with M2 or M3-selective antagonists blunts lipid-induced GLP-1 secretion 319,335. In contrast, GIP secretion is stimulated by very low gastric glucose delivery rates, consistent with the higher abundance of GIP-producing K-cells compared to GLP-1-producing L-cells in the proximal intestine . While sulphonylureas potently promote insulin secretion in type-2 diabetic patients via inhibition of KATP channel activity , , , , there is no clear evidence that sulphonylureas affect GLP-1 secretion in humans (as reviewed in ). Underlining the role of the KATP channels in mediating this process, glucose-stimulated Ca2+ entry and GLP-1 secretion are mimicked upon treatment of GLUTag cells with the KATP channel inhibitor tolbutamide . Notably, the circulating glucagon-like material was also detected in 1967 by Samols and Marks in pancreatectomized humans and in the following year by Roger Unger and Isabel Valverde in dogs . It was subsequently found by Ellis Samols and Vincent Marks in and confirmed by others that glucagon-like immunoreactivity was also present in extra-pancreatic tissues, in particular in the intestine , , , , , . In 1959, Roger Unger generated and characterized the first glucagon-detecting antibody and thus paved the path to the development of the first radioimmunoassays (RIA) to detect glucagon in blood and tissue samples . Over the subsequent decades, substantial research efforts were directed toward unravelling the molecular underpinnings of glucose regulation by the two opposing pancreatic hormones (as reviewed in 4,5). The LEADER trial is underway to examine the long-term effects of liraglutide 1.8 mg on cardiovascular death, nonfatal myocardial infarction, and stroke as a primary outcome in 6000 patients. Overall, GLP-1 receptor agonists have demonstrated positive cardiovascular outcomes with slight improvements in blood pressure and lipid parameters and modest improvements in weight. Table 5 compares common adverse effects between the marketed GLP-1 receptor agonists.

If you miss a dose…

Furthermore, the administration of exogenous GLP-1 resulted in elevated calcitonin expression in the thyroids of normal (wild-type) mice.362 The administration of calcitonin successfully reduced the levels of urinary deoxypyridinoline in GLP-1R knockout mice. These findings suggest that liraglutide specifically reduces bone resorption without influencing bone formation.368 These findings provide further evidence for the impact of GLP-1RAs on osteoclastic bone resorption.367 A study involving 12-week-old ovariectomized mice revealed that administering liraglutide for 4 weeks effectively prevented the loss of trabecular bone. The quality of bone depends on bone metabolism, and the main factors affecting bone metabolism include osteoclasts, osteoblasts, and calcitonin.355,356,357 According to most related studies, osteoclasts and osteoblasts are indispensable for bone remodeling, and bone resorption and bone formation are mediated by osteoclasts and osteoblasts, respectively.358 GLP-1R is present in bone marrow stem cells (BMSCs),15,359 osteoblasts,15 osteocytes,360 and osteoclasts,361 and GLP-1RAs have the potential to impact these cells. While GLP-1 (7-36amide) and GLP-1 (7–37) are equally potent to stimulate the secretion of insulin and c-peptide , GLP-1 (1–37) has a much lower insulinotropic efficacy , , . Multiple lines of evidence are accumulating that challenge current dogma and imply that pancreatic GLP-1 production also has a role, under some circumstances, in regulating insulin secretion via paracrine action , , . Together, these data point to a potential role of the α-cells in compensating for increased β-cell functional demand under conditions of insulin resistance, pregnancy, and cellular stress through intra-islet GLP-1 production 168,169. Lastly, upon streptozotocin-induced destruction of the β-cells, there is an acute increase in islet PCSK1 and Gcg expression and increased processing of proglucagon to GLP-1 . In healthy and type-2 diabetic humans, it has been consistently demonstrated, that GIP, even in rather high (supraphysiological) doses, does not lead to GLP-1 secretion , , . Consistent with this, glycine-sarcosine (Gly-Sar) stimulation of GLP-1 secretion from purified murine L-cell cultures is blocked in the absence of extracellular Ca2+ and is inhibited upon treatment with the L-type Ca2+-channel blocker nifedipine . In rats, the LWP-induced GLP-1 secretion further improves glucose tolerance and enhances insulin secretion, an effect that is blocked by pre-administration of the GLP-1R antagonist exendin (9–39) . While prospective studies comparing various therapies in type 2 diabetes patients belonging to different subgroups are lacking, this sub-classification promises to be a helpful tool assisting in a more individualized approach toward selecting glucose-lowering medications for a given patient. A recent real-world retrospective observational study showed that dulaglutide users were less likely to interrupt treatment than semaglutide and exenatide BCise users . The reduced exposure to ROS after GLP-1 receptor stimulation slows the process of foam cell formation (e.g., GLP-1 148,149 and liraglutide ) and reduces caspase-mediated apoptosis of foam cells (e.g., GLP-1 and semaglutide ) and the formation of necrosis in the core of atherosclerotic plaques (e.g., GLP-1 and lixisenatide ). The oxLDL-mediated activation of monocytes and macrophages and the consecutive activation of adhesion molecules such as VCAM-1, MCP-1, E-selectin, and ICAM-1 is successfully reduced by GLP-1 receptor stimulation (e.g., GLP-1 , exenatide , , , dulaglutide , and liraglutide ). GLP-1R expression is lower in α cells compared to β and δ cells, resulting in relatively less direct action of GLP-1 on α cells. This pathway also supports β cell survival and proliferation, ensuring an adequate β cell mass to maintain normal insulin secretion. This illustration demonstrates how GLP-1 reduces blood glucose levels by acting on different pancreatic cell types. Recent studies show that GLP-1(9–36) can activate the inhibitory G protein (Gi/o), leading to the translocation of secretory granules (SG) beneath the cell membrane, thereby inhibiting glucagon secretion.241 This mechanism is unaffected by genetic or pharmaceutical inhibition of GLP-1R, but it is sensitive to pertussis toxin. This finding suggests a direct correlation between the analgesic effects of GLP-1R signaling and its Anti-neuroinflammatory activity.411 In another study, 3D fluorescence microscopy was used to eliminate proteins within chondrocytes in the subchondral bone of cartilage, resulting in bone transparency and the acquisition of high-resolution 3D images. GLP-1RAs can alleviate neuroinflammation by acting on the nervous system, thereby offering additional relief from pain in patients.6,409,410 During a previous experiment, researchers induced pain and observed symptoms of cognitive impairment in rats through spinal nerve ligation. This observation led them to speculate that GLP-1 analogs might possess distinct neurotrophic properties and exert protective effects specifically on the nerve.71,395,401,402,403 Activation of its receptor by GLP-1 can promote the phosphorylation of CREB, subsequently fostering the expression of genes related to neuronal survival and regeneration.396,397,398,399 Hence, factors to be considered before/during the use of GLP-1 analogues in such cases could be a pragmatic approach based on prescribing information, available clinical evidence and clinical sense of physicians . Although the use of these agents is encouraged in patients with asymptomatic and stable CAD, there is no clear evidence regarding their usage in acute myocardial infarction. A few clinical studies and meta-analyses focussing on pancreatitis are presented in Table 20. GLP-1 RAs are recommended to be used with caution/not used in patients with a familial/personal history of pancreatitis depending on the respective prescribing information . Similarly, the small changes in eGFR trajectories (i.e. subtle reductions in eGFR decline versus placebo or titrated insulin) do not necessarily indicate renoprotection. In addition, they improve blood pressure, body weight and dyslipidemia and are consistently shown to reduce CVD in a high-risk T2D population. On the other end of the equation, GLP-1 induced changes in substrate metabolism through improvements in insulin sensitivity and mitochondrial dysfunction could enhance ATP production, as was suggested in a study in rodents . The less oxygen-efficient fuel profile observed in people with T2D is thought to be secondary to insulin resistance and mitochondrial dysfunction altering substrate metabolism as indicated previously.

• Schematic on the GPCR Repertoire Involved in Control of Hormone Secretion from Gastric cells expressing either ghrelin or GLP-1.
• GLP-1 has different effects on left ventricular function and cardiac contractility under healthy vs. pathological conditions.
• We advise starting slowly, beginning with a low dose and increasing it gradually.
• Introduced in the United States market in 2012, exenatide long-acting release (Bydureon®) was the first once-weekly GLP-1 receptor agonist to receive FDA-approved labeling as adjunctive therapy to diet and exercise for patients with type 2 diabetes .
• Only a minor proportion (estimated 1–2%) of liraglutide circulates in a free (non-albumin-bound) form, ready to diffuse into tissues and bind receptors.
• In fibroblast-like RA synoviocytes, the administration of lixisenatide resulted in a reduction in the inflammatory response.347 This was achieved by decreasing the expression of proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-8 (IL-8).15,351,352 Moreover, lixisenatide has been shown to inhibit matrix metalloproteinase (MMP) activity and effectively block various cell signaling pathways, including the JNK, activator protein-1, and NF-κB pathways.353 These findings confirm that in the synovium, GLP-1R is expressed on two different cell types, macrophages and fibroblast-like synoviocytes, which are specialized cells distributed within the synovial intima and subintima, and these cell types play important roles in hyaluronic acid synthesis, metabolite processing, and clearance of matrix degradation fragments.354
• Skip the missed dose and resume on your next scheduled day to avoid stacking medication that could increase side effects.
• GLP-1R agonism also promotes β-cell growth and survival by stimulating the expression of the insulin receptor substrate 2 (Irs2) via mechanisms that include activation of CREB .
• Dr Vaduganathan reported receiving a grant from Harvard Catalyst and personal fees from Amgen, AstraZeneca, Baxter HealthCare, Bayer AG, Boehringer Ingelheim, Cytokinetics, and Relypsa outside the submitted work, as well as participating on clinical committees for studies sponsored by Novartis and the National Institutes of Health (NIH).

Using slightly different approaches, mediation analyses have been published on the effects of liraglutide in the LEADER trial and the effects of dulaglutide in the REWIND study . These data suggest a potential to prevent CV complications even in lower-risk type 2 diabetes patients, yet fall short of definite proof. Therefore, the results of these trials cannot be extrapolated to the general population of type 2 diabetes patients including those with short disease duration and lack of CV comorbidities. Most CV outcome trials with GLP-1 RAs recruited patients with type 2 diabetes characterized by established CV disease (e.g., previous CV events) or indicators of a high risk of CV events. Remarkably, the reduction in MACE events with albiglutide is very much comparable if not more pronounced than with other effective GLP-1 RAs (Figure 7A) despite its reduced ability to lower HbA1c, fasting plasma glucose, and body weight in clinical trials (Figure 4) . Injected low-dose liraglutide and exendin-4 were also attenuated by subdiaphragmatic vagal deafferentation 687,691, but longer-term effects of these compounds on food intake did not depend on intact vagal afferents . In mice, liraglutide reduces angiotensin II (Ang-II) stimulation of systolic and diastolic BP, an effect that is absent GLP-1R KO mice or by pretreatment with exendin (9–39) or the natriuretic peptide receptor antagonist anantin . These data align with an integrated analysis of 36 clinical studies that affirmed cardiovascular safety with up to 4-years’ treatment with either DPP-4 inhibitors or GLP-1R agonists . Diabetic patients have a higher risk of fractures than does the general population.366 Mice with type 1 diabetes (T1D) exhibit a reduction in bone mineral density (BMD) and compromised microstructural integrity.367 The administration of liraglutide also impeded osteoclastic bone formation, thereby inhibiting bone resorption and exerting protective effects on bone health in T1D mice.367 Specifically, liraglutide, both alone and in combination with insulin, effectively suppressed the formation of osteoclasts. Through these molecular mechanisms, GLP-1 not only plays a crucial role in the treatment of diabetes by enhancing the function and protecting pancreatic β-cells from apoptosis, but it may also offer potential therapeutic benefits in fields such as cardiovascular and neural protection.198,205,206 GLP-1 can also enhance the uptake and utilization of glucose in muscle and adipose tissues.207,208,209 And GLP-1’s action in the brain reduces appetite and may influence energy expenditure.176,210,211 These effects involve interactions with other satiety and hunger signals, such as PYY, CCK, insulin, and leptin.212,213 In summary, dual and triple agonists related to GLP-1 represent significant advances in the field of diabetes treatment,167,168 demonstrating the future trend of enhancing therapeutic effects by targeting multiple biomarkers.136,169,170 With the accumulation of more clinical data and the development of new drugs, these treatment options are expected to provide more effective and comprehensive treatment choices for diabetes patients.161,167 In July 2009, they published a paper in Nature Chemical Biology, reporting for the first time that dual agonists targeting GLP-1R and glucagon receptor (GCGR) had a better weight loss effect.26 This marked a significant advancement in obesity treatment research, especially in combining multiple drug targets. After 52 weeks of treatment, oral semaglutide reduced A1C significantly more than liraglutide (−1.3% versus −1.1%, p The PIONEER-9 trial compared oral semaglutide monotherapy to liraglutide in a 52-week randomized controlled trial.25 Patients were assigned randomly to one of three doses of oral semaglutide (3 mg, 7 mg, and 14 mg), liraglutide 0.9 mg, or placebo for 52 weeks. Through a review of phase III clinical trials studying dulaglutide, exenatide twice daily, exenatide once weekly, liraglutide, lixisenatide, semaglutide, and oral semaglutide, 14 head-to-head trials were identified that evaluated the safety and efficacy of GLP-1 RA active comparators. GLP-1 agonists, like semaglutide and tirzepatide, are groundbreaking treatments for managing type 2 diabetes and obesity. Long-term use can lead to sustained weight loss and improvements in overall metabolic health. For many people, the weight-loss journey with semaglutide extends beyond the initial 5 to 6 months. As your dose gradually increases in line with prescribing guidelines, semaglutide continues to influence appetite. This activation sets off a cascade of events that influence appetite, digestion, and ultimately contribute to weight loss. At the heart of semaglutide's effectiveness lies its activation of the GLP-1 agonists. While these data collectively emphasize the importance of neuronal GLP-1R for the food intake inhibition by long-acting GLP-1 analogs, it is unclear whether and to what extend this accounts for physiological doses of intestinal-derived native GLP-1. Or i.p., exendin-4 and liraglutide induced acute neuronal activation (measured by activation of cFos) in PVN, AP, and NTS 686,690. Injected liraglutide and exendin-4 , and bilateral neurochemical lesions of the lateral parabrachial nucleus (IPBN) with ibotenic acid blunted the anorexigenic effect of peripherally administered exendin-4 . Regardless of which drug is ultimately selected, the dose should be gradually titrated according to the recommended product labeling to minimize toxicity, and patients should be monitored for efficacy and tolerability. Renal function is an important consideration, and while all should be monitored closely in patients with renal impairment, exenatide should not be used in patients with a creatinine clearance less than 30 mL/min. Important differences between agents include dosing frequency and whether they have stronger effects on postprandial or fasting blood glucose. These data collectively suggest that some of the acute cardiovascular effects of GLP-1 might be due to brain enhancement of catecholamine outflow and elevation of sympathetic tone. Both central and peripheral administration of GLP-1R agonists increase HR and BP in rodents , , , with induction of c-Fos expression in adrenal medullary catecholamine neurons and activation of tyrosine hydroxylase, the key enzyme involved in production of norepinephrine, in the brainstem . Whether the low endogenous concentration and the restricted pharmacokinetic action profile of endogenous GLP-1 metabolites are sufficient to elicit such effects under physiological circumstances remains questionable. The infarct-limiting potential of exendin-4 is abolished by treatment with exendin (9–39), thus indicating that this cardioprotective effect is GLP-1R-dependent . Accumulating evidence indicates that some cardiac effects of GLP-1 (7-36amide) are actually mediated via the DPP-4-generated GLP-1 (9-36amide) and its smaller degradation products and, thus, are independent of GLP-1R signaling. Based on their effects on endothelial function, GLP-1 receptors could improve renal vascularization and oxygen supply, whilst lowering oxygen consumption by attenuating in obesity-related hyperfiltration. This reduction in inflammatory tone could certainly contribute to improved renal outcomes and has also been speculated to underlie the cardiovascular benefits of GLP-1 receptor agonists. Thus, at present there is insufficient evidence to support attenuation of glomerular hyperfiltration in response to GLP-1 receptor agonists, as seems the case for RAS blockers or SGLT2 inhibitors. In contrast to the results of earlier studies, exenatide infusion increased GFR, ERPF and estimated glomerular hydraulic pressure in overweight but otherwise healthy men . Several subsequent studies have more comprehensively detailed the effects of GLP-1 receptor agonism on glomerular hemodynamics using state-of-the-art inulin and para-aminohippuric acid (PAH) clearance techniques to measure GFR and effective renal plasma flow (ERPF), respectively. Some patients experience fatigue or headaches, particularly during the first few weeks. Some patients find that avoiding fatty, spicy, or very sweet foods helps reduce nausea. Some patients find that certain foods become less appealing or cause more digestive discomfort than others.

• Indeed, liraglutide stimulates relaxation of the aorta but GLP-1 might also indirectly lower BP via its ability to reduce body weight.
• Most adverse effects are dose-dependent, meaning they tend to be less severe at lower doses.
• At some point, the ligand-induced receptor activation has to be terminated, and the sensitivity of the receptor to be activated by its ligand has to be restored.
• Ageing is described as a progressive impairment in carbohydrate tolerance which may be related to disorderly insulin release, reduced insulin production, reduced GLP-1 secretion, increased adiposity, sarcopenia and physical inactivity.
• In the trials reporting discontinuation because of any adverse events and those specifically due to gastrointestinal side effects, the latter were responsible for approximately one-half of the withdrawals.
• The GetGoal-X trial compared the efficacy and safety of lixisenatide with exenatide twice daily in patients with uncontrolled T2D on metformin.17 The mean change in A1C was −0.79% in the lixisenatide group compared with −0.96% in the exenatide twice daily group, which met predefined criteria for non-inferiority (95% CI 0.033–0.297).
• This report is based on a review of published guidelines and clinical evidence from meta-analyses, systematic reviews, randomised controlled trials, prospective and retrospective studies, and real-world data on GLP-1 RA use in the management of T2DM.
• For example, albiglutide demonstrated less of an effect on hemoglobin A1C reduction in clinical trials compared to liraglutide, but also had less incidence of adverse effects .

In murine and human islets, GLP-1, via phospholipase C (PLC), leads to an activation of PKC, followed by membrane depolarization and stimulation of insulin secretion. Epac2 interaction with Rim2 and Piccolo is crucial for cAMP-induced Ca2+-dependent insulin secretion and is not blocked by inhibition of PKA 493,512,513. GLP-1-stimulation of exocytosis is partially inhibited when isolated mouse β-cells are treated with the PKA inhibitor H89 but is fully inhibited upon co-treatment with H89 with an antiserum against Epac2 (a.k.a. cAMP-GEFII) . Beyond its ability to increase the intracellular pool of Ca2+, GLP-1 also affects insulin secretion via cAMP-mediated regulation of exocytosis (Figure 6). The corresponding estimates in the diabetes reference group were 69%, 26% and 6%, while in the overweight/obese reference group, they were 63%, 29% and 8%. A total of 483 women were included in the cumulative incidence analysis, including 167 in the GLP1-RA group, 154 in the diabetes reference group and 162 in the overweight/obese reference group. In the group exposed to GLP1-RA, a substantial proportion of patients had a BMI of 25 kg/m2 or higher (86.6%), and 27.4% had pregestational diabetes. Starting with a lower dose and gradually increasing it may help mitigate constipation. Starting with a lower dose and gradually increasing it may help mitigate vomiting. Starting with a lower dose and gradually increasing it may help mitigate diarrhea. Starting with a lower dose and gradually increasing it may help mitigate nausea. There have been reports of increased thoughts of self-harm or suicidal behavior in some patients taking GLP-1 medications. The Mayo Clinic Diet for Weight-Loss Medications is designed to support you when taking semaglutide for weight loss. During the initial weeks of semaglutide use, you may witness early signs of weight loss. The speed at which semaglutide begins its weight-loss effects can vary from person to person. However, semaglutide is not for everyone and is only one of many ways to achieve healthy, lasting weight loss. Semaglutide, originally approved for the management of type 2 diabetes, has become popular as a weight-loss medication. Additionally, 156 pregnant women with a diagnosis of diabetes mellitus and 163 pregnant overweight or obese were included in two distinct reference groups. The second reference group primarily included pregnancies of patients classified as overweight (body mass index (BMI) ≥25 kg/m2) or obese (BMI ≥30 kg/m2) (ICD-10 code E66). The first reference group included pregnancies of patients diagnosed with pre-existing diabetes mellitus (International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10 codes E10–E13), who were exposed to non-GLP1-RA antidiabetic drugs during the first trimester of pregnancy (in most cases metformin). Detailed information regarding drug exposure and drug treatment indication, including dose, timing of therapy initiation, duration and concurrent medications, is also documented during the initial contact with the TIS.

Molecular mechanisms underlying GLP-1-induced insulin secretion

Diphtheria toxin-induced ablation of preproglucagon-positive neurons in the NTS demonstrated that this small population of neurons is the primary source of endogenous GLP-1 in the brain . Studies in humans with resection of different parts of the small intestine demonstrated that the incretin effect and the GIP response to oral glucose did not correlate – the incretin effect was better correlated with preservation of the ileum . In 1965, Ellis Samols and colleagues had already hypothesized that the intestinal glucagon-like material might somehow be related to the incretin effect . The neuroprotective effect of GLP-1R agonism is similar to that conferred by nerve growth factor (NGF) and is blocked when PC12 cells are co-incubated with exendin (9–39) . GLP-1 and exendin-4 enhance differentiation and neurite outgrowth in rat pheochromocytoma (PC12) cells and in human neuroblastoma SK-N-SH cells . Ablation of hindbrain catecholamine neurons using anti-dopamine-β-hydroxylase-saporin (DSAP) blunts the ability of exendin-4 to increase corticosterone secretion but interestingly potentiates the food intake inhibition by exendin-4 . In one study GLP-1 infused into the vena cava or hepatic portal vein of rats had similar effects on food intake , whereas in another study in rats GLP-1 infusions into the jugular vein inhibited food intake more potently than infusions into the hepatic portal vein . GLP-1 infusion on food intake was lost after truncal vagotomy , indicating that vagal afferents are involved in mediating the effects of circulating native GLP-1 on appetite. Administration of a supposedly “physiological” dose of GLP-1 (7-36amide) depends on the integrity of abdominal vagal afferents , indicating that peripheral GLP-1 can inhibit eating via at least two partly separate pathways. GLP-1s, like Zepound or Wegovy, are powerful medications that help manage type 2 diabetes and support weight loss, providing significant health benefits. The best representatives of this class are capable of lowering plasma glucose comparable to insulin regimens, but with a lower risk of hypoglycemia and the added benefit of weight loss. Two subsequent prospective studies found positive effects on psoriasis severity scores in type 2 diabetes patients treated with GLP-1 RAs 237,238, a finding that could not be confirmed in non-diabetes subjects . Those with high antibody titers overall had a smaller improvement in hemoglobin A1C values; however, there was no correlation found in hemoglobin A1C values between patients with negative titers versus those with low titers . Among the two exenatide formulations, exenatide weekly produces more antibodies than exenatide twice daily . Increased hypersensitivity reactions occurred with tapsoglutide, which was one of the reasons for discontinuing clinical trials and for the agent not coming to market. The PIONEER-10 trial randomized Japanese patients with T2D on oral antihyperglycemic therapy to receive either oral semaglutide 3 mg, 7 mg, 14 mg, or SC dulaglutide 0.75 mg for 57 weeks.26 A dose of 0.75 mg of dulaglutide was selected based on the maximum dose approved for use in Japan. The PIONEER-9 trial compared oral semaglutide monotherapy to liraglutide in a 52-week randomized controlled trial.25 Patients were assigned randomly to one of three doses of oral semaglutide (3 mg, 7 mg, and 14 mg), liraglutide 0.9 mg, or placebo for 52 weeks. Two different doses of dulaglutide (1.5 mg and 0.75 mg) given weekly were compared with exenatide twice daily and placebo in the AWARD-1 study.19 Patients had uncontrolled T2D on either metformin or thiazolidinediones. GLP-1 RAs increase glucose-dependent insulin secretion and decrease inappropriate glucagon secretion, delay gastric emptying and increase satiety. POMC/CART neurons expressing GLP-1 receptors activate PB neurons and directly or indirectly suppress NPY/AgRP neurons 72,73, leading to disinhibition of suppressive signals to the PB (Figure 6). These findings point to a role of the arcuate nucleus within the hypothalamus, area postrema (AP), and nucleus tractus solitarii (NTS) for the influence of systemically administered GLP-1 RAs on appetite, satiety, calorie intake, and body weight as schematically summarized in Figure 6. In addition, the risk of hypoglycemic episodes and gastrointestinal side effects was slightly, but significantly lower with long-acting GLP-1 RAs . Apparently smaller steps of increasing GLP-1 RA exposure better support an adaptation process increasing patients’ tolerance to such adverse reactions. In this case, combining it with insulin (mainly basal insulin) is a well-documented method of improving fasting, post-prandial, and overall (HbA1c) glycemic control , , , , , , . GPR40, the other long chain FFA receptor, is also highly expressed and the most enriched GPCR in L-cells 266,293. The FFA-induced rise in intracellular Ca2+ is substantially reduced when cells are cultured in a Ca2+ free medium, and is abolished upon treatment of cells with the Ca2+ channel inhibitor nicardipine or when using BSA (which binds fatty acids) . Fatty acid induction of GLP-1 secretion has been demonstrated in vitro using murine enteroendocrine STC-1 cells and human intestinal NCI-H716 cells 251,253 and in vivo by direct administration of lipids into the duodenum 288,289 or ileum . In summary, the most obvious metabolic phenotype of the global germline GLP-1R KO mice is diminished insulin secretion in response to oral glucose, and a paradoxical protection from diet-induced obesity despite impaired glycemic control. However, these mice are mildly hyperglycemic under conditions of fasting and display impaired glucose clearance during oral and intraperitoneal glucose tolerance tests (OGTT and ipGTT), with decreased glucose-stimulated insulin secretion 460,461 and normal pre- and postprandial levels of glucagon . Pharmacological inhibition of GLP-1R endocytosis by dynasor attenuates cAMP formation in BRIN BD11 pancreatic β-cells and lowers PKA substrate phosphorylation, resulting in a lesser magnitude of glucose-stimulated insulin secretion . In subjects tolerating these higher doses of GLP-1 RAs, substantially greater reductions in body weight were observed than with “conventional” doses typically employed to treat type 2 diabetes. However, in contrast to some recent findings in rodents , studies in human subjects did not observe any interference of semaglutide treatment with a reduction in energy expenditure that usually accompanies weight loss (as one important mechanism for maintaining body weight close to a pre-determined “set point”) 66,79. The fact that some GLP-1 RAs have particularly weak effects with respect to body weight (e.g., albiglutide), whereas other compounds seem to have more pronounced effects (e.g., semaglutide) even if their glucose-lowering effects are similar, has sparked interest in characterizing the mechanism of action.