Efficacy and safety of semaglutide injection in comparison with reference semaglutide for chronic weight management in indian adults with obesity: A phase III randomized non-inferiority trial.

Current and emerging medications for the management of obesity in adults.

Diabetes mellitus, defined as a fasting plasma glucose of ≥126 mg/dL or a glycosylated hemoglobin A1c level (HbA1c) of ≥6.5%, afflicts ≈12.9% of adults in the United States and nearly 285 million adults worldwide.1,2 Diabetes mellitus is a major risk factor for the development of cardiovascular disease, independently conferring a 2-fold excess risk of coronary heart disease and stroke.3 Macrovascular events in diabetes mellitus remain the leading cause of mortality, and the burden of cardiovascular disease attributable to diabetes mellitus has increased over the past decade.4 An increase in the prevalence of obesity has contributed to the rise in diabetes mellitus. Additionally, obesity independently increases the risk of cardiovascular disease in patients with diabetes mellitus.5 Although strict glycemic control unequivocally reduces the microvascular complications of diabetes mellitus, the macrovascular benefits of intensive therapy have been difficult to establish, with conflicting results from large clinical trials.6–9 Multifactorial strategies are recommended to reduce cardiovascular risk in diabetes mellitus through enhanced glycemic control, blood pressure reduction, lipid management, weight loss, and physical activity.10 Unfortunately, despite aggressive interventions for hyperglycemia, <50% of patients achieve standard HbA1c targets with conventional therapy.11 Polypharmacy is required to achieve glycemic control in the majority of patients within 3 years of diagnosis.12 Although combinations of drug classes can synergistically target multiple pathophysiological defects, novel therapies are required to manage diabetes mellitus and mitigate cardiovascular risks. Dipeptidyl-peptidase IV (DPP-IV) inhibitor and glucagon-like peptide-1 (GLP-1) receptor agonist incretin therapies were developed to complement conventional treatment options for diabetes mellitus. Despite promising initial reports of cardioprotective effects, DPP-IV inhibitors have failed to demonstrate improved cardiovascular outcomes in large clinical trials.13–15 Randomized studies to evaluate cardiovascular outcomes associated with GLP-1 receptor agonists are currently underway. This review presents …

An Albumin-Exendin-4 Conjugate Engages Central and Peripheral Circuits Regulating Murine Energy and Glucose Homeostasis

Efficacy and safety of novel formulation of semaglutide injection: A multicentre, randomized, comparative, active controlled, phase 3 study in comparison with reference biologic in Indian patients with type 2 diabetes mellitus

New Medications for the Treatment of Diabetes

Insulin and glucagon are well-known peptide hormones that keep glucose levels within a healthy range in the body. But they are only part of a complex network that controls concentrations of this ubiquitous sugar in blood and tissues. Other molecules regulate glucose by controlling insulin secretion from the pancreas or protecting pancreatic β cells against stresses that lead to cellular dysfunction or cell death (1). One of these protective regulators is glucagon-like peptide 1 (GLP-1), a 30-amino-acid-long peptide produced in specialized epithelial cells of the intestine, called L cells, and also in the brain and other organs and tissues (2). GLP-1 belongs to a group of peptides that mediate the “incretin effect,” an endocrine response to glucose arising from food digestion in the intestines (2, 3). This response helps regulate food intake and the fate of dietary glucose. Specifically, GLP-1 is released from the intestinal cells when food is ingested and then binds to and activates the GLP-1 receptor (GLP-1R), a G protein–coupled receptor on many cell types, including β cells in which GLP-1R signaling stimulates insulin synthesis and secretion (3). Notably, the incretin effect stimulates insulin secretion from pancreatic β cells more strongly than exposure to glucose alone. An article published in the Journal of Biological Chemistry (4), recognized as a Classic here, added to our understanding of the incretin effect by showing that GLP-1R signaling protects β cells from cell death (Fig. 1). This finding was significant for preventing or managing type 2 diabetes, in which β-cell apoptosis occurs (5) and may contribute to insufficient pancreatic insulin production (6). Open in a separate window Figure 1. Li et al. (4) have shown that binding of the receptor agonist exendin-4 to GLP-1R on pancreatic β cells protects the cells from cellular injury and cytokine-induced apoptosis and thereby preserves glucose homeostasis in mice. Binding of GLP-1 to its cognate receptor on pancreatic β cells up-regulates intracellular cAMP levels, in turn reducing streptozotocin-induced β-cell death. Images of exendin-4 and GLP-1R (with GLP-1 bound) are from Ref. 7; image of cAMP is from Wikimedia, used under Creative Commons.

The recent surge in the use of glucagon-like peptide-1 (GLP-1) receptor agonists, such as Mounjaro (tirzepatide) licensed by Eli Lilly and Company, and Ozempic (semaglutide) licensed by Novo Nordisk A/S., for the management of type 2 diabetes and obesity, has sparked significant interest in their broader physiological effects (Jensterle et al., 2019; Syed, 2022; Watanabe et al., 2024). While these medications are celebrated for their role in improving glycemic control and aiding weight loss, their potential impact on male fertility remains an underexplored area that warrants attention.GLP-1 receptor agonists work by mimicking the action of the GLP-1 hormone, which plays a crucial role in regulating blood sugar levels and appetite. The mechanisms through which these drugs exert their effects, including enhancing insulin secretion, slowing gastric emptying, and promoting satiety, have been well documented (Shaefer et al., 2015; Drucker, 2018). However, emerging evidence suggests that GLP-1 receptors are also present in male reproductive tissues, such as the testes, raising questions about the potential implications of these drugs on male fertility (Jeibmann et al., 2005; Alves et al., 2016; Rago et al., 2020).The interplay between metabolic health and reproductive function is well established, with conditions like obesity and diabetes often linked to reduced sperm quality and male infertility (Cabler et al., 2010; Du Plessis et al., 2010; Service et al., 2023). By improving metabolic parameters, GLP-1 receptor agonists could theoretically contribute to better reproductive outcomes. However, this is not entirely the case, especially from previously investigated GLP-1 receptor agonists, such as liraglutide, where controversy exist in the findings. Also, the direct effects of these medications on sperm function, hormone levels, and overall male fertility remain largely unexplored in clinical studies.A search conducted on August 27, 2024, in the PubMed database using the MeSH terms: &quot;Glucagon-Like Peptide-1&quot; OR &quot;Glucagon-Like Peptide-1 Receptor&quot; AND Fertility identified 50 published articles between 2011 and 2024. Upon reviewing the titles and abstracts, only 16 articles discussed or evaluated the potential effects on the male factor, either in humans or other models.High-fat diet-fed mice exhibited lower serum testosterone, and administration of GLP-1 receptor agonists did not restore these levels. However, sperm motility, mitochondrial activity, and sperm DNA fragmentation improved (Zhang et al., 2015). Other animal studies have provided insights indicating that GLP-1 receptor activation may influence testicular function and spermatogenesis (Jensterle et al., 2019). In humans, patients treated with liraglutide exhibited a significant increase in serum testosterone and significant improvement in conventional sperm parameters such as sperm count, progressive motility and normal morphology (La Vignera et al., 2023). Additionally, findings from a randomized, double-blind, controlled trial showed that after an initial eight-week diet weight loss, the percentage of men with oligozoospermia reduced, and was sustained over a year in participants who maintained their weight loss (Andersen et al., 2022). Another study which evaluated healthy men of normal weight reported no negative effects of a four-week treatment with dulaglutide on sexual desire, hormone levels, or sperm parameters (Lengsfeld et al., 2024).Conversely, a study reported the adverse effect of liraglutide on sperm quality, which was restored after 5 months of discontinuation of liraglutide. However, it did not reach the initial values for semen volume, or sperm concentration and motility (Fontoura et al., 2014). Another study showed that GLP-1 signalling down-regulated testosterone production and potentially impacts sperm quality. (Jeibmann et al., 2005). Given the importance of fertility preservation in patients of reproductive age, it is crucial to investigate the long-term effects of GLP-1 receptor agonists on male reproductive health. Additionally, gametogenesis is a long process, taking approximately three months, coupled with its high sensitivity to biological variations, such that minor changes could have significant impact on the population. This further iterate the need for dedicated clinical studies that examine parameters such as sperm count, motility, morphology, and hormonal profiles in men undergoing treatment with these medications. Additionally, it is essential to consider the potential for differential effects based on dosage, treatment duration, and underlying health conditions. In conclusion, while GLP-1 receptor agonists offer significant benefits in managing metabolic disorders, their potential impact on male fertility remains an area of concern that deserves further research. Understanding these effects is vital not only for the informed use of these medications but also for the broader implications of reproductive health in men undergoing treatment for chronic conditions. The temporary benefits of any treatment should not obscure the understanding of potential long-term harm that could impact fertility; in some cases, the treatment may be more detrimental than the condition itself. We advocate for increased attention to this topic in future clinical trials and encourage the scientific community to explore this promising yet uncharted territory in reproductive medicine.

New Glucose-Lowering Agents for Diabetic Kidney Disease.

nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to steatohepatitis (NASH), increasing fibrosis and eventually, cirrhosis ([22][1]). Importantly, NASH accompanied by fibrosis and severe inflammation is the most relevant predictor for disease progression

glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from gut enteroendocrine L cells in response to nutrient ingestion that potentiates glucose-stimulated insulin secretion via direct actions on the islet β-cell GLP-1 receptor (GLP-1R) ([4][1]). Because of these properties, manipulation

Diabetes is a global emergency involving >463 million people as of 2019 and a projection for growth to nearly 700 million by 2045. The vast majority of people (>95%) with diabetes have type 2 diabetes. Despite what is known about effective lifestyle and pharmacologic interventions, the number of people living with diabetes will expand dramatically for the foreseeable future. As a consequence, the number with diabetes complications, including diabetic kidney disease, will also multiply. Diabetic kidney disease occurs in about 40% of those with type 2 diabetes, and it is the most common cause of CKD and kidney failure worldwide. However, death largely due to cardiovascular diseases outcompetes diabetic kidney disease progression by >2:1, and only 10% reach kidney failure. The standard of care for treatment of diabetic kidney disease is use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker—a strategy that has been in place for over two decades. Yet, residual risk of kidney disease progression remained high, and prevalence of diabetic kidney disease and kidney failure attributable to diabetes only escalated over the same time period. The arrival of sodium-glucose cotransporter 2 (SGLT2) inhibitors as kidney-protective agents for diabetic kidney disease prevention and treatment is a welcome advance (1). However, even with application of canagliflozin on top of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, many patients with diabetic kidney disease still have considerable residual risk for kidney disease progression or death. Therefore, great unmet need remains for a broad selection of agents to prevent or treat diabetic kidney disease. The glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), a class of newer glucose-lowering agents, represent another potential avenue for diabetic kidney disease therapeutics. Similar to SGLT2 inhibitors, the initial observations for kidney protection came from postmarket-approval cardiovascular disease safety trials of GLP-1 RA that had kidney disease end points as secondary or exploratory outcomes. The Trial to Evaluate Cardiovascular and Other Long-Term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (n=3297) and the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER; n=9340) trial tested semaglutide and liraglutide, respectively, versus placebo in participants with type 2 diabetes at high cardiovascular risk. Both trials demonstrated reductions in new or worsening “nephropathy” (albuminuria, doubling of serum creatinine, kidney failure, or kidney disease death), which was mainly driven by a decrease in macroalbuminuria (2,3). Notably, in the LEADER trial, liraglutide reduced risk of atherosclerotic cardiovascular disease in participants with eGFR<60 ml/min per 1.73 m2, with a significant between-group interaction indicating even greater benefit in those with low eGFR (4). In the largest cardiovascular disease trial to date, the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (n=9901) trial, testing dulaglutide versus placebo, similar results for kidney disease outcomes were reproduced along with a new exploratory finding of risk reductions for 40% or 50% eGFR decline (5). The Study Comparing Dulaglutide with Insulin Glargine on Glycemic Control in Participants with Type 2 Diabetes (T2D) and Moderate or Severe CKD (n=577) trial tested dulaglutide versus an active comparator for glycemic control (insulin glargine) in patients with type 2 diabetes and moderate to severe CKD (mean eGFR =38 ml/min per m2, 29% had microalbuminuria, and 46% had macroalbuminuria) (6). Following 52 weeks of treatment, both dulaglutide treatment groups experienced significantly less eGFR decline compared with those in the insulin glargine group. This benefit was greatest in participants with macroalbuminuria. In this group, mean eGFR decline was −5.5 ml/min per 1.73 m2 in the insulin glargine group compared with −0.7 and −0.5 ml/min per 1.73 m2 in the lower- and higher-dose dulaglutide groups, respectively. A prespecified exploratory analysis demonstrated that, in the higher-dose dulaglutide group, a composite end point of kidney failure or >40% eGFR decline was decreased by half compared with the insulin glargine group (5.2% versus 10.8%; P=0.04). In time to event analysis, the hazard ratio for this composite end point in macroalbuminuric participants was 0.25; 95% confidence interval, 0.10 to 0.86 (P=0.006) among those receiving higher-dose dulaglutide versus those receiving insulin glargine. Although the mechanism of action of GLP-1 RA leading to kidney protection has not been fully elucidated, both indirect and direct pathways may be involved as reviewed elsewhere (7). For indirect pathways, GLP-1 RA reduces hyperglycemia, weight, and BP, all of which may decrease risk of diabetic kidney disease. Beyond affecting such traditional risk factors for diabetic kidney disease progression, activation of GLP-1 augments proximal tubular natriuresis via blocking the sodium-hydrogen exchanger-3, which could theoretically promote tubuloglomerular feedback, afferent constriction, and reduced glomerular hypertension. Studies in patients with and without diabetes have, however, shown that, although natriuresis does occur, kidney function does not change (7). Outside of solute handling, GLP-1 activation also inhibits a variety of injurious pathways within the kidney, including oxidative stress (NADPH oxidase inhibition), inflammation (reduced expression of cytokines and chemokines), and fibrosis (reduced expression of TGF-β1 and collagen IV) (7). Despite their emerging salutary effects, the use of GLP-1 RA is generally low in patients with diabetic kidney disease and low kidney function—a situation perhaps in part related to uncertainty about safety or use of these agents in moderate to severe CKD. Accordingly, in their manuscript in this issue of CJASN, Mann et al. (8) report the result of a post hoc analysis assessing the safety of liraglutide in patients with and without CKD in the LEADER trial (2). In this cohort, 2158 patients had CKD defined as eGFR<60 ml/min per 1.73 m2, and 220 participants had an eGFR<30 ml/min per 1.73 m2. In the overall cohort, 966 patients had macroalbuminuria, and 2456 had microalbuminuria. Mean eGFR at baseline was 45.7±10.9 ml/min per 1.73 m2 in patients with CKD and 90.8±21.6 ml/min per 1.73 m2 in those without CKD. Participants with CKD had more serious adverse events versus patients without CKD, but there was no imbalance between liraglutide- versus placebo-treated patients. Fewer liraglutide- versus placebo-treated participants experienced a serious adverse event leading to treatment discontinuation. Although numerically more patients with CKD had nausea leading to discontinuation and acute gallstone disease in the liraglutide group versus the placebo group, these differences were not statistically significant. For other gastrointestinal adverse events, nausea, vomiting, and diarrhea leading to permanent discontinuation were, as expected, numerically more common with liraglutide versus placebo (not significantly different), but they occurred at similar rates in patients with CKD versus patients without CKD. From a metabolic perspective, severe hypoglycemia risk was 27% lower in patients with CKD randomized to liraglutide versus placebo, and a similar trend was present in participants without CKD. For AKI, the risk was higher in participants with CKD versus participants without CKD, but there were no differences observed across liraglutide- versus placebo-treated participants. In summary, no new safety concerns were identified in the CKD cohort, and liraglutide was associated with less hypoglycemia, an important cause of morbidity and mortality in patients with diabetes. Several major themes have, therefore, emerged from recent GLP1-RA trials. First, these agents exert clinically significant glycemic and weight-lowering effects in patients with and without CKD. Importantly, glycemic lowering is similar compared with insulin therapy with reduced risk of hypoglycemia (6,9). Second, GLP1-RA agents are (in cardiovascular safety trials and in a dedicated study of patients with CKD) associated with clinically relevant reductions in albuminuria and lower risk of eGFR decline (6,9). Third, as shown in the analysis by Mann et al. (8), GLP1-RA therapy with liraglutide was safe and well tolerated by patients with CKD compared with patients without CKD. In patients with CKD, as kidney function declines toward 30 ml/min per 1.73 m2, patients tend to be switched from oral agents to insulin, which promotes volume expansion, weight gain, higher BP, and an increased risk of hypoglycemia. The analysis by Mann et al. (8) is clinically important because it offers additional evidence around both efficacy and safety with liraglutide—a drug in a class that avoids many deleterious effects associated with insulin. Accordingly, as with other newer glucose-lowering therapies that have major cardiovascular- and/or kidney-protective effects, such as SGLT2 inhibitors, nephrologists need to become familiar with GLP-1 RA, which has been shown to reduce cardiovascular risk. Regardless of the mechanism, it is becoming increasingly clear that GLP-1 RA should be used preferentially in appropriate patient groups, including those with atherosclerotic cardiovascular disease and patients with diabetic kidney disease who do not tolerate SGLT2 inhibition (10). In clinical practice, uptitration of GLP-1 RA agents should occur approximately every 4 weeks to reduce gastrointestinal side effects. In addition, in patients taking other agents that can induce hypoglycemia, such as insulin or sulfonylureas with appropriate glycemic control (hemoglobin A1c about <7%), these background therapies may be downtitrated. Ultimately, the completion of dedicated diabetic kidney disease trials with GLP-1 RAs is required to fully understand the role of these agents in kidney protection. Fortunately, the Research Study to See How Semaglutide Works Compared with Placebo in People with Type 2 Diabetes and CKD with Semaglutide (NCT00696657) is recruiting patients across a range of eGFR and albuminuria—including patients with and without SGLT2 inhibition as background therapy. Until the results of these studies are complete, the analysis by Mann et al. (8) offers clinicians reassurance that GLP-1 RA can be used safely in patients with diabetic kidney disease. Disclosures Dr. Cherney has received honoraria from Abbvie, AstraZeneca, Bayer, BMS, Boehringer Ingelheim-Lilly, Janssen, Merck, Mitsubishi-Tanabe, Novo-Nordisk, Prometic, and Sanofi and has received operational funding for clinical trials from AstraZeneca, Boehringer Ingelheim-Lilly, Janssen, Merck, Novo-Nordisk, and Sanofi. Dr. Tuttle has received consulting fees, speaking honorarium, or both from Astra Zeneca, Bayer, Boehringer Ingelheim, Gilead, Goldfinch Bio, Janssen, Lilly, and Novo Nordisk.

1842-P: GLP-1 Receptor Agonists Induce Lasting Cyclic-AMP Generation and Insulin Secretion in Beta Cells

BackgroundGlucagon-like peptide-1 (GLP-1) plays a crucial role in metabolic disorders by enhancing insulin secretion, inhibiting glucagon release, and slowing gastric emptying, thereby improving glycemic control. In recent years, GLP-1 role in neuronal pathways has expanded its therapeutic potential. We aim to comprehensively evaluate the relevance of GLP-1 in headache and pain disorders.MethodsA systematic literature search was conducted on PubMed and Embase (Ovid) databases using the search terms “GLP-1” and “pain”. Animal and human studies published in English language were included. s, reviews, and articles on other disorders than “pain” were excluded.ResultsThe search strategy identified 833 hits, of which 42 studies were included in the final review. The studies were categorized into four groups: inflammatory pain and osteoarthritis, headaches, neuropathic pain and diabetic neuropathy, and visceral pain and irritable bowel syndrome. GLP-1 receptor (GLP-1R) agonists, like liraglutide, have shown analgesic effects by modulating pain hypersensitivity in animal models of inflammatory and neuropathic pain. GLP-1 is involved in migraine mechanisms and GLP-1R agonists are beneficial in individuals with idiopathic intracranial hypertension. Additionally, GLP-1R agonists reduce visceral hypersensitivity and ameliorate symptoms in patients with irritable bowel syndrome.ConclusionsThe therapeutic scope of GLP-1R agonists is expanding beyond traditional metabolic targets, highlighting its potential for headache and pain disorders. Engineering bimodal molecules that integrate GLP-1R agonism with specific pain-related mechanisms may offer innovative therapeutic options.

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are incretin-derived glucose-lowering agents that have been used for the treatment of type 2 diabetes since 2007. Agents such as exenatide (short-acting and once weekly preparations), liraglutide, taspoglutide, albiglutide and lixisenatide lower fasting glucose and HbA1c upon subcutaneous injection, leading to glycaemic control that is equivalent to, or better than, that observed with other oral glucose-lowering agents or bedtime insulin. However, varying proportions of patients report nausea and vomiting, adverse events that typically narrow the therapeutic dose range. Furthermore, GLP-1 RAs reduce fasting glucose to a clinically meaningful extent, but not into the normal range. In contrast, where GLP-1 is administered as a short-term intravenous infusion, a full normalisation of glucose concentrations (approximately 5 mmol/l) has been observed without any risk of gastrointestinal side effects. Subcutaneous infusions or injections of GLP-1 are much less effective. The present analysis relates the proportion of patients who report nausea following treatment with GLP-1 and GLP-1 RAs to the clinical effectiveness of the treatment (represented by the fasting glucose concentration achieved with treatment). The results suggest that GLP-1 RAs injected into the subcutaneous compartment do not exploit the full potential inherent in GLP-1 receptor activation. Reasons for this may include modifications of the peptide molecules in the subcutaneous environment or high local concentrations triggering side effects through GLP-1 receptors on autonomic nerves in subcutaneous adipose tissue. Elucidation of the mechanisms underlying differential responses to GLP-1/GLP-1 RAs administered intravenously vs subcutaneously may help to develop improved agents or modes of administration that are more effective and have fewer side effects.

Overweight and obesity seriously damages human health. The World Health Organization estimates that 1.5 billion adults were overweight in the year of 2011. Of this overweight population, over 200 million men and nearly 300 million women were obese. At least 2.8 million adults die each year as a result of being overweight or obese. A total of 44% of the diabetes burden and 23% of the ischemic heart disease burden are attributable to overweight and obesity1. More than 70% of diabetic patients will experience macrovascular disease that is strongly associated with overweight and obesity2. Type 2 diabetes is continuing to be the leading cause of cardiovascular disorders, end-stage renal disease, blindness and amputations. Therefore, effective interventions designed to achieve weight reduction are a critical part of type 2 diabetes management to prevent the development of microvascular and macrovascular complications. However, the majority of diabetic patients gain rather than lose weight, particularly during intensifying glycemic control. Many antidiabetic agents are currently available for glycemic control, but less than 50% of type 2 diabetic patients can reach their therapeutic goal. This problem might be related to the side-effects of antidiabetic agents, including hypoglycemia (insulin, sulfonylureas and repaglinides) and bodyweight increase (insulin, thiazolidinediones, sulfonylureas and lifestyle). Action to Control Cardiovascular Risk in Diabetes (ACCORD) initially aimed to investigate the effects of intensive glycemic control on cardiovascular end-points in type 2 diabetes patients at high risk of cardiovascular events, but a 22% increase in total mortality was observed in this group, mainly driven by cardiovascular mortality. The explanation for higher cardiovascular (CV) mortality remains unclear, but hypoglycemia and weight gain were responsible for the adverse outcomes3. These results make a great impact on the concept of hyperglycemic management in type 2 diabetes, and patients should receive treatment that enables them to safely achieve an ideal glycemic control without a risk of hypoglycemia or higher gain in bodyweight. Hyperglycemia in type 2 diabetes has been well investigated and can be attributed to increased hepatic glucose production, defective insulin-stimulated glucose disposal in target tissues, abnormal islet cell function and hypersecretion of glucagon. Antihyperglycemic agents are directed to one or more of the aforementioned defects of type 2 diabetes, or to modify physiological processes relating to appetite or to nutrient absorption or excretion. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are secreted from the intestines, and can enhance the endogenous secretion of insulin induced by meal ingestion and inhibit glucagon secretion, thereby improving glucose homoeostasis. Notably, GLP-1 also suppresses food intake and appetite. Abnormalities in this incretin system were found in type 2 diabetes. GLP-1 receptor (GLP-1R) agonists were recently introduced as a new treatment for patients with type 2 diabetes. Several clinical trials have shown that GLP-1R agonists can effectively and safely lower hyperglycemic parameters by dependently stimulating insulin secretion and inhibiting glucagon secretion. They have a rather low risk of hypoglycemia because of their mode of action. GLP-1 can slow down gastric emptying after a meal. Additionally, GLP-1 binds to its receptor on hypothalamic neurons and stimulates satiety by directly acting on its receptor. All clinical trials of GLP-1R agonists have shown that agonists could lead to weight reduction in type 2 diabetes. Recently, Vilsbøll et al.4 carried out a systematic review with meta-analyses to determine whether treatment with GLP-1R agonist resulted in weight reduction in overweight or obese patients with type 2 diabetes. Adult participants with a body mass index of 25 or higher were included in these randomized controlled trials. They received exenatide twice daily, exenatide once weekly or liraglutide once daily for at least 20 weeks. Control interventions were placebo, oral antidiabetic drugs or insulin. Vilsbøll et al. carried out a random effects meta-analysis of 3,395 participants randomly assigned to GLP-1R agonists and 3,016 assigned to control groups for the change of bodyweight from 21 trials. They found that the mean change in bodyweight was larger for patients with GLP-1R agonist treatment than those in the control groups (weighted mean difference −2.9 kg; 95% confidence interval −3.6 to −2.2; Table 1). In the overall analysis, GLP-1R agonists improved glycemic control, with an increase in patients who achieved the therapeutic glycated hemoglobin (HbA1c) goals. Additionally, GLP-1R agonists had beneficial effects on systolic and diastolic blood pressure, and plasma concentrations of cholesterol. Importantly, they also found that GLP-1R agonists were not associated with hypoglycemia, despite the side-effects of nausea, diarrhea and vomiting. The present meta-analysis provides convincing evidence that GLP-1R agonists should be considered in patients with diabetes who are obese or overweight4. Several once-weekly GLP-1R agonists have been found to decrease HbA1c, and fasting and postprandial hyperglycemia. They can also greatly reduce bodyweight. More recently, the position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) for the management of hyperglycemia in type 2 diabetes was published. In this statement, metformin is the preferred first agent if it is not contraindicated or if tolerated. If metformin alone does not achieve or maintain a HbA1c target over 3 months, a second oral agent, GLP-1R agonist or basal insulin, would be added. When a two-drug combination is not yet or no longer achieving the glycemic target, this statement suggests adding a third non-insulin agent, including GLP-1R agonist5. Some studies have shown advantages from the addition of GLP-1R to a combination therapy. Over 80% of individuals with type 2 diabetes are overweight or obese. GLP-1R agonists show their beneficial effects on weight loss and safety without hypoglycemia in type 2 diabetes. The systematic review with meta-analysis carried out by Vilsbøll et al. convincingly confirms the place of GLP-1R agonists in guidelines for management of hyperglycemia in type 2 diabetes.